Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties
Pharmacotherapeutic group: Nucleosides and nucleotides (excl. reverse transcriptase inhibitors), ATC code: J05A B04.

Mechanism of Action: Ribavirin is a synthetic nucleoside analog that shows in vitro activity against some RNA and DNA viruses. The mechanism by which ribavirin in combination with peginterferon alfa-2a or interferon alfa-2a exerts its effects against HCV is unknown.

HCV RNA levels decline in a biphasic manner in responding patients with hepatitis C who have received treatment with 180 µg peginterferon alfa-2a. The first phase of decline occurs 24 to 36 hours after the first dose of peginterferon alfa-2a and is followed by the second phase of decline which continues over the next 4 to 16 weeks in patients who achieve a sustained response. Copegus had no significant effect on the initial viral kinetics over the first 4 to 6 weeks in patients treated with the combination of Copegus and pegylated interferon alfa-2a or interferon alfa.

Oral formulations of ribavirin monotherapy have been investigated as therapy for chronic hepatitis C in several clinical trials. Results of these investigations showed that ribavirin monotherapy had no effect on eliminating hepatitis virus (HCV-RNA) or improving hepatic histology after 6 to 12 months of therapy and 6 months of follow-up.

Clinical efficacy and safety

Copegus in combination with peginterferon alfa-2a
Predictability of response
Please refer to the peginterferon alfa-2a Prescribing Information


COPEGUS                                                                 MoH Approved Prescribing Information Tablets 200 mg                                                                                 October 2015 Study results in treatment-naive patients
Efficacy and safety of the combination of Copegus and peginterferon alfa-2a were established in two pivotal studies (NV15801 + NV15942), including a total of 2405 patients. The study population comprised interferon-naive patients with CHC confirmed by detectable levels of serum HCV RNA, elevated levels of ALT, and a liver biopsy consistent with chronic hepatitis C infection. Only HIV-HCV co-infected patients were included in the study NR15961 (see Table 15). These patients had stable HIV disease and mean CD4 T-cell count was about 500 cells/µl.

Study NV15801 (1121 patients treated) compared the efficacy of 48 weeks of treatment with peginterferon alfa-2a (180 µg once weekly) and Copegus (1000/1200 mg daily) with either peginterferon alfa-2a monotherapy or combination therapy with interferon-alfa-2b and ribavirin. The combination of peginterferon alfa-2a and Copegus was significantly more efficacious than either the combination of interferon alfa-2b and ribavirin or peginterferon alfa-2a monotherapy.

Study NV15942 (1284 patients treated) compared the efficacy of two durations of treatment (24 weeks with 48 weeks) and two dosages of Copegus (800 mg with 1000/1200 mg).
For HCV monoinfected patients and HIV-HCV co-infected patients, for treatment regimens, duration of therapy and study outcome see tables 9, 11 and 15 respectively. Virological response was defined as undetectable HCV RNA as measured by the COBAS AMPLICOR HCV Test, version 2.0 (limit of detection 100 copies/ml equivalent to 50 International Units/ml) and sustained response as one negative sample approximately 6 months after the end of therapy.

Table 7          Virological Response in the overall population (including non-cirrhotic and cirrhotic patients)
Study NV15942                   Study NV15801

Copegus                       Copegus                     Ribavirin
1,000/1,200 mg                1,000/1,200 mg               1,000/1,200 mg &                             &                            &
Peginterferon alfa-2a         Peginterferon alfa-2a         Interferon alfa-2b 180 µg                        180 µg                       3 MIU

(N=436)                       (N=453)                    (N=444)
48 weeks                      48 weeks                   48 weeks
Response at End of
Treatment                            68%                          69%                        52% 
Overall Sustained
Response                             63%                          54%*                       45%* * 95% CI for difference: 3% to 16% p-value (stratified Cochran-Mantel-Haenszel test) = 0.003 
The virological responses of HCV monoinfected patients treated with Copegus and peginterferon alfa- 2a combination therapy in relation to genotype and pre-treatment viral load and in relation to genotype,
pre-treatment viral load and rapid virological response at week 4 are summarised in Table 8 and Table 9 respectively. The results of study NV15942 provide the rationale for recommending treatment regimens based on genotype, baseline viral load and virological response at week 4 (see Tables 9 and 10).

The difference between treatment regimens was in general not influenced by presence/absence of cirrhosis; therefore treatment recommendations for genotype 1, 2 or 3 are independent of this baseline characteristic.


COPEGUS                                                               MoH Approved Prescribing Information Tablets 200 mg                                                                               October 2015 Table 8      Sustained Virological Response based on Genotype and Pre-treatment Viral Load after Copegus Combination Therapy with peginterferon alfa-2a
Study NV15942                             Study NV15801
Copegus        Copegus            Copegus            Copegus             Copegus           Ribavirin 800 mg       1000/1200 mg         800 mg           1000/1200 mg        1000/1200 mg      1000/1200 mg 
&               &                 &                 &                     &                  & PEG-IFN         PEG-IFN           PEG-IFN          PEG-IFN alfa-          PEG-IFN           Interferon alfa-2a         alfa-2a           alfa-2a              2a                 alfa-2a            alfa-2b 180 µg          180 µg            180 µg             180 µg               180 µg             3 MIU 
24 weeks        24 weeks           48 weeks            48 weeks           48 weeks          48 weeks

Genotype         29% (29/101)   42% (49/118)†     41% (102/250)*     52% (142/271)*†     45% (134/298)      36% (103/285) 1

Low viral        41% (21/51)    52% (37/71)       55% (33/60)        65% (55/85)         53% (61/115)       44% (41/94) load

High viral       16% (8/50)     26% (12/47)       36% (69/190)       47% (87/186)        40% (73/182)       33% (62/189) load


Genotype         84% (81/96)    81% (117/144)     79% (78/99)        80% (123/153)       71% (100/140)      61% (88/145)  2/3

Low viral        85% (29/34)    83% (39/47)       88% (29/33)        77% (37/48)         76% (28/37)        65% (34/52) load

High viral       84% (52/62)    80% (78/97)       74% (49/66)        82% (86/105)        70% (72/103)       58% (54/93) load

Genotype         0% (0/5)       67% (8/12)        63% (5/8)          82% (9/11)          77% (10/13)        45% (5/11) 4


Low viral load= ≤800,000 IU/ml; High viral load= >800,000 IU/ml
*Copegus 1000/1200 mg + peginterferon alfa-2a 180 µg, 48 w vs. Copegus 800 mg + peginterferon alfa-2a 180 µg, 48 w: Odds Ratio (95% CI) = 1.52 (1.07 to 2.17) P-value (stratified Cochran-Mantel-Haenszel test) = 0.020 †Copegus 1000/1200 mg + peginterferon alfa-2a 180 µg, 48 w vs. Copegus 1000/1200 mg + peginterferon alfa-2a 180 µg, 24 w: Odds Ratio (95% CI) = 2.12 (1.30 to 3.46) P-value (stratified Cochran-Mantel-Haenszel test) = 0.002 
The possibility to consider shortening treatment duration to 24 weeks in genotype 1 and 4 patients was examined based on a sustained rapid virological response observed in patients with rapid virological response at week 4 in studies NV15942 and ML17131 (see Table 9).


COPEGUS                                                               MoH Approved Prescribing Information Tablets 200 mg                                                                               October 2015 Table 9       Sustained Virological Response Based on Rapid Viral Response at week 4 for Genotype 1 and 4 after Copegus Combination Therapy with Peginterferon alfa-2a in HCV Patients
Study NV15942                                Study ML17131
Copegus                     Copegus                          Copegus
1000/1200 mg                 1000/1200 mg                    1000/1200 mg &                          &                                &
Peginterferon alfa-2a       Peginterferon alfa-2a            Peginterferon alfa-2a 180 µg                      180 µg                           180 µg 
24 weeks                     48 weeks                           24 weeks 
Genotype 1 RVR                 90% (28/31)                    92% (47/51)                   77% (59/77) Low viral load                 93% (25/27)                    96% (26/27)                   80% (52/65) High viral load                 75% (3/4)                     88% (21/24)                   58% (7/12) Genotype 1 non                 24% (21/87)                   43% (95/220)                        - RVR
Low viral load                 27% (12/44)                    50% (31/62)                        - High viral load                 21% (9/43)                   41% (64/158)                        - Genotype 4 RVR                    (5/6)                          (5/5)                      92% (22/24) 
Genotype 4 non                     (3/6)                        (4/6)                               - RVR

Low viral load= ≤800,000 IU/ml; High viral load= >800,000 IU/ml
RVR = rapid viral response (HCV RNA undetectable) at week 4 and HCV RNA undetectable at week 24 
Although limited, data indicated that shortening treatment to 24 weeks might be associated with a higher risk of relapse (see Table 10).

Table 10      Relapse of Virological Response at the End of Treatment for Rapid Virological Response Population
Study NV15942                              Study NV15801
Copegus                    Copegus                        Copegus
1000/1200 mg               1000/1200 mg                   1000/1200 mg &                          &                              &
Peginterferon alfa-2a      Peginterferon alfa-2a          Peginterferon alfa-2a 180 µg                     180 µg                         180 µg

24 weeks                    48 weeks                        48 weeks

Genotype 1 RVR                      6.7% (2/30)                 4.3% (2/47)                      0% (0/24) 
Low viral load                      3.8% (1/26)                  0% (0/25)                       0% (0/17) High viral load                      25% (1/4)                  9.1% (2/22)                       0% (0/7) Genotype 4 RVR                         (0/5)                       (0/5)                          0% (0/4) 

The possibility of shortening treatment duration to 16 weeks in genotype 2 or 3 patients was examined based on the sustained rapid virological response observed in patients with rapid virological response by week 4 in study NV17317 (see Table 11).

In study NV17317 in patients infected with viral genotype 2 or 3, all patients received peginterferon alfa-2a 180 µg sc qw and a Copegus dose of 800 mg and were randomised to treatment for either 16 or  24 weeks. Overall treatment for 16 weeks resulted in lower sustained viral response (65%) than treatment for 24 weeks (76%) (p < 0.0001).

The sustained viral response achieved with 16 weeks of treatment and with 24 weeks of treatment was also examined in a retrospective subgroup analysis of patients who were HCV RNA negative by week 4 and had a LVL at baseline (see Table 11).


COPEGUS                                                                  MoH Approved Prescribing Information Tablets 200 mg                                                                                  October 2015 Table 11        Sustained Virological Response Overall and Based on Rapid Viral Response by Week 4 for Genotype 2 or 3 after Copegus Combination Therapy with
Peginterferon alfa-2a in HCV Patients
Study NV17317
Copegus 800 mg       Copegus 800 mg         Treatment difference        p value &                    &                     95%CI
Peginterferon        Peginterferon alfa-2a              alfa-2a
180 µg               180 µg

16 weeks             24 weeks

Genotype 2 or 3             65% (443/679)        76% (478/630)        -10.6% [-15.5% ; -0.06%]    P<0.0001 Genotype 2 or 3 RVR         82% (378/461)        90% (370/410)         -8.2% [-12.8% ; -3.7%]     P=0.0006 Low viral load              89% (147/166)        94% (141/150)          -5.4% [-12% ; 0.9%]        P=0.11 High viral load             78% (231/295)        88% (229/260)         -9.7% [-15.9% ; -3.6%]     P=0.002 
Low viral load= ≤800,000 IU/ml at baseline; High viral load= >800,000 IU/ml at baseline RVR = rapid viral response (HCV RNA negative) by week 4

It is presently not clear whether a higher dose of Copegus (e.g.1000/1200 mg/day based on body weight) results in higher SVR rates than does the 800 mg/day, when treatment is shortened to 16 weeks.

The data indicated that shortening treatment to 16 weeks is associated with a higher risk of relapse (see Table 12)

Table 12        Relapse of Virological Response after the End of Treatment in Genotype 2 or 3 Patients with a Rapid Viral Response
Study NV17317
Copegus 800 mg       Copegus 800 mg         Treatment difference        p value &                    &                     95%CI
Peginterferon        Peginterferon alfa-2a              alfa-2a
180 µg               180 µg

16 weeks             24 weeks

Genotype 2 or 3 RVR          15% (67/439)         6% (23/386)           9.3% [5.2% ; 13.6%]       P<0.0001 Low viral load                6% (10/155)          1% (2/141)            5% [0.6% ; 10.3%]         P=0.04 High viral load              20% (57/284)         9% (21/245)          11.5% [5.6% ; 17.4%]       P=0.0002 

Chronic hepatitis C prior treatment non-responder patients
In study MV17150, patients who were non-responders to previous therapy with pegylated interferon alfa-2b plus ribavirin were randomised to four different treatments:
• peginterferon alfa-2a 360 µg/week for 12 weeks, followed by 180 µg/week for a further 60 weeks • peginterferon alfa-2a 360 µg/week for 12 weeks, followed by 180 µg/week for a further 36 weeks • peginterferon alfa-2a 180 µg/week for 72 weeks
• peginterferon alfa-2a 180 µg/week for 48 weeks
All patients received Copegus (1000 or 1200 mg/day) in combination with peginterferon alfa-2a. All treatment arms had 24 week treatment-free follow-up.

Multiple regression and pooled group analyses evaluating the influence of treatment duration and use of induction dosing clearly identified treatment duration for 72 weeks as the primary driver for achieving a sustained virological response. Differences in sustained virological response (SVR) based on treatment duration, demographics and best responses to previous treatment are displayed in Table 13.


COPEGUS                                                                 MoH Approved Prescribing Information Tablets 200 mg                                                                                 October 2015 Table 13    Week 12 Virological Response (VR) and Sustained Virological Response (SVR) in Patients with Virological Response at Week 12 after Treatment with Copegus and Peginterferon alfa-2a Combination Therapy in Non-Responders to Peginterferon alfa-2b plus Ribavirin
Copegus             Copegus              Copegus
1000/1200 mg        1000/1200 mg         1000/1200 mg
&                   &                     &
Peginterferon       Peginterferon        Peginterferon alfa-2a 360/180 or  alfa-2a 360/180 or   alfa-2a 360/180 or
180 µg             180 µg                180 µg
72 or 48 Weeks          72 Weeks             48 Weeks
(N = 942)           (N = 473)            (N = 469)
Pts with       SVR in Pts with    SVR in Pts with VR
VR at Wk 12 a       VR at Wk 12 b          at Wk 12 b
(N = 876)           (N = 100)             (N = 57)
Overall                            18% (157/876)         57% (57/100)         35% (20/57) Low viral load                   35% (56/159)          63% (22/35)          38% (8/21) High viral load                  14% (97/686)          54% (34/63)          32% (11/34) Genotype 1/4                       17% (140/846)         55% (52/94)          35% (16/46) Low viral load                    35% (54/154)          63% (22/35)          37% (7/19) High viral load                   13% (84/663)          52% (30/58)          35% (9/26) Genotype 2/3                       58% (15/26)                 (4/5)                (3/10) Low viral load                          (2/5)                  —                   (1/2) High viral load                         (11/19)               (3/4)                (1/7) Cirrhosis Status
Cirrhosis                          8% (19/239)               (6/13)                (3/6) Noncirrhosis                     22% (137/633)         59% (51/87)          34% (17/50) Best Response during
Previous Treatment
2log10 decline in HCV RNA        28% (34/121)             68% (15/22)              (6/12) <2log10 decline in HCV RNA        12% (39/323)             64% (16/25)              (5/14) Missing best previous response     19% (84/432)             49% (26/53)       29% (9/31) 
High viral load = >800,000 IU/ml, low viral load = 800,000 IU/ml.
a Patients who achieved viral suppression (undetectable HCV RNA, <50 IU/ml) at week 12 were considered to have a virological response at week 12. Patients missing HCV RNA results at week 12 have been excluded from the analysis.
b Patients who achieved viral suppression at week 12 but were missing HCV RNA results at the end of follow-up were considered to be non-responders

In the HALT-C study, patients with chronic hepatitis C and advanced fibrosis or cirrhosis who were non-responders to previous treatment with interferon alfa or pegylated interferon alfa, monotherapy or in combination therapy with ribavirin, were treated with peginterferon alfa-2a 180 µg/week and Copegus 1000/1200 mg daily. Patients who achieved undetectable levels of HCV RNA after 20 weeks of treatment remained on peginterferon alfa-2a plus Copegus combination therapy for a total of 48 weeks and were then followed for 24 weeks after the end of treatment. The probability for sustained virological response varied depending upon the previous treatment regimen (see Table 14).


COPEGUS                                                                  MoH Approved Prescribing Information Tablets 200 mg                                                                                  October 2015 

Table 14          Sustained Virological Response in HALT-C by Previous Treatment Regimen in Non-Responder Population

Copegus 1000/1200 mg
&
Peginterferon alfa-2a 180 µg
Previous Treatment                                            48 weeks Interferon                                                   27% (70/255) Pegylated interferon                                          34% (13/38) Interferon plus ribavirin                                    13% (90/692) Pegylated interferon plus ribavirin                            11% (7/61) 
HCV patients with normal ALT
In study NR16071, HCV patients with normal ALT values were randomised to receive peginterferon alfa-2a 180 µg/week with a Copegus dose of 800 mg/day for either 24 or 48 weeks followed by a 24 week treatment free follow-up period or an untreated control group for 72 weeks. The SVRs reported in the treatment arms of this study were similar to the corresponding treatment arms from study NV15942.

Children and adolescents
In the investigator sponsored CHIPS study (Chronic Hepatitis C International Paediatric Study), 65 children and adolescents (6-18 years) with chronic HCV infection were treated with peginterferon alfa- 2a 100 µg/m2 sc once weekly and Copegus 15 mg/kg/day, for 24 weeks (genotypes 2 and 3) or 48 weeks (all other genotypes). Preliminary and limited safety data demonstrated no obvious departure from the known safety profile of the combination in adults with chronic HCV infection, but, importantly, the potential impact on growth has not been reported. Efficacy results were similar to those reported in adults.

HIV-HCV co-infected patients
The virological responses of patients treated with Copegus and peginterferon alfa-2a combination therapy in relation to genotype and pre-treatment viral load for HIV-HCV co-infected patients are summarised below in Table 15.

Table 15              Sustained Virological Response based on Genotype and Pre-treatment Viral Load after Copegus Combination Therapy with peginterferon alfa-2a in
HIV-HCV co-infected patients
Study NR15961
Interferon alfa-2a      Peginterferon alfa-2a            Peginterferon alfa-2a 3 MIU                    180 µg                           180 µg
&                        &                                &
Copegus 800 mg               Placebo                      Copegus 800 mg 48 weeks                 48 weeks                         48 weeks
All patients                    12% (33/285)*               20% (58/286)*                 40% (116/289)* 

Genotype 1                       7% (12/171)                 14% (24/175)                   29% (51/176) Low viral load                   19% (8/42)                   38% (17/45)                    61% (28/46) High viral load                  3% (4/129)                   5% (7/130)                    18% (23/130) 
Genotype 2-3                     20% (18/89)                    36% (32/90)                 62% (59/95) Low viral load                   27% (8/30)                     38% (9/24)                  61% (17/28) High viral load                  17% (10/59)                    35% (23/66)                 63% (42/67) 
Low viral load= ≤800,000 IU/ml; High viral load= >800,000 IU/ml
* peginterferon alfa-2a 180 µg + Copegus 800 mg vs. Interferon alfa-2a 3 MIU + Copegus 800 mg: Odds Ratio (95% CI) = 5.40 (3.42 to 8.54), P-value (stratified Cochran-Mantel-Haenszel test) = <0.0001; peginterferon alfa-2a 180 µg + Copegus 800 mg vs. peginterferon alfa-2a 180 g: Odds Ratio ( 95% CI) = 2.89 (1.93 to 4.32), P-value (stratified Cochran-Mantel- Haenszel test) = <0.0001; Interferon alfa-2a 3 MIU + Copegus 800 mg vs. peginterferon alfa-2a 180 µg: Odds Ratio ( 95% CI) = 0.53 (0.33 to 0.85), P-value (stratified Cochran-Mantel-Haenszel test) = <0.0084 

COPEGUS                                                       MoH Approved Prescribing Information Tablets 200 mg                                                                       October 2015 A subsequent study (NV18209) in patients co-infected with HCV genotype 1 and HIV compared treatment using peginterferon alfa-2a 180 µg/week and either Copegus 800 mg or 1000 mg (<75 kg)/1200 mg (≥75 kg) daily for 48 weeks. The study was not powered for efficacy considerations.
The safety profiles in both Copegus groups were consistent with the known safety profile of peginterferon alfa-2a plus Copegus combination treatment and not indicative of any relevant differences, with the exception of a slight increase in anaemia in the high dose Copegus arm.

Ribavirin in combination with interferon alfa-2a

The therapeutic efficacy of interferon alfa-2a alone and in combination with oral ribavirin was compared in clinical trials in naive (previously untreated) and relapsed patients who had virologically, biochemically and histologically documented chronic hepatitis C. Six months after end of treatment sustained biochemical and virological response as well as histological improvement were assessed.

A statistically significant 10-fold increase (from 4% to 43%; p <0.01) in sustained virological and biochemical response was observed in relapsed patients (M23136; N=99). The favourable profile of the combination therapy was also reflected in the response rates relative to HCV genotype or baseline viral load. In the combination and interferon monotherapy arms, respectively, the sustained response rates in patients with HCV genotype-1 were 28% versus 0% and with genotype non-1 were 58% versus 8%. In addition the histological improvement favoured the combination therapy. Supportive favourable results (monotherapy vs combination; 6% vs 48%, p<0.04) from a small published study in naive patients (N=40) were reported using interferon alfa-2a (3 MIU 3 times per week) with ribavirin.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Ribavirin is absorbed rapidly following oral administration of a single dose of Copegus (median Tmax = 1-2 hours). The mean terminal phase half-life of ribavirin following single doses of Copegus range from 140 to 160 hours. Ribavirin data from the literature demonstrates absorption is extensive with approximately 10% of a radiolabelled dose excreted in the faeces. However, absolute bioavailability is approximately 45%-65%, which appears to be due to first pass metabolism. There is an approximately linear relationship between dose and AUCtf following single doses of 200-1,200 mg ribavirin. Mean apparent oral clearance of ribavirin following single 600 mg doses of Copegus ranges from 22 to 29 litres/hour. Volume of distribution is approximately 4,500 1itres following administration of Copegus. Ribavirin does not bind to plasma proteins.

Ribavirin has been shown to produce high inter- and intra-subject pharmacokinetic variability following single oral doses of Copegus (intra-subject variability of 25% for both AUC and Cmax), which may be due to extensive first pass metabolism and transfer within and beyond the blood compartment.

Ribavirin transport in non-plasma compartments has been most extensively studied in red cells, and has been identified to be primarily via an es-type equilibrative nucleoside transporter. This type of transporter is present on virtually all cell types and may account for the high volume of distribution of ribavirin. The ratio of whole blood: plasma ribavirin concentrations is approximately 60:1; the excess of ribavirin in whole blood exists as ribavirin nucleotides sequestered in erythrocytes.

Ribavirin has two pathways of metabolism: 1) a reversible phosphorylation pathway, 2) a degradative pathway involving deribosylation and amide hydrolysis to yield a triazole carboxyacid metabolite.
Ribavirin and both its triazole carboxamide and triazole carboxylic acid metabolites are excreted renally.

Upon multiple dosing, ribavirin accumulates extensively in plasma with a six-fold ratio of multiple-dose to single-dose AUC12hr based on literature data. Following oral dosing with 600 mg BID, steady-state was reached by approximately 4 weeks, with mean steady state plasma concentrations of approximately 2,200 ng/ml. Upon discontinuation of dosing the half-life was approximately 300 hours, which probably reflects slow elimination from non-plasma compartments.

Food effect: The bioavailability of a single oral 600 mg dose Copegus was increased by coadministration of a high fat meal. The ribavirin exposure parameters of AUC(0-192h) and Cmax increased 
COPEGUS                                                        MoH Approved Prescribing Information Tablets 200 mg                                                                        October 2015 by 42% and 66%, respectively, when Copegus was taken with a high fat breakfast compared to being taken in the fasted state. The clinical relevance of results from this single dose study is unknown.
Ribavirin exposure after multiple dosing when taken with food was comparable in patients receiving peginterferon alfa-2a and Copegus and interferon alfa-2b and ribavirin. In order to achieve optimal ribavirin plasma concentrations, it is recommended to take ribavirin with food.

Renal function: The apparent clearance of ribavirin is reduced in patients with creatinine clearance ≤50 ml/min, including patients with ESRD on chronic haemodialysis, exhibiting approximately 30% of the value found in patients with normal renal function. Based on a small study in patients with moderate or severe renal impairment (creatinine clearance ≤50 ml/min) receiving reduced daily doses of 600 mg and 400 mg of Copegus, respectively ribavirin plasma exposure (AUC) was found to be 20 to 30% higher compared to patients with normal renal function (creatinine clearance >80 ml/min) receiving the standard Copegus dose. In patients with ESRD on chronic haemodialysis and who received 200 mg daily doses of Copegus, mean ribavirin exposure (AUC) was found to be approximately 20% lower compared to patients with normal renal function receiving the standard 1000/1200 mg Copegus daily dose. Plasma ribavirin is removed by haemodialysis with an extraction ratio of approximately 50%; however, due to the large volume of distribution of ribavirin, significant amounts of ribavirin are not effectively removed from the body by haemodialysis. Increased rates of adverse drug reactions were observed in patients with moderate and severe renal impairment receiving the doses evaluated in this study.

Based on pharmacokinetic modelling and simulation, dose adjustments are recommended in patients with significant renal impairment (see section 4.2). These adjusted doses are expected to provide ribavirin plasma exposures comparable to those achieved in patients with normal renal function receiving the standard Copegus dose. Most of the recommended doses were derived from PK modelling and simulation and have not been studied in clinical trials.

Hepatic function: Single-dose pharmacokinetics of ribavirin in patients with mild, moderate or severe hepatic dysfunction (Child-Pugh Classification A, B or C) are similar to those of normal controls.

Use in elderly patients over the age of 65: Specific pharmacokinetic evaluations for elderly subjects have not been performed. However, in a published population pharmacokinetic study, age was not a key factor in the kinetics of ribavirin; renal function is the determining factor.

Patients under the age of 18 years: Refer to the PI of interferon alfa-2a or peginterferon alfa-2a that are indicated in combination with Copegus for this population.
No Copegus pharmacokinetic analysis has been performed in patients under the age of 18 years.

Population Pharmacokinetics: A population pharmacokinetic analysis was performed using plasma concentration values from five clinical trials. While body weight and race were statistically significant covariates in the clearance model, only the effect of body weight was clinically significant. Clearance increased as a function of body weight and was predicted to vary from 17.7 to 24.8 L/h over a weight range of 44 to 155 kg. Creatinine clearance (as low as 34 ml/min) did not affect ribavirin clearance.

Transfer into seminal fluid: Seminal transfer of ribavirin has been studied. Ribavirin concentrations in seminal fluid are approximately two-fold higher compared to serum. However, ribavirin systemic exposure of a female partner after sexual intercourse with a treated patient has been estimated and remains extremely limited compared to therapeutic plasma concentrations of ribavirin.