Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1    Pharmacodynamic properties
Pharmacotherapeutic group: Antivirals for systemic use, nucleoside and nucleotide reverse transcriptase inhibitors, ATC code: J05AF11.

SEB API AUG17 CL V7                                       REF EMA SmPC 23Jun2017 
Mechanism of action
Telbivudine is a synthetic thymidine nucleoside analogue with activity against HBV DNA polymerase. It is efficiently phosphorylated by cellular kinases to the active triphosphate form, which has an intracellular half-life of 14 hours. Telbivudine-5'-triphosphate inhibits HBV DNA polymerase (reverse transcriptase) by competing with the natural substrate, thymidine 5'-triphosphate. Incorporation of telbivudine-5'-triphosphate into viral DNA causes DNA chain termination, resulting in inhibition of HBV replication.

Pharmacodynamic effects
Telbivudine is an inhibitor of both HBV first strand (EC50 = 0.4-1.3 µM) and second strand (EC50 = 0.12-0.24 µM) synthesis, and shows a distinct preference for inhibiting second-strand production. By contrast, telbivudine-5'-triphosphate at concentrations up to 100 µM did not inhibit cellular DNA polymerases , β, or . In assays relating to mitochondrial structure, function and DNA content, telbivudine lacked appreciable toxic effect at concentrations up to at 10 µM and did not increase lactic acid production in vitro.

The in vitro antiviral activity of telbivudine was assessed in the HBV-expressing human hepatoma cell line 2.2.15. The concentration of telbivudine that effectively inhibited 50% of viral synthesis (EC50) was approximately 0.2 M. The antiviral activity of telbivudine is specific to the hepatitis B virus and related hepadnaviruses. Telbivudine was not active against HIV in vitro. The absence of activity of telbivudine against HIV has not been evaluated in clinical trials. Transient reductions in HIV-1 RNA have been reported in a small number of patients after administration of telbivudine in the absence of antiretroviral therapy.
The clinical significance of these reductions has not been determined.
Clinical experience
The safety and efficacy of long term (104 weeks) Sebivo treatment were evaluated in two active-controlled clinical studies that included 1,699 patients with chronic hepatitis B (NV- 02B-007 (GLOBE) and NV-02B-015).



Study NV-02B-007 (GLOBE)
The NV-02B-007 (GLOBE) study is a randomised, double-blind, multinational phase III study of telbivudine compared to lamivudine for a treatment period of 104 weeks in 1,367 nucleoside-naïve chronic hepatitis B HBeAg-positive and HBeAg-negative patients. The majority of the population enrolled was Asian. The most common HBV genotypes were B SEB API AUG17 CL V7                                        REF EMA SmPC 23Jun2017 (26%) and C (51%). A small number (total of 98) of Caucasian patients were treated with telbivudine. The primary data analysis was conducted after all patients had reached week 52.
HBeAg-positive patients: The mean age of patients was 32 years, 74% were male, 82% were Asian, 12% were Caucasian, and 6% had previously received alfa-interferon therapy.
HBeAg-negative patients: The mean age of patients was 43 years, 79% were male, 65% were Asian, 23% were Caucasian, and 11% had previously received alfa-interferon therapy.
Clinical results at week 52
Clinical and virological efficacy endpoints were evaluated separately in the HBeAg-positive and HBeAg-negative patient populations. The primary endpoint of therapeutic response was a composite serological endpoint requiring suppression of HBV DNA to <5 log10 copies/mL in conjunction with either loss of serum HBeAg or ALT normalised. Secondary endpoints included histological response, ALT normalisation, and various measures of antiviral Regardless of baseline characteristics, the majority of patients taking Sebivo showed efficacy.
histological, virological, biochemical, and serological responses to treatment. Baseline ALT levels > 2x ULN and baseline HBV DNA < 9 log10 copies/ml were associated with higher rates of HBeAg seroconversion in HBeAg-positive patients. Patients who achieve HBV DNA levels < 3 log10 copies/ml by week 24 had optimal responses to treatment; conversely patients with HBV DNA levels > 4 log10 copies/ml at 24 weeks had less favourable outcomes at week 52.

In HBeAg-positive patients, telbivudine was superior to lamivudine in therapeutic response (75.3% vs 67.0% responders; p = 0.0047). In HBeAg-negative patients, telbivudine was non- inferior to lamivudine (75.2% and 77.2% responders; p = 0.6187). Caucasian ethnicity was associated with lower treatment response to both antiviral agents used in the NV-02B-007 (GLOBE) study; however the Caucasian patient population was very limited (n = 98).

At week 24, 203 HBeAg-positive and 177 HBeAg-negative subjects achieved non-detectable HBV DNA levels. Of those HBeAg-positive subjects, 95% achieved non-detectable HBV DNA, 39% achieved HBeAg seroconversion, 90% achieved ALT normalisation at week 52 and 0.5% exhibited resistance at week 48. Similarly of those HBeAg-negative subjects, 96% achieved non-detectable HBV DNA, 79% achieved ALT normalisation at week 52 and 0% exhibited resistance at week 48.

Selected virological, biochemical and serological outcome measures are shown in Table 5 and histological response in Table 6.

Table 5          Virological, biochemical and serological endpoints at week 52 in NV- 02B-007 (GLOBE) study
HBeAg-positive (n = 921)               HBeAg-negative (n = 446)



SEB API AUG17 CL V7                                      REF EMA SmPC 23Jun2017 Response parameter          Telbivudine           Lamivudine           Telbivudine      Lamivudine 600 mg                100 mg               600 mg           100 mg
(n = 458)            (n = 463)             (n = 222)        (n = 224) Mean HBV DNA                -6.45 (0.11) *        -5.54 (0.11)         -5.23 (0.13) *    -4.40 (0.13) reduction from baseline
(log10
1,2,3 copies/mL) ± SEM
% Patients HBV DNA              60%*                  40%                  88%*             71% undetectable by PCR
4
ALT normalisation               77%                   75%                  74%              79% 4
HBeAg seroconversion            23%                   22%                    -                - 5
HBeAg loss                      26%                   23%                    -                - 1
SEM: Standard error of mean
2
Roche COBAS Amplicor® PCR Assay (lower limit of quantification  300 copies/ml).
3
HBeAg-positive n = 443 and 444, HBeAg-negative n = 219 and 219, for both telbivudine and lamivudine groups, respectively. The difference in populations is due to patient discontinuation from the study and missing HBV DNA assessment at week 52.
4
HBeAg-positive n = 440 and 446, HBeAg-negative n = 203 and 207, for telbivudine and lamivudine groups, respectively. ALT normalisation assessed only in patients with ALT > ULN at baseline.
5 n = 432 and 442, for telbivudine and lamivudine groups, respectively. HBeAg seroconversion and loss assessed only in patients with detectable HBeAg at baseline.
*p < 0.0001



Table 6          Histological improvement and change in Ishak Fibrosis Score at week 52 in NV-02B-007 (GLOBE) study

SEB API AUG17 CL V7                                              REF EMA SmPC 23Jun2017 
HBeAg-positive (n = 921)                   HBeAg-negative (n = 446)
Telbivudine           Lamivudine            Telbivudine           Lamivudine 600 mg               100 mg                600 mg                100 mg 1                    1                       1
(n = 384)             (n = 386)             (n = 199)             (n = 207)1 2
Histological response
Improvement                                   71%*                  61%                   71%                   70% No Improvement                                17%                   24%                   21%                   24% 3
Ishak Fibrosis Score
Improvement                                   42%                   47%                   49%                   45% No change                                     39%                   32%                   34%                   43% Worsening                                      8%                    7%                    9%                    5% Missing week 52 biopsy                        12%                   15%                    9%                    7% 1
Patients with ≥ one dose of study drug with evaluable baseline liver biopsies and baseline Knodell Histological Activity Index (HAI) score >3
2
Histological response defined as a ≥2 point decrease in Knodell Necroinflammatory Score from baseline with no worsening of the Knodell Fibrosis Score.
3
For Ishak Fibrosis Score, improvement measured as ≥1 point reduction in Ishak Fibrosis Score from baseline to week 52.
*p = 0.0024


Clinical results at Week 104
Overall, clinical results at week 104 in telbivudine-treated patients were consistent with those at week 52, demonstrating durability of efficacy responses for telbivudine-treated patients with continued treatment.
Among HBeAg-positive patients, therapeutic response (63% vs 48%; p <0.0001), and key secondary endpoints (mean log10 HBV DNA reduction: -5.74 vs -4.42; p <0.0001, HBV DNA undetectability: 56% vs 39%; p <0.0001 and ALT normalisation of 70% vs 62%) demonstrated a widening difference at week 104 between telbivudine and lamivudine, respectively. A trend towards higher rates of HBeAg loss (35% vs 29%) and seroconversion (30% vs 25%) was also observed for telbivudine. Moreover, in the subgroup of patients with baseline ALT levels ≥ 2x ULN (320), a significantly higher proportion of telbivudine patients than lamivudine patients achieved HBeAg seroconversions at week 104 (36% vs 28%, respectively).
Among HBeAg-negative patients, differences in therapeutic response (78% vs 66%) and key secondary endpoints (mean log10 HBV DNA reduction: -5.00 vs -4.17, and HBV DNA undetectability: 82% vs 57%; p <0.0001) were higher for telbivudine up to week 104. ALT normalisation rates (78% vs 70%) continued to be higher by week 104.

Predictability at week 24
At week 24, 203 HBeAg-positive (44%) and 177 HBeAg-negative (80%) telbivudine-treated subjects achieved undetectable HBV DNA levels.


SEB API AUG17 CL V7                                                              REF EMA SmPC 23Jun2017 For both HBeAg-positive and HBeAg-negative patients, week 24 HBV DNA results were a predictor of long-term favourable outcomes. Telbivudine-treated patients who achieved undetectable HBV DNA by PCR by week 24 had the highest rates of HBV DNA undetectability and HBeAg seroconversion (in HBeAg-positive patients), and the lowest overall rates of virological breakthrough at week 104.

Outcome results at week 104, based on level of HBV DNA at week 24, for either HBeAg- positive or HBeAg-negative patients are presented in Table 7.

Table 7     Key efficacy endpoints at week 104 by serum HBV DNA levels at week 24, telbivudine-treated patients in NV-02B-007 (GLOBE) study
Outcome for key efficacy end points at 104 weeks based on week 24 results Therapeutic       HBV DNA           HBeAg          ALT         Virological HBV DNA at            response       undetectability seroconversion normalisation breakthrough* week 24               n/N (%)           n/N (%)         n/N (%)       n/N (%)        n/N (%) HBeAg-positive
< 300 copies/ml      172/203 (85)     166/203 (82)     84/183 (46)      160/194 (82)   22/203 (11) 300 copies/ml to      36/57 (63)       35/57 (61)       21/54 (39)       40/54 (74)    18/57 (32) < 3 log10 copies/ml
≥ 3 log10             82/190 (43)      54/190 (28)     23/188 (12)      106/184 (58)   90/190 (47) copies/ml
HBeAg-negative
< 300 copies/ml      146/177 (82)     156/177 (88)         N/A          131/159 (82)   11/177 (6) 300 copies/ml to      13/18 (72)       14/18 (78)          N/A           13/17 (76)     4/18 (22) < 3 log10 copies/ml
≥ 3 log10             13/26 (50)       12/26 (46)          N/A           14/26 (54)    12/26 (46) copies/ml
N/A = not applicable
* Virological breakthrough: “1 log above nadir” definition assessed at week 104 


Study NV-02B-015

The efficacy and safety results of the NV-02B-007 (GLOBE) study were confirmed in study NV-02B-015. This study is a phase III, randomised, double-blind study of telbivudine 600 mg once daily compared to lamivudine 100 mg once daily for a treatment period of 104 weeks in 332 nucleoside-naïve chronic hepatitis B HBeAg-positive and HBeAg-negative Chinese patients.
SEB API AUG17 CL V7                                            REF EMA SmPC 23Jun2017 Study CLDT600A2303 – Clinical results over 208 weeks
Study CLDT600A2303 was an open-label 104-week extension study in patients with compensated chronic hepatitis B who were previously treated with telbivudine for 2 years including patients from studies NV-02B-007 (GLOBE) and NV-02B-015 , providing efficacy and safety data after 156 and 208 weeks of continuous telbivudine therapy. Patients with undetectable HBV DNA at week 24 had better outcomes at 156 and 208 weeks (Table 8).

Table 8       Efficacy analysis in pooled data from NV-02B-007 (GLOBE), NV-02B-015 and CLDT600A2303 studies
Week 52     Week 104   Week 156      Week 208
HBeAg-positive patients (n = 293*)
Maintained undetectable HBV DNA                70.3%        77.3%       75.0%        76.2% (< 300 copies/ml)                            (206/293)    (218/282)  (198/264)     (163/214) Maintained undetectable HBV DNA                99.4%        94.9%       86.7%        87.9% (< 300 copies/ml) with undetectable          (161/162)    (150/158)  (130/150)     (109/124) HBV DNA at week 24
Cumulative HBeAg seroconversion                27.6%        41.6%       48.5%        53.2% rates (%)                                     (81/293)    (122/293)  (142/293)     (156/293) Cumulative HBeAg seroconversion                40.1%        52.5%       59.3%        65.4% rates in patients with undetectable HBV       (65/162)     (85/162)   (96/162)     (106/162) DNA at week 24 (%)
Maintained ALT normalisation                   81.4%        87.5%       82.9%        86.4% (228/280)    (237/271)  (209/252)     (178/106)
HBeAg-negative patients (n = 209*)
Maintained undetectable HBV DNA                95.2%        96.5%       84.7%        86.0% (< 300 copies/ml)                            (199/209)    (195/202)  (160/189)     (141/164) Maintained undetectable HBV DNA                97.8%        96.5%       86.7%        87.5% (< 300 copies/ml) with undetectable          (175/179)    (166/172)  (143/165)     (126/144) HBV DNA at week 24
Maintained ALT normalisation                   80.3%        89.0%       83.5%        89.6% (151/188)    (161/181)  (142/170)     (129/144)

* The population without viral resistance at entry into study CLDT600A2303 consisted of 502 patients (293 HBeAg-positive and 209 HBeAg-negative).



SEB API AUG17 CL V7                                      REF EMA SmPC 23Jun2017 Study CLDT600ACN04E1- Impact of treatment on liver histology
In study CLDT600ACN04E1, 57 patients with available paired liver biopsies at baseline and after mean treatment of 260.8 weeks were evaluated for changes in liver histology (38 HBeAg- positive and 19 HBeAg-negative patients).

•   The mean Knodell necroinflammatory score of 7.6 (SD 2.9) at baseline improved (p < 0.0001) to 1.4 (SD 0.9) with a mean change of -6.3 (SD 2.8). Knodell necroinflammatory score ≤ 3 (no or minimal necroinflammation) was observed in 98.2% (56/57) of patients.

•   The mean Ishak score of 2.2 (SD 1.1) at baseline improved (p < 0.0001) to 0.9 (SD 1.0) with a mean change of -1.3 (SD 1.3). Ishak fibrosis score ≤ 1 (no or minimal fibrosis) was observed in 84.2% (48/57) of patients.
Changes in Knodell necroinflammatory and Ishak scores were similar for HBeAg-positive and HBeAg-negative patients.


CLDT600A2303 - Off-treatment durability of HBeAg responses
Study CLDT600A2303 included HBeAg-positive patients from studies NV-02B-007 (GLOBE) or NV-02B-015 for off-treatment follow up. These patients had completed ≥ 52 weeks of telbivudine treatment, and had exhibited HBeAg loss for ≥ 24 weeks with HBV DNA < 5 log10 copies/ml at the last on-treatment visit. The median treatment duration was 104 weeks. After a median off-treatment follow-up period of 120 weeks, the majority of HBeAg-positive telbivudine treated-patients showed sustained HBeAg loss (83.3%; 25/30), and sustained HBeAg seroconversion (79.2%; 19/24). Patients with sustained HBeAg seroconversion had a mean HBV DNA of 3.3 log10 copies/ml; and 73.7% had HBV DNA < 4 log10 copies/ml.

Clinical resistance
Genotypic resistance test was performed in study NV-02B-007 (GLOBE; n = 680) in patients with virological rebound (confirmed increase of ≥ 1 log10 copies/ml HBV DNA from nadir).

At week 48 among HBeAg-positive and HBeAg-negative patients, 5% (23/458) and 2% (5/222), respectively, had virological rebound with detectable HBV resistance mutations.



Studies NV-02B-007 (GLOBE) and CLDT600A2303 - cumulative genotypic resistance rates
The original analysis for cumulative genotypic resistance at week 104 and 208 was based on the ITT population and included all patients who continued treatment until 4 years, regardless SEB API AUG17 CL V7                                           REF EMA SmPC 23Jun2017 of HBV DNA levels. Out of the 680 telbivudine-treated patients initially included in the pivotal study NV-02B-007 (GLOBE), 517 (76%) enrolled into study CLDT600A2303 for continued telbivudine treatment for up to 208 weeks. Out of these 517 patients 159 patients (HBeAg-positive=135, HBeAg-negative=24) had detectable HBV DNA.

The cumulative genotypic rates by week 104 were 25.1% (115/458) for HBeAg-positive patients and 10.8% (24/222) for HBeAg-negative patients.

In the overall ITT population the cumulative resistance rates at year 4 for HBeAg-positive and HBeAg-negative patients, was 40.8% (131/321) and 18.9% (37/196), respectively.

Cumulative genotypic resistance rates were also assessed by applying a mathematical model where only patients with undetectable HBV DNA at the beginning of the respective year are considered. Cumulative resistance rates at year 4 were 22.3% for HBeAg-positive patients and 16.0% for HBeAg-negative patients in this analysis.

When considering patients with viral breakthrough by 104 weeks in NV-02B-007 (GLOBE), the rate of resistance was lower in patients with HBV DNA < 300 copies/ml at week 24 than in patients with HBV DNA ≥ 300 copies/ml at week 24. In HBeAg-positive patients with HBV DNA < 300 copies/ml at week 24, resistance was 1% (3/203) at 48 weeks and 9% (18/203) at week 104, whilst in patients with HBV DNA ≥ 300 copies/ml resistance was 8% (20/247) at 48 weeks and 39% (97/247) at week 104. In HBeAg-negative patients with HBV DNA < 300 copies/ml at week 24, resistance was 0% (0/177) at 48 weeks and 5% (9/177) at week 104, whilst in patients with HBV DNA ≥ 300 copies/ml resistance was 11% (5/44) at 48 weeks and 34% (15/44) at week 104.
Genotypic mutation pattern and cross-resistance
Genotypic analysis of 203 evaluable sample pairs with HBV DNA ≥ 1000 copies/mL at week 104 (NV-02B-007 (GLOBE)) demonstrated that the primary mutation associated with telbivudine resistance was rtM204I often associated with mutations rtL180M and rtL80I/V and infrequently with rtV27A, rtL82M, rtV173L, rtT184I, and rtA200V. Baseline factors associated with development of genotypic drug resistance included: lamivudine treatment, higher baseline HBV DNA, lower baseline serum ALT, and increased body weight/BMI. On treatment response parameters at week 24 that predicted emergence of drug resistant virus by week 104 were HBV DNA >300 copies/ml and elevation of serum ALT.
Genotypic analysis of 50 HBV isolates from telbivudine-treated patients at week 208 (CLDT600A2303) revealed a similar resistance profile as reported at week 104. Conversions at position 80, 180 and polymorphic positions 91, 229 were always detected in sequences that harboured the M204I mutation that confers genotypic resistance. These mutations most likely are compensatory mutations. One isolated rtM204V mutation and two rtM204I/V/M mutations were reported in telbivudine-treated patients experiencing viral breakthrough up to week 208. No novel mutation was reported.

SEB API AUG17 CL V7                                       REF EMA SmPC 23Jun2017 Cross-resistance has been observed among HBV nucleoside analogues (see section 4.4). In cell-based assays, lamivudine-resistant HBV strains containing either the rtM204I mutation or the rtL180M/rtM204V double mutation had ≥1,000-fold reduced susceptibility to telbivudine. HBV encoding the adefovir resistance-associated substitutions rtN236T or rtA181V had around 0.3- and 4-fold change in susceptibility to telbivudine in cell culture, respectively (see section 4.4).

Pharmacokinetic Properties

5.2    Pharmacokinetic properties
The single- and multiple-dose pharmacokinetics of telbivudine were evaluated in healthy subjects and in patients with chronic hepatitis B. The pharmacokinetics of telbivudine were not evaluated with the recommended dose of 600 mg in patients with chronic hepatitis B.
However telbivudine pharmacokinetics are similar between both populations.

Absorption
Following oral administration of a 600 mg single dose of telbivudine to healthy subjects (n = 42), the peak plasma concentration (Cmax) of telbivudine was 3.2 ± 1.1 g/ml (mean ± SD) and occurred at median 3.0 hours post dose. The telbivudine area under the plasma concentration-time curve (AUC0-∞) was 28.0 ± 8.5 gh/ml (mean ± SD). Inter-subject variability (CV%) for measures of systemic exposures (Cmax, AUC) was typically approximately 30%.
Effect of food on oral absorption
Telbivudine absorption and exposure were unaffected when a single 600 mg dose was administered with food.

Distribution
In vitro binding of telbivudine to human plasma proteins is low (3.3%).

Biotransformation
No metabolites of telbivudine were detected following administration of 14C-telbivudine in humans. Telbivudine is not a substrate, inhibitor or inducer of the cytochrome P450 (CYP450) enzyme system.



Elimination
After reaching peak concentration, plasma disposition of telbivudine declined in a bi- exponential manner with a terminal elimination half-life (t1/2) of 41.8 ± 11.8 hours.
Telbivudine is eliminated primarily by urinary excretion of unchanged substance. The renal clearance of telbivudine approaches normal glomerular filtration rate, suggesting that SEB API AUG17 CL V7                                       REF EMA SmPC 23Jun2017 filtration is the main mechanism of excretion. Approximately 42% of the dose is recovered in the urine over 7 days following a single 600 mg oral dose of telbivudine. As renal excretion is the predominant route of elimination, patients with moderate to severe renal dysfunction and those undergoing haemodialysis require a dose interval adjustment (see section 4.2).

Linearity/non-linearity
Telbivudine pharmacokinetics are dose proportional over the range of 25 to 1,800 mg. Steady state was achieved after 5 to 7 days of once-daily administration with an approximate 1.5-fold accumulation in systemic exposure, suggesting an effective accumulation half-life of approximately 15 hours. Following once-daily administration of telbivudine 600 mg, steady- state trough plasma concentrations were approximately 0.2-0.3 g/ml.

Special populations
Gender
There are no significant gender-related differences in telbivudine pharmacokinetics.
Race
There are no significant race-related differences in telbivudine pharmacokinetics.
Paediatrics and elderly (65 years age and above)
Pharmacokinetic studies have not been conducted in paediatric or elderly subjects.
Renal impairment
The single-dose pharmacokinetics of telbivudine (200, 400 and 600 mg) have been evaluated in patients (without chronic hepatitis B) with various degrees of renal impairment (as assessed by creatinine clearance). Based on the results shown in Table 9, adjustment of the dose interval for telbivudine is recommended in patients with creatinine clearance of 50 mL/min (see sections 4.2 and 4.4).



SEB API AUG17 CL V7                                        REF EMA SmPC 23Jun2017 Table 9           Pharmacokinetic parameters (mean ± SD) of telbivudine in subjects with various degrees of renal function
Renal function (creatinine clearance in mL/min)
Normal (>80)      Mild (50–80)       Moderate (30–49)     Severe (<30)   ESRD/ (n = 8)           (n = 8)            (n = 8)              (n = 6)        Haemodialysis 600 mg            600 mg             400 mg               200 mg         (n = 6) 200 mg
Cmax (µg/mL)        3.4 ± 0.9         3.2 ± 0.9          2.8 ± 1.3            1.6 ± 0.8      2.1 ± 0.9 AUC0-∞ (g•h/ml)    28.5 ± 9.6        32.5 ± 10.1        36.0 ± 13.2          32.5 ± 13.2    67.4 ±3 6.9 CLRENAL (ml/min)                                                                                     - 126.7 ± 48.3      83.3 ± 20.0        43.3 ± 20.0          11.7 ± 6.7 

Renally impaired patients on haemodialysis
Haemodialysis (up to 4 hours) reduces systemic telbivudine exposure by approximately 23%.
Following dose interval adjustment for creatinine clearance, no additional dose modification is necessary during routine haemodialysis (see section 4.2). Telbivudine should be administered after haemodialysis.
Hepatic impairment
The pharmacokinetics of telbivudine have been studied in patients (without chronic hepatitis B) with various degrees of hepatic impairment and in some patients with decompensated liver disease. There were no significant changes in telbivudine pharmacokinetics in hepatically impaired subjects compared to unimpaired subjects. Results of these studies indicate that no dosage adjustment is necessary for patients with hepatic impairment (see section 4.2).