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新型艾滋病毒药物每日1次复方片剂：Stribild(cobicistat，elvitegravir，emtricitabine和tenofovir)
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2 These studies were performed with ritonavir boosted elvitegravir. 3 These are drugs within class where similar interactions could be predicted. 4 This study was conducted using Stribild. Studies conducted with other medicinal products Based on drug interaction studies conducted with the components of Stribild, no clinically significant drug interactions have been either observed or are expected between the components of Stribild and the following drugs: entecavir, famciclovir, famotidine, omeprazole, and ribavirin. 4.6 Fertility, pregnancy and lactation Women of childbearing potential / contraception in males and females The use of Stribild must be accompanied by the use of effective contraception (see section 4.5). Pregnancy There are no or limited clinical data with Stribild 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. Animal studies do not indicate direct or indirect harmful effects of elvitegravir, cobicistat, emtricitabine and tenofovir disoproxil fumarate with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3). Stribild should be used during pregnancy only if the potential benefit justifies the potential risk. Breast-feeding It is not known whether elvitegravir or cobicistat are excreted in human milk. Emtricitabine and tenofovir have been shown to be excreted in human milk. In animal studies it has been shown that elvitegravir, cobicistat and tenofovir are excreted in milk. There is insufficient information on the effects of elvitegravir, cobicistat, emtricitabine and tenofovir disoproxil fumarate in newborns/infants. Therefore Stribild 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 Stribild on fertility are available. Animal studies do not indicate harmful effects of elvitegravir, cobicistat, emtricitabine or tenofovir disoproxil fumarate on fertility. 4.7 Effects on 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 dizziness has been reported during treatment with Stribild. 4.8 Undesirable effects Summary of the safety profile The most frequently reported adverse reactions considered possibly or probably related to Stribild in clinical studies of treatment-naïve patients were nausea (16%) and diarrhoea (12%) (pooled data from Phase 3 clinical studies GS-US-236-0102 and GS-US-236-0103, through 144 weeks). The safety profile of Stribild in virologically-suppressed patients derived from Studies GS-US-236-0115, GS-US-236-0121 and GS-US-236-0123 is consistent with the safety profile of Stribild in treatment-naïve patients through Week 48. The most frequently reported adverse reactions to Stribild in clinical studies of virologically-suppressed patients were nausea (3% in Study GS-US-236-0115 and 5% in Study GS-US-236-0121) and fatigue (6% in Study GS-US-236-0123). 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 Stribild (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 Stribild 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 Adverse reactions to Stribild from Phase 3 clinical studies GS-US-236-0102 and GS-US-236-0103 and adverse reactions to treatment with emtricitabine and tenofovir disoproxil fumarate from clinical studies and post-marketing experience, when used with other antiretrovirals, are listed in Table 2, below, by body system organ class and highest frequency observed. 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 Stribild based on experience from Phase 3 studies GS-US-236-0102 and GS-US-236-0103 and adverse reactions to treatment with emtricitabine and tenofovir disoproxil fumarate from clinical studies and post-marketing experience, when used with other antiretrovirals
2 Anaemia was common and skin discolouration (increased pigmentation) was very common when emtricitabine was administered to paediatric patients. 3 This adverse reaction may occur as a consequence of proximal renal tubulopathy. It is not considered to be causally associated with tenofovir disoproxil fumarate in the absence of this condition. 4 See section 4.8, Description of selected adverse reactions for more details. 5 This adverse reaction was identified through post-marketing surveillance for emtricitabine or tenofovir disoproxil fumarate 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). Description of selected adverse reactions Renal impairment 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). In the clinical studies of Stribild over 144 weeks, 13 (1.9%) subjects in the Stribild group (n = 701) and 8 (2.3%) subjects in the ATV/r+FTC/TDF group (n = 355) discontinued study drug due to a renal adverse reaction. Of these discontinuations, 7 in the Stribild group and 1 in the ATV/r+FTC/TDF group occurred during the first 48 weeks. The types of renal adverse reactions seen with Stribild were consistent with previous experience with tenofovir disoproxil fumarate. Four (0.6%) of the subjects who received Stribild developed laboratory findings consistent with proximal tubulopathy leading to discontinuation of Stribild during the first 48 weeks. No additional proximal renal tubular dysfunction cases were reported from Week 48 to Week 144. Two of the four subjects had renal impairment (i.e. estimated creatinine clearance less than 70 mL/min) at baseline. The laboratory findings in these 4 subjects with evidence of proximal tubulopathy improved without clinical consequence upon discontinuation of Stribild, but did not completely resolve in all subjects. Three (0.8%) subjects who received ATV/r+FTC/TDF developed laboratory findings consistent with proximal renal tubular dysfunction leading to discontinuation of ATV/r+FTC/TDF after Week 96 (see section 4.4). The cobicistat component of Stribild has been shown to decrease estimated creatinine clearance due to inhibition of tubular secretion of creatinine without affecting renal glomerular function. In studies GS-US-236-0102 and GS-US-236-0103, decreases in estimated creatinine clearance occurred early in treatment with Stribild, after which they stabilised. The mean change in estimated glomerular filtration rate (eGFR) by Cockcroft-Gault method after 144 weeks of treatment was -14.0 ± 16.6 mL/min for Stribild, -1.9 ± 17.9 mL/min for EFV/FTC/TDF, and -9.8 ± 19.4 mL/min for ATV/r+FTC/TDF. Interaction with didanosine Stribild is not to be given with other antiretroviral agents. However, in case of initiation of Stribild in patients previously taking didanosine or discontinuation of Stribild and change to a regimen including didanosine there could be a short period when measurable plasma levels of didanosine and tenofovir occur. Note then that co-administration of tenofovir disoproxil fumarate 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. Rarely, cases of 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 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 below 18 years of age. Stribild is not recommended in this population (see section 4.2). Other special population(s) Elderly Stribild has not been studied in patients over the age of 65. Elderly patients are more likely to have decreased renal function, therefore caution should be exercised when treating elderly patients with Stribild (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 Stribild (see sections 4.2, 4.4 and 5.2). 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 Reporting 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. There is no specific antidote for overdose with Stribild. As elvitegravir and cobicistat are highly bound to plasma proteins it is unlikely that elvitegravir and cobicistat will be significantly removed by haemodialysis or peritoneal dialysis. 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. 5. Pharmacological properties 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Antiviral for systemic use; antivirals for treatment of HIV infections, combinations. ATC code: J05AR09 Mechanism of action and pharmacodynamic effects Elvitegravir is an HIV-1 integrase strand transfer inhibitor (INSTI). Integrase is an HIV-1 encoded enzyme that is required for viral replication. Inhibition of integrase prevents the integration of HIV-1 DNA into host genomic DNA, blocking the formation of the HIV-1 provirus and propagation of the viral infection. Cobicistat is a selective, mechanism-based inhibitor of cytochromes P450 of the CYP3A subfamily. Inhibition of CYP3A-mediated metabolism by cobicistat enhances the systemic exposure of CYP3A substrates, such as elvitegravir, where bioavailability is limited and half-life is shortened by CYP3A-dependent metabolism. 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. 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 reverse transcriptase, 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. Antiviral activity in vitro The dual-drug combinations and the triple combination of elvitegravir, emtricitabine and tenofovir demonstrated synergistic activity in cell culture. Antiviral synergy was maintained for elvitegravir, emtricitabine, and tenofovir when tested in the presence of cobicistat. No antagonism was observed for any of these combinations. The antiviral activity of elvitegravir against laboratory and clinical isolates of HIV-1 was assessed in lymphoblastoid cells, monocyte/macrophage cells, and peripheral blood lymphocytes and the 50% effective concentration (EC50) values were in the range of 0.02 to 1.7 nM. Elvitegravir displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, G, and O (EC50 values ranged from 0.1 to 1.3 nM) and activity against HIV-2 (EC50 of 0.53 nM). Cobicistat has no detectable anti-HIV activity and does not antagonise or enhance the antiviral effects of elvitegravir, emtricitabine, or tenofovir. 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 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 clades 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). 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 clades 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 to 5.5 µM). Resistance In cell culture Resistance to emtricitabine or tenofovir has been seen in vitro and in the HIV-1 from some patients due to the development of the M184V or M184I emtricitabine resistance substitution in reverse transcriptase or the K65R tenofovir resistance substitution in reverse transcriptase. In addition, a K70E substitution in HIV-1 reverse transcriptase has been selected clinically by tenofovir disoproxil fumarate and results in low-level reduced susceptibility to abacavir, emtricitabine, tenofovir, and lamivudine. Emtricitabine-resistant viruses with the M184V/I substitution were cross-resistant to lamivudine, but retained sensitivity to didanosine, stavudine, tenofovir and zidovudine. The K65R substitution can also be selected by abacavir, stavudine or didanosine and results in reduced susceptibility to these agents plus lamivudine, emtricitabine and tenofovir. Tenofovir disoproxil fumarate should be avoided in patients with HIV-1 harbouring the K65R substitution. In patients, HIV-1 expressing three or more thymidine analogue associated mutations (TAMs) that included either the M41L or L210W reverse transcriptase mutation showed reduced susceptibility to tenofovir disoproxil fumarate. HIV-1 isolates with reduced susceptibility to elvitegravir have been selected in cell culture. Reduced susceptibility to elvitegravir was most commonly associated with the integrase substitutions T66I, E92Q and Q148R. Additional integrase substitutions observed in cell culture selection included H51Y, F121Y, S147G, S153Y, E157Q, and R263K. HIV-1 with the raltegravir-selected substitutions T66A/K, Q148H/K, and N155H showed cross-resistance to elvitegravir. No development of resistance to cobicistat can be demonstrated in HIV-1 in vitro due to its lack of antiviral activity. Substantial cross-resistance was observed between most elvitegravir-resistant HIV-1 isolates and raltegravir, and between emtricitabine-resistant isolates and lamivudine. Patients who failed treatment with Stribild and who had HIV-1 with emergent Stribild resistance substitutions harboured virus that remained susceptible to all PIs, NNRTIs, and most other NRTIs. In treatment-naïve patients In a pooled analysis of antiretroviral-naïve patients receiving Stribild in Phase 3 studies GS-US-236-0102 and GS-US-236-0103 through Week 144, genotyping was performed on plasma HIV-1 isolates from all patients with confirmed virologic failure or who had HIV-1 RNA > 400 copies/mL at virologic failure, at Week 48, at Week 96, at Week 144 or at the time of early study drug discontinuation. As of Week 144, the development of one or more primary elvitegravir, emtricitabine, or tenofovir resistance-associated substitutions was observed in 18 of the 42 patients with evaluable genotypic data from paired baseline and Stribild treatment-failure isolates (2.6%, 18/701 patients). Of the 18 patients with viral resistance development, 13 occurred through Week 48, 3 occurred between Week 48 to Week 96, and 2 occurred between Week 96 to Week 144 of treatment. The substitutions that emerged were M184V/I (n = 17) and K65R (n = 5) in reverse transcriptase and E92Q (n = 9), N155H (n = 5), Q148R (n = 3), T66I (n = 2), and T97A (n = 1) in integrase. Other substitutions in integrase that occurred in addition to a primary INSTI resistance substitution each in single cases were H51Y, L68V, G140C, S153A, E157Q, and G163R. Most patients who developed resistance substitutions to elvitegravir developed resistance substitutions to both emtricitabine and elvitegravir. In phenotypic analyses of isolates from patients in the resistance analysis population, 13 patients (31%) had HIV-1 isolates with reduced susceptibility to elvitegravir, 17 patients (40%) had reduced susceptibility to emtricitabine, and 2 patients (5%) had reduced susceptibility to tenofovir. In study GS-US-236-0103, 27 patients treated with Stribild had HIV-1 with the NNRTI-associated K103N substitution in reverse transcriptase at baseline and had virologic success (82% at Week 144) similar to the overall population (78%), and no emergent resistance to elvitegravir, emtricitabine, or tenofovir in their HIV-1. In virologically-suppressed patients No emergent resistance to Stribild was identified in clinical studies of virologically-suppressed patients who switched from a regimen containing a ritonavir-boosted protease inhibitor (PI+RTV) (Study GS-US-236-0115), an NNRTI (Study GS-US-236-0121) or raltegravir (RAL) (Study-GS-US-236-0123). Twenty patients from these studies who switched to Stribild had the NNRTI-associated K103N substitution in their historical genotype prior to starting initial antiretroviral therapy. Eighteen of these 20 patients maintained virologic suppression through 48 weeks. Due to protocol violation, two patients with historical K103N substitutions discontinued early with HIV-1 RNA < 50 copies/mL. Clinical experience The efficacy of Stribild in HIV-1 infected treatment-naïve patients is based on the analyses of 144-week data from 2 randomised, double-blinded, active-controlled, Phase 3 studies, GS-US-236-0102 and GS-US-236-0103 (n = 1,408). The efficacy of Stribild in HIV-1 infected virologically-suppressed patients is based on the analyses of 48-week data from two randomised, open-label studies (Studies GS-US-236-0115 and GS-US-236-0121) and a single group open-label study (Study GS-US-236-0123) (n = 910; 628 receiving Stribild). Treatment-naïve HIV-1 infected patients In study GS-US-236-0102 HIV-1 infected antiretroviral treatment-naïve adult patients received once-daily treatment of Stribild or once-daily treatment of fixed-dose combination of efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV/FTC/TDF). In study GS-US-236-0103 HIV-1 infected antiretroviral treatment-naïve adult patients received once daily treatment of Stribild or ritonavir-boosted atazanavir (ATV/r) plus fixed-dose combination of emtricitabine/tenofovir disoproxil fumarate (FTC/TDF). For both studies at 48 weeks, the virologic response rate was evaluated in both treatment arms. Virologic response was defined as achieving an undetectable viral load (< 50 HIV-1 RNA copies/mL, snapshot analysis). Baseline characteristics and treatment outcomes for both studies GS-US-236-0102 and GS-US-236-0103 are presented in Tables 3 and 4, respectively. Table 3: Demographic and baseline characteristics of antiretroviral treatment-naïve HIV-1 infected adult subjects in studies GS-US-236-0102 and GS-US-236-0103
Table 4: Virologic outcome of randomised treatment of studies GS-US-236-0102 and GS-US-236-0103 at Week 48 (snapshot analysis)a and Week 144b
b Week 144 window is between Day 967 and 1,050 (inclusive). c Includes subjects who had ≥ 50 copies/mL in the Week 48 or Week 144 window, subjects who discontinued early due to lack or loss of efficacy, subjects who discontinued for reasons other than an adverse event, death or lack or loss of efficacy 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 time window if this resulted in no virologic data on treatment during the specified window. e Includes subjects 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. Stribild met the non-inferiority criteria in achieving HIV-1 RNA < 50 copies/mL when compared to efavirenz/emtricitabine/tenofovir disoproxil fumarate and when compared to atazanavir/ritonavir + emtricitabine/tenofovir disoproxil fumarate. In study GS-US-236-0102, the mean increase from baseline in CD4+ cell count at Week 48 was 239 cells/mm3 in the Stribild-treated patients and 206 cells/mm3 in the EFV/FTC/TDF-treated patients. At Week 144, the mean increase from baseline in CD4+ cell count was 321 cells/mm3 in the Stribild-treated patients and 300 cells/mm3 in the EFV/FTC/TDF-treated patients. In study GS-US-236-0103, the mean increase from baseline in CD4+ cell count at Week 48 was 207 cells/mm3 in the Stribild-treated patients and 211 cells/mm3 in the ATV/r+FTC/TDF-treated patients. At Week 144, the mean increase from baseline in CD4+ cell count was 280 cells/mm3 in the Stribild-treated patients and 293 cells/mm3 in the ATV/r+FTC/TDF-treated patients. Virologically-suppressed HIV-1 infected patients In Study GS-US-236-0115 and Study GS-US-236-0121, 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 the antiretroviral components of Stribild and must have been suppressed on a PI+RTV or an NNRTI in combination with FTC/TDF (HIV 1 RNA < 50 copies/mL) for at least six months prior to screening. Patients were randomised in a 2:1 ratio to either switch to Stribild or stay on their baseline antiretroviral regimen (SBR) for 48 weeks. In Study GS-US-236-0115, virologic success rates were: Stribild 93.8% (272 of 290 patients); SBR 87.1% (121 of 139 patients). The mean increase from baseline in CD4+ cell count at Week 48 was 40 cells/mm3 in the Stribild-treated patients and 32 cells/mm3 in the PI+RTV+FTC/TDF-treated patients. In Study GS-US-236-0121, virologic success rates were: Stribild 93.4% (271 of 290 patients) and SBR 88.1% (126 of 143 patients). The mean increase from baseline in CD4+ cell count at Week 48 was 56 cells/mm3 in the Stribild-treated patients and 58 cells/mm3 in the NNRTI+FTC/TDF-treated patients. In Study GS-US-236-0123, patients had to have previously only received RAL in combination with FTC/TDF as their first antiretroviral regimen for at least six months. Patients had to be stably suppressed for at least six months prior to study entry, have no current or past history of resistance to the antiretroviral components of Stribild, and have HIV-1 RNA < 50 copies/mL at screening. All 48 patients who received at least one dose of Stribild remained suppressed (HIV-1 RNA < 50 copies/mL) through Week 48. The mean increase from baseline in CD4+ cell count at Week 48 was 23 cells/mm3. Paediatric population The European Medicines Agency has deferred the obligation to submit the results of studies with Stribild in one or more subsets of the paediatric population in treatment of HIV-1 infection (see section 4.2 for information on paediatric use). 5.2 Pharmacokinetic properties Absorption Following oral administration of Stribild with food in HIV-1 infected subjects, peak plasma concentrations were observed 4 hours post-dose for elvitegravir, 3 hours post-dose for cobicistat, 3 hours post-dose for emtricitabine, and 2 hours for tenofovir following the rapid conversion of tenofovir disoproxil fumarate. The steady-state mean Cmax, AUCtau, and Ctrough (mean ± SD) following multiple doses of Stribild in HIV-1 infected subjects, respectively, were 1.7 ± 0.39 µg/mL, 23 ± 7.5 µg•h/mL, and 0.45 ± 0.26 µg/mL for elvitegravir, which provides inhibitory quotient of ~ 10 (ratio of Ctrough: protein binding-adjusted IC95 for wild-type HIV-1 virus). Corresponding steady-state mean Cmax, AUCtau, and Ctrough (mean ± SD) were 1.1 ± 0.40 µg/mL, 8.3 ± 3.8 µg•h/mL, and 0.05 ± 0.13 µg/mL for cobicistat, 1.9 ± 0.5 µg/mL, 13 ± 4.5 µg•h/mL, and 0.14 ± 0.25 µg/mL for emtricitabine, and 0.45 ± 0.16 µg/mL, 4.4 ± 2.2 µg•h/mL, and 0.1 ± 0.08 µg/mL for tenofovir. Relative to fasting conditions, the administration of Stribild with a light meal (~373 kcal, 20% fat) or high-fat meal (~800 kcal, 50% fat) resulted in increased exposures of elvitegravir and tenofovir. For elvitegravir, Cmax and AUC increased 22% and 36% with a light meal, while increasing 56% and 91% with a high-fat meal, respectively. The Cmax and AUC of tenofovir increased 20% and 25% respectively with a light meal, while the Cmax was unaffected and AUC increased 25% with a high fat meal. Cobicistat exposures were unaffected by a light meal and although there was a modest decrease of 24% and 18% in Cmax and AUC respectively with a high-fat meal, no difference was observed in its pharmacoenhancing effect on elvitegravir. Emtricitabine exposures were unaffected with light or high-fat meal. Distribution Elvitegravir is 98-99% bound to human plasma proteins and binding is independent of drug concentration over the range of 1 ng/mL to 1,600 ng/mL. The mean plasma to blood drug concentration ratio was 1.37. Cobicistat is 97-98% bound to human plasma proteins and the mean plasma to blood drug concentration ratio was 2. Following intravenous administration the volume of distribution of emtricitabine and tenofovir was approximately 1,400 mL/kg and 800 mL/kg, respectively. After oral administration of emtricitabine or 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. At peak plasma concentration, the mean plasma to blood drug concentration ratio was ~ 1.0 and the mean semen to plasma drug concentration ratio was ~ 4.0. In vitro protein 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 Elvitegravir undergoes oxidative metabolism by CYP3A (major route), and glucuronidation by UGT1A1/3 enzymes (minor route). Following oral administration of boosted [14C]elvitegravir, elvitegravir was the predominant species in plasma, representing ~94% of the circulating radioactivity. Aromatic and aliphatic hydroxylation or glucuronidation metabolites are present in very low levels, display considerably lower anti-HIV activity and do not contribute to the overall antiviral activity of elvitegravir. Cobicistat is metabolised via CYP3A and/or CYP2D6-mediated oxidation and does not undergo glucuronidation. Following oral administration of [14C]cobicistat, 99% of circulating radioactivity in plasma was unchanged cobicistat. In vitro studies indicate that emtricitabine is not an inhibitor of human CYP450 enzymes. Following administration of [14C]emtricitabine, complete recovery of the emtricitabine dose was achieved in urine (~ 86%) and faeces (~ 14%). Thirteen percent of the dose was recovered in the urine as three putative metabolites. The biotransformation of emtricitabine includes oxidation of the thiol moiety to form the 3'-sulfoxide diastereomers (~ 9% of dose) and conjugation with glucuronic acid to form 2'-O-glucuronide (~ 4% of dose). No other metabolites were identifiable. In vitro studies have determined that neither tenofovir disoproxil fumarate nor tenofovir are substrates for the CYP450 enzymes. Moreover, at concentrations substantially higher (approximately 300-fold) than those observed in vivo, tenofovir did not inhibit in vitro drug metabolism mediated by any of the major human CYP450 isoforms involved in drug biotransformation (CYP3A4, CYP2D6, CYP2C9, CYP2E1, or CYP1A1/2). Tenofovir disoproxil fumarate had no effect on any of the CYP450 isoforms, except CYP1A1/2, where a small (6%) but statistically significant reduction in metabolism of a CYP1A1/2 substrate was observed. Elimination Following oral administration of [14C]elvitegravir/ritonavir, 94.8% of the dose was recovered in faeces, consistent with the hepatobiliary elimination of elvitegravir; 6.7% of the administered dose was recovered in urine. The median terminal plasma half-life of elvitegravir following administration of Stribild is approximately 12.9 hours. Following oral administration of [14C]cobicistat, 86% and 8.2% of the dose were recovered in faeces and urine, respectively. The median terminal plasma half-life of cobicistat following administration of Stribild is approximately 3.5 hours and the associated cobicistat exposures provide elvitegravir Ctrough approximately 10-fold above the protein-binding adjusted IC95 for wild-type HIV-1 virus. 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. Tenofovir is primarily excreted by the kidney by both filtration and an active tubular transport system (human organic anion transporter [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. Elderly Pharmacokinetics of elvitegravir, cobicistat, emtricitabine and tenofovir have not been evaluated in the elderly (over 65 years). Gender No clinically relevant pharmacokinetic differences due to gender have been identified for cobicistat-boosted elvitegravir, emtricitabine and tenofovir disoproxil fumarate. Ethnicity No clinically relevant pharmacokinetic differences due to ethnicity have been identified for cobicistat-boosted elvitegravir, emtricitabine and tenofovir disoproxil fumarate. Paediatric population The pharmacokinetics of elvitegravir or cobicistat in paediatric subjects have not been fully established. In general, elvitegravir pharmacokinetics in paediatric patients (12 to < 18 years of age) and emtricitabine pharmacokinetics in children (aged 4 months to 18 years of age) are similar to those seen in adults. Tenofovir exposure achieved in 8 paediatric patients (12 to < 18 years of age) receiving oral daily doses of tenofovir disoproxil fumarate 300 mg (tablet) was similar to exposures achieved in adults receiving once-daily doses of 300 mg. Renal impairment A study of pharmacokinetics of cobicistat-boosted elvitegravir was performed in non-HIV-1 infected subjects with severe renal impairment (creatinine clearance below 30 mL/min). No clinically relevant differences in elvitegravir or cobicistat pharmacokinetics were observed between subjects with severe renal impairment and healthy subjects. No dose adjustment of elvitegravir or cobicistat is necessary for patients with renal impairment. The pharmacokinetics of emtricitabine and tenofovir are altered in subjects with renal impairment. In subjects with creatinine clearance below 50 mL/min or with end stage renal disease requiring dialysis, Cmax, and AUC of emtricitabine and tenofovir were increased (see section 4.4). Hepatic impairment Both elvitegravir and cobicistat are primarily metabolised and eliminated by the liver. A study of pharmacokinetics of cobicistat-boosted elvitegravir was performed in non-HIV-1 infected subjects with moderate hepatic impairment. No clinically relevant differences in elvitegravir or cobicistat pharmacokinetics were observed between subjects with moderate impairment and healthy subjects. No dose adjustment of elvitegravir or cobicistat is necessary for patients with mild to moderate hepatic impairment. The effect of severe hepatic impairment on the pharmacokinetics of elvitegravir or cobicistat has not been studied. The pharmacokinetics of emtricitabine have not been studied in subjects with hepatic impairment; however, emtricitabine is not significantly metabolised by liver enzymes, so the impact of liver impairment should be limited. Clinically relevant changes in tenofovir pharmacokinetics in patients with hepatic impairment were not observed. Therefore, no tenofovir disoproxil fumarate dose adjustment is required in patients with hepatic impairment. Hepatitis B and/or hepatitis C virus co-infection Pharmacokinetics of emtricitabine and tenofovir disoproxil fumarate have not been fully evaluated in hepatitis B and/or C virus co-infected patients. Limited data from population pharmacokinetic analysis (n = 24) indicated that hepatitis B and/or C virus infection had no clinically relevant effect on the exposure of boosted elvitegravir. 5.3 Preclinical safety data Elvitegravir was negative in an in vitro bacterial mutagenicity test (Ames test) and negative in an in vivo rat micronucleus assay at doses up to 2,000 mg/kg. In an in vitro chromosomal aberration test, elvitegravir was negative with metabolic activation; however, an equivocal response was observed without activation. Cobicistat was not mutagenic or clastogenic in conventional genotoxicity assays. Ex vivo rabbit studies and in vivo dog studies suggest that cobicistat has a low potential for QT prolongation, and may slightly prolong the PR interval and decrease left ventricular function at concentrations at least 11-fold higher than the human exposure at the recommended 150 mg daily dose. In a human clinical study of 35 healthy subjects, echocardiograms performed at baseline and after receiving 150 mg cobicistat once daily for at least 15 days indicated no clinically significant change in left ventricular function. Reproductive toxicity studies in rats and rabbits with cobicistat showed no effects on mating, fertility, pregnancy or foetal parameters. However increased postimplantation loss and decreased fetal weights were observed in rats associated with significant decreases in maternal body weights at 125 mg/kg/day. Long term oral carcinogenicity studies with elvitegravir and cobicistat did not show any carcinogenic potential in mice and rats. Non-cinical data on emtricitabine reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated-dose toxicity, genotoxicity, carcinogenic potential, and toxicity to reproduction and development. 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). Reproductive toxicity studies in rats and rabbits showed no effects on mating, fertility, pregnancy or foetal parameters. However, tenofovir disoproxil fumarate reduced the viability index and weight of pups in a peri-postnatal toxicity study at maternally toxic doses. The active substances elvitegravir, cobicistat and tenofovir disoproxil fumarate are persistent in the environment. 6. Pharmaceutical particulars 6.1 List of excipients Tablet core Croscarmellose sodium Hydroxypropyl cellulose Lactose (as monohydrate) Magnesium stearate Microcrystalline cellulose Silicon dioxide Sodium lauryl sulfate Film-coating Indigo carmine aluminium lake (E132) Macrogol 3350 (E1521) Polyvinyl alcohol (partially hydrolysed) (E1203) Talc (E553B) Titanium dioxide (E171) Yellow iron oxide (E172) 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 Limited Cambridge CB21 6GT United Kingdom 8. Marketing authorisation number(s) EU/1/13/830/001 EU/1/13/830/002 9. Date of first authorisation/renewal of the authorisation Date of first authorisation: 24 May 2013 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. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Stribild film-coated tablets（埃替拉韦/恩曲他滨/富马酸/替诺福韦酯薄膜片）简介：
新型艾滋病毒药物每日1次复方片剂：Stribild(cobicistat，elvitegravir，emtricitabine和tenofovir)欧盟批准日期：2013年5月30日；公司：Gilead Sciences，Inc.为治疗HIV感染2013年5月30日，吉利德科学 ... 责任编辑：admin |
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