Virazole Pediátrico

In clinical trials with Virazole Pediátrico used in combination with peginterferon alfa-2b or interferon alfa-2b, the maximum overdose reported was a total dose of 10 g of Virazole Pediátrico (50 x 200 mg capsules) and 39 MIU of interferon alfa-2b (13 subcutaneous injections of 3 MIU each) taken in one day by a patient in an attempt at suicide. The patient was observed for two days in the emergency room, during which time no adverse reaction from the overdose was noted.

In clinical trials with Virazole Pediátrico used in combination with interferon alfa-2b, the maximum overdose reported was a total dose of 10 g of Virazole Pediátrico (50 x 200 mg capsules) and 39 MIU of interferon alfa-2b (13 subcutaneous injections of 3 MIU each) taken in one day by a patient in an attempt at suicide. The patient was observed for two days in the emergency room, during which time no adverse reaction from the overdose was noted.

No overdosage with Virazole Pediátrico (ribavirin) by aerosol administration has been reported in humans. The LDM in mice is 2 g orally and is associated with hypoactivity and gastrointestinal symptoms (estimated human equivalent dose of 0.17 g/kg, based on body surface area conversion). The mean plasma half-life after administration of aerosolized Virazole Pediátrico (ribavirin) for pediatric patients is 9.5 hours. Virazole Pediátrico (ribavirin) is concentrated and persists in red blood cells for the life of the erythrocyte (see Pharmacokinetics).

No cases of overdose of Virazole Pediátrico have been reported in clinical trials. Hypocalcaemia and hypomagnesaemia have been observed in persons administered dosages greater than four times the maximal recommended dosages. In many of these instances ribavirin was administered intravenously. Due to the large volume of distribution of ribavirin, significant amounts of ribavirin are not effectively removed by haemodialysis.

Pharmacotherapeutic group: antivirals for systemic use, nucleosides and nucleotides excl.reverse transcriptase inhibitors, ATC code: J05AB04.

Mechanism of action

Virazole Pediátrico is a synthetic nucleoside analogue which has shown in vitro activity against some RNA and DNA viruses. The mechanism by which Virazole Pediátrico in combination with other medicinal products exerts its effects against HCV is unknown. Oral formulations of Virazole Pediátrico monotherapy have been investigated as therapy for chronic hepatitis C in several clinical trials. Results of these investigations showed that Virazole Pediátrico 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

Virazole Pediátrico in combination with Direct Antiviral Agent (DAA):

Please refer to the SmPC of the corresponding DAA for a full description of the clinical data with such combination.

Only the description of the use of Virazole Pediátrico from the original development with interferon alfa-2b is detailed in the current SmPC:

Bitherapy with interferon alfa-2b:

The use of Virazole Pediátrico in combination treatment with interferon alfa-2b was evaluated in a number of clinical trials. Eligible patients for these trials had chronic hepatitis C confirmed by a positive HCV-RNA polymerase chain reaction assay (PCR) (> 30 IU/ml), a liver biopsy consistent with a histological diagnosis of chronic hepatitis with no other cause for the chronic hepatitis, and abnormal serum ALT.

Naïve patients

Three trials examined the use of interferon in naïve patients, two with Virazole Pediátrico + interferon alfa-2b (C95-132 and I95-143) and one with Virazole Pediátrico + peginterferon alfa-2b (C/I98-580). In all cases the treatment was for one year with a follow-up of six months. The sustained response at the end of follow-up was significantly increased by the addition of Virazole Pediátrico to interferon alfa-2b (41 % vs 16 %, p < 0.001).

In clinical trials C95-132 and I95-143, Virazole Pediátrico + interferon alfa-2b combination therapy proved to be significantly more effective than interferon alfa-2b monotherapy (a doubling in sustained response). Combination therapy also decreased the relapse rate. This was true for all HCV genotypes.

In clinical trial C/I98-580, 1,530 naïve patients were treated for one year with one of the following combination regimens:

- Virazole Pediátrico (800 mg/day) + peginterferon alfa-2b (1.5 micrograms/kg/week) (n = 511).

- Virazole Pediátrico (1,000/1,200 mg/day) + peginterferon alfa-2b (1.5 micrograms/kg/week for one month followed by 0.5 microgram/kg/week for 11 months) (n = 514).

- Virazole Pediátrico (1,000/1,200 mg/day) + interferon alfa-2b (3 MIU three times a week) (n = 505).

In this trial, the combination of Virazole Pediátrico and peginterferon alfa-2b (1.5 micrograms/kg/week) was significantly more effective than the combination of Virazole Pediátrico and interferon alfa-2b, particularly in patients infected with Genotype 1. Sustained response was assessed by the response rate six months after the cessation of treatment.

HCV genotype and baseline virus load are prognostic factors which are known to affect response rates. However, response rates in this trial were shown to be dependent also on the dose of Virazole Pediátrico administered in combination with peginterferon alfa-2b or interferon alfa-2b. In those patients that received > 10.6 mg/kg Virazole Pediátrico (800 mg dose in typical 75 kg patient), regardless of genotype or viral load, response rates were significantly higher than in those patients that received 10.6 mg/kg Virazole Pediátrico (Table7), while response rates in patients that received > 13.2 mg/kg Virazole Pediátrico were even higher.

P1.5/R Virazole Pediátrico (800 mg) + peginterferon alfa-2b (1.5 micrograms/kg)

P0.5/R Virazole Pediátrico (1,000/1,200 mg) + peginterferon alfa-2b (1.5 to 0.5 microgram/kg)

I/R Virazole Pediátrico (1,000/1,200 mg) + interferon alfa-2b (3 MIU)

HCV/HIV Co-infected patients

Two trials have been conducted in patients co-infected with HIV and HCV. The response to treatment in both of these trials is presented in Table 7. Study 1 (RIBAVIC; P01017) was a randomized, multicentre study which enrolled 412 previously untreated adult patients with chronic hepatitis C who were co-infected with HIV. Patients were randomized to receive either Virazole Pediátrico (800 mg/day) plus peginterferon alfa-2b (1.5 µg/kg/week) or Virazole Pediátrico (800 mg/day) plus interferon alfa-2b (3 MIU TIW) for 48 weeks with a follow-up period of 6 months. Study 2 (P02080) was a randomized, single centre study that enrolled 95 previously untreated adult patients with chronic hepatitis C who were co-infected with HIV. Patients were randomized to receive either Virazole Pediátrico (800-1,200 mg/day based on weight) plus peginterferon alfa-2b (100 or 150 µg/week based on weight) or Virazole Pediátrico (800-1,200 mg/day based on weight) plus interferon alfa-2b (3 MIU TIW). The duration of therapy was 48 weeks with a follow-up period of 6 months except for patients infected with genotypes 2 or 3 and viral load < 800,000 IU/ml (Amplicor) who were treated for 24 weeks with a 6 month follow-up period.

MIU = million international units; TIW = three times a week.

a: p value based on Cochran-Mantel Haenszel Chi square test.

b: p value based on chi-square test.

c: subjects < 75 kg received 100 µg/week peginterferon alfa-2b and subjects > 75 kg received 150 µg/week peginterferon alfa-2b.

d: Virazole Pediátrico dosing was 800 mg for patients < 60 kg, 1,000 mg for patients 60-75 kg, and 1,200 mg for patients > 75 kg.

¹Carrat F, Bani-Sadr F, Pol S et al. JAMA 2004; 292(23): 2839-2848.

² Laguno M, Murillas J, Blanco J.L et al. AIDS 2004; 18(13): F27-F36.

Histological response

Liver biopsies were obtained before and after treatment in Study 1 and were available for 210 of the 412 subjects (51 %). Both the Metavir score and Ishak grade decreased among subjects treated with Virazole Pediátrico in combination with peginterferon alfa-2b. This decline was significant among responders (-0.3 for Metavir and -1.2 for Ishak) and stable (-0.1 for Metavir and -0.2 for Ishak) among non-responders. In terms of activity, about one-third of sustained responders showed improvement and none showed worsening. There was no improvement in terms of fibrosis observed in this study. Steatosis was significantly improved in patients infected with HCV Genotype 3.

-Retreatment of relapse patients with Virazole Pediátrico and interferon alfa-2b combination treatment

Two trials examined the use of Virazole Pediátrico and interferon alfa-2b combination treatment in relapse patients (C95-144 and I95-145); 345 chronic hepatitis patients who had relapsed after previous interferon treatment were treated for six months with a six month follow-up. Combination therapy with Virazole Pediátrico and interferon alfa-2b resulted in a sustained virological response that was ten-fold higher than that with interferon alfa-2b alone (49 % vs 5 %, p < 0.0001). This benefit was maintained irrespective of standard predictors of response to interferon alfa-2b such as virus level, HCV genotype and histological staging.

Long-term efficacy data - Adults

Two large long-term follow-up studies enrolled 1,071 patients and 567 patients after treatment in prior studies with non-pegylated interferon alfa-2b (with or without Virazole Pediátrico) and pegylated interferon alfa-2b (with or without Virazole Pediátrico), respectively. The purpose of the studies was to evaluate the durability of sustained virologic response (SVR) and assess the impact of continued viral negativity on clinical outcomes. At least 5 years of long-term follow-up was completed after treatment in 462 patients and 327 patients, respectively. Twelve out of 492 sustained responders and only 3 out of 366 sustained responders relapsed, respectively, in the studies.

The Kaplan-Meier estimate for continued sustained response over 5 years is 97 % (95 % CI: 95-99 %) for patients receiving non-pegylated interferon alfa-2b (with or without Virazole Pediátrico), and is 99 % (95 % CI: 98-100 %) for patients receiving pegylated interferon alfa-2b (with or without Virazole Pediátrico).

SVR after treatment of chronic HCV with interferon alfa-2b (pegylated and non-pegylated,with or without Virazole Pediátrico) results in long-term clearance of the virus providing resolution of the hepatic infection and clinical 'cure' from chronic HCV. However, this does not preclude the occurrence of hepatic events in patients with cirrhosis (including hepatocarcinoma).

Paediatric population

Clinical efficacy and safety

Virazole Pediátrico in combination with interferon alfa-2b

Children and adolescents 3 to 16 years of age with compensated chronic hepatitis C and detectable HCV-RNA (assessed by a central laboratory using a research-based RT-PCR assay) were enrolled in two multicentre trials and received Virazole Pediátrico 15 mg/kg per day plus interferon alfa-2b 3 MIU/m² 3 times a week for 1 year followed by 6 months follow-up after treatment. A total of 118 patients were enrolled: 57 % male, 80 % Caucasian, and 78 % genotype 1, 64 % ≤12 years of age. The population enrolled mainly consisted in children with mild to moderate hepatitis C. In the two multicentre trials, sustained virological response rates in children and adolescents were similar to those in adults. Due to the lack of data in these two multicentre trials for children with severe progression of the disease, and the potential for undesirable effects, the benefit/risk of the combination of Virazole Pediátrico and interferon alfa-2b needs to be carefully considered in this population.

The study results are summarized in Table 9.

* Number (%) of patients

a. Defined as HCV-RNA below limit of detection using a research based RT-PCR assay at end of treatment and during follow-up period.

Long-term efficacy data

Virazole Pediátrico in combination with interferon alfa-2b

A five-year long-term, observational, follow-up study enrolled 97 paediatric chronic hepatitis C patients after treatment in two previously mentioned multicentre trials. Seventy percent (68/97) of all enrolled subjects completed this study of which 75 % (42/56) were sustained responders. The purpose of the study was to annually evaluate the durability of sustained virologic response (SVR) and assess the impact of continued viral negativity on clinical outcomes for patients who were sustained responders 24 weeks post-treatment of the 48-week interferon alfa-2b and Virazole Pediátrico treatment. All but one of the paediatric subjects remained sustained virologic responders during long-term follow-up after completion of treatment with interferon alfa-2b plus Virazole Pediátrico. The Kaplan-Meier estimate for continued sustained response over 5 years is 98 % [95 % CI: 95 %, 100 %] for paediatric patients treated with interferon alfa-2b and Virazole Pediátrico. Additionally, 98 % (51/52) with normal ALT levels at follow-up week 24 maintained normal ALT levels at their last visit.

SVR after treatment of chronic HCV with non-pegylated interferon alfa-2b with Virazole Pediátrico results in long-term clearance of the virus providing resolution of the hepatic infection and clinical 'cure' from chronic HCV. However, this does not preclude the occurrence of hepatic events in patients with cirrhosis (including hepatocarcinoma).

Pharmacotherapeutic group: antivirals for systemic use, nucleosides and nucleotides excl. reverse transcriptase inhibitors, ATC code: J05A B04.

Mechanism of action

Ribavirin (Virazole Pediátrico) is a synthetic nucleoside analogue which has shown in vitro activity against some RNA and DNA viruses. The mechanism by which Virazole Pediátrico in combination with other medicinal products exerts its effects against HCV is unknown. Oral formulations of Virazole Pediátrico monotherapy have been investigated as therapy for chronic hepatitis C in several clinical trials. Results of these investigations showed that Virazole Pediátrico 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

Only the description of the use of Virazole Pediátrico from the original development with (peg)interferon alfa-2b is detailed in the current SmPC.

Paediatric population

Virazole Pediátrico in combination with peginterferon alfa-2b

Children and adolescents 3 to 17 years of age with compensated chronic hepatitis C and detectable HCV-RNA were enrolled in a multicentre trial and treated with Virazole Pediátrico 15 mg/kg per day plus pegylated interferon alfa-2b 60 µg/m² once weekly for 24 or 48 weeks, based on HCV genotype and baseline viral load. All patients were to be followed for 24 weeks post-treatment. A total of 107 patients received treatment of whom 52 % were female, 89 % Caucasian, 67 % with HCV Genotype 1 and 63 % < 12 years of age. The population enrolled mainly consisted of children with mild to moderate hepatitis C. Due to the lack of data in children with severe progression of the disease, and the potential for undesirable effects, the benefit/risk of the combination of Virazole Pediátrico and pegylated interferon alfa-2b needs to be carefully considered in this population.The study results are summarized in Table 6

a: Response to treatment was defined as undetectable HCV-RNA at 24 weeks post-treatment, lower limit of detection = 125 IU/mL.

b: n = number of responders/number of subjects with given genotype, and assigned treatment duration.

c: Patients with genotype 3 low viral load (< 600,000 IU/mL) were to receive 24 weeks of treatment while those with genotype 3 and high viral load (> 600,000 IU/mL) were to receive 48 weeks of treatment.

Virazole Pediátrico in combination with interferon alfa-2b

Children and adolescents 3 to 16 years of age with compensated chronic hepatitis C and detectable HCV-RNA (assessed by a central laboratory using a research-based RT-PCR assay) were enrolled in two multicentre trials and received Virazole Pediátrico 15 mg/kg per day plus interferon alfa-2b 3 MIU/m² three times a week for 1 year followed by 6 months follow-up after-treatment. A total of 118 patients were enrolled: 57 % male, 80 % Caucasian, and 78 % genotype 1, 64 % ≤ 12 years of age. The population enrolled mainly consisted in children with mild to moderate hepatitis C. The population enrolled mainly consisted in children with mild to moderate hepatitis C. In the two multicentre trials, sustained virological response rates in children and adolescents were similar to those in adults (see Table 7). Due to the lack of data in these two multicentre trials for children with severe progression of the disease, and the potential for undesirable effects, the benefit/risk of the combination of Virazole Pediátrico and interferon alfa-2b needs to be carefully considered in this population. The study results are summarized in Table 7.

*Number (%) of patients

a. Defined as HCV RNA below limit of detection using a research based RT-PCR assay at end of treatment and during follow-up period

Long-term efficacy data

Virazole Pediátrico in combination with peginterferon alfa-2b

A five-year long-term, observational, follow-up study enrolled 94 paediatric chronic hepatitis C patients after treatment in a multicentre trial. Of these, sixty-three were sustained responders. The purpose of the study was to annually evaluate the durability of sustained virologic response (SVR) and assess the impact of continued viral negativity on clinical outcomes for patients who were sustained responders 24 weeks post-treatment with 24 or 48 weeks of peginterferon alfa-2b and ribavirin treatment. At the end of 5 years, 85 % (80/94) of all enrolled subjects and 86 % (54/63) of sustained responders completed the study. No paediatric subjects with SVR relapsed during the 5 years of follow-up.

Virazole Pediátrico in combination with interferon alfa-2b

A five-year long-term, observational, follow-up study enrolled 97 paediatric chronic hepatitis C patients after treatment in two previously mentioned multicentre trials. Seventy percent (68/97) of all enrolled subjects completed this study of which 75 % (42/56) were sustained responders. The purpose of the study was to annually evaluate the durability of sustained virologic response (SVR) and assess the impact of continued viral negativity on clinical outcomes for patients who were sustained responders 24 weeks post-treatment of the 48-week interferon alfa-2b and ribavirin treatment. All but one of the paediatric subjects remained sustained virologic responders during long-term follow-up after completion of treatment with interferon alfa-2b plus ribavirin. The Kaplan-Meier estimate for continued sustained response over 5 years is 98 % [95 % CI: 95 %, 100 %] for paediatric patients treated with interferon alfa-2b and ribavirin. Additionally, 98 % (51/52) with normal ALT levels at follow-up week 24 maintained normal ALT levels at their last visit.

SVR after treatment of chronic HCV with non-pegylated interferon alfa-2b with Virazole Pediátrico results in long-term clearance of the virus providing resolution of the hepatic infection and clinical 'cure' from chronic HCV. However, this does not preclude the occurrence of hepatic events in patients with cirrhosis (including hepatocarcinoma).

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 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. Virazole Pediátrico had no significant effect on the initial viral kinetics over the first 4 to 6 weeks in patients treated with the combination of Virazole Pediátrico 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

Virazole Pediátrico in combination with DAA

Please refer to the SmPC of the corresponding direct antiviral agent for a full description of the clinical data with such combination. Only the description of the use of Virazole Pediátrico with (peg)interferon are detailed in the current SmPC

Virazole Pediátrico in combination with peginterferon alfa-2a

Predictability of response

Please refer to the peginterferon alfa-2a SmPC.

Study results in treatment-naive patients

Efficacy and safety of the combination of Virazole Pediátrico 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 13). 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 Virazole Pediátrico (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 Virazole Pediátrico 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 Virazole Pediátrico (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 5, 6, 7 and 13 respectively. Virological response was defined as undetectable HCV RNA as measured by the COBAS AMPLICORâ„¢ 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.

* 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 Virazole Pediátrico 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 6 and Table 7 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 1, 6 and 7).

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.

Low viral load= ≤800,000 IU/ml; High viral load= >800,000 IU/ml

*Virazole Pediátrico 1000/1200 mg + peginterferon alfa-2a 180 µg, 48 w vs. Virazole Pediátrico 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

†Virazole Pediátrico 1000/1200 mg + peginterferon alfa-2a 180 µg, 48 w vs. Virazole Pediátrico 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 7).

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 8).

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 9).

In study NV17317 in patients infected with viral genotype 2 or 3, all patients received peginterferon alfa-2a 180 µg sc qw and a Virazole Pediátrico 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 9).

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 Virazole Pediátrico (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 10)

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 Virazole Pediátrico (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 11.

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 Virazole Pediátrico 1000/1200 mg daily. Patients who achieved undetectable levels of HCV RNA after 20 weeks of treatment remained on peginterferon alfa-2a plus Virazole Pediátrico 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 12).

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 Virazole Pediátrico 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 Virazole Pediátrico 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 Virazole Pediátrico 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 13.

Low viral load= ≤800,000 IU/ml; High viral load= >800,000 IU/ml

* peginterferon alfa-2a 180 µg + Virazole Pediátrico 800 mg vs. Interferon alfa-2a 3 MIU + Virazole Pediátrico 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 + Virazole Pediátrico 800 mg vs. peginterferon alfa-2a 180 μg: 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 + Virazole Pediátrico 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

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 Virazole Pediátrico 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 Virazole Pediátrico groups were consistent with the known safety profile of peginterferon alfa-2a plus Virazole Pediátrico combination treatment and not indicative of any relevant differences, with the exception of a slight increase in anaemia in the high dose Virazole Pediátrico 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

In a single dose, crossover study of Virazole Pediátrico in healthy adult subjects, the capsule and oral solution formulations were found to be bioequivalent.

Absorption

Virazole Pediátrico is absorbed rapidly following oral administration of a single dose (mean T_max= 1.5 hours), followed by rapid distribution and prolonged elimination phases (single dose half-lives of absorption, distribution and elimination are 0.05, 3.73 and 79 hours, respectively). 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 a linear relationship between dose and AUC_tf following single doses of 200-1,200 mg Virazole Pediátrico. Volume of distribution is approximately 5,000 l. Virazole Pediátrico does not bind to plasma proteins.

Distribution

Virazole Pediátrico transport in non-plasma compartments has been most extensively studied in red cells, and has been identified to be primarily via an e_s-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 Virazole Pediátrico. The ratio of whole blood:plasma Virazole Pediátrico concentrations is approximately 60:1; the excess of Virazole Pediátrico in whole blood exists as Virazole Pediátrico nucleotides sequestered in erythrocytes.

Biotransformation

Virazole Pediátrico 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. Both Virazole Pediátrico and its triazole carboxamide and triazole carboxylic acid metabolites are also excreted renally.

Virazole Pediátrico has been shown to produce high inter- and intra-subject pharmacokinetic variability following single oral doses (intrasubject variability of approximately 30 % for both AUC and Cmax), which may be due to extensive first pass metabolism and transfer within and beyond the blood compartment.

Elimination

Upon multiple dosing, Virazole Pediátrico accumulates extensively in plasma with a six-fold ratio of multiple-dose to single-dose AUC_12hr. Following oral dosing with 600 mg BID, steady-state was reached by approximately four weeks, with mean steady state plasma concentrations approximately 2,200 ng/ml. Upon discontinuation of dosing the half-life was approximately 298 hours, which probably reflects slow elimination from non-plasma compartments.

Transfer into seminal fluid

Seminal transfer of Virazole Pediátrico has been studied. Virazole Pediátrico concentration in seminal fluid is approximately two-fold higher compared to serum. However, Virazole Pediátrico systemic exposure of a female partner after sexual intercourse with a treated patient has been estimated and remains extremely limited compared to therapeutic plasma concentration of Virazole Pediátrico.

Food effect

The bioavailability of a single oral dose of Virazole Pediátrico was increased by co-administration of a high fat meal (AUC_tf and C_max both increased by 70 %). It is possible that the increased bioavailability in this study was due to delayed transit of Virazole Pediátrico or modified pH. The clinical relevance of results from this single dose study is unknown. In the pivotal clinical efficacy trial, patients were instructed to take Virazole Pediátrico with food to achieve the maximal plasma concentration of Virazole Pediátrico.

Renal function

Based on published data,Single-dose Virazole Pediátrico pharmacokinetics was altered (increased AUC_tf and C_max) in patients with renal dysfunction compared with control subjects (creatinine clearance > 90 ml/minute). The mean AUCtf was threefold greater in subjects with creatinine clearance between 10 and 30 mL/min compared with control subjects. In subjects with creatinine clearance between 30 and 50 mL/min, AUC_tf was twofold greater compared with control subjects. This appears to be due to reduction of apparent clearance in these patients. Virazole Pediátrico concentrations are essentially unchanged by haemodialysis.

Hepatic function

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

Elderly patients (> 65 years of age)

Specific pharmacokinetic evaluations for elderly subjects have not been performed. However, in a population pharmacokinetic study, age was not a key factor in the kinetics of Virazole Pediátrico; renal function is the determining factor.

Population pharmacokinetic analysis was performed using sparsely sampled serum concentration values from four controlled clinical trials. The clearance model developed showed that body weight, gender, age, and serum creatinine were the main covariates. For males, clearance was approximately 20 % higher than for females. Clearance increased as a function of body weight and was reduced at ages greater than 40 years. Effects of these covariates on Virazole Pediátrico clearance appear to be of limited clinical significance due to the substantial residual variability not accounted for by the model.

Paediatric population

Virazole Pediátrico in combination with interferon alfa-2b

Multiple-dose pharmacokinetic properties for Virazole Pediátrico capsules and interferon alfa-2b in children and adolescents with chronic hepatitis C between 5 and 16 years of age are summarized in Table 10. The pharmacokinetics of Virazole Pediátrico and interferon alfa-2b (dose-normalized) are similar in adults and children or adolescents.

*AUC12 (ng.hr/ml) for Virazole Pediátrico; AUC0-24 (IU.hr/ml) for interferon alfa-2b

In a single dose, crossover study of ribavirin in healthy adult subjects, the capsule and oral solution formulations were found to be bioequivalent.

Absorption

Ribavirin is absorbed rapidly following oral administration of a single dose (mean T_max= 1.5 hours), followed by rapid distribution and prolonged elimination phases (single dose half-lives of absorption, distribution and elimination are 0.05, 3.73 and 79 hours, respectively). 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 a linear relationship between dose and AUC_tf following single doses of 200-1,200 mg ribavirin. Volume of distribution is approximately 5,000 l. Ribavirin does not bind to plasma proteins.

Distribution

Ribavirin transport in non-plasma compartments has been most extensively studied in red cells, and has been identified to be primarily via an e_s-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.

Biotransformation

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. Both ribavirin and its triazole, carboxamide and triazole carboxylic acid metabolites are also excreted renally.

Ribavirin has been shown to produce high inter- and intra-subject pharmacokinetic variability following single oral doses (intrasubject variability of approximately 30 % for both AUC and C_max), which may be due to extensive first pass metabolism and transfer within and beyond the blood compartment.

Elimination

Upon multiple dosing, ribavirin accumulates extensively in plasma with a six-fold ratio of multiple-dose to single-dose AUC_12hr. Following oral dosing with 600 mg BID, steady-state was reached by approximately four weeks, with mean steady state plasma concentrations approximately 2,200 ng/mL. Upon discontinuation of dosing the half-life was approximately 298 hours, which probably reflects slow elimination from non-plasma compartments.

Transfer into seminal fluid

Seminal transfer of ribavirin has been studied. Ribavirin concentration in seminal fluid is 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 concentration of ribavirin.

Food effect

The bioavailability of a single oral dose of ribavirin was increased by co-administration of a high fat meal (AUC_tf and C_max both increased by 70 %). It is possible that the increased bioavailability in this study was due to delayed transit of ribavirin or modified pH. The clinical relevance of results from this single dose study is unknown. In the pivotal clinical efficacy trial, patients were instructed to take ribavirin with food to achieve the maximal plasma concentration of ribavirin.

Renal function

Based on published data, single-dose ribavirin pharmacokinetics was altered (increased AUC_tf and C_max) in patients with renal dysfunction compared with control subjects (creatinine clearance > 90 mL/minute). The mean AUC_tf was threefold greater in subjects with creatinine clearance between 10 and 30 mL/min compared with control subjects. In subjects with creatinine clearance between 30 and 50 mL/min, AUC_tf was twofold greater compared with control subjects. This appears to be due to reduction of apparent clearance in these patients. Ribavirin concentrations are essentially unchanged by haemodialysis.

Hepatic function

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

Paediatric population

Virazole Pediátrico in combination with peginterferon alfa-2b

Multiple-dose pharmacokinetic properties for Virazole Pediátrico and peginterferon alfa-2b in children and adolescent patients with chronic hepatitis C have been evaluated during a clinical study. In children and adolescent patients receiving body surface area-adjusted dosing of peginterferon alfa-2b at 60 µg/m²/week, the log transformed ratio estimate of exposure during the dosing interval is predicted to be 58 % (90 % CI: 141-177 %) higher than observed in adults receiving 1.5 µg/kg/week. The pharmacokinetics of Virazole Pediátrico (dose-normalized) in this trial was similar to those reported in a prior study of Virazole Pediátrico in combination with interferon alfa-2b in children and adolescent patients and in adult patients.

Virazole Pediátrico in combination with interferon alfa-2b

Multiple-dose pharmacokinetic properties for Virazole Pediátrico capsules and interferon alfa-2b in children and adolescents with chronic hepatitis C between 5 and 16 years of age are summarized in Table 8. The pharmacokinetics of Virazole Pediátrico and interferon alfa-2b (dose-normalized) is similar in adults and children or adolescents.

*AUC₁₂ (ng.hr/mL) for Virazole Pediátrico; AUC_0-24 (IU.hr/mL) for interferon alfa-2b

In vivo carcinogenicity studies with ribavirin are incomplete. However, results of a chronic feeding study with ribavirin in rats, at doses of 16-100 mg/kg/day (estimated human equivalent of 2.3-14.3 mg/kg/day, based on body surface area adjustment for the adult), suggest that ribavirin may induce benign mammary, pancreatic, pituitary and adrenal tumors. Preliminary results of 2 oral gavage oncogenicity studies in the mouse and rat (18-24 months; doses of 20-75 and 10-40 mg/kg/day, respectively [estimated human equivalent of 1.67-6.25 and 1.43-5.71 mg/kg/day, respectively, based on body surface area adjustment for the adult]) are inconclusive as to the carcinogenic potential of ribavirin (see Pharmacokinetics). However, these studies have demonstrated a relationship between chronic ribavirin exposure and increased incidences of vascular lesions (microscopic hemorrhages in mice) and retinal degeneration (in rats).

Impairment of Fertility

The fertility of ribavirin-treated animals (male or female) has not been fully investigated. However, in the mouse, administration of ribavirin at doses between 35-150 mg/kg/day (estimated human equivalent of 2.92-12.5 mg/kg/day, based on body surface area adjustment for the adult) resulted in significant seminiferous tubule atrophy, decreased sperm concentrations, and increased numbers of sperm with abnormal morphology. Partial recovery of sperm production was apparent 3-6 months following dose cessation. In several additional toxicology studies, ribavirin has been shown to cause testicular lesions (tubular atrophy) in adult rats at oral dose levels as low as 16 mg/kg/day (estimated human equivalent of 2.29 mg/kg/day, based on body surface area adjustment; see Pharmacokinetics). Lower doses were not tested. The reproductive capacity of treated male animals has not been studied

Pregnancy: Category X

Ribavirin has demonstrated significant teratogenic and/or embryocidal potential in all animal species in which adequate studies have been conducted. Teratogenic effects were evident after single oral doses of 2.5 mg/kg or greater in the hamster, and after daily oral doses of 0.3 and 1.0 mg/kg in the rabbit and rat, respectively (estimated human equivalent doses of 0.12 and 0.14 mg/kg, based on body surface area adjustment for the adult). Malformations of the skull, palate, eye, jaw, limbs, skeleton, and gastrointestinal tract were noted. The incidence and severity of teratogenic effects increased with escalation of the drug dose. Survival of fetuses and offspring was reduced. Ribavirin caused embryo lethality in the rabbit at daily oral dose levels as low as 1 mg/kg. No teratogenic effects were evident in the rabbit and rat administered daily oral doses of 0.1 and 0.3 mg/kg, respectively with estimated human equivalent doses of 0.01 and 0.04 mg/kg, based on body surface area adjustment (see Pharmacokinetics). These doses are considered to define the "No Observable Teratogenic Effects Level" (NOTEL) for ribavirin in the rabbit and rat.

Following oral administration of ribavirin in the pregnant rat (1.0 mg/kg) and rabbit (0.3 mg/kg), mean plasma levels of drug ranged from 0.104.20 µM[0.024-0.049 u/mL] at 1 hour after dosing, to undetectable levels at 24 hours. At 1 hour following the administration of 0.3 or 0.1 mg/kg in the rat and rabbit (NOTEL), respectively, mean plasma levels of drug in both species were near or below the limit of detection (0.05 µM; see Pharmacokinetics).

Although clinical studies have not been performed, Virazole Pediátrico (ribavirin) may cause fetal harm in humans. As noted previously, ribavirin is concentrated in red blood cells and persists for the life of the cell. Thus the terminal half-life for the systemic elimination of ribavirin is essentially that of the half-life of circulating erythrocytes. The minimum interval following exposure to Virazole Pediátrico (ribavirin) before pregnancy may be safely initiated is unknown (see CONTRAINDICATIONS, WARNINGS, and Information for Health Care Personnel).

Nursing Mothers

Virazole Pediátrico (ribavirin) has been shown to be toxic to lactating animals and their offspring. It is not known if Virazole Pediátrico (ribavirin) is excreted in human milk.

Information for Health Care Personnel

Health care workers directly providing care to patients receiving aerosolized Virazole Pediátrico should be aware that ribavirin has been shown to be teratogenic in all animal species in which adequate studies have been conducted (rodents and rabbits). Although no reports of teratogenesis in offspring of mothers who were exposed to aerosolized Virazole Pediátrico (ribavirin) during pregnancy have been confirmed, no controlled studies have been conducted in pregnant women. Studies of environmental exposure in treatment settings have shown that the drug can disperse into the immediate bedside area during routine patient care activities with highest ambient levels closest to the patient and extremely low levels outside of the immediate bedside area. Adverse reactions resulting from actual occupational exposure in adults are described below (see Adverse Events in Health Care Workers). Some studies have documented ambient drug concentrations at the bedside that could potentially lead to systemic exposures above those considered safe for exposure during pregnancy (1/1000 of the NOTEL dose in the most sensitive animal species).^7,8,9

A1992 study conducted by the National Institute of Occupational Safety and Health (NIOSH) demonstrated measurable urine levels of ribavirin in health care workers exposed to aerosol in the course of direct patient care.7 Levels were lowest in workers caring for infants receiving aerosolized Virazole Pediátrico (ribavirin) with mechanical ventilation and highest in those caring for patients being administered the drug via an oxygen tent or hood. This study employed a more sensitive assay to evaluate ribavirin levels in urine than was available for several previous studies of environmental exposure that failed to detect measurable ribavirin levels in exposed workers. Creatinine adjusted urine levels in the NIOSH study ranged from less than 0.001 to 0.140 µM of ribavirin per gram of creatinine in exposed workers. However, the relationship between urinary ribavirin levels in exposed workers, plasma levels in animal studies, and the specific risk of teratogenesis in exposed pregnant women is unknown.

It is good practice to avoid unnecessary occupational exposure to chemicals wherever possible. Hospitals are encouraged to conduct training programs to minimize potential occupational exposure to Virazole Pediátrico (ribavirin). Health care workers who are pregnant should consider avoiding direct care of patients receiving aerosolized Virazole Pediátrico (ribavirin). If close patient contact cannot be avoided, precautions to limit exposure should be taken. These include administration of Virazole Pediátrico (ribavirin) in negative pressure rooms; adequate room ventilation (at least six air exchanges per hour); the use of Virazole Pediátrico (ribavirin) aerosol scavenging devices; turning off the SPAG-2 device for 5 to 10 minutes prior to prolonged patient contact; and wearing appropriately fitted respirator masks. Surgical masks do not provide adequate filtration of Virazole Pediátrico (ribavirin) particles. Further information is available from NIOSH's Hazard Evaluation and Technical Assistance Branch and additional recommendations have been published in an Aerosol Consensus Statement by the American Respiratory Care Foundation and the American Association for Respiratory Care¹⁰

REFERENCES

7. Decker, John, Shultz, Ruth A., Health Hazaid Evaluation Report: Florida Hospital, Orlando, Florida. Cincinnati OH: U.S. Department of Health and Human Services, Public Health Service, Centers for NIOSH Report No. HETA 91 -104-2229.*

8. Barnes, D.J. and Doursew, M. Reference dose: Description and use in health risk assessments. Regul Tox. and Pharm. Vol. 8; p. 471-486, 1988.

9. Federal Register Vol. 53 No. 126 Thurs. June 30,1988 p. 2483424847.

10. American Association for Respiratory Care [1991]. Aerosol Consensus Statement-1991. Respiratory Care 36(9): 916-921.

OVERDOSE

No overdosage with Virazole Pediátrico (ribavirin) by aerosol administration has been reported in humans. The LDM in mice is 2 g orally and is associated with hypoactivity and gastrointestinal symptoms (estimated human equivalent dose of 0.17 g/kg, based on body surface area conversion). The mean plasma half-life after administration of aerosolized Virazole Pediátrico (ribavirin) for pediatric patients is 9.5 hours. Virazole Pediátrico (ribavirin) is concentrated and persists in red blood cells for the life of the erythrocyte (see Pharmacokinetics).

CONTRAINDICATIONS

Virazole Pediátrico (ribavirin) is contraindicated in individuals who have shown Hypersensitivity to the drug or its components, and in women who are or may become pregnant during exposure to the drug. Ribavirin has demonstrated significant teratogenic and/or embryocidal potential in all animal species in which adequate studies have been conducted (rodents and rabbits). Therefore, although clinical studies have not been performed, it should be assumed that Virazole Pediátrico (ribavirin) may cause fetal harm in humans. Studies in which the drug has been administered systemically demonstrate that ribavirin is concentrated in the red blood cells and persists for the life of the erythrocyte.

CLINICAL PHARMACOLOGY

Mechanism of Action

In cell cultures the inhibitory activity of ribavirin for respiratory syncytial virus (RSV) is selective. The mechanism of action is unknown. Reversal of the in vitroantiviral activity by guanosine or xanthosine suggests ribavirin may act as an analogue of these cellular metabolites.

Microbiology

Rfvavirin has demonstrated antiviral activity against RSV in vitro and in experimentally infected cotton rats.² Several clinical isolates of RSV were evaluated for ribavirin susceptibility by plaque reduction in tissue culture. Plaques were reduced 85-98% by 16 µg/mL; however, results may vary with the test system. The development of resistance has not been evaluated in vitro or in clinical trials.

In addition to the above, ribavirin has been shown to have in vitro activity against influenza A and B viruses and herpes simplex virus, but the clinical significance of these data is unknown.

Immunologic Effects

Neutralizing antibody responses to RSV were decreased in aerosolized Virazole Pediátrico (ribavirin) treated infants compared to placebo treated infants.³ One study also showed that RSV-specific IgE antibody in bronchial secretions was decreased in patients treated with aerosolized Virazole Pediátrico. In rats, ribavirin administration resulted in lymphoid atrophy of the thymus, spleen and lymph nodes. Humoral immunity was reduced in guinea pigs and ferrets. Cellular immunity was also mildly depressed in animal studies. The clinical significance of these observations is unknown.

Pharmacokinetics

Assay for Virazole Pediátrico (ribavirin) in human materials is by a radio immunoassay which detects ribavirin and at least one metabolite.

Virazole Pediátrico brand of ribavirin, when administered by aerosol, is absorbed systemically. Four pediatric patients inhaling Virazole Pediátrico (ribavirin) aerosol administered by face mask for 2.5 hours each day for 3 days had plasma concentrations ranging from 0.44 to 1.55 fJM, with a mean concentration of 0.76 µM. The plasma half-life was reported to be 9.5 hours. Three pediatric patients inhaling aerosolized Virazole Pediátrico (ribavirin) administered by face mask or mist tent for 20 hours each day for 5 days had plasma concentrations ranging from 1.5 to 14.3 µM, with a mean concentration of 6.8 µM.

The bioavailability of aerosolized Virazole Pediátrico (ribavirin) is unknown and may depend on the mode of aerosol delivery. After aerosol treatment, peak plasma concentrations of ribavirin are 85% to 98% less than the concentration that reduced RSV plaque formation in tissue culture. After aerosol treatment, respiratory tract secretions are likely to contain ribavirin in concentrations many fold higher than those required to reduce plaque formation. However, RSV is an intracellular virus and it is unknown whether plasma concentrations or respiratory secretion concentrations of the drug better reflect intracellular concentrations in the respiratory tract.

In man, rats, and rhesus monkeys, accumulation of ribavirin and/or metabolites in the red blood cells has been noted, plateauing in red cells in man in about 4 days and gradually declining with an apparent half-life of 40 days (the half-life of erythrocytes). The extent of accumulation of ribavirin following inhalation therapy is not well defined.

Animal Toxicology

Ribavirin, when administered orally or as an aerosol, produced cardiac lesions in mice, rats, and monkeys, when given at doses of 30,36 and f 20 mg/kg or greater for 4 weeks or more (estimated human equivalent doses of 4.8,12.3 and 111.4 mg/kg for a 5 kg child, or 2.5,5.1 and 40 mg/kg for a 60 kg adult, based on body surface area adjustment). Aerosolized ribavirin administered to developing ferrets at 60 mg/kg for 10 or 30 days resulted in inflammatory and possibly emphysematous changes in the lungs. Proliferative changes were seen in the lungs following exposure at 131 mg/kg for 30 days. The significance of these findings to human administration is unknown.

Description of Studies

Non-Mechanlcally-Ventllated Infants: In two placebo controlled trials in infants hospitalized with RSV lower respiratory tract infection, aerosolized Virazole Pediátrico (ribavirin) treatment had a therapeutic effect, as judged by the reduction in severity of clinical manifestations of disease by treatment day 3.3, < Treatment was most effective when instituted within the first 3 days of clinical illness. Virus titers in respiratory secretions were also significantly reduced with Virazole Pediátrico (ribavirin) in one of these original studies.4 Additional controlled studies conducted since these initial trials of aerosolized Virazole Pediátrico (ribavirin) in the treatment of RSV infection have supported these data.

Mechanically-Ventilated Infants: A randomized, double-blind, placebo controlled evaluation of aerosolized Virazole Pediátrico (ribavirin) at the recommended dose was conducted in 28 infants requiring mechanical ventilation for respiratory failure caused by documented RSV infection.8 Mean age was 1.4 months (SD, 1.7 months). Seven patients had underlying diseases predisposing them to severe infection and 21 were previously normal. Aerosolized Virazole Pediátrico (ribavirin) treatment significantly decreased the duration of mechanical ventilation required (4.9 vs. 9.9 days, p=0.01) and duration of required supplemental oxygen (8.7 vs. 13.5 days, p=0.01). Intensive patient management and monitoring techniques were employed in this study. These included endotracheal tube suctioning every 1 to 2 hours; recording of proximal airway pressure, ventilatory rate, and F₁0₂ every hour; and arterial blood gas monitoring every 2 to 6 hours. To reduce the risk of Virazole Pediátrico (ribavirin) precipitation and ventilator malfunction, heated wire tubing, two bacterial filters connected in series in the expiratory limb of the ventilator (with filter changes every 4 hours), and water column pressure release valves to monitor internal ventilator pressures were used in connecting ventilator circuits to the SPAG-2.

Employing these techniques, no technical difficulties with Virazole Pediátrico (ribavirin) administration were encountered during the study. Adverse events consisted of bacterial pneumonia in one case, staphyloma bacteremia in one case and two cases of post-extubation stridor. None were felt to be related to Virazole Pediátrico (ribavirin) administration.

REFERENCES

1. Hruska JF, Bernstein JM, Douglas Jr., RG, and Hall CB. Effects of Virazole Pediátrico (ribavirin) on respiratory syncytial virus in vitro. Antimicrob Agents Chemother 17:770-775,1 1980.

2. Hruska JF, Morrow PE, Suffin SC, and Douglas Jr., RG. In vivo inhibition of respiratory syncytial virus by Virazole Pediátrico (ribavirin). Antimicrob Agents Chemother 21:125-130,1982.

3. Taber LH, Knight V, Gilbert BE, McClung HW et al. Virazole Pediátrico (ribavirin) aerosol treatment of bronchiolitis associated with respiratory tract infection in infants. Pediatrics 72:613-618,1983.

Ribavirin is absorbed rapidly following oral administration of a single dose of Virazole Pediátrico (median T_max = 1-2 hours). The mean terminal phase half-life of ribavirin following single doses of Virazole Pediátrico 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 AUC_tf following single doses of 200-1,200 mg ribavirin. Mean apparent oral clearance of ribavirin following single 600 mg doses of Virazole Pediátrico ranges from 22 to 29 litres/hour. Volume of distribution is approximately 4,500 1itres following administration of Virazole Pediátrico. 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 Virazole Pediátrico (intra-subject variability of ≤25% for both AUC and C_max), 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 e_s-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 AUC_12hr 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 Virazole Pediátrico was increased by coadministration of a high fat meal. The ribavirin exposure parameters of AUC_(0-192h) and C_max increased by 42% and 66%, respectively, when Virazole Pediátrico 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 Virazole Pediátrico 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 Virazole Pediátrico, 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 Virazole Pediátrico dose. In patients with ESRD on chronic haemodialysis and who received 200 mg daily doses of Virazole Pediátrico, mean ribavirin exposure (AUC) was found to be approximately 20% lower compared to patients with normal renal function receiving the standard 1000/1200 mg Virazole Pediátrico 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. These adjusted doses are expected to provide ribavirin plasma exposures comparable to those achieved in patients with normal renal function receiving the standard Virazole Pediátrico 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 SmPC of the medicinal products that are indicated in combination with Virazole Pediátrico for this population.

No Virazole Pediátrico 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.

Virazole Pediátrico

Virazole Pediátrico is embryotoxic or teratogenic, or both, at doses well below the recommended human dose in all animal species in which studies have been conducted. Malformations of the skull, palate, eye, jaw, limbs, skeleton and gastrointestinal tract were noted. The incidence and severity of teratogenic effects increased with escalation of the dose. Survival of foetuses and offspring was reduced.

In a juvenile rat toxicity study, pups dosed from postnatal day 7 to 63 with 10, 25 and 50 mg/kg of Virazole Pediátrico demonstrated a dose-related decrease in overall growth, which was subsequently manifested as slight decreases in body weight, crown-rump length and bone length. At the end of the recovery period, tibial and femoral changes were minimal although generally statistically significant compared to controls in males at all dose levels and in females dosed with the two highest doses compared to controls. No histopathological effects on bone were observed. No Virazole Pediátrico effects were observed regarding neurobehavioural or reproductive development. Plasma concentrations achieved in rat pups were below human plasma concentrations at the therapeutic dose.

Erythrocytes are a primary target of toxicity for Virazole Pediátrico in animal studies. Anaemia occurs shortly after initiation of dosing, but is rapidly reversible upon cessation of treatment.

In 3- and 6-month studies in mice to investigate Virazole Pediátrico-induced testicular and sperm effects, abnormalities in sperm, occurred at doses of 15 mg/kg and above. These doses in animals produce systemic exposures well below those achieved in humans at therapeutic doses. Upon cessation of treatment, essentially total recovery from Virazole Pediátrico-induced testicular toxicity occurred within one or two spermatogenic cycles.

Genotoxicity studies have demonstrated that Virazole Pediátrico does exert some genotoxic activity. Virazole Pediátrico was active in the Balb/3T3 in vitro Transformation Assay. Genotoxic activity was observed in the mouse lymphoma assay, and at doses of 20-200 mg/kg in a mouse micronucleus assay. A dominant lethal assay in rats was negative, indicating that if mutations occurred in rats they were not transmitted through male gametes.

Conventional carcinogenicity rodent studies with low exposures compared to human exposure under therapeutic conditions (factor 0.1 in rats and 1 in mice) did not reveal tumorigenicity of Virazole Pediátrico. In addition, in a 26 week carcinogenicity study using the heterozygous p53(+/-) mouse model, Virazole Pediátrico did not produce tumours at the maximally tolerated dose of 300 mg/kg (plasma exposure factor approximately 2.5 compared to human exposure). These studies suggest that a carcinogenic potential of Virazole Pediátrico in humans is unlikely.

Virazole Pediátrico plus interferon

When used in combination with peginterferon alfa-2b or interferon alfa-2b, Virazole Pediátrico did not cause any effects not previously seen with either active substance alone. The major treatment-related change was a reversible mild to moderate anaemia, the severity of which was greater than that produced by either active substance alone.

Ribavirin

Ribavirin is embryotoxic or teratogenic, or both, at doses well below the recommended human dose in all animal species in which studies have been conducted. Malformations of the skull, palate, eye, jaw, limbs, skeleton and gastrointestinal tract were noted. The incidence and severity of teratogenic effects increased with escalation of the dose. Survival of foetuses and offspring was reduced.

In a juvenile rat toxicity study, pups dosed from postnatal day 7 to 63 with 10, 25 and 50 mg/kg of ribavirin demonstrated a dose-related decrease in overall growth, which was subsequently manifested as slight decreases in body weight, crown-rump length and bone length. At the end of the recovery period, tibial and femoral changes were minimal although generally statistically significant compared to controls in males at all dose levels and in females dosed with the two highest doses compared to controls. No histopathological effects on bone were observed. No ribavirin effects were observed regarding neurobehavioural or reproductive development. Plasma concentrations achieved in rat pups were below human plasma concentrations at the therapeutic dose.

Erythrocytes are a primary target of toxicity for ribavirin in animal studies. Anaemia occurs shortly after initiation of dosing, but is rapidly reversible upon cessation of treatment.

In 3-and 6-month studies in mice to investigate ribavirin-induced testicular and sperm effects, abnormalities in sperm occurred at doses of 15 mg/kg and above. These doses in animals produce systemic exposures well below those achieved in humans at therapeutic doses. Upon cessation of treatment, essentially total recovery from ribavirin-induced testicular toxicity occurred within one or two spermatogenic cycles.

Genotoxicity studies have demonstrated that ribavirin does exert some genotoxic activity. Ribavirin was active in the Balb/3T3 in vitro transformation assay. Genotoxic activity was observed in the mouse lymphoma assay, and at doses of 20-200 mg/kg in a mouse micronucleus assay. A dominant lethal assay in rats was negative, indicating that if mutations occurred in rats they were not transmitted through male gametes.

Conventional carcinogenicity rodent studies with low exposures compared to human exposure under therapeutic conditions (factor 0.1 in rats and 1 in mice) did not reveal tumorigenicity of ribavirin. In addition, in a 26 week carcinogenicity study using the heterozygous p53(+/-) mouse model, ribavirin did not produce tumours at the maximally tolerated dose of 300 mg/kg (plasma exposure factor approximately 2.5 compared to human exposure). These studies suggest that a carcinogenic potential of ribavirin in humans is unlikely.

Ribavirin plus interferon

When used in combination with peginterferon alfa-2b or interferon alfa-2b, ribavirin did not cause any effects not previously seen with either active substance alone. The major treatment-related change was a reversible mild to moderate anaemia, the severity of which was greater than that produced by either active substance alone.

Ribavirin is embryotoxic and/or teratogenic at doses well below the recommended human dose in all animal species in which adequate studies have been conducted. Malformations of the skull, palate, eye, jaw, limbs, skeleton and gastrointestinal tract were noted. The incidence and severity of teratogenic effects increased with escalation of the dose. Survival of foetuses and offspring is reduced.

Erythrocytes are a primary target of toxicity for ribavirin in animal studies, including studies in dogs and monkeys. Anaemia occurs shortly after initiation of dosing, but is rapidly reversible upon cessation of treatment. Hypoplastic anaemia was observed only in rats at the high dose of 160 mg/kg/day in the subchronic study.

Reduced leucocyte and/or lymphocyte counts were consistently noted in the repeat-dose rodent and dog toxicity studies with ribavirin and transiently in monkeys administered ribavirin in the subchronic study. Repeat-dose rat toxicity studies showed thymic lymphoid depletion and/or depletion of thymus-dependent areas of the spleen (periarteriolar lymphoid sheaths, white pulp) and mesenteric lymph node. Following repeat-dosing of dogs with ribavirin, increased dilatation/necrosis of the intestinal crypts of the duodenum was noted, as well as chronic inflammation of the small intestine and erosion of the ileum.

In repeat dose studies in mice to investigate ribavirin-induced testicular and sperm effects, abnormalities in sperm occurred at doses in animals well below therapeutic doses. Upon cessation of treatment, essentially total recovery from ribavirin-induced testicular toxicity occurred within one or two spermatogenic cycles.

Genotoxicity studies have demonstrated that ribavirin does exert some genotoxic activity. Ribavirin was active in an in vitro Transformation Assay. Genotoxic activity was observed in in vivo mouse micronucleus assays. A dominant lethal assay in rats was negative, indicating that if mutations occurred in rats they were not transmitted through male gametes. Ribavirin is a possible human carcinogen.

Administration of ribavirin and peginterferon alfa-2a in combination did not produce any unexpected toxicity in monkeys. The major treatment-related change was reversible mild to moderate anaemia, the severity of which was greater than that produced by either active substance alone.

No special requirements

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

No special requirements.

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