тенофолек

Overdose

Symptoms

If overdose occurs the patient must be monitored for evidence of toxicity , and standard supportive treatment applied as necessary.

Management

ТЕНОФОЛЕК can be removed by haemodialysis; the median haemodialysis clearance of ТЕНОФОЛЕК is 134 ml/min. It is not known whether ТЕНОФОЛЕК can be removed by peritoneal dialysis.

Incompatibilities

Not applicable.

Pharmaceutical form

Undesirable effects

Summary of the safety profile

HIV-1 and hepatitis B: In patients receiving ТЕНОФОЛЕК disoproxil, 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 ТЕНОФОЛЕК disoproxil.

HIV-1: Approximately one third of patients can be expected to experience adverse reactions following treatment with ТЕНОФОЛЕК disoproxil in combination with other antiretroviral agents. These reactions are usually mild to moderate gastrointestinal events. Approximately 1% of ТЕНОФОЛЕК disoproxil-treated adult patients discontinued treatment due to the gastrointestinal events.

Co-administration of ТЕНОФОЛЕК disoproxil and didanosine is not recommended as this may result in an increased risk of adverse reactions. Rarely, pancreatitis and lactic acidosis, sometimes fatal, have been reported.

Hepatitis B: Approximately one quarter of patients can be expected to experience adverse reactions following treatment with ТЕНОФОЛЕК disoproxil, most of which are mild. In clinical trials of HBV infected patients, the most frequently occurring adverse reaction to ТЕНОФОЛЕК disoproxil 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.

Tabulated summary of adverse reactions

Assessment of adverse reactions for ТЕНОФОЛЕК disoproxil 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 ТЕНОФОЛЕК disoproxil (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 ТЕНОФОЛЕК disoproxil 245 mg (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 ТЕНОФОЛЕК disoproxil 245 mg 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 ТЕНОФОЛЕК disoproxil. 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 ТЕНОФОЛЕК disoproxil 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 ТЕНОФОЛЕК disoproxil 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 ТЕНОФОЛЕК disoproxil (n=45) or emtricitabine plus ТЕНОФОЛЕК disoproxil (n=45) or entecavir (n=22) for 48 weeks.

In the ТЕНОФОЛЕК disoproxil 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 ТЕНОФОЛЕК-containing arms and the entecavir arm. After 168 weeks, 16% (7/45) of the ТЕНОФОЛЕК disoproxil group, 4% (2/45) of the emtricitabine plus ТЕНОФОЛЕК disoproxil group, and 14% (3/22) of the entecavir group experienced tolerability failure. Thirteen percent (6/45) of the ТЕНОФОЛЕК disoproxil group, 13% (6/45) of the emtricitabine plus ТЕНОФОЛЕК disoproxil 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 ТЕНОФОЛЕК disoproxil group, 11% (5/45) in the emtricitabine plus ТЕНОФОЛЕК disoproxil group and 14% (3/22) in the entecavir group. The rate of hepatocellular carcinoma was 18% (8/45) in the ТЕНОФОЛЕК disoproxil group, 7% (3/45) in the emtricitabine plus ТЕНОФОЛЕК disoproxil 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.

Patients with lamivudine-resistant chronic hepatitis B: No new adverse reactions to ТЕНОФОЛЕК disoproxil were identified from a randomised, double-blind study (GS-US-174-0121) in which 280 lamivudine-resistant patients received treatment with ТЕНОФОЛЕК disoproxil (n=141) or emtricitabine/ТЕНОФОЛЕК disoproxil (n=139) for 240 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 ТЕНОФОЛЕК disoproxil based on clinical study and post-marketing experience.

1 This adverse reaction may occur as a consequence of proximal renal tubulopathy. It is not considered to be causally associated with ТЕНОФОЛЕК disoproxil in the absence of this condition.

2 This adverse reaction was identified through post-marketing surveillance but not observed in randomised controlled clinical trials or the ТЕНОФОЛЕК disoproxil expanded access program. The frequency category was estimated from a statistical calculation based on the total number of patients exposed to ТЕНОФОЛЕК disoproxil 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

HIV-1:

Interaction with didanosine

Co-administration of ТЕНОФОЛЕК disoproxil 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, pancreatitis and lactic acidosis, sometimes fatal, have been reported.

Metabolic parameters

Weight and levels of blood lipids and glucose may increase during antiretroviral therapy.

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.

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.

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 ТЕНОФОЛЕК disoproxil-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.

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.

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 ТЕНОФОЛЕК disoproxil (n=93) or placebo/active comparator (n=91) in combination with other antiretroviral agents for 48 weeks.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 ТЕНОФОЛЕК disoproxil 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 ТЕНОФОЛЕК disoproxil were lower than those observed in subjects who remained on their stavudine- or zidovudine-containing regimen.

In study GS-US-104-0352, 4 out of 89 paediatric patients exposed to ТЕНОФОЛЕК disoproxil (median ТЕНОФОЛЕК disoproxil exposure 312 weeks), discontinued due to adverse reactions consistent with proximal renal tubulopathy. Seven patients had estimated glomerular filtration rate (GFR) values between 70 and 90 mL/min/1.73 m2. Among them, two patients experienced a clinically meaningful decline in estimated GFR which improved after discontinuation of ТЕНОФОЛЕК disoproxil.

Chronic hepatitis B

Reductions in BMD have been observed in HBV infected adolescents. The BMD Z-scores observed in subjects who received ТЕНОФОЛЕК disoproxil were lower than those observed in subjects who received placebo.

Other special population(s)

Elderly

ТЕНОФОЛЕК disoproxil 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 ТЕНОФОЛЕК disoproxil.

Patients with renal impairment

Since ТЕНОФОЛЕК disoproxil can cause renal toxicity, close monitoring of renal function is recommended in adult patients with renal impairment treated with ТЕНОФОЛЕК disoproxil tablets. The use of ТЕНОФОЛЕК disoproxil is not recommended in paediatric patients with renal impairment.

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 Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard.

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, ТЕНОФОЛЕК disoproxil reduced the viability index and weight of pups in peri-postnatal toxicity studies at maternally toxic doses.

The active substance ТЕНОФОЛЕК disoproxil and its main transformation products are persistent in the environment.

Therapeutic indications

HIV-1 infection

ТЕНОФОЛЕК disoproxil tablets 245 mg film-coated tablets are indicated in combination with other antiretroviral medicinal products for the treatment of HIV-1 infected adults.

In adults, the demonstration of the benefit of ТЕНОФОЛЕК disoproxil tablets in HIV-1 infection is based on results of one study in treatment-naïve patients, including patients with a high viral load (>100,000 copies/ml) and studies in which ТЕНОФОЛЕК disoproxil tablets was added to stable background therapy (mainly tritherapy) in antiretroviral pre-treated patients experiencing early virological failure (<10,000 copies/ml, with the majority of patients having <5,000 copies/ml).

ТЕНОФОЛЕК disoproxil 245 mg film-coated tablets are also indicated for the treatment of HIV-1 infected adolescents, with NRTI resistance or toxicities precluding the use of first line agents, aged 12 to <18 years.

The choice of ТЕНОФОЛЕК disoproxil tablets to treat antiretroviral-experienced patients with HIV-1 infection should be based on individual viral resistance testing and/or treatment history of patients.

Hepatitis B infection

ТЕНОФОЛЕК disoproxil 245 mg film-coated tablets are indicated for the treatment of chronic hepatitis B in adults with:

- compensated liver disease, with evidence of active viral replication, persistently elevated serum alanine aminotransferase (ALT) levels and histological evidence of active inflammation and/or fibrosis.

- evidence of lamivudine-resistant hepatitis B virus.

- decompensated liver disease.

ТЕНОФОЛЕК disoproxil 245 mg film-coated tablets are indicated for the treatment of chronic hepatitis B in adolescents 12 to <18 years of age with:

- compensated liver disease and evidence of immune active disease, i.e. active viral replication, persistently elevated serum ALT levels and histological evidence of active inflammation and/or fibrosis.

Pharmacotherapeutic group

Pharmacodynamic properties

Pharmacotherapeutic group: Antiviral for systemic use; nucleoside and nucleotide reverse transcriptase inhibitors, ATC code: J05AF07.

Mechanism of action and pharmacodynamic effects

ТЕНОФОЛЕК disoproxil is absorbed and converted to the active substance ТЕНОФОЛЕК, which is a nucleoside monophosphate (nucleotide) analogue. ТЕНОФОЛЕК is then converted to the active metabolite, ТЕНОФОЛЕК diphosphate, an obligate chain terminator, by constitutively expressed cellular enzymes. ТЕНОФОЛЕК diphosphate has an intracellular half-life of 10 hours in activated and 50 hours in resting peripheral blood mononuclear cells (PBMCs). ТЕНОФОЛЕК 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. ТЕНОФОЛЕК diphosphate is a weak inhibitor of cellular polymerases α, β, and γ. At concentrations of up to 300 μmol/l, ТЕНОФОЛЕК 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 ТЕНОФОЛЕК 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. ТЕНОФОЛЕК is also active against HIV-1 subtypes A, C, D, E, F, G, and O and against HIVBaL in primary monocyte/macrophage cells. ТЕНОФОЛЕК 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 ТЕНОФОЛЕК and a K65R mutation in reverse transcriptase have been selected in vitro and in some patients (see Clinical efficacy and safety). ТЕНОФОЛЕК disoproxil should be avoided in antiretroviral-experienced patients with strains harbouring the K65R mutation. In addition, a K70E substitution in HIV-1 reverse transcriptase has been selected by ТЕНОФОЛЕК and results in low-level reduced susceptibility to ТЕНОФОЛЕК.

Clinical studies in treatment-experienced patients have assessed the anti-HIV activity of ТЕНОФОЛЕК disoproxil 245 mg 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 ТЕНОФОЛЕК disoproxil 245 mg therapy.

Clinical efficacy and safety

The effects of ТЕНОФОЛЕК disoproxil 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 ТЕНОФОЛЕК disoproxil 245 mg 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 ТЕНОФОЛЕК disoproxil 245 mg recipients (p <0.0001). A statistically significant difference in favour of ТЕНОФОЛЕК disoproxil 245 mg was seen in the time-weighted average change from baseline at week 24 (DAVG24) for CD4 count (+13 cells/mm3 for ТЕНОФОЛЕК disoproxil 245 mg versus -11 cells/mm3 for placebo, p-value=0.0008). The antiviral response to ТЕНОФОЛЕК disoproxil 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%) ТЕНОФОЛЕК disoproxil 245 mg 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 ТЕНОФОЛЕК disoproxil 245 mg 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 ТЕНОФОЛЕК disoproxil 245 mg 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 ТЕНОФОЛЕК disoproxil 245 mg 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 ТЕНОФОЛЕК disoproxil 245 mg 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 ТЕНОФОЛЕК disoproxil 245 mg and stavudine groups, respectively). A consistent response to treatment with ТЕНОФОЛЕК disoproxil 245 mg was seen regardless of baseline HIV-1 RNA and CD4 count.

The K65R mutation occurred in a slightly higher percentage of patients in the ТЕНОФОЛЕК disoproxil 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 ТЕНОФОЛЕК disoproxil 245 mg 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 ТЕНОФОЛЕК disoproxil 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 ТЕНОФОЛЕК.

Data pertaining to HBV

HBV antiviral activity in vitro: The in vitro antiviral activity of ТЕНОФОЛЕК against HBV was assessed in the HepG2 2.2.15 cell line. The EC50 values for ТЕНОФОЛЕК 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 ТЕНОФОЛЕК disoproxil 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 ТЕНОФОЛЕК 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 ТЕНОФОЛЕК 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 ТЕНОФОЛЕК ranging from 2.9- to 10-fold that of wild- type virus. Viruses containing the rtA181T mutation remained susceptible to ТЕНОФОЛЕК with EC50 values 1.5-fold that of wild-type virus.

Clinical efficacy and safety

The demonstration of benefit of ТЕНОФОЛЕК disoproxil 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 ТЕНОФОЛЕК disoproxil 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 ТЕНОФОЛЕК disoproxil 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 ТЕНОФОЛЕК disoproxil 245 mg 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 ТЕНОФОЛЕК disoproxil 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

* p-value versus adefovir dipivoxil < 0.05.

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.

ТЕНОФОЛЕК disoproxil 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 ТЕНОФОЛЕК disoproxil 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 ТЕНОФОЛЕК disoproxil 245 mg or adefovir dipivoxil 10 mg), patients rolled over with no interruption in treatment to open-label ТЕНОФОЛЕК disoproxil. 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 ТЕНОФОЛЕК disoproxil 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

a Based upon Long Term Evaluation algorithm (LTE Analysis) - Patients who discontinued the study at any time prior to week 384 due to a protocol defined endpoint, as well as those completing week 384, are included in the denominator.

b 48 weeks of double-blind ТЕНОФОЛЕК disoproxil followed by 48 weeks open-label.

c 48 weeks of double-blind adefovir dipivoxil followed by 48 weeks open-label ТЕНОФОЛЕК disoproxil.

d The population used for analysis of ALT normalisation included only patients with ALT above ULN at baseline.

e 48 weeks of double-blind ТЕНОФОЛЕК disoproxil followed by 96 weeks open-label.

f 48 weeks of double-blind adefovir dipivoxil followed by 96 weeks open-label ТЕНОФОЛЕК disoproxil.

g 48 weeks of double-blind ТЕНОФОЛЕК disoproxil followed by 144 weeks open-label.

h 48 weeks of double-blind adefovir dipivoxil followed by 144 weeks open-label ТЕНОФОЛЕК disoproxil.

i 48 weeks of double-blind ТЕНОФОЛЕК disoproxil followed by 192 weeks open-label.

j 48 weeks of double-blind adefovir dipivoxil followed by 192 weeks open-label ТЕНОФОЛЕК disoproxil.

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 ТЕНОФОЛЕК disoproxil followed by 240 weeks open-label.

m 48 weeks of double-blind adefovir dipivoxil followed by 240 weeks open-label ТЕНОФОЛЕК disoproxil.

n Figures presented are cumulative percentages based upon a Kaplan Meier analysis excluding data collected after the addition of emtricitabine to open-label ТЕНОФОЛЕК disoproxil (KM-TDF).

o 48 weeks of double-blind ТЕНОФОЛЕК disoproxil followed by 336 weeks open-label.

p 48 weeks of double-blind adefovir dipivoxil followed by 336 weeks open-label ТЕНОФОЛЕК disoproxil.

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

a Based upon Long Term Evaluation algorithm (LTE Analysis) - Patients who discontinued the study at any time prior to week 384 due to a protocol defined endpoint, as well as those completing week 384, are included in the denominator.

b 48 weeks of double-blind ТЕНОФОЛЕК disoproxil followed by 48 weeks open-label.

c 48 weeks of double-blind adefovir dipivoxil followed by 48 weeks open-label ТЕНОФОЛЕК disoproxil.

d The population used for analysis of ALT normalisation included only patients with ALT above ULN at baseline.

e 48 weeks of double-blind ТЕНОФОЛЕК disoproxil followed by 96 weeks open-label.

f 48 weeks of double-blind adefovir dipivoxil followed by 96 weeks open-label ТЕНОФОЛЕК disoproxil.

g Figures presented are cumulative percentages based upon a Kaplan Meier analysis including data collected after the addition of emtricitabine to open-label ТЕНОФОЛЕК disoproxil (KM-ITT).

h 48 weeks of double-blind ТЕНОФОЛЕК disoproxil followed by 144 weeks open-label.

i 48 weeks of double-blind adefovir dipivoxil followed by 144 weeks open-label ТЕНОФОЛЕК disoproxil.

j 48 weeks of double-blind ТЕНОФОЛЕК disoproxil followed by 192 weeks open-label.

k 48 weeks of double-blind adefovir dipivoxil followed by 192 weeks open-label ТЕНОФОЛЕК disoproxil.

l Figures presented are cumulative percentages based upon a Kaplan Meier analysis excluding data collected after the addition of emtricitabine to open-label ТЕНОФОЛЕК disoproxil (KM-TDF).

m 48 weeks of double-blind ТЕНОФОЛЕК disoproxil followed by 240 weeks open-label.

n 48 weeks of double-blind adefovir dipivoxil followed by 240 weeks open-label ТЕНОФОЛЕК disoproxil.

o 48 weeks of double-blind ТЕНОФОЛЕК disoproxil followed by 336 weeks open-label.

p 48 weeks of double-blind adefovir dipivoxil followed by 336 weeks open-label ТЕНОФОЛЕК disoproxil.

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

a The population used for analysis of histology included only patients with available liver biopsy data (Missing = Excluded) by week 240. Response after addition of emtricitabine is excluded (total of 17 subjects across both studies).

b Knodell necroinflammatory score improvement of at least 2 points without worsening in Knodell fibrosis score.

c 48 weeks double-blind ТЕНОФОЛЕК disoproxil followed by up to 192 weeks open-label.

d 48 weeks double-blind adefovir dipivoxil followed by up to 192 weeks open-label ТЕНОФОЛЕК disoproxil.

Experience in patients with HIV co-infection and prior lamivudine experience

In a randomised, 48-week double-blind, controlled study of ТЕНОФОЛЕК disoproxil 245 mg 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 ТЕНОФОЛЕК arm were 9.45 log10 copies/ml (n = 27). Treatment with ТЕНОФОЛЕК disoproxil 245 mg 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 ТЕНОФОЛЕК disoproxil 245 mg or ТЕНОФОЛЕК disoproxil 245 mg 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 ТЕНОФОЛЕК disoproxil versus 60% of patients randomised to emtricitabine plus ТЕНОФОЛЕК disoproxil treatment group had previously been treated with lamivudine. Overall at week 24, treatment with ТЕНОФОЛЕК disoproxil 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 ТЕНОФОЛЕК disoproxil (p = 0.672). In addition 55% (29/53) of patients treated with ТЕНОФОЛЕК disoproxil 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 ТЕНОФОЛЕК disoproxil (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 ТЕНОФОЛЕК disoproxil. Long-term studies to evaluate the benefit/risk of bitherapy with emtricitabine plus ТЕНОФОЛЕК disoproxil 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 ТЕНОФОЛЕК disoproxil (n = 45), emtricitabine plus ТЕНОФОЛЕК disoproxil (n = 45), and entecavir (n = 22), in patients with decompensated liver disease. In th

Pharmacokinetic properties

ТЕНОФОЛЕК disoproxil is a water soluble ester prodrug which is rapidly converted in vivo to ТЕНОФОЛЕК.

ТЕНОФОЛЕК is converted intracellularly to ТЕНОФОЛЕК monophosphate and to the active component, ТЕНОФОЛЕК diphosphate.

Absorption

Following oral administration of ТЕНОФОЛЕК disoproxil to HIV infected patients, ТЕНОФОЛЕК disoproxil is rapidly absorbed and converted to ТЕНОФОЛЕК. Administration of multiple doses of ТЕНОФОЛЕК disoproxil with a meal to HIV infected patients resulted in mean (%CV) ТЕНОФОЛЕК 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 ТЕНОФОЛЕК 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 ТЕНОФОЛЕК from ТЕНОФОЛЕК disoproxil in fasted patients was approximately 25%. Administration of ТЕНОФОЛЕК disoproxil with a high fat meal enhanced the oral bioavailability, with an increase in ТЕНОФОЛЕК AUC by approximately 40% and Cmax by approximately 14%. Following the first dose of ТЕНОФОЛЕК disoproxil in fed patients, the median Cmax in serum ranged from 213 to 375 ng/ml. However, administration of ТЕНОФОЛЕК disoproxil with a light meal did not have a significant effect on the pharmacokinetics of ТЕНОФОЛЕК.

Distribution

Following intravenous administration the steady-state volume of distribution of ТЕНОФОЛЕК was estimated to be approximately 800 ml/kg. After oral administration of ТЕНОФОЛЕК disoproxil, ТЕНОФОЛЕК 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 ТЕНОФОЛЕК to plasma or serum protein was less than 0.7 and 7.2%, respectively, over the ТЕНОФОЛЕК concentration range 0.01 to 25 μg/ml.

Biotransformation

In vitro studies have determined that neither ТЕНОФОЛЕК disoproxil nor ТЕНОФОЛЕК are substrates for the CYP450 enzymes. Moreover, at concentrations substantially higher (approximately 300-fold) than those observed in vivo, ТЕНОФОЛЕК 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). ТЕНОФОЛЕК disoproxil 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 ТЕНОФОЛЕК disoproxil and medicinal products metabolised by CYP450 would occur.

Elimination

ТЕНОФОЛЕК 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 ТЕНОФОЛЕК. Following oral administration the terminal half-life of ТЕНОФОЛЕК is approximately 12 to 18 hours.

Studies have established the pathway of active tubular secretion of ТЕНОФОЛЕК 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 ТЕНОФОЛЕК were independent of ТЕНОФОЛЕК disoproxil 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 ТЕНОФОЛЕК 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 ТЕНОФОЛЕК 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. ТЕНОФОЛЕК exposure achieved in adolescent patients receiving oral daily doses of ТЕНОФОЛЕК disoproxil 245 mg was similar to exposures achieved in adults receiving once-daily doses of ТЕНОФОЛЕК disoproxil 245 mg.

Chronic hepatitis B: Steady-state ТЕНОФОЛЕК exposure in HBV infected adolescent patients (12 to < 18 years of age) receiving an oral daily dose of ТЕНОФОЛЕК disoproxil 245 mg was similar to exposures achieved in adults receiving once-daily doses of ТЕНОФОЛЕК disoproxil 245 mg.

Pharmacokinetic studies have not been performed with ТЕНОФОЛЕК disoproxil 245 mg tablets in children under 12 years or with renal impairment.

Renal impairment

Pharmacokinetic parameters of ТЕНОФОЛЕК were determined following administration of a single dose of ТЕНОФОЛЕК 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) ТЕНОФОЛЕК 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 ТЕНОФОЛЕК 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 ТЕНОФОЛЕК disoproxil 245 mg is modified in adult patients with creatinine clearance < 50 ml/min or in patients who already have ESRD and require dialysis.

The pharmacokinetics of ТЕНОФОЛЕК 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 ТЕНОФОЛЕК in paediatric patients with renal impairment have not been studied. No data are available to make dose recommendations.

Hepatic impairment

A single 245 mg dose of ТЕНОФОЛЕК 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. ТЕНОФОЛЕК pharmacokinetics were not substantially altered in subjects with hepatic impairment suggesting that no dose adjustment is required in these subjects. The mean (%CV) ТЕНОФОЛЕК 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 ТЕНОФОЛЕК diphosphate was found to be approximately 50 hours, whereas the half-life in phytohaemagglutinin-stimulated PBMCs was found to be approximately 10 hours.

Qualitative and quantitative composition

Special warnings and precautions for use

General

HIV antibody testing should be offered to all HBV infected patients before initiating ТЕНОФОЛЕК disoproxil therapy (see below Co-infection with HIV-1 and hepatitis B).

HIV-1

While effective viral suppression with antiretroviral therapy has been proven to substantially reduce the risk of sexual transmission, a residual risk cannot be excluded. Precautions to prevent transmission should be taken in accordance with national guidelines.

Chronic hepatitis B

Patients must be advised that ТЕНОФОЛЕК disoproxil has not been proven to prevent the risk of transmission of HBV to others through sexual contact or contamination with blood. Appropriate precautions must continue to be used.

Co-administration of other medicinal products

- ТЕНОФОЛЕК disoproxil tablets should not be administered concomitantly with other medicinal products containing ТЕНОФОЛЕК disoproxil.

- ТЕНОФОЛЕК disoproxil tablets should not be administered concomitantly with adefovir dipivoxil.

- Co-administration of ТЕНОФОЛЕК disoproxil and didanosine is not recommended. Co-administration of ТЕНОФОЛЕК disoproxil and didanosine results in a 40-60% increase in systemic exposure to didanosine that may increase the risk of didanosine-related adverse reactions. Rarely, pancreatitis and lactic acidosis, sometimes fatal, have been reported. Co-administration of ТЕНОФОЛЕК disoproxil and didanosine at a dose of 400 mg daily has been associated with a significant decrease in CD4 cell count, possibly due to an intracellular interaction increasing phosphorylated (i.e. active) didanosine. A decreased dosage of 250 mg didanosine co-administered with ТЕНОФОЛЕК disoproxil therapy has been associated with reports of high rates of virological failure within several tested combinations for the treatment of HIV-1 infection.

Triple therapy with nucleosides/nucleotides

There have been reports of a high rate of virological failure and of emergence of resistance at an early stage in HIV patients when ТЕНОФОЛЕК disoproxil was combined with lamivudine and abacavir as well as with lamivudine and didanosine as a once-daily regimen.

Renal and bone effects in adult population

Renal effects

ТЕНОФОЛЕК is principally eliminated via the kidney. Renal failure, renal impairment, elevated creatinine, hypophosphataemia and proximal tubulopathy (including Fanconi syndrome) have been reported with the use of ТЕНОФОЛЕК disoproxil in clinical practice.

Renal monitoring

It is recommended that creatinine clearance is calculated in all patients prior to initiating therapy with ТЕНОФОЛЕК disoproxil and renal function (creatinine clearance and serum phosphate) is also monitored after two to four weeks of treatment, after three months of treatment and every three to six months thereafter in patients without renal risk factors. In patients at risk for renal impairment, a more frequent monitoring of renal function is required.

Renal management

Co-administration and risk of renal toxicity

Use of ТЕНОФОЛЕК disoproxil should be avoided with concurrent or recent use of a nephrotoxic medicinal product (e.g. aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir or interleukin-2). If concomitant use of ТЕНОФОЛЕК disoproxil and nephrotoxic agents is unavoidable, renal function should be monitored weekly.

Cases of acute renal failure after initiation of high dose or multiple non-steroidal anti-inflammatory drugs (NSAIDs) have been reported in patients treated with ТЕНОФОЛЕК disoproxil and with risk factors for renal dysfunction. If ТЕНОФОЛЕК disoproxil is co-administered with an NSAID, renal function should be monitored adequately.

A higher risk of renal impairment has been reported in patients receiving ТЕНОФОЛЕК disoproxil in combination with a ritonavir or cobicistat boosted protease inhibitor. A close monitoring of renal function is required in these patients. In patients with renal risk factors, the co-administration of ТЕНОФОЛЕК disoproxil with a boosted protease inhibitor should be carefully evaluated.

ТЕНОФОЛЕК disoproxil has not been clinically evaluated in patients receiving medicinal products which are secreted by the same renal pathway, including the transport proteins human organic anion transporter (hOAT) 1 and 3 or MRP 4 (e.g. cidofovir, a known nephrotoxic medicinal product). These renal transport proteins may be responsible for tubular secretion and in part, renal elimination of ТЕНОФОЛЕК and cidofovir. Consequently, the pharmacokinetics of these medicinal products, which are secreted by the same renal pathway including transport proteins hOAT 1 and 3 or MRP 4, might be modified if they are co-administered. Unless clearly necessary, concomitant use of these medicinal products which are secreted by the same renal pathway is not recommended, but if such use is unavoidable, renal function should be monitored weekly.

Renal impairment

Renal safety with ТЕНОФОЛЕК disoproxil has only been studied to a very limited degree in adult patients with impaired renal function (creatinine clearance <80 ml/min).

Adult patients with creatinine clearance <50 ml/min, including haemodialysis patients:

There are limited data on the safety and efficacy of ТЕНОФОЛЕК disoproxil in patients with impaired renal function. Therefore, ТЕНОФОЛЕК disoproxil should only be used if the potential benefits of treatment are considered to outweigh the potential risks. In patients with severe renal impairment (creatinine clearance <30 ml/min) and in patients who require haemodialysis use of ТЕНОФОЛЕК disoproxil is not recommended. If no alternative treatment is available, the dosing interval must be adjusted and renal function should be closely monitored.

Bone effects

In HIV infected patients, in a 144-week controlled clinical study that compared ТЕНОФОЛЕК disoproxil with stavudine in combination with lamivudine and efavirenz in antiretroviral-naïve adult patients, small decreases in bone mineral density (BMD) of the hip and spine were observed in both treatment groups. Decreases in BMD of spine and changes in bone biomarkers from baseline were significantly greater in the ТЕНОФОЛЕК disoproxil treatment group at 144 weeks. Decreases in BMD of hip were significantly greater in this group until 96 weeks. However, there was no increased risk of fractures or evidence for clinically relevant bone abnormalities over 144 weeks.

In other studies (prospective and cross-sectional), the most pronounced decreases in BMD were seen in patients treated with ТЕНОФОЛЕК disoproxil as part of a regimen containing a boosted protease inhibitor. Alternative treatment regimens should be considered for patients with osteoporosis that are at a high risk for fractures.

Bone abnormalities (infrequently contributing to fractures) may be associated with proximal renal tubulopathy.

If bone abnormalities are suspected or detected then appropriate consultation should be obtained.

Renal and bone effects in paediatric population

There are uncertainties associated with the long term effects of bone and renal toxicity. Moreover, the reversibility of renal toxicity cannot be fully ascertained. Therefore, a multidisciplinary approach is recommended to adequately weigh on a case by case basis the benefit/risk balance of treatment, decide the appropriate monitoring during treatment (including decision for treatment withdrawal) and consider the need for supplementation.

Renal effects

Renal adverse reactions consistent with proximal renal tubulopathy have been reported in HIV-1 infected paediatric patients aged 2 to <12 years in clinical study GS-US-104-0352.

Renal monitoring

Renal function (creatinine clearance and serum phosphate) should be evaluated prior to treatment, and monitored during treatment as in adults (see above).

Renal management

Interrupting treatment with ТЕНОФОЛЕК disoproxil should also be considered in case of progressive decline of renal function when no other cause has been identified.

Co-administration and risk of renal toxicity

The same recommendations apply as in adults (see above).

Renal impairment

The use of ТЕНОФОЛЕК disoproxil is not recommended in paediatric patients with renal impairment. ТЕНОФОЛЕК disoproxil should not be initiated in paediatric patients with renal impairment and should be discontinued in paediatric patients who develop renal impairment during ТЕНОФОЛЕК disoproxil therapy.

Bone effects

ТЕНОФОЛЕК disoproxil may cause a reduction in BMD. The effects of ТЕНОФОЛЕК disoproxil-associated changes in BMD on long-term bone health and future fracture risk are currently unknown.

If bone abnormalities are detected or suspected in paediatric patients, consultation with an endocrinologist and/or nephrologist should be obtained.

Liver disease

Safety and efficacy data are very limited in liver transplant patients.

There are limited data on the safety and efficacy of ТЕНОФОЛЕК disoproxil in HBV infected patients with decompensated liver disease and who have a Child-Pugh-Turcotte (CPT) score >9. These patients may be at higher risk of experiencing serious hepatic or renal adverse reactions. Therefore, hepatobiliary and renal parameters should be closely monitored in this patient population.

Exacerbations of hepatitis

Flares on treatment: Spontaneous exacerbations in chronic hepatitis B are relatively common and are characterised by transient increases in serum ALT. After initiating antiviral therapy, serum ALT may increase in some patients. In patients with compensated liver disease, these increases in serum ALT are generally not accompanied by an increase in serum bilirubin concentrations or hepatic decompensation. Patients with cirrhosis may be at a higher risk for hepatic decompensation following hepatitis exacerbation, and therefore should be monitored closely during therapy.

Flares after treatment discontinuation: Acute exacerbation of hepatitis has also been reported in patients who have discontinued hepatitis B therapy. Post-treatment exacerbations are usually associated with rising HBV DNA, and the majority appears to be self-limited. However, severe exacerbations, including fatalities, have been reported. Hepatic function should be monitored at repeated intervals with both clinical and laboratory follow-up for at least 6 months after discontinuation of hepatitis B therapy. If appropriate, resumption of hepatitis B therapy may be warranted. In patients with advanced liver disease or cirrhosis, treatment discontinuation is not recommended since post-treatment exacerbation of hepatitis may lead to hepatic decompensation.

Liver flares are especially serious, and sometimes fatal in patients with decompensated liver disease.

Co-infection with hepatitis C or D: There are no data on the efficacy of ТЕНОФОЛЕК in patients co-infected with hepatitis C or D virus.

Co-infection with HIV-1 and hepatitis B: Due to the risk of development of HIV resistance, ТЕНОФОЛЕК disoproxil should only be used as part of an appropriate antiretroviral combination regimen in HIV/HBV co-infected patients. Patients with pre-existing liver dysfunction, including chronic active hepatitis, have an increased frequency of liver function abnormalities during combination antiretroviral therapy (CART) and should be monitored according to standard practice. If there is evidence of worsening liver disease in such patients, interruption or discontinuation of treatment must be considered. However, it should be noted that increases of ALT can be part of HBV clearance during therapy with ТЕНОФОЛЕК, see above Exacerbations of hepatitis.

Use with certain hepatitis C virus antiviral agents

Co-administration of ТЕНОФОЛЕК disoproxil with ledipasvir/sofosbuvir has been shown to increase plasma concentrations of ТЕНОФОЛЕК, especially when used together with an HIV regimen containing ТЕНОФОЛЕК disoproxil and a pharmacokinetic enhancer (ritonavir or cobicistat). The safety of ТЕНОФОЛЕК disoproxil in the setting of ledipasvir/sofosbuvir and a pharmacokinetic enhancer has not been established. The potential risks and benefits associated with co-administration of ledipasvir/sofosbuvir with ТЕНОФОЛЕК disoproxil given in conjunction with a boosted HIV protease inhibitor (e.g. atazanavir or darunavir) should be considered, particularly in patients at increased risk of renal dysfunction. Patients receiving ledipasvir/sofosbuvir concomitantly with ТЕНОФОЛЕК disoproxil and a boosted HIV protease inhibitor should be monitored for adverse reactions related to ТЕНОФОЛЕК disoproxil.

Weight and metabolic parameters

An increase in weight and in levels of blood lipids and glucose may occur during antiretroviral therapy. Such changes may in part be linked to disease control and life style. For lipids, there is in some cases evidence for a treatment effect, while for weight gain there is no strong evidence relating this to any particular treatment. For monitoring of blood lipids and glucose reference is made to established HIV treatment guidelines. Lipid disorders should be managed as clinically appropriate.

Mitochondrial dysfunction following exposure in utero

Nucleoside and nucleotide may impact mitochondrial function to a variable degree, which is most pronounced with stavudine, didanosine and zidovudine. There have been reports of mitochondrial dysfunction in HIV negative infants exposed in utero and/or postnatally to nucleoside analogues, these have predominantly concerned treatment with regimens containing zidovudine. The main adverse reactions reported are haematological disorders (anaemia, neutropenia) and metabolic disorders (hyperlactataemia, hyperlipasaemia). These events have often been transitory. Late-onset neurological disorders have been reported rarely (hypertonia, convulsion, abnormal behaviour). Whether such neurological disorders are transient or permanent is currently unknown. These findings should be considered for any child exposed in utero to nucleos(t)ide analogues, who present with severe clinical findings of unknown etiology, particularly neurologic findings. These findings do not affect current national recommendations to use antiretroviral therapy in pregnant women to prevent vertical transmission of HIV.

Immune reactivation syndrome

In HIV infected patients with severe immune deficiency at the time of institution of CART, an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first few weeks or months of initiation of CART. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections, and Pneumocystis jirovecii pneumonia. Any inflammatory symptoms should be evaluated and treatment instituted when necessary.

Autoimmune disorders (such as Graves' disease) have also been reported to occur in the setting of immune reactivation; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment.

Osteonecrosis

Although the aetiology is considered to be multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported, particularly in patients with advanced HIV disease and/or long-term exposure to CART. Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.

Elderly

ТЕНОФОЛЕК disoproxil 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 ТЕНОФОЛЕК disoproxil.

ТЕНОФОЛЕК disoproxil 245 mg film-coated tablets contain lactose monohydrate. Consequently, patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

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 ТЕНОФОЛЕК disoproxil.

Dosage (Posology) and method of administration

Therapy should be initiated by a physician experienced in the management of HIV infection and/or treatment of chronic hepatitis B.

Posology

Adults

The recommended dose of ТЕНОФОЛЕК disoproxil tablets for the treatment of HIV or for the treatment of chronic hepatitis B is 245 mg (one tablet) once daily taken orally with food.

Chronic hepatitis B

The optimal duration of treatment is unknown. Treatment discontinuation may be considered as follows:

- In HBeAg positive patients without cirrhosis, treatment should be administered for at least 6-12 months after HBe seroconversion (HBeAg loss and HBV DNA loss with anti-HBe detection) is confirmed or until HBs seroconversion or there is loss of efficacy. Serum ALT and HBV DNA levels should be followed regularly after treatment discontinuation to detect any late virological relapse.

- In HBeAg negative patients without cirrhosis, treatment should be administered at least until HBs seroconversion or there is evidence of loss of efficacy. With prolonged treatment for more than 2 years, regular reassessment is recommended to confirm that continuing the selected therapy remains appropriate for the patient.

ТЕНОФОЛЕК disoproxil may also be available as 33 mg/g granules for the treatment of HIV-1 infection and chronic hepatitis B in adults for whom a solid dosage form is not appropriate.

Paediatric population

HIV-1: In adolescents aged 12 to <18 years and weighing >35 kg, the recommended dose of ТЕНОФОЛЕК disoproxil is 245 mg (one tablet) once daily taken orally with food.

ТЕНОФОЛЕК disoproxil may also be available as granules for use in HIV-1 infected paediatric patients aged 2 to <12 years and as reduced tablet strengths for use in HIV-1 infected paediatric patients aged 6 to <12 years. Please refer to the Summary of Product Characteristics for ТЕНОФОЛЕК disoproxil 33 mg/g granules and ТЕНОФОЛЕК disoproxil 123 mg, 163 mg and 204 mg film-coated tablets.

The safety and efficacy of ТЕНОФОЛЕК disoproxil in HIV-1 infected children under 2 years of age have not been established. No data are available.

Chronic hepatitis B: In adolescents aged 12 to <18 years and weighing >35 kg, the recommended dose of ТЕНОФОЛЕК disoproxil tablets is 245 mg (one tablet) once daily, taken orally with food. The optimal duration of treatment is currently unknown.

The safety and efficacy of ТЕНОФОЛЕК disoproxil in children with chronic hepatitis B aged 2 to <12 years or weighing <35 kg have not been established. No data are available.

ТЕНОФОЛЕК disoproxil may also be available as 33 mg/g granules for the treatment of HIV-1 infection and chronic hepatitis B in adolescents aged 12 to <18 years for whom a solid dosage form is not appropriate.

Missed dose

If a patient misses a dose of ТЕНОФОЛЕК disoproxil tablets within 12 hours of the time it is usually taken, the patient should take ТЕНОФОЛЕК disoproxil tablets with food as soon as possible and resume their normal dosing schedule. If a patient misses a dose of ТЕНОФОЛЕК disoproxil tablets by more than 12 hours and it is almost time for their next dose, the patient should not take the missed dose and simply resume the usual dosing schedule.

If the patient vomits within 1 hour of taking ТЕНОФОЛЕК disoproxil tablets, another tablet should be taken. If the patient vomits more than 1 hour after taking ТЕНОФОЛЕК disoproxil tablets they do not need to take another dose.

Special populations

Elderly

No data are available on which to make a dose recommendation for patients over the age of 65 years.

Renal impairment

ТЕНОФОЛЕК is eliminated by renal excretion and the exposure to ТЕНОФОЛЕК increases in patients with renal dysfunction.

Adults

There are limited data on the safety and efficacy of ТЕНОФОЛЕК disoproxil in adult patients with moderate and severe renal impairment (creatinine clearance <50 ml/min) and long-term safety data has not been evaluated for mild renal impairment (creatinine clearance 50-80 ml/min). Therefore, in adult patients with renal impairment ТЕНОФОЛЕК disoproxil should only be used if the potential benefits of treatment are considered to outweigh the potential risks. If available, administration of ТЕНОФОЛЕК disoproxil 33 mg/g granules to provide a reduced daily dose of ТЕНОФОЛЕК disoproxil is recommended for adult patients with creatinine clearance <50 ml/min, including haemodialysis patients. Please refer to the Summary of Product Characteristics for ТЕНОФОЛЕК disoproxil 33 mg/g granules.

Mild renal impairment (creatinine clearance 50-80 ml/min)

Limited data from clinical studies support once daily dosing of 245 mg ТЕНОФОЛЕК disoproxil in patients with mild renal impairment.

Moderate renal impairment (creatinine clearance 30-49 ml/min)

For patients unable to take the granule formulation of ТЕНОФОЛЕК disoproxil, prolonged dose intervals using the 245 mg film-coated tablets may be used. Administration of 245 mg ТЕНОФОЛЕК disoproxil every 48 hours can be used based on modelling of single-dose pharmacokinetic data in HIV negative and non-HBV infected subjects with varying degrees of renal impairment, including end-stage renal disease requiring haemodialysis, but has not been confirmed in clinical studies. Therefore, clinical response to treatment and renal function should be closely monitored in these patients.

Severe renal impairment (creatinine clearance <30 ml/min) and haemodialysis patients

For patients unable to take the granule formulation of ТЕНОФОЛЕК disoproxil and with no alternative treatment available, prolonged dose intervals using the 245 mg film-coated tablets may be used as follows:

Severe renal impairment: 245 mg ТЕНОФОЛЕК disoproxil may be administered every 72-96 hours (dosing twice a week).

Haemodialysis patients: 245 mg ТЕНОФОЛЕК disoproxil may be administered every 7 days following completion of a haemodialysis session*.

These dose interval adjustments have not been confirmed in clinical studies. Simulations suggest that the prolonged dose interval using ТЕНОФОЛЕК disoproxil tablets 245 mg film-coated tablets is not optimal and could result in increased toxicity and possibly inadequate response. Therefore, clinical response to treatment and renal function should be closely monitored.

* Generally, once weekly dosing assuming three haemodialysis sessions per week, each of approximately 4 hours duration or after 12 hours cumulative haemodialysis.

No dosing recommendations can be given for non-haemodialysis patients with creatinine clearance <10 ml/min.

Paediatrics

The use of ТЕНОФОЛЕК disoproxil is not recommended in paediatric patients with renal impairment.

Hepatic impairment

No dose adjustment is required in patients with hepatic impairment.

If ТЕНОФОЛЕК disoproxil tablets is discontinued in patients with chronic hepatitis B with or without HIV co-infection, these patients should be closely monitored for evidence of exacerbation of hepatitis.

Method of administration

ТЕНОФОЛЕК disoproxil tablets should be taken once daily, orally with food.

A granules formulation of ТЕНОФОЛЕК disoproxil may be available for patients having difficulty in swallowing film-coated tablets. However, in exceptional circumstances ТЕНОФОЛЕК disoproxil 245 mg film-coated tablets can be administered following disintegration of the tablet in at least 100 ml of water, orange juice or grape juice.

Special precautions for disposal and other handling

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.