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英文药名：Viread（tenofovir disoproxil filmcoated tablets） 中文药名：替诺福韦薄膜衣片 生产厂家：GLIEAD 德国
There were no clinically significant pharmacokinetic interactions when tenofovir disoproxil fumarate was co-administered with emtricitabine, lamivudine, indinavir, efavirenz, nelfinavir, saquinavir (ritonavir boosted), methadone, ribavirin, rifampicin, tacrolimus, or the hormonal contraceptive norgestimate/ethinyl oestradiol. Tenofovir disoproxil fumarate must be taken with food, as food enhances the bioavailability of tenofovir (see section 5.2). 4.6 Fertility, pregnancy and lactation Pregnancy A moderate amount of data on pregnant women (between 300-1,000 pregnancy outcomes) indicate no malformations or foetal/neonatal toxicity associated with tenofovir disoproxil fumarate. Animal studies do not indicate reproductive toxicity (see section 5.3). The use of tenofovir disoproxil fumarate may be considered during pregnancy, if necessary. Breast-feeding Tenofovir has been shown to be excreted in human milk. There is insufficient information on the effects of tenofovir in newborns/infants. Therefore Viread should not be used during breast-feeding. As a general rule, it is recommended that HIV and HBV infected women do not breast-feed their infants in order to avoid transmission of HIV and HBV to the infant. Fertility There are limited clinical data with respect to the effect of tenofovir disoproxil fumarate on fertility. Animal studies do not indicate harmful effects of 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 tenofovir disoproxil fumarate. 4.8 Undesirable effects Summary of the safety profile HIV-1 and hepatitis B: 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 Viread (see section 4.4). HIV-1: Approximately one third of patients can be expected to experience adverse reactions following treatment with tenofovir disoproxil fumarate in combination with other antiretroviral agents. These reactions are usually mild to moderate gastrointestinal events. Approximately 1% of tenofovir disoproxil fumarate-treated adult patients discontinued treatment due to the gastrointestinal events. Lipodystrophy is associated with tenofovir disoproxil fumarate (see sections 4.4 and 4.8 Description of selected adverse reactions). Co-administration of Viread and didanosine is not recommended as this may result in an increased risk of adverse reactions (see section 4.5). Rarely, pancreatitis and lactic acidosis, sometimes fatal, have been reported (see section 4.4). Hepatitis B: Approximately one quarter of patients can be expected to experience adverse reactions following treatment with tenofovir disoproxil fumarate, most of which are mild. In clinical trials of HBV infected patients, the most frequently occurring adverse reaction to tenofovir disoproxil fumarate was nausea (5.4%). Acute exacerbation of hepatitis has been reported in patients on treatment as well as in patients who have discontinued hepatitis B therapy (see section 4.4). Tabulated summary of adverse reactions Assessment of adverse reactions for tenofovir disoproxil fumarate is based on safety data from clinical studies and post-marketing experience. All adverse reactions are presented in Table 2. HIV-1 clinical studies: Assessment of adverse reactions from HIV-1 clinical study data is based on experience in two studies in 653 treatment-experienced patients receiving treatment with tenofovir disoproxil fumarate (n = 443) or placebo (n = 210) in combination with other antiretroviral medicinal products for 24 weeks and also in a double-blind comparative controlled study in which 600 treatment-naïve patients received treatment with tenofovir disoproxil 245 mg (as fumarate) (n = 299) or stavudine (n = 301) in combination with lamivudine and efavirenz for 144 weeks. Hepatitis B clinical studies: Assessment of adverse reactions from HBV clinical study data is primarily based on experience in two double-blind comparative controlled studies in which 641 adult patients with chronic hepatitis B and compensated liver disease received treatment with tenofovir disoproxil 245 mg (as fumarate) daily (n = 426) or adefovir dipivoxil 10 mg daily (n = 215) for 48 weeks. The adverse reactions observed with continued treatment for 384 weeks were consistent with the safety profile of tenofovir disoproxil fumarate. After an initial decline of approximately -4.9 ml/min (using Cockcroft-Gault equation) or -3.9 ml/min/1.73 m2 (using modification of diet in renal disease [MDRD] equation) after the first 4 weeks of treatment, the rate of annual decline post baseline of renal function reported in tenofovir disoproxil fumarate treated patients was -1.41 ml/min per year (using Cockcroft-Gault equation) and -0.74 ml/min/1.73 m2 per year (using MDRD equation). Patients with decompensated liver disease: The safety profile of tenofovir disoproxil fumarate in patients with decompensated liver disease was assessed in a double-blind active controlled study (GS-US-174-0108) in which adult patients received treatment with tenofovir disoproxil fumarate (n = 45) or emtricitabine plus tenofovir disoproxil fumarate (n = 45) or entecavir (n = 22) for 48 weeks. In the tenofovir disoproxil fumarate treatment arm, 7% of patients discontinued treatment due to an adverse event; 9% of patients experienced a confirmed increase in serum creatinine of ≥ 0.5 mg/dl or confirmed serum phosphate of < 2 mg/dl through week 48; there were no statistically significant differences between the combined tenofovir-containing arms and the entecavir arm. After 168 weeks, 16% (7/45) of the tenofovir disoproxil fumarate group, 4% (2/45) of the emtricitabine plus tenofovir disoproxil fumarate group, and 14% (3/22) of the entecavir group experienced tolerability failure. Thirteen percent (6/45) of the tenofovir disoproxil fumarate group, 13% (6/45) of the emtricitabine plus tenofovir disoproxil fumarate group, and 9% (2/22) of the entecavir group had a confirmed increase in serum creatinine ≥ 0.5 mg/dl or confirmed serum phosphate of < 2 mg/dl. At week 168, in this population of patients with decompensated liver disease, the rate of death was of 13% (6/45) in the tenofovir disoproxil fumarate group, 11% (5/45) in the emtricitabine plus tenofovir disoproxil fumarate group and 14% (3/22) in the entecavir group. The rate of hepatocellular carcinoma was 18% (8/45) in the tenofovir disoproxil fumarate group, 7% (3/45) in the emtricitabine plus tenofovir disoproxil fumarate group and 9% (2/22) in the entecavir group. Subjects with a high baseline CPT score were at higher risk of developing serious adverse events (see section 4.4). Patients with lamivudine-resistant chronic hepatitis B: No new adverse reactions to tenofovir disoproxil fumarate were identified from a randomised, double-blind study (GS-US-174-0121) in which 280 lamivudine-resistant patients received treatment with tenofovir disoproxil fumarate (n = 141) or emtricitabine/tenofovir disoproxil fumarate (n = 139) for 96 weeks. The adverse reactions with suspected (at least possible) relationship to treatment are listed 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 tenofovir disoproxil fumarate based on clinical study and post-marketing experience
2 This adverse reaction was identified through post-marketing surveillance but not observed in randomised controlled clinical trials or the tenofovir disoproxil fumarate expanded access program. The frequency category was estimated from a statistical calculation based on the total number of patients exposed to tenofovir disoproxil fumarate in randomised controlled clinical trials and the expanded access program (n = 7,319). Description of selected adverse reactions HIV-1 and hepatitis B: Renal impairment As Viread 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). HIV-1: Interaction with didanosine 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 (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 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). In a 144-week controlled clinical study in antiretroviral-naïve adult patients that compared tenofovir disoproxil fumarate with stavudine in combination with lamivudine and efavirenz, patients who received tenofovir disoproxil had a significantly lower incidence of lipodystrophy compared with patients who received stavudine. The tenofovir disoproxil fumarate arm also had significantly smaller mean increases in fasting triglycerides and total cholesterol than the comparator arm. 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). Hepatitis B: Exacerbations of hepatitis during treatment In studies with nucleoside-naïve patients, on-treatment ALT elevations > 10 times ULN (upper limit of normal) and > 2 times baseline occurred in 2.6% of tenofovir disoproxil fumarate-treated patients. ALT elevations had a median time to onset of 8 weeks, resolved with continued treatment, and, in a majority of cases, were associated with a ≥ 2 log10 copies/ml reduction in viral load that preceded or coincided with the ALT elevation. Periodic monitoring of hepatic function is recommended during treatment (see section 4.4). Exacerbations of hepatitis after discontinuation of treatment In HBV infected patients, clinical and laboratory evidence of exacerbations of hepatitis have occurred after discontinuation of HBV therapy (see section 4.4). Paediatric population HIV-1 Assessment of adverse reactions is based on two randomised trials (studies GS-US-104-0321 and GS-US-104-0352) in 184 HIV-1 infected paediatric patients (aged 2 to < 18 years) who received treatment with tenofovir disoproxil fumarate (n = 93) or placebo/active comparator (n = 91) in combination with other antiretroviral agents for 48 weeks (see section 5.1). The adverse reactions observed in paediatric patients who received treatment with tenofovir disoproxil fumarate were consistent with those observed in clinical studies of tenofovir disoproxil fumarate in adults (see section 4.8 Tabulated summary of adverse reactions and 5.1). Reductions in BMD have been reported in paediatric patients. In HIV-1 infected adolescents, the BMD Z-scores observed in subjects who received tenofovir disoproxil fumarate were lower than those observed in subjects who received placebo. In HIV-1 infected children, the BMD Z-scores observed in subjects who switched to tenofovir disoproxil fumarate were lower than those observed in subjects who remained on their stavudine- or zidovudine-containing regimen (see sections 4.4 and 5.1). Of 89 patients (2 to < 12 years) who received tenofovir disoproxil fumarate in study GS-US-104-0352 (median exposure 104 weeks), 4 patients discontinued from the study due to adverse reactions consistent with proximal renal tubulopathy. Chronic hepatitis B Assessment of adverse reactions is based on one randomised study (study GS-US-174-0115) in 106 adolescent patients (12 to < 18 years of age) with chronic hepatitis B receiving treatment with tenofovir disoproxil 245 mg (as fumarate) (n = 52) or placebo (n = 54) for 72 weeks. The adverse reactions observed in adolescent patients who received treatment with tenofovir disoproxil fumarate were consistent with those observed in clinical studies of tenofovir disoproxil fumarate in adults (see section 4.8 Tabulated summary of adverse reactions and 5.1). Reductions in BMD have been observed in HBV infected adolescents. The BMD Z-scores observed in subjects who received tenofovir disoproxil fumarate were lower than those observed in subjects who received placebo (see sections 4.4 and 5.1). Other special population(s) Older people Tenofovir disoproxil fumarate 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 tenofovir disoproxil fumarate (see section 4.4) Patients with renal impairment Since tenofovir disoproxil fumarate can cause renal toxicity, close monitoring of renal function is recommended in adult patients with renal impairment treated with Viread (see sections 4.2, 4.4 and 5.2). The use of tenofovir disoproxil fumarate is not recommended in paediatric patients with renal impairment (see sections 4.2 and 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 Symptoms If overdose occurs the patient must be monitored for evidence of toxicity (see sections 4.8 and 5.3), and standard supportive treatment applied as necessary. Management Tenofovir can be removed by haemodialysis; the median haemodialysis clearance of tenofovir is 134 ml/min. It is not known whether tenofovir can be removed by peritoneal dialysis. 5. Pharmacological properties 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Antiviral for systemic use; nucleoside and nucleotide reverse transcriptase inhibitors, ATC code: J05AF07 Mechanism of action and pharmacodynamic effects Tenofovir disoproxil fumarate is the fumarate salt of the prodrug tenofovir disoproxil. Tenofovir disoproxil is absorbed and converted to the active substance tenofovir, which is a nucleoside monophosphate (nucleotide) analogue. Tenofovir is then converted to the active metabolite, tenofovir diphosphate, an obligate chain terminator, by constitutively expressed cellular enzymes. Tenofovir diphosphate has an intracellular half-life of 10 hours in activated and 50 hours in resting peripheral blood mononuclear cells (PBMCs). Tenofovir diphosphate inhibits HIV-1 reverse transcriptase and the HBV polymerase by direct binding competition with the natural deoxyribonucleotide substrate and, after incorporation into DNA, by DNA chain termination. Tenofovir diphosphate is a weak inhibitor of cellular polymerases α, β, and γ. At concentrations of up to 300 µmol/l, tenofovir has also shown no effect on the synthesis of mitochondrial DNA or the production of lactic acid in in vitro assays. Data pertaining to HIV HIV antiviral activity in vitro: The concentration of tenofovir required for 50% inhibition (EC50) of the wild-type laboratory strain HIV-1IIIB is 1-6 µmol/l in lymphoid cell lines and 1.1 µmol/l against primary HIV-1 subtype B isolates in PBMCs. Tenofovir is also active against HIV-1 subtypes A, C, D, E, F, G, and O and against HIVBaL in primary monocyte/macrophage cells. Tenofovir shows activity in vitro against HIV-2, with an EC50 of 4.9 µmol/l in MT-4 cells. Resistance: Strains of HIV-1 with reduced susceptibility to tenofovir and a K65R mutation in reverse transcriptase have been selected in vitro and in some patients (see Clinical efficacy and safety). Tenofovir disoproxil fumarate should be avoided in antiretroviral-experienced patients with strains harbouring the K65R mutation (see section 4.4). In addition, a K70E substitution in HIV-1 reverse transcriptase has been selected by tenofovir and results in low-level reduced susceptibility to tenofovir. Clinical studies in treatment-experienced patients have assessed the anti-HIV activity of tenofovir disoproxil 245 mg (as fumarate) against strains of HIV-1 with resistance to nucleoside inhibitors. The results indicate that patients whose HIV expressed 3 or more thymidine-analogue associated mutations (TAMs) that included either the M41L or L210W reverse transcriptase mutation showed reduced response to tenofovir disoproxil 245 mg (as fumarate) therapy. Clinical efficacy and safety The effects of tenofovir disoproxil fumarate in treatment-experienced and treatment-naïve HIV-1 infected adults have been demonstrated in trials of 48 weeks and 144 weeks duration, respectively. In study GS-99-907, 550 treatment-experienced adult patients were treated with placebo or tenofovir disoproxil 245 mg (as fumarate) for 24 weeks. The mean baseline CD4 cell count was 427 cells/mm3, the mean baseline plasma HIV-1 RNA was 3.4 log10 copies/ml (78% of patients had a viral load of < 5,000 copies/ml) and the mean duration of prior HIV treatment was 5.4 years. Baseline genotypic analysis of HIV isolates from 253 patients revealed that 94% of patients had HIV-1 resistance mutations associated with nucleoside reverse transcriptase inhibitors, 58% had mutations associated with protease inhibitors and 48% had mutations associated with non-nucleoside reverse transcriptase inhibitors. At week 24 the time-weighted average change from baseline in log10 plasma HIV-1 RNA levels (DAVG24) was -0.03 log10 copies/ml and -0.61 log10 copies/ml for the placebo and tenofovir disoproxil 245 mg (as fumarate) recipients (p < 0.0001). A statistically significant difference in favour of tenofovir disoproxil 245 mg (as fumarate) was seen in the time-weighted average change from baseline at week 24 (DAVG24) for CD4 count (+13 cells/mm3 for tenofovir disoproxil 245 mg (as fumarate) versus -11 cells/mm3 for placebo, p-value = 0.0008). The antiviral response to tenofovir disoproxil fumarate was durable through 48 weeks (DAVG48 was -0.57 log10 copies/ml, proportion of patients with HIV-1 RNA below 400 or 50 copies/ml was 41% and 18% respectively). Eight (2%) tenofovir disoproxil 245 mg (as fumarate) treated patients developed the K65R mutation within the first 48 weeks. The 144-week, double-blind, active controlled phase of study GS-99-903 evaluated the efficacy and safety of tenofovir disoproxil 245 mg (as fumarate) versus stavudine when used in combination with lamivudine and efavirenz in HIV-1 infected adult patients naïve to antiretroviral therapy. The mean baseline CD4 cell count was 279 cells/mm3, the mean baseline plasma HIV-1 RNA was 4.91 log10 copies/ml, 19% of patients had symptomatic HIV-1 infection and 18% had AIDS. Patients were stratified by baseline HIV-1 RNA and CD4 count. Forty-three percent of patients had baseline viral loads > 100,000 copies/ml and 39% had CD4 cell counts < 200 cells/ml. By intent to treat analysis (missing data and switch in antiretroviral therapy (ART) considered as failure), the proportion of patients with HIV-1 RNA below 400 copies/ml and 50 copies/ml at 48 weeks of treatment was 80% and 76% respectively in the tenofovir disoproxil 245 mg (as fumarate) arm, compared to 84% and 80% in the stavudine arm. At 144 weeks, the proportion of patients with HIV-1 RNA below 400 copies/ml and 50 copies/ml was 71% and 68% respectively in the tenofovir disoproxil 245 mg (as fumarate) arm, compared to 64% and 63% in the stavudine arm. The average change from baseline for HIV-1 RNA and CD4 count at 48 weeks of treatment was similar in both treatment groups (-3.09 and -3.09 log10 copies/ml; +169 and 167 cells/mm3 in the tenofovir disoproxil 245 mg (as fumarate) and stavudine groups, respectively). At 144 weeks of treatment, the average change from baseline remained similar in both treatment groups (-3.07 and -3.03 log10 copies/ml; +263 and +283 cells/mm3 in the tenofovir disoproxil 245 mg (as fumarate) and stavudine groups, respectively). A consistent response to treatment with tenofovir disoproxil 245 mg (as fumarate) was seen regardless of baseline HIV-1 RNA and CD4 count. The K65R mutation occurred in a slightly higher percentage of patients in the tenofovir disoproxil fumarate group than the active control group (2.7% versus 0.7%). Efavirenz or lamivudine resistance either preceded or was coincident with the development of K65R in all cases. Eight patients had HIV that expressed K65R in the tenofovir disoproxil 245 mg (as fumarate) arm, 7 of these occurred during the first 48 weeks of treatment and the last one at week 96. No further K65R development was observed up to week 144. One patient in the tenofovir disoproxil (as fumarate) arm developed the K70E substitution in the virus. From both the genotypic and phenotypic analyses there was no evidence for other pathways of resistance to tenofovir. Data pertaining to HBV HBV antiviral activity in vitro: The in vitro antiviral activity of tenofovir against HBV was assessed in the HepG2 2.2.15 cell line. The EC50 values for tenofovir were in the range of 0.14 to 1.5 µmol/l, with CC50 (50% cytotoxicity concentration) values > 100 µmol/l. Resistance: No HBV mutations associated with tenofovir disoproxil fumarate resistance have been identified (see Clinical efficacy and safety). In cell based assays, HBV strains expressing the rtV173L, rtL180M, and rtM204I/V mutations associated with resistance to lamivudine and telbivudine showed a susceptibility to tenofovir ranging from 0.7- to 3.4-fold that of wild-type virus. HBV strains expressing the rtL180M, rtT184G, rtS202G/I, rtM204V and rtM250V mutations associated with resistance to entecavir showed a susceptibility to tenofovir ranging from 0.6- to 6.9-fold that of wild-type virus. HBV strains expressing the adefovir-associated resistance mutations rtA181V and rtN236T showed a susceptibility to tenofovir ranging from 2.9- to 10-fold that of wild-type virus. Viruses containing the rtA181T mutation remained susceptible to tenofovir with EC50 values 1.5-fold that of wild-type virus. Clinical efficacy and safety The demonstration of benefit of tenofovir disoproxil fumarate in compensated and decompensated disease is based on virological, biochemical and serological responses in adults with HBeAg positive and HBeAg negative chronic hepatitis B. Treated patients included those who were treatment-naïve, lamivudine-experienced, adefovir dipivoxil-experienced and patients with lamivudine and/or adefovir dipivoxil resistance mutations at baseline. Benefit has also been demonstrated based on histological responses in compensated patients. Experience in patients with compensated liver disease at 48 weeks (studies GS-US-174-0102 and GS-US-174-0103) Results through 48 weeks from two randomised, phase 3 double-blind studies comparing tenofovir disoproxil fumarate to adefovir dipivoxil in adult patients with compensated liver disease are presented in Table 3 below. Study GS-US-174-0103 was conducted in 266 (randomised and treated) HBeAg positive patients while study GS-US-174-0102 was conducted in 375 (randomised and treated) patients negative for HBeAg and positive for HBeAb. In both of these studies tenofovir disoproxil fumarate was significantly superior to adefovir dipivoxil for the primary efficacy endpoint of complete response (defined as HBV DNA levels < 400 copies/ml and Knodell necroinflammatory score improvement of at least 2 points without worsening in Knodell fibrosis). Treatment with tenofovir disoproxil 245 mg (as fumarate) was also associated with significantly greater proportions of patients with HBV DNA < 400 copies/ml, when compared to adefovir dipivoxil 10 mg treatment. Both treatments produced similar results with regard to histological response (defined as Knodell necroinflammatory score improvement of at least 2 points without worsening in Knodell fibrosis) at week 48 (see Table 3 below). In study GS-US-174-0103 a significantly greater proportion of patients in the tenofovir disoproxil fumarate group than in the adefovir dipivoxil group had normalised ALT and achieved HBsAg loss at week 48 (see Table 3 below). Table 3: Efficacy parameters in compensated HBeAg negative and HBeAg positive patients at week 48
a Complete response defined as HBV DNA levels < 400 copies/ml and Knodell necroinflammatory score improvement of at least 2 points without worsening in Knodell fibrosis. b Knodell necroinflammatory score improvement of at least 2 points without worsening in Knodell fibrosis. c Median change from baseline HBV DNA merely reflects the difference between baseline HBV DNA and the limit of detection (LOD) of the assay. d The population used for analysis of ALT normalisation included only patients with ALT above ULN at baseline. n/a = not applicable. Tenofovir disoproxil fumarate was associated with significantly greater proportions of patients with undetectable HBV DNA (< 169 copies/ml [< 29 IU/ml]; the limit of quantification of the Roche Cobas Taqman HBV assay), when compared to adefovir dipivoxil (study GS-US-174-0102; 91%, 56% and study GS-US-174-0103; 69%, 9%), respectively. Response to treatment with tenofovir disoproxil fumarate was comparable in nucleoside-experienced (n = 51) and nucleoside-naïve (n = 375) patients and in patients with normal ALT (n = 21) and abnormal ALT (n = 405) at baseline when studies GS-US-174-0102 and GS-US-174-0103 were combined. Forty-nine of the 51 nucleoside-experienced patients were previously treated with lamivudine. Seventy-three percent of nucleoside-experienced and 69% of nucleoside-naïve patients achieved complete response to treatment; 90% of nucleoside-experienced and 88% of nucleoside-naïve patients achieved HBV DNA suppression < 400 copies/ml. All patients with normal ALT at baseline and 88% of patients with abnormal ALT at baseline achieved HBV DNA suppression < 400 copies/ml. Experience beyond 48 weeks in studies GS-US-174-0102 and GS-US-174-0103 In studies GS-US-174-0102 and GS-US-174-0103, after receiving double-blind treatment for 48 weeks (either tenofovir disoproxil 245 mg (as fumarate) or adefovir dipivoxil 10 mg), patients rolled over with no interruption in treatment to open-label tenofovir disoproxil fumarate. In studies GS-US-174-0102 and GS-US-174-0103, 77% and 61% of patients continued in the study through to 384 weeks, respectively. At weeks 96, 144, 192, 240, 288 and 384, viral suppression, biochemical and serological responses were maintained with continued tenofovir disoproxil fumarate treatment (see Tables 4 and 5 below). Table 4: Efficacy parameters in compensated HBeAg negative patients at week 96, 144, 192, 240, 288 and 384 open-label treatment
b 48 weeks of double-blind tenofovir disoproxil fumarate followed by 48 weeks open-label. c 48 weeks of double-blind adefovir dipivoxil followed by 48 weeks open-label tenofovir disoproxil fumarate. d The population used for analysis of ALT normalisation included only patients with ALT above ULN at baseline. e 48 weeks of double-blind tenofovir disoproxil fumarate followed by 96 weeks open-label. f 48 weeks of double-blind adefovir dipivoxil followed by 96 weeks open-label tenofovir disoproxil fumarate. g 48 weeks of double-blind tenofovir disoproxil fumarate followed by 144 weeks open-label. h 48 weeks of double-blind adefovir dipivoxil followed by 144 weeks open-label tenofovir disoproxil fumarate. i 48 weeks of double-blind tenofovir disoproxil fumarate followed by 192 weeks open-label. j 48 weeks of double-blind adefovir dipivoxil followed by 192 weeks open-label tenofovir disoproxil fumarate k One patient in this group became HBsAg negative for the first time at the 240 week visit and was ongoing in the study at the time of the data cut-off. However, the subject's HBsAg loss was ultimately confirmed at the subsequent visit. l 48 weeks of double-blind tenofovir disoproxil fumarate followed by 240 weeks open-label. m 48 weeks of double-blind adefovir dipivoxil followed by 240 weeks open-label tenofovir disoproxil fumarate. n Figures presented are cumulative percentages based upon a Kaplan Meier analysis excluding data collected after the addition of emtricitabine to open-label tenofovir disoproxil fumarate (KM-TDF). o 48 weeks of double-blind tenofovir disoproxil fumarate followed by 336 weeks open-label. p 48 weeks of double-blind adefovir dipivoxil followed by 336 weeks open-label tenofovir disoproxil fumarate. n/a = not applicable. Table 5: Efficacy parameters in compensated HBeAg positive patients at week 96, 144, 192, 240, 288 and 384 open-label treatment
b 48 weeks of double-blind tenofovir disoproxil fumarate followed by 48 weeks open-label. c 48 weeks of double-blind adefovir dipivoxil followed by 48 weeks open-label tenofovir disoproxil fumarate. d The population used for analysis of ALT normalisation included only patients with ALT above ULN at baseline. e 48 weeks of double-blind tenofovir disoproxil fumarate followed by 96 weeks open-label. f 48 weeks of double-blind adefovir dipivoxil followed by 96 weeks open-label tenofovir disoproxil fumarate. g Figures presented are cumulative percentages based upon a Kaplan Meier analysis including data collected after the addition of emtricitabine to open-label tenofovir disoproxil fumarate (KM-ITT). h 48 weeks of double-blind tenofovir disoproxil fumarate followed by 144 weeks open-label. i 48 weeks of double-blind adefovir dipivoxil followed by 144 weeks open-label tenofovir disoproxil fumarate. j 48 weeks of double-blind tenofovir disoproxil fumarate followed by 192 weeks open-label. k 48 weeks of double-blind adefovir dipivoxil followed by 192 weeks open-label tenofovir disoproxil fumarate. l Figures presented are cumulative percentages based upon a Kaplan Meier analysis excluding data collected after the addition of emtricitabine to open-label tenofovir disoproxil fumarate (KM-TDF). m 48 weeks of double-blind tenofovir disoproxil fumarate followed by 240 weeks open-label. n 48 weeks of double-blind adefovir dipivoxil followed by 240 weeks open-label tenofovir disoproxil fumarate. o 48 weeks of double-blind tenofovir disoproxil fumarate followed by 336 weeks open-label. p 48 weeks of double-blind adefovir dipivoxil followed by 336 weeks open-label tenofovir disoproxil fumarate. Paired baseline and week 240 liver biopsy data were available for 331/489 patients who remained in studies GS-US-174-0102 and GS-US-174-0103 at week 240 (see Table 6 below). Ninety-five percent (225/237) of patients without cirrhosis at baseline and 99% (93/94) of patients with cirrhosis at baseline had either no change or an improvement in fibrosis (Ishak fibrosis score). Of the 94 patients with cirrhosis at baseline (Ishak fibrosis score: 5 - 6), 26% (24) experienced no change in Ishak fibrosis score and 72% (68) experienced regression of cirrhosis by week 240 with a reduction in Ishak fibrosis score of at least 2 points Table 6: Histological response (%) in compensated HBeAg negative and HBeAg positive subjects at week 240 compared to baseline
b Knodell necroinflammatory score improvement of at least 2 points without worsening in Knodell fibrosis score. c 48 weeks double-blind tenofovir disoproxil fumarate followed by up to 192 weeks open-label. d 48 weeks double-blind adefovir dipivoxil followed by up to 192 weeks open-label tenofovir disoproxil fumarate. Experience in patients with HIV co-infection and prior lamivudine experience In a randomised, 48-week double-blind, controlled study of tenofovir disoproxil 245 mg (as fumarate) in adult patients co-infected with HIV-1 and chronic hepatitis B with prior lamivudine experience (study ACTG 5127), the mean serum HBV DNA levels at baseline in patients randomised to the tenofovir arm were 9.45 log10 copies/ml (n = 27). Treatment with tenofovir disoproxil 245 mg (as fumarate) was associated with a mean change in serum HBV DNA from baseline, in the patients for whom there was 48-week data, of -5.74 log10 copies/ml (n = 18). In addition, 61% of patients had normal ALT at week 48. Experience in patients with persistent viral replication (study GS-US-174-0106) The efficacy and safety of tenofovir disoproxil 245 mg (as fumarate) or tenofovir disoproxil 245 mg (as fumarate) plus 200 mg emtricitabine has been evaluated in a randomised, double-blind study (study GS-US-174-0106), in HBeAg positive and HBeAg negative adult patients who had persistent viraemia (HBV DNA ≥ 1,000 copies/ml) while receiving adefovir dipivoxil 10 mg for more than 24 weeks. At baseline, 57% of patients randomised to tenofovir disoproxil fumarate versus 60% of patients randomised to emtricitabine plus tenofovir disoproxil fumarate treatment group had previously been treated with lamivudine. Overall at week 24, treatment with tenofovir disoproxil fumarate resulted in 66% (35/53) of patients with HBV DNA < 400 copies/ml (< 69 IU/ml) versus 69% (36/52) of patients treated with emtricitabine plus tenofovir disoproxil fumarate (p = 0.672). In addition 55% (29/53) of patients treated with tenofovir disoproxil fumarate had undetectable HBV DNA (< 169 copies/ml [< 29 IU/ml]; the limit of quantification of the Roche Cobas TaqMan HBV assay) versus 60% (31/52) of patients treated with emtricitabine plus tenofovir disoproxil fumarate (p = 0.504). Comparisons between treatment groups beyond week 24 are difficult to interpret since investigators had the option to intensify treatment to open-label emtricitabine plus tenofovir disoproxil. Long-term studies to evaluate the benefit/risk of bitherapy with emtricitabine plus tenofovir disoproxil fumarate in HBV monoinfected patients are ongoing. Experience in patients with decompensated liver disease at 48 weeks (study GS-US-174-0108) Study GS-US-174-0108 is a randomised, double-blind, active controlled study evaluating the safety and efficacy of tenofovir disoproxil fumarate (n = 45), emtricitabine plus tenofovir disoproxil fumarate (n = 45), and entecavir (n = 22), in patients with decompensated liver disease. In the tenofovir disoproxil fumarate treatment arm, patients had a mean CPT score of 7.2, mean HBV DNA of 5.8 log10 copies/ml and mean serum ALT of 61 U/l at baseline. Forty-two percent (19/45) of patients had at least 6 months of prior lamivudine experience, 20% (9/45) of patients had prior adefovir dipivoxil experience and 9 of 45 patients (20%) had lamivudine and/or adefovir dipivoxil resistance mutations at baseline. The co-primary safety endpoints were discontinuation due to an adverse event and confirmed increase in serum creatinine ≥ 0.5 mg/dl or confirmed serum phosphate of < 2 mg/dl. In patients with CPT scores ≤ 9, 74% (29/39) of tenofovir disoproxil fumarate, and 94% (33/35) of emtricitabine plus tenofovir disoproxil fumarate treatment groups achieved HBV DNA < 400 copies/ml after 48 weeks of treatment. Overall, the data derived from this study are too limited to draw any definitive conclusions on the comparison of emtricitabine plus tenofovir disoproxil fumarate versus tenofovir disoproxil fumarate, (see Table 7 below). Table 7: Safety and efficacy parameters in decompensated patients at week 48
b p-value comparing the combined tenofovir-containing arms versus the entecavir arm = 1.000. Experience beyond 48 weeks in study GS-US-174-0108 Using a noncompleter/switch = failure analysis, 50% (21/42) of subjects receiving tenofovir disoproxil fumarate, 76% (28/37) of subjects receiving emtricitabine plus tenofovir disoproxil fumarate and 52% (11/21) of subjects receiving entecavir achieved HBV DNA < 400 copies/ml at week 168. Experience in patients with lamivudine-resistant HBV at 96 weeks (study GS-US-174-0121) The efficacy and safety of 245 mg tenofovir disoproxil (as fumarate) was evaluated in a randomised, double-blind study (GS-US-174-0121) in HBeAg positive and HBeAg negative patients (n = 280) with compensated liver disease, viraemia (HBV DNA ≥ 1,000 IU/ml), and genotypic evidence of lamivudine resistance (rtM204I/V +/- rtL180M). Only five had adefovir-associated resistance mutations at baseline. One hundred forty-one and 139 adult subjects were randomised to a tenofovir disoproxil fumarate and emtricitabine plus tenofovir disoproxil fumarate treatment arm, respectively. Baseline demographics were similar between the two treatment arms: At baseline, 52.5% of subjects were HBeAg negative, 47.5% were HBeAg positive, mean HBV DNA level was 6.5 log10 copies/ml, and mean ALT was 79 U/l, respectively. After 96 weeks of treatment, 126 of 141 subjects (89%) randomised to tenofovir disoproxil fumarate had HBV DNA < 400 copies/ml, and 49 of 79 subjects (62%) had ALT normalisation. After 96 weeks of treatment with emtricitabine plus tenofovir disoproxil fumarate, 120 of 139 subjects (86%) had HBV DNA < 400 copies/ml, and 52 of 83 subjects (63%) had ALT normalisation. Among the HBeAg positive subjects randomised to tenofovir disoproxil fumarate, 10 of 65 subjects (15%) experienced HBeAg loss, and 7 of 65 subjects (11%) experienced anti-HBe seroconversion through week 96. In the HBeAg positive subjects randomised to emtricitabine plus tenofovir disoproxil fumarate, 9 of 68 subjects (13%) experienced HBeAg loss, and 7 of 68 subjects (10%) experienced anti-HBe seroconversion through week 96. No subject randomised to tenofovir disoproxil fumarate experienced HBsAg loss or seroconversion to anti-HBs. One subject randomised to emtricitabine plus tenofovir disoproxil fumarate experienced HBsAg loss. Clinical resistance Four hundred and twenty-six HBeAg negative (GS-US-174-0102, n = 250) and HBeAg positive (GS-US-174-0103, n = 176) patients initially randomised to double-blind tenofovir disoproxil fumarate treatment and then switched to open-label tenofovir disoproxil fumarate treatment were evaluated for genotypic changes in HBV polymerase from baseline. Genotypic evaluations performed on all patients with HBV DNA > 400 copies/ml at week 48 (n = 39), 96 (n = 24), 144 (n = 6), 192 (n = 5), 240 (n = 4), 288 (n = 6) and 384 (n = 2) of tenofovir disoproxil fumarate monotherapy showed that no mutations associated with tenofovir disoproxil fumarate resistance have developed. Two hundred and fifteen HBeAg negative (GS-US-174-0102, n = 125) and HBeAg positive (GS-US-174-0103, n = 90) patients initially randomised to double-blind adefovir dipivoxil treatment and then switched to open-label tenofovir disoproxil fumarate treatment were evaluated for genotypic changes in HBV polymerase from baseline. Genotypic evaluations performed on all patients with HBV DNA > 400 copies/ml at week 48 (n = 16), 96 (n = 5), 144 (n = 1), 192 (n = 2), 240 (n = 1), 288 (n = 1) and 384 (n = 2) of tenofovir disoproxil fumarate monotherapy showed that no mutations associated with tenofovir disoproxil fumarate resistance have developed. In study GS-US-174-0108, 45 patients (including 9 patients with lamivudine and/or adefovir dipivoxil resistance mutations at baseline) received tenofovir disoproxil fumarate for up to 168 weeks. Genotypic data from paired baseline and on treatment HBV isolates were available for 6/8 patients with HBV DNA > 400 copies/ml at week 48. No amino acid substitutions associated with resistance to tenofovir disoproxil fumarate were identified in these isolates. Genotypic analysis was conducted for 5 subjects in the tenofovir disoproxil fumarate arm post week 48. No amino acid substitutions associated with tenofovir disoproxil fumarate resistance were detected in any subject. In study GS-US-174-0121, 141 patients with lamivudine resistance substitutions at baseline received tenofovir disoproxil fumarate for up to 96 weeks. Genotypic data from paired baseline and on treatment HBV isolates were available for 6 of 9 patients with HBV DNA > 400 copies/ml at their last time point on tenofovir disoproxil fumarate. No amino acid substitutions associated with resistance to tenofovir disoproxil fumarate were identified in these isolates. In a paediatric study (GS-US-174-0115), 52 patients (including 6 patients with lamivudine resistance mutations at baseline) received tenofovir disoproxil fumarate for up to 72 weeks. Genotypic evaluations were performed on all patients with HBV DNA > 400 copies/ml at week 48 (n = 6) and week 72 (n = 5). No amino acid substitutions associated with resistance to tenofovir disoproxil fumarate were identified in these isolates. Paediatric populatio HIV-1: In study GS-US-104-0321, 87 HIV-1 infected treatment-experienced patients 12 to < 18 years of age were treated with tenofovir disoproxil fumarate (n = 45) or placebo (n = 42) in combination with an optimised background regimen (OBR) for 48 weeks. Due to limitations of the study, a benefit of tenofovir disoproxil fumarate over placebo was not demonstrated based on plasma HIV-1 RNA levels at week 24. However, a benefit is expected for the adolescent population based on extrapolation of adult data and comparative pharmacokinetic data (see section 5.2). In patients who received treatment with tenofovir disoproxil fumarate or placebo, mean lumbar spine BMD Z-score was -1.004 and -0.809, and mean total body BMD Z-score was -0.866 and -0.584, respectively, at baseline. Mean changes at week 48 (end of double-blind phase) were -0.215 and -0.165 in lumbar spine BMD Z-score, and -0.254 and -0.179 in total body BMD Z-score for the tenofovir disoproxil fumarate and placebo groups, respectively. The mean rate of BMD gain was less in the tenofovir disoproxil fumarate group compared to the placebo group. At week 48, six adolescents in the tenofovir disoproxil fumarate group and one adolescent in the placebo group had significant lumbar spine BMD loss (defined as > 4% loss). Among 28 patients receiving 96 weeks of treatment with tenofovir disoproxil fumarate, BMD Z-scores declined by -0.341 for lumbar spine and -0.458 for total body. In study GS-US-104-0352, 97 treatment-experienced patients 2 to < 12 years of age with stable, virologic suppression on stavudine- or zidovudine-containing regimens were randomised to either replace stavudine or zidovudine with tenofovir disoproxil fumarate (n = 48) or continue on their original regimen (n = 49) for 48 weeks. At week 48, 83% of patients in the tenofovir disoproxil fumarate treatment group and 92% of patients in the stavudine or zidovudine treatment group had HIV-1 RNA concentrations < 400 copies/ml. The difference in the proportion of patients who maintained < 400 copies/ml at week 48 was mainly influenced by the higher number of discontinuations in the tenofovir disoproxil fumarate treatment group. When missing data were excluded, 91% of patients in the tenofovir disoproxil fumarate treatment group and 94% of patients in the stavudine or zidovudine treatment group had HIV-1 RNA concentrations < 400 copies/ml at week 48. Reductions in BMD have been reported in paediatric patients. In patients who received treatment with tenofovir disoproxil fumarate, or stavudine or zidovudine, mean lumbar spine BMD Z-score was -1.034 and -0.498, and mean total body BMD Z-score was -0.471 and -0.386, respectively, at baseline. Mean changes at week 48 (end of randomised phase) were 0.032 and 0.087 in lumbar spine BMD Z-score, and -0.184 and -0.027 in total body BMD Z-score for the tenofovir disoproxil fumarate and stavudine or zidovudine groups, respectively. The mean rate of lumbar spine bone gain at week 48 was similar between the tenofovir disoproxil fumarate treatment group and the stavudine or zidovudine treatment group. Total body bone gain was less in the tenofovir disoproxil fumarate treatment group compared to the stavudine or zidovudine treatment group. One tenofovir disoproxil fumarate treated subject and no stavudine or zidovudine treated subjects experienced significant (> 4%) lumbar spine BMD loss at week 48. BMD Z-scores declined by -0.012 for lumbar spine and by -0.338 for total body in the 64 subjects who were treated with tenofovir disoproxil fumarate for 96 weeks. BMD Z-scores were not adjusted for height and weight. In study GS-US-104-0352, 4 out of 89 paediatric patients exposed to tenofovir disoproxil fumarate discontinued due to adverse reactions consistent with proximal renal tubulopathy (median tenofovir disoproxil fumarate exposure 104 weeks). Chronic hepatitis B: In study GS-US-174-0115, 106 HBeAg negative and HBeAg positive patients aged 12 to < 18 years with chronic HBV infection [HBV DNA ≥ 105 copies/ml, elevated serum ALT (≥ 2 x ULN) or a history of elevated serum ALT levels in the past 24 months] were treated with tenofovir disoproxil 245 mg (as fumarate) (n = 52) or placebo (n = 54) for 72 weeks. Subjects must have been naïve to tenofovir disoproxil fumarate, but could have received interferon based regimens (> 6 months prior to screening) or any other non-tenofovir disoproxil fumarate containing oral anti-HBV nucleoside/nucleotide therapy (> 16 weeks prior to screening). At week 72, overall 88% (46/52) of patients in the tenofovir disoproxil fumarate treatment group and 0% (0/54) of patients in the placebo group had HBV DNA < 400 copies/ml. Seventy-four percent (26/35) of patients in the tenofovir disoproxil fumarate group had normalised ALT at week 72 compared to 31% (13/42) in the placebo group. Response to treatment with tenofovir disoproxil fumarate was comparable in nucleos(t)ide-naïve (n = 20) and nucleos(t)ide-experienced (n = 32) patients, including lamivudine-resistant patients (n = 6). Ninety-five percent of nucleos(t)ide-naïve patients, 84% of nucleos(t)ide-experienced patients, and 83% of lamivudine-resistant patients achieved HBV DNA < 400 copies/ml at week 72. Thirty-one of the 32 nucleos(t)ide-experienced patients had prior lamivudine experience. At week 72, 96% (27/28) of immune-active patients (HBV DNA ≥ 105 copies/ml, serum ALT > 1.5 x ULN) in the tenofovir disoproxil fumarate treatment group and 0% (0/32) of patients in the placebo group had HBV DNA < 400 copies/ml. Seventy-five percent (21/28) of immune-active patients in the tenofovir disoproxil fumarate group had normal ALT at week 72 compared to 34% (11/32) in the placebo group. No subjects met the primary safety endpoint of a 6% decrease in lumbar spine BMD. In subjects receiving tenofovir disoproxil fumarate or placebo, mean (SD) lumbar spine BMD Z-score was -0.43 (0.764) and -0.28 (0.813), and mean total body BMD Z-score was -0.20 (1.126) and -0.26 (0.878), respectively, at baseline. The mean (SD) change in lumbar spine BMD Z-score from baseline to week 72 in subjects receiving tenofovir disoproxil fumarate was -0.05 (0.310) and 0.07 (0.377) in those receiving placebo. The mean change in whole body BMD Z-score in subjects receiving tenofovir disoproxil fumarate was -0.15 (0.379) and 0.06 (0.361) in those receiving placebo. BMD Z-scores were not adjusted for height and weight. The mean percentage increase in whole body and lumbar spine BMD from baseline to week 72 was 2.84% and 4.95%, respectively, in subjects receiving tenofovir disoproxil fumarate. These mean percentage increases in whole body and lumbar spine BMD were 2.53% and 3.19% less, respectively, when compared to subjects receiving placebo. Three subjects in the tenofovir disoproxil fumarate group and 2 subjects in the placebo group had a decrease of > 4% in spine BMD. The European Medicines Agency has deferred the obligation to submit the results of studies with Viread in one or more subsets of the paediatric population in HIV and chronic hepatitis B (see section 4.2 for information on paediatric use). 5.2 Pharmacokinetic properties Tenofovir disoproxil fumarate is a water soluble ester prodrug which is rapidly converted in vivo to tenofovir and formaldehyde. Tenofovir is converted intracellularly to tenofovir monophosphate and to the active component, tenofovir diphosphate. Absorption Following oral administration of tenofovir disoproxil fumarate to HIV infected patients, tenofovir disoproxil fumarate is rapidly absorbed and converted to tenofovir. Administration of multiple doses of tenofovir disoproxil fumarate with a meal to HIV infected patients resulted in mean (%CV) tenofovir Cmax, AUC, and Cmin values of 326 (36.6%) ng/ml, 3,324 (41.2%) ng·h/ml and 64.4 (39.4%) ng/ml, respectively. Maximum tenofovir concentrations are observed in serum within one hour of dosing in the fasted state and within two hours when taken with food. The oral bioavailability of tenofovir from tenofovir disoproxil fumarate in fasted patients was approximately 25%. Administration of tenofovir disoproxil fumarate with a high fat meal enhanced the oral bioavailability, with an increase in tenofovir AUC by approximately 40% and Cmax by approximately 14%. Following the first dose of tenofovir disoproxil fumarate in fed patients, the median Cmax in serum ranged from 213 to 375 ng/ml. However, administration of tenofovir disoproxil fumarate with a light meal did not have a significant effect on the pharmacokinetics of tenofovir. Distribution Following intravenous administration the steady-state volume of distribution of tenofovir was estimated to be approximately 800 ml/kg. After oral administration of tenofovir disoproxil fumarate, tenofovir is distributed to most tissues with the highest concentrations occurring in the kidney, liver and the intestinal contents (preclinical studies). 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 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 at a concentration of 100 µmol/l had no effect on any of the CYP450 isoforms, except CYP1A1/2, where a small (6%) but statistically significant reduction in metabolism of CYP1A1/2 substrate was observed. Based on these data, it is unlikely that clinically significant interactions involving tenofovir disoproxil fumarate and medicinal products metabolised by CYP450 would occur. Elimination Tenofovir is primarily excreted by the kidney by both filtration and an active tubular transport system with approximately 70-80% of the dose excreted unchanged in urine following intravenous administration. Total clearance has been estimated to be approximately 230 ml/h/kg (approximately 300 ml/min). Renal clearance has been estimated to be approximately 160 ml/h/kg (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 terminal half-life of tenofovir is approximately 12 to 18 hours. Studies have established the pathway of active tubular secretion of tenofovir to be influx into proximal tubule cell by the human organic anion transporters (hOAT) 1 and 3 and efflux into the urine by the multidrug resistant protein 4 (MRP 4). Linearity/non-linearity The pharmacokinetics of tenofovir were independent of tenofovir disoproxil fumarate dose over the dose range 75 to 600 mg and were not affected by repeated dosing at any dose level. Age Pharmacokinetic studies have not been performed in the elderly (over 65 years of age). Gender Limited data on the pharmacokinetics of tenofovir in women indicate no major gender effect. Ethnicity Pharmacokinetics have not been specifically studied in different ethnic groups. Paediatric population HIV-1: Steady-state pharmacokinetics of tenofovir were evaluated in 8 HIV-1 infected adolescent patients (aged 12 to < 18 years) with body weight ≥ 35 kg. Mean (± SD) Cmax and AUCtau are 0.38 ± 0.13 μg/ml and 3.39 ± 1.22 μg·h/ml, respectively. Tenofovir exposure achieved in adolescent patients receiving oral daily doses of tenofovir disoproxil 245 mg (as fumarate) was similar to exposures achieved in adults receiving once-daily doses of tenofovir disoproxil 245 mg (as fumarate). Chronic hepatitis B: Steady-state tenofovir exposure in HBV infected adolescent patients (12 to < 18 years of age) receiving an oral daily dose of tenofovir disoproxil 245 mg (as fumarate) was similar to exposures achieved in adults receiving once-daily doses of tenofovir disoproxil 245 mg (as fumarate). Pharmacokinetic studies have not been performed with tenofovir disoproxil (as fumarate) 245 mg tablets in children under 12 years or with renal impairment. Renal impairment Pharmacokinetic parameters of tenofovir were determined following administration of a single dose of tenofovir disoproxil 245 mg to 40 non-HIV, non-HBV infected adult patients with varying degrees of renal impairment defined according to baseline creatinine clearance (CrCl) (normal renal function when CrCl > 80 ml/min; mild with CrCl = 50-79 ml/min; moderate with CrCl = 30-49 ml/min and severe with CrCl = 10-29 ml/min). Compared with patients with normal renal function, the mean (%CV) tenofovir exposure increased from 2,185 (12%) ng·h/ml in subjects with CrCl > 80 ml/min to respectively 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. The dosing recommendations in patients with renal impairment, with increased dosing interval, are expected to result in higher peak plasma concentrations and lower Cmin levels in patients with renal impairment compared with patients with normal renal function. The clinical implications of this are unknown. In patients with end-stage renal disease (ESRD) (CrCl < 10 ml/min) requiring haemodialysis, between dialysis tenofovir concentrations substantially increased over 48 hours achieving a mean Cmax of 1,032 ng/ml and a mean AUC0-48h of 42,857 ng·h/ml. It is recommended that the dosing interval for tenofovir disoproxil 245 mg (as fumarate) is modified in adult patients with creatinine clearance < 50 ml/min or in patients who already have ESRD and require dialysis (see section 4.2). The pharmacokinetics of tenofovir in non-haemodialysis patients with creatinine clearance < 10 ml/min and in patients with ESRD managed by peritoneal or other forms of dialysis have not been studied. The pharmacokinetics of tenofovir in paediatric patients with renal impairment have not been studied. No data are available to make dose recommendations (see sections 4.2 and 4.4). Hepatic impairment A single 245 mg dose of tenofovir disoproxil was administered to non-HIV, non-HBV infected adult patients with varying degrees of hepatic impairment defined according to Child-Pugh-Turcotte (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. Intracellular pharmacokinetics In non-proliferating human peripheral blood mononuclear cells (PBMCs) the half-life of tenofovir diphosphate was found to be approximately 50 hours, whereas the half-life in phytohaemagglutinin-stimulated PBMCs was found to be approximately 10 hours. 5.3 Preclinical safety data Non-clinical safety pharmacology studies reveal no special hazard for humans. Findings in repeated 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 include renal and bone toxicity and a decrease in serum phosphate concentration. Bone toxicity was diagnosed as osteomalacia (monkeys) and reduced bone mineral density (BMD) (rats and dogs). The bone toxicity in young adult rats and dogs occurred at exposures ≥ 5-fold the exposure in paediatric or adult patients; bone toxicity occurred in juvenile infected monkeys at very high exposures following subcutaneous dosing (≥ 40-fold the exposure in patients). Findings in the rat and monkey studies indicated that there was a substance-related decrease in intestinal absorption of phosphate with potential secondary reduction in BMD. Genotoxicity studies revealed positive results in the in vitro mouse lymphoma assay, equivocal results in one of the strains used in the Ames test, and weakly positive results in an UDS test in primary rat hepatocytes. However, it was negative in an in vivo mouse bone marrow micronucleus assay. Oral carcinogenicity studies in rats and mice only revealed a low incidence of duodenal tumours at an extremely high dose in mice. These tumours are unlikely to be of relevance to humans. Reproductive 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 peri-postnatal toxicity studies at maternally toxic doses. The active substance tenofovir disoproxil fumarate and its main transformation products are persistent in the environment. 6. Pharmaceutical particulars 6.1 List of excipients Tablet core Croscarmellose sodium Lactose monohydrate Magnesium stearate (E572) Microcrystalline cellulose (E460) Starch pregelatinised Film-coating Glycerol triacetate (E1518) Hypromellose (E464) Indigo carmine aluminium lake (E132) Lactose monohydrate Titanium dioxide (E171) 6.2 Incompatibilities Not applicable. 6.3 Shelf life 5 years. 6.4 Special precautions for storage This medicinal product does not require any special storage conditions. 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/1/01/200/001 EU/1/01/200/002 9. Date of first authorisation/renewal of the authorisation Date of first authorisation: 5 February 2002 Date of latest renewal: 14 December 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 Gilead将于今年第四季度完成在美国和欧洲以乙型肝炎为扩大适应症的上市申请。 Gilead公司3月8日宣布，美国FDA已授予其抗逆转录病毒药物Viread（替诺福韦）和Truvada（恩曲他滨/替诺福韦）传统批准地位。Truvada含有该公司两种抗逆转录药Emtriva（恩曲他滨）和Viread。 *替诺福韦VIREAD 的使用 VIREAD(tenofovir disoproxil fumarate)是一种称为核苷酸类似物逆转录酶和乙型肝炎病毒 (HBV)聚合酶抑制剂(NRTI)的药物。VIREAD被用来治疗18岁以上的慢性乙型肝炎（感染 HBV）成人患者。 VIREAD的作用机理是干扰乙型肝炎病毒自身复制所必需的一种酶（HBV DNA 聚合酶）的正常运作。 VIREAD可以通过降低病毒繁殖和感染新的肝细胞的能力，来帮助减少患者体内乙型肝炎病毒的数量。 VIREAD也被用来治疗18岁以上感染艾滋病病毒1(HIV-1)的成人患者。VIREAD一直与其他抗HIV-1 药物配合使用，治疗感染HIV-1的患者。 VIREAD无法治愈HIV-1感染或艾滋病，或降低将HIV-1或HBV传染给他人的风险。 VIREAD的长期效果目前尚不得而知。 如果您对VIREAD或其中任何一种成分过敏，请勿服用VIREAD。VIREAD不应同TRUVADA®（emtricitabine 200毫克/tenofovir disoproxil fumarate 300毫克或ATRIPLA®（efavirenz 600毫克/emtricitabine 200毫克/tenofovir disoproxil fumarate 300毫克）一起使用，因为VIREAD是TRUVADA和ATRIPLA中的一种有效成分。VIREAD不应同 HEPSERA®(adefovir dipivoxil) 一起使用。 VIREAD的常用剂量为每天一次，每次一片300毫克的片剂。如果您有肾脏问题，您的医护人员可能会建议您减少服用VIREAD的频率。服用 VIREAD 期间必须接受医护人员的照料。 *重要安全信息 如果在服用VIREAD期间出现下列任何一种副作用或情况，请立即与医护人员联系： - 恶心、呕吐、不寻常或意想不到的胃部不适和虚弱。这些可能是血液中乳酸浓度升高的迹象（乳酸性酸中毒）这是一种严重的医学症状 - 大便颜色淡、尿液颜色深和/或者如果皮肤或眼白变黄。这些可能是严重肝脏疾病（肝脏毒性），以及肝脏变大（肝肿大）和脂肪肝（脂肪变性）的迹象 - 如果您有乙型肝炎病毒感染或是同时有HIV和HBV感染情况，在停止服用VIREAD后，您可能会出现乙型肝炎「再度突然发作」的现象，并且您的肝脏疾病可能会突然恶化。非经由医护人员的建议，请勿停止服用VIREAD。在您停止服用VIREAD后的几个月内，医护人员仍然需要检查您的身体并且进行血液检验，以观察您的肝脏状况。 - 有一些接受VIREAD治疗的患者曾有肾脏问题。如果您过去曾有肾脏问题或是服用其它可能造成肾脏问题的药物，医护人员可能需要对您进行其他的血液检验。 - 化验室检验结果显示接受 VIREAD 治疗的患者骨骼会发生变化。如果您过去曾有骨骼方面的问题，医护人员可能需要对您进行其他检验，或者建议您服用其他药物。肾脏疾病也可能导致出现骨痛和骨质松软（可能导致骨折）。 已经发现某些服用抗VIREAD和其它抗HIV-1药物的患者体内脂肪发生改变的现象。 如果您在开始HIV-1治疗后不久发现任何感染症状，请立即告诉医护人员。 针对慢性乙型肝炎患者所进行的研究显示：VIREAD最常见的副作用为恶心。较不常见的副作用包括腹痛、腹泻、头痛、眩晕、疲惫、鼻咽炎、背痛以及皮疹。 针对HIV-1患者所进行的研究显示：VIREAD最常见的副作用为：皮疹、头痛、疼痛、腹泻、抑郁、虚弱以及恶心。较不常见的副作用包括呕吐、眩晕以及肠胃胀气。 ------------------------------------------ 产地国家：德国 原产地英文商品名: VIREAD 245mg/Tablets 30Tabletsx3/box 原产地英文药品名: Tenofovir Disoproxil 中文参考商品译名: 韦瑞德片 245mg毫克/片 30片x3瓶/盒 中文参考药品译名: 替诺福韦酯 生产厂家中文参考译名: 吉利德科学公司 生产厂家英文名 GLIEAD ------------------------------------------ 产地国家：德国 原产地英文商品名: VIREAD 245mg/Tablets 30Tablets/bottle 原产地英文药品名: Tenofovir Disoproxil 中文参考商品译名: 韦瑞德片 245mg毫克/片 30片/瓶 中文参考药品译名: 替诺福韦酯 生产厂家中文参考译名: 吉利德科学公司 生产厂家英文名 GLIEAD ----------------------------------------------- 产地国家: 英国 原产地英文商品名: Viread Granules 33mg/g 60g 原产地英文药品名: TENOFOVIR DISOPROXIL 中文参考商品译名: 替诺福韦酯 33毫克/克 60克 中文参考药品译名: 替诺福韦酯 生产厂家中文参考译名: 吉利德科学公司 生产厂家英文名: Gilead ----------------------------------------------- 产地国家: 土耳其 原产地英文商品名: VIREAD(known as 300mg in the US) 245mg/tab 30tabs/box 原产地英文药品名: TENOFOVIR DISOPROXIL FUMARATE 中文参考商品译名: VIREAD(相当于美国的300毫克) 245毫克/片 30片/盒 中文参考药品译名: 替诺福韦酯富马酸盐 生产厂家中文参考译名: 吉利德科学公司 生产厂家英文名: GILEAD 该药品相关信息网址1: http://www.viread.com/ 该药品相关信息网址2: http://www.viread.com/ch/100.cfm | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
