No cases of overdose of Ribavirin Mylan 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.
- pregnant women. Ribavirin Mylan must not be initiated until a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy.
- women who are breast-feeding.
- a history of severe pre-existing cardiac disease, including unstable or uncontrolled cardiac disease, in the previous six months.
- haemoglobinopathies (e.g. thalassaemia, sickle-cell anaemia).
Refer also to the SmPC of the medicinal products that are used in combination with Ribavirin Mylan for contraindications related to those products.
Not applicable
The salient safety issue of ribavirin is hemolytic anemia occurring within the first weeks of therapy.).
The adverse events listed in this section are reported in clinical trials and/or as adverse drug reactions from spontaneous reports primarily when Ribavirin Mylan was used in combination with interferon alfa-2a or peginterferon alfa-2a.
Adverse events reported in patients receiving Ribavirin Mylan in combination with interferon alfa-2a are essentially the same as for those reported for Ribavirin Mylan in combination with peginterferon alfa-2a.
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Refer also to the SmPC of the medicinal products that are used in combination with Ribavirin Mylan for additional undesirable effects reported with these products.
Chronic hepatitis C
The most frequently reported adverse events with Ribavirin Mylan in combination with peginterferon alfa-2a 180 µg were mostly mild to moderate in severity. Most of them were manageable without the need for discontinuation of therapy.
Chronic hepatitis C in prior non-responder patients
Overall, the safety profile for Ribavirin Mylan in combination with peginterferon alfa-2a in prior non-responder patients was similar to that in naive patients. In a clinical trial of non-responder patients to prior pegylated interferon alfa-2b/ribavirin, which exposed patients to either 48 or 72 weeks of treatment, the frequency of withdrawal for adverse events or laboratory abnormalities from peginterferon alfa-2a treatment and Ribavirin Mylan treatment was 6% and 7%, respectively, in the 48 week arms and 12% and 13%, respectively, in the 72 week arms. Similarly, for patients with cirrhosis or transition to cirrhosis, the frequencies of withdrawal from peginterferon alfa-2a treatment and Ribavirin Mylan treatment were higher in the 72-week treatment arms (13% and 15%) than in the 48-week arms (6% and 6%). Patients who withdrew from previous therapy with pegylated interferon alfa-2b/ribavirin because of haematological toxicity were excluded from enrolling in this trial.
In another clinical trial, non-responder patients with advanced fibrosisis or cirrhosis (Ishak score of 3 to 6) and baseline platelet counts as low as 50,000/mm3 were treated for 48 weeks. Haematologic laboratory abnormalities observed during the first 20 weeks of the trial included anaemia (26% of patients experienced a haemoglobin level of <10 g/dl), neutropenia (30% experienced an ANC <750/mm3), and thrombocytopenia (13% experienced a platelet count <50,000/mm3).
Chronic hepatitis C and Human Immunodeficiency Virus Co-infection
In HIV-HCV co-infected patients, the clinical adverse event profiles reported for peginterferon alfa-2a, alone or in combination with ribavirin, were similar to those observed in HCV mono-infected patients. For HIV-HCV patients receiving Ribavirin Mylan and peginterferon alfa-2a combination therapy other undesirable effects have been reported in >1% to ≤ 2% of patients: hyperlactacidaemia/lactic acidosis, influenza, pneumonia, affect lability, apathy, pharyngolaryngeal pain, cheilitis, acquired lipodystrophy and chromaturia. Peginterferon alfa-2a treatment was associated with decreases in absolute CD4+ cell counts within the first 4 weeks without a reduction in CD4+ cell percentage. The decrease in CD4+ cell counts was reversible upon dose reduction or cessation of therapy. The use of peginterferon alfa-2a had no observable negative impact on the control of HIV viraemia during therapy or follow-up. Limited safety data are available in co-infected patients with CD4+ cell counts <200/µl (see peginterferon alfa-2a SmPC).
Table 4 shows the undesirable effects reported in patients who have received Ribavirin Mylan primarily in combination with peginterferon alfa-2a or interferon alfa-2a.
Table 4 Undesirable Effects Reported with Ribavirin Mylan primarily in combination with Peginterferon alfa-2a or Interferon alfa-2a for HCV Patients | ||||||
| Body system | Very common >1/10 | Common >1/100 to <1/10 | Uncommon >1/1000 to <1/100 | Rare >1/10,000 to <1/1000 | Very rare <1/10,000 | Frequency not known* |
| Infections and infestations | Upper respiratory infection, bronchitis, oral candidiasis, herpes simplex | Lower respiratory tract infection, pneumonia, urinary tract infection, skin infection | Endocarditis, Otitis externa | |||
| Blood and lymphatic system disorders | Anaemia, neutropenia | Thrombo-cytopenia, lymphadeno-pathy | Pancytopenia | Aplastic anaemia | Pure red cell aplasia | |
| Immune system disorders | Sarcoidosis, thyroiditis | Anaphylaxis, systemic lupus erythematosus, rheumatoid arthritis | idiopathic or thrombotic thrombocyto-penic purpura | Liver and renal graft rejection, Vogt-Koyanagi-Harada disease | ||
| Endocrine disorders | Hypo-thyroidism, hyper-thyroidism | Diabetes | ||||
| Metabolism and Nutrition Disorders | Anorexia | Dehydration | ||||
| Psychiatric disorders | Depression, insomnia | Mood alteration, emotional disorders, anxiety, aggression, nervousness, libido decreased | Suicidal ideation, hallucinations, anger | Suicide, psychotic disorder | Mania, bipolar disorders, homicidal ideation | |
| Nervous system disorders | Headache, dizziness, concentration impaired | Memory impairment, syncope, weakness, migraine, hypoaesthesia, hyperaesthe-sia, paraesthesia, tremor, taste disturbance, nightmares, somnolence | Peripheral neuropathy | Coma, convulsions, facial palsy | Cerebral ischaemia | |
| Eye disorders | Vision blurred, eye pain, eye inflammation, xerophthalmia | Retinal haemorrhage | Optic neuropathy, papilloedema, retinal vascular disorder, retinopathy, corneal ulcer | Vision loss | Serous retinal detachment | |
| Ear and labyrinth disorders | Vertigo, earache, tinnitus | Hearing loss | ||||
| Cardiac disorders | Tachycardia, palpitations, oedema peripheral | Myocardial infarction, congestive heart failure, angina, supraventri-cular tachycardia arrhythmia, atrial fibrillation, pericarditis | ||||
| Vascular disorders | Flushing, hypotension | Hypertension | Cerebral haemorrhage, vasculitis | |||
| Respiratory, thoracic and mediastinal disorders | Dyspnoea, cough | Dyspnoea exertional, epistaxis, nasopharyn-gitis, sinus congestion, nasal congestion, rhinitis, sore throat | Wheezing | Interstitial pneumonitis with fatal outcome, pulmonary embolism | ||
| Gastrointestinal disorders | Diarrhoea, nausea, abdominal pain | Vomiting, dyspepsia, dysphagia, mouth ulceration, gingival bleeding, glossitis, stomatitis, flatulence, constipation, dry mouth | Gastrointestinal bleeding, cheilitis, gingivitis | Peptic ulcer, pancreatitis | Colitis ischaemic, colitis ulcerative, tongue pigmentation | |
| Hepato-biliary disorders | Hepatic dysfunction | Hepatic failure, cholangitis, fatty liver | ||||
| Skin and subcutaneous tissue disorders | Alopecia, dermatitis, pruritus, dry skin | Rash, sweating increased, psoriasis, urticaria, eczema, skin disorder, photosensitivity reaction, night sweats | Toxic epidermal necrolysis, Stevens-Johnson syndrome, angioedema, erythema multiforme | |||
| Musculoskeletal and connective tissue disorders | Myalgia, arthralgia | Back pain, arthritis, muscle weakness, bone pain, neck pain, musculoskeletal pain, muscle cramps | Myositis | Rhabdomyo-lysis | ||
| Renal and Urinary Disorders | Renal failure, nephrotic syndrome | |||||
| Reproductive system and breast disorders | Impotence | |||||
| General disorders and administration site conditions | Pyrexia, rigors, pain, asthenia, fatigue, irritability | Chest pain, influenza like illness, malaise, lethargy, hot flushes, thirst | ||||
| Investigations | Weight decreased | |||||
| Injury and poisoning | Substance overdose | |||||
* Identified in postmarketing experience
Laboratory values: In clinical trials of Ribavirin Mylan in combination with peginterferon alfa-2a or interferon alfa-2a, the majority of cases of abnormal laboratory values were managed with dose modifications. With peginterferon alfa-2a and Ribavirin Mylan combination treatment, up to 2% of patients experienced increased ALT levels that led to dose modification or discontinuation of treatment.
Haemolysis is the dose limiting toxicity of ribavirin therapy. A decrease in haemoglobin levels to <10 g/dl was observed in up to 15% of patients treated for 48 weeks with Ribavirin Mylan 1000/1200 mg in combination with peginterferon alfa-2a and up to 19% of patients in combination with interferon alfa-2a. When Ribavirin Mylan 800 mg was combined with peginterferon alfa-2a for 24 weeks, 3% of patients had a decrease in haemoglobin levels to <10 g/dl. In most cases the decrease in haemoglobin occurred early in the treatment period and stabilised concurrently with a compensatory increase in reticulocytes.
Most cases of anaemia, leucopenia and thrombocytopenia were mild (WHO grade 1). WHO grade 2 laboratory changes were reported for haemoglobin (4% of patients), leucocytes (24% of patients) and thrombocytes (2% of patients). Moderate (absolute neutrophil count (ANC): 0.749-0.5x109/l) and severe (ANC: <0.5x109/l) neutropenia was observed in 24% (216/887) and 5% (41/887) of patients receiving 48 weeks of Ribavirin Mylan 1000/1200 mg in combination with peginterferon alfa-2a.
An increase in uric acid and indirect bilirubin values associated with haemolysis were observed in some patients treated with Ribavirin Mylan used in combination with peginterferon alfa-2a or interferon alfa-2a and values returned to baseline levels within 4 weeks after the end of therapy. In rare cases (2/755) this was associated with clinical manifestation (acute gout).
Laboratory values for HIV-HCV co-infected patients
Although haematological toxicities of neutropenia, thrombocytopenia and anaemia occurred more frequently in HIV-HCV patients, the majority could be managed by dose modification and the use of growth factors and infrequently required premature discontinuation of treatment. Decrease in ANC levels below 500 cells/mm3 was observed in 13% and 11% of patients receiving peginterferon alfa-2a monotherapy and combination therapy, respectively. Decrease in platelets below 50,000/mm3 was observed in 10% and 8% of patients receiving peginterferon alfa-2a monotherapy and combination therapy, respectively. Anaemia (haemoglobin <10 g/dl) was reported in 7% and 14% of patients treated with peginterferon alfa-2a monotherapy or in combination therapy, respectively.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard.
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.
Ribavirin Mylan is indicated in combination with other medicinal products, for the treatment of chronic hepatitis C (CHC).
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. Ribavirin Mylan had no significant effect on the initial viral kinetics over the first 4 to 6 weeks in patients treated with the combination of Ribavirin Mylan 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
Ribavirin Mylan 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 Ribavirin Mylan with (peg)interferon are detailed in the current SmPC
Ribavirin Mylan 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 Ribavirin Mylan 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 Ribavirin Mylan (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 Ribavirin Mylan 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 Ribavirin Mylan (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.
| Table 5 Virological Response in the overall population (including non-cirrhotic and cirrhotic patients) | |||
| Study NV15942 | Study NV15801 | ||
| Ribavirin Mylan 1,000/1,200 mg & Peginterferon alfa-2a 180 µg | Ribavirin Mylan 1,000/1,200 mg & Peginterferon alfa-2a 180 µg | Ribavirin 1,000/1,200 mg & Interferon alfa-2b 3 MIU | |
| (N=436) 48 weeks | (N=453) 48 weeks | (N=444) 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 Ribavirin Mylan 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.
| Table 6Sustained Virological Response based on Genotype and Pre-treatment Viral Load after Ribavirin Mylan Combination Therapy with peginterferon alfa-2a | ||||||
| Study NV15942 | Study NV15801 | |||||
| Ribavirin Mylan 800 mg & PEG-IFN alfa-2a 180 µg 24 weeks | Ribavirin Mylan 1000/1200 mg & PEG-IFN alfa-2a 180 µg 24 weeks | Ribavirin Mylan 800 mg & PEG-IFN alfa-2a 180 µg 48 weeks | Ribavirin Mylan 1000/1200 mg & PEG-IFN alfa- 2a 180 µg 48 weeks | Ribavirin Mylan 1000/1200 mg & PEG-IFN alfa-2a 180 µg 48 weeks | Ribavirin 1000/1200 mg & Interferon alfa-2b 3 MIU 48 weeks | |
| Genotype 1 Low viral load High viral load | 29% (29/101) 41% (21/51) 16% (8/50) | 42% (49/118)†52% (37/71) 26% (12/47) | 41% (102/250)* 55% (33/60) 36% (69/190) | 52% (142/271)*†65% (55/85) 47% (87/186) | 45% (134/298) 53% (61/115) 40% (73/182) | 36%(103/285) 44% (41/94) 33% (62/189) |
| Genotype 2/3 Low viral load High viral load | 84% (81/96) 85% (29/34) 84% (52/62) | 81% (117/144) 83% (39/47) 80% (78/97) | 79% (78/99) 88% (29/33) 74% (49/66) | 80% (123/153) 77% (37/48) 82% (86/105) | 71% (100/140) 76% (28/37) 70% (72/103) | 61% (88/145) 65% (34/52) 58% (54/93) |
| Genotype 4 | 0% (0/5) | 67% (8/12) | 63% (5/8) | 82% (9/11) | 77% (10/13) | 45% (5/11) |
Low viral load= ≤800,000 IU/ml; High viral load= >800,000 IU/ml
*Ribavirin Mylan 1000/1200 mg + peginterferon alfa-2a 180 µg, 48 w vs. Ribavirin Mylan 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
†Ribavirin Mylan 1000/1200 mg + peginterferon alfa-2a 180 µg, 48 w vs. Ribavirin Mylan 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).
| Table 7 Sustained Virological Response Based on Rapid Viral Response at week 4 for Genotype 1 and 4 after Ribavirin Mylan Combination Therapy with Peginterferon alfa-2a in HCV Patients | |||
| Study NV15942 | Study ML17131 | ||
| Ribavirin Mylan 1000/1200 mg & Peginterferon alfa-2a 180 µg 24 weeks | Ribavirin Mylan 1000/1200 mg & Peginterferon alfa-2a 180 µg 48 weeks | Ribavirin Mylan 1000/1200 mg & Peginterferon alfa-2a 180 µg 24 weeks | |
| Genotype 1 RVR Low viral load High viral load | 90% (28/31) 93% (25/27) 75% (3/4) | 92% (47/51) 96% (26/27) 88% (21/24) | 77% (59/77) 80% (52/65) 58% (7/12) |
| Genotype 1 non RVR Low viral load High viral load | 24% (21/87) 27% (12/44) 21% (9/43) | 43% (95/220) 50% (31/62) 41% (64/158) | - - - |
| Genotype 4 RVR | (5/6) | (5/5) | 92% (22/24) |
| Genotype 4 non RVR | (3/6) | (4/6) | - |
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).
| Table 8 Relapse of Virological Response at the End of Treatment for Rapid Virological Response Population | |||
| Study NV15942 | Study NV15801 | ||
| Ribavirin Mylan 1000/1200 mg & Peginterferon alfa-2a 180 µg 24 weeks | Ribavirin Mylan 1000/1200 mg & Peginterferon alfa-2a 180 µg 48 weeks | Ribavirin Mylan 1000/1200 mg & Peginterferon alfa-2a 180 µg 48 weeks | |
| Genotype 1 RVR Low viral load High viral load | 6.7% (2/30) 3.8% (1/26) 25% (1/4) | 4.3% (2/47) 0% (0/25) 9.1% (2/22) | 0% (0/24) 0% (0/17) 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 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 Ribavirin Mylan 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).
| Table 9 Sustained Virological Response Overall and Based on Rapid Viral Response by Week 4 for Genotype 2 or 3 after Ribavirin Mylan Combination Therapy with Peginterferon alfa-2a in HCV Patients | ||||
| Study NV17317 | ||||
| Ribavirin Mylan 800 mg & Peginterferon alfa-2a 180 µg 16 weeks | Ribavirin Mylan 800 mg & Peginterferon alfa-2a 180 µg 24 weeks | Treatment difference 95%CI | p value | |
| Genotype 2 or 3 | 65% (443/679) | 76% (478/630) | -10.6% [-15.5% ; -0.06%] | P<0.0001 |
| Genotype 2 or 3 RVR Low viral load High viral load | 82% (378/461) 89% (147/166) 78% (231/295) | 90% (370/410) 94% (141/150) 88% (229/260) | -8.2% [-12.8% ; -3.7%] -5.4% [-12% ; 0.9%] -9.7% [-15.9% ; -3.6%] | P=0.0006 P=0.11 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 Ribavirin Mylan (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)
| Table 10 Relapse of Virological Response after the End of Treatment in Genotype 2 or 3 Patients with a Rapid Viral Response | ||||
| Study NV17317 | ||||
| Ribavirin Mylan 800 mg & Peginterferon alfa-2a 180 µg 16 weeks | Ribavirin Mylan 800 mg & Peginterferon alfa-2a 180 µg 24 weeks | Treatment difference 95%CI | p value | |
| Genotype 2 or 3 RVR Low viral load High viral load | 15% (67/439) 6% (10/155) 20% (57/284) | 6% (23/386) 1% (2/141) 9% (21/245) | 9.3% [5.2% ; 13.6%] 5% [0.6% ; 10.3%] 11.5% [5.6% ; 17.4%] | P<0.0001 P=0.04 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 Ribavirin Mylan (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.
| Table 11 Week 12 Virological Response (VR) and Sustained Virological Response (SVR) in Patients with Virological Response at Week 12 after Treatment with Ribavirin Mylan and Peginterferon alfa-2a Combination Therapy in Non-Responders to Peginterferon alfa-2b plus Ribavirin | |||
| Ribavirin Mylan 1000/1200 mg & Peginterferon alfa-2a 360/180 or 180 µg 72 or 48 Weeks (N = 942) Pts with VR at Wk 12 a
(N = 876) | Ribavirin Mylan 1000/1200 mg & Peginterferon alfa-2a 360/180 or 180 µg 72 Weeks (N = 473) SVR in Pts with VR at Wk 12 b (N = 100) | Ribavirin Mylan 1000/1200 mg & Peginterferon alfa-2a 360/180 or 180 µg 48 Weeks (N = 469) SVR in Pts with VR at Wk 12 b
(N = 57) | |
| Overall Low viral load High viral load | 18% (157/876) 35% (56/159) 14% (97/686) | 57% (57/100) 63% (22/35) 54% (34/63) | 35% (20/57) 38% (8/21) 32% (11/34) |
| Genotype 1/4 Low viral load High viral load | 17% (140/846) 35% (54/154) 13% (84/663) | 55% (52/94) 63% (22/35) 52% (30/58) | 35% (16/46) 37% (7/19) 35% (9/26) |
| Genotype 2/3 Low viral load High viral load | 58% (15/26) (2/5) (11/19) | (4/5) — (3/4) | (3/10) (1/2) (1/7) |
| Cirrhosis Status Cirrhosis Noncirrhosis |
8% (19/239) 22% (137/633) |
(6/13) 59% (51/87) |
(3/6) 34% (17/50) |
| Best Response during Previous Treatment >2log10 decline in HCV RNA <2log10 decline in HCV RNA Missing best previous response |
28% (34/121) 12% (39/323) 19% (84/432) |
68% (15/22) 64% (16/25) 49% (26/53) |
(6/12) (5/14) 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 Ribavirin Mylan 1000/1200 mg daily. Patients who achieved undetectable levels of HCV RNA after 20 weeks of treatment remained on peginterferon alfa-2a plus Ribavirin Mylan 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).
| Table 12 Sustained Virological Response in HALT-C by Previous Treatment Regimen in Non-Responder Population | |
| Previous Treatment | Ribavirin Mylan 1000/1200 mg & Peginterferon alfa-2a 180 µg 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 Ribavirin Mylan 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 Ribavirin Mylan 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 Ribavirin Mylan 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.
| Table 13 Sustained Virological Response based on Genotype and Pre-treatment Viral Load after Ribavirin Mylan Combination Therapy with peginterferon alfa-2a in HIV-HCV co-infected patients | |||
| Study NR15961 | |||
|
| Interferon alfa-2a 3 MIU & Ribavirin Mylan 800 mg 48 weeks | Peginterferon alfa-2a 180 µg & Placebo 48 weeks | Peginterferon alfa-2a 180 µg & Ribavirin Mylan 800 mg 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 + Ribavirin Mylan 800 mg vs. Interferon alfa-2a 3 MIU + Ribavirin Mylan 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 + Ribavirin Mylan 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 + Ribavirin Mylan 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 Ribavirin Mylan 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 Ribavirin Mylan groups were consistent with the known safety profile of peginterferon alfa-2a plus Ribavirin Mylan combination treatment and not indicative of any relevant differences, with the exception of a slight increase in anaemia in the high dose Ribavirin Mylan 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
Ribavirin is absorbed rapidly following oral administration of a single dose of Ribavirin Mylan (median Tmax = 1-2 hours). The mean terminal phase half-life of ribavirin following single doses of Ribavirin Mylan 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 Ribavirin Mylan ranges from 22 to 29 litres/hour. Volume of distribution is approximately 4,500 1itres following administration of Ribavirin Mylan. 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 Ribavirin Mylan (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 Ribavirin Mylan was increased by coadministration of a high fat meal. The ribavirin exposure parameters of AUC(0-192h) and Cmax increased by 42% and 66%, respectively, when Ribavirin Mylan 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 Ribavirin Mylan 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 Ribavirin Mylan, 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 Ribavirin Mylan dose. In patients with ESRD on chronic haemodialysis and who received 200 mg daily doses of Ribavirin Mylan, mean ribavirin exposure (AUC) was found to be approximately 20% lower compared to patients with normal renal function receiving the standard 1000/1200 mg Ribavirin Mylan 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 Ribavirin Mylan 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 Ribavirin Mylan for this population.
No Ribavirin Mylan 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.
Ribavirin Mylan monotherapy must not be used
Combination therapy of ribavirin with (peg)interferon alfa.
There are several severe adverse reactions associated with the combination therapy of ribavirin with (peg)interferon alfa.
Prior to initiation of treatment with ribavirin the physician must comprehensively inform the patient of the teratogenic risk of ribavirin, the necessity of effective and continuous contraception, the possibility that contraceptive methods may fail and the possible consequences of pregnancy should it occur during treatment with ribavirin. For laboratory monitoring of pregnancy please refer to Laboratory tests.
Carcinogenicity: Ribavirin is mutagenic in some in vivo and in vitro genotoxicity assays. A potential carcinogenic effect of ribavirin cannot be excluded.
Haemolysis and Cardiovascular system: A decrease in haemoglobin levels to <10 g/dl was observed in up to 15% of patients treated for 48 weeks with Ribavirin Mylan 1000/1200 mg in combination with peginterferon alfa-2a and up to 19% of patients in combination with interferon alfa-2a. When Ribavirin Mylan 800 mg was combined with peginterferon alfa-2a for 24 weeks, 3% of patients had a decrease in haemoglobin levels to <10 g/dl. The risk of developing anaemia is higher in the female population. Although ribavirin has no direct cardiovascular effects, anaemia associated with Ribavirin Mylan may result in deterioration of cardiac function, or exacerbation of the symptoms of coronary disease, or both. Thus, Ribavirin Mylan must be administered with caution to patients with pre-existing cardiac disease. Cardiac status must be assessed before the start of therapy and monitored clinically during therapy; if any deterioration occurs, stop therapy. Patients with a history of congestive heart failure, myocardial infarction, and/or previous or current arrhythmic disorders must be closely monitored. It is recommended that those patients who have pre-existing cardiac abnormalities have electrocardiograms taken prior to and during the course of treatment. Cardiac arrhythmias (primarily supraventricular) usually respond to conventional therapy but may require discontinuation of therapy.
Pancytopenia and bone marrow suppression have been reported in the literature to occur within 3 to 7 weeks after the administration of ribavirin and a peginterferon concomitantly with azathioprine. This myelotoxicity was reversible within 4 to 6 weeks upon withdrawal of HCV antiviral therapy and concomitant azathioprine and did not recur upon reintroduction of either treatment alone.
The use of Ribavirin Mylan and peginterferon alfa-2a combination therapy in chronic hepatitis C patients who failed prior treatment has not been adequately studied in patients who discontinued prior therapy for haematological adverse events. Physicians considering treatment in these patients should carefully weigh the risks versus the benefits of re-treatment.
Acute hypersensitivity: If an acute hypersensitivity reaction (e.g. urticaria, angioedema, bronchoconstriction, anaphylaxis) develops, Ribavirin Mylan must be discontinued immediately and appropriate medical therapy instituted. Transient rashes do not necessitate interruption of treatment.
Liver function: In patients who develop evidence of hepatic decompensation during treatment, Ribavirin Mylan in combination with other medicinal products should be discontinued. When the increase in ALT levels is progressive and clinically significant, despite dose reduction, or is accompanied by increased direct bilirubin, therapy should be discontinued.
Renal impairment: The pharmacokinetics of ribavirin are altered in patients with renal dysfunction due to reduction of apparent clearance in these patients. Therefore, it is recommended that renal function be evaluated in all patients prior to initiation of Ribavirin Mylan, preferably by estimating the patient's creatinine clearance. Substantial increases in ribavirin plasma concentrations are seen in patients with serum creatinine >2 mg/dl or with creatinine clearance <50 ml/minute, therefore Ribavirin Mylan dose adjustments are recommended in these patients.
Haemoglobin concentrations should be monitored intensively during treatment and corrective action taken as necessary.
Transplantation: The safety and efficacy of peginterferon-alfa-2a and Ribavirin Mylan treatment have not been established in patients with liver and other transplantations. Liver and renal graft rejections have been reported with peginterferon-alfa-2a, alone or in combination with Ribavirin Mylan.
HIV/HCV Co-infection: Please refer to the respective Summary of Product Characteristics of the antiretroviral medicinal products that are to be taken concurrently with HCV therapy for awareness and management of toxicities specific for each product and the potential for overlapping toxicities with ribavirin and the other medicinal products. In study NR15961, patients concurrently treated with stavudine and interferon therapy with or without ribavirin, the incidence of pancreatitis and/or lactic acidosis was 3% (12/398).
Chronic hepatitis C patients co-infected with HIV and receiving Highly Active Anti-Retroviral Therapy (HAART) may be at increased risk of serious adverse effects (e.g. lactic acidosis; peripheral neuropathy; pancreatitis).
Co-infected patients with advanced cirrhosis receiving HAART may also be at increased risk of hepatic decompensation and possibly death if treated with Ribavirin Mylan in combination with interferons. Baseline variables in co-infected cirrhotic patients that may be associated with hepatic decompensation include: increased serum bilirubin, decreased haemoglobin, increased alkaline phosphatase or decreased platelet count, and treatment with didanosine (ddI). Caution should therefore be exercised when adding peginterferon alfa-2a and Ribavirin Mylan to HAART.
The concomitant use of ribavirin with zidovudine is not recommended due to an increased risk of anaemia.
During treatment co-infected patients should be closely monitored for signs and symptoms of hepatic decompensation (including ascites, encephalopathy, variceal bleeding, impaired hepatic synthetic function; e.g., Child-Pugh score of 7 or greater). The Child-Pugh scoring may be affected by factors related to treatment (i.e. indirect hyperbilirubinemia, decreased albumin) and not necessarily attributable to hepatic decompensation. Treatment with Ribavirin Mylan in combination with other medicinal products should be discontinued immediately in patients with hepatic decompensation.
Co-administration of Ribavirin Mylan and didanosine is not recommended due to the risk of mitochondrial toxicity. Moreover, co-administration of Ribavirin Mylan and stavudine should be avoided to limit the risk of overlapping mitochondrial toxicity.
Laboratory tests: Standard haematologic tests and blood chemistries (complete blood count [CBC] and differential, platelet count, electrolytes, glucose, serum creatinine, liver function tests, uric acid) must be conducted in all patients prior to initiating therapy. Acceptable baseline values that may be considered as a guideline prior to initiation of Ribavirin Mylan:
Haemoglobin >12 g/dl (females); >13 g/dl (males)
In patients co-infected with HIV-HCV, limited efficacy and safety data are available in subjects with CD4 counts less than 200 cells/μL. Caution is therefore warranted in the treatment of patients with low CD4 counts.
Laboratory evaluations are to be conducted at weeks 2 and 4 of therapy, and periodically thereafter as clinically appropriate.
For women of childbearing potential: Female patients must have a routine pregnancy test performed monthly during treatment and for 4 months thereafter. Female partners of male patients must have a routine pregnancy test performed monthly during treatment and for 7 months thereafter.
Uric acid may increase with Ribavirin Mylan due to haemolysis and therefore predisposed patients should be carefully monitored for development of gout.
Ribavirin Mylan has no or negligible influence on the ability to drive and use machines. However peginterferon alfa or interferon alfa or other medicinal products used in combination with Ribavirin Mylan may have an effect. Refer to the SmPC of the medicinal products that are used in combination with Ribavirin Mylan for further information.
Treatment should be initiated, and monitored, by a physician experienced in the management of chronic hepatitis C.
Refer also to the SmPC of the medicinal products that are used in combination with Ribavirin Mylan for the treatment of hepatitis C.
Method of Administration
Ribavirin Mylan film-coated tablets are administered orally in two divided doses with food (morning and evening). Due to the teratogenic potential of ribavirin, the tablets should not be broken or crushed.
Posology
Dose to be administered
The dose of Ribavirin Mylan is based on patient body weight, viral genotype and the medicinal product that is used in combination (see Table1). Ribavirin Mylan tablets are to be administered orally each day in two divided doses (morning and evening) with food.
| Table 1. Ribavirin Mylan dosing recommendation according to the medicinal product used in combination | ||
| Medicinal product used in combination | Daily Ribavirin Mylan Dose | Number of 200/400mg tablets |
| Direct acting antivirals (DAA) | <75kg=1000mg
=>75 kg = 1200 mg | 5 x 200 mg (2 morning, 3 evening) 6 x 200 mg (3 morning, 3 evening) |
| PegIFN alfa-2a with DAA | <75kg=1000mg
=>75 kg = 1200 mg | 5 x 200 mg (2 morning, 3 evening) 6 x 200 mg (3 morning, 3 evening) |
| PegIFN alfa-2a without DAA | Genotype 2/3 treatment-naïve Genotype 2/3/4 with HIV-coinfection 800mg |
4 x 200 mg (2 morning, 2 evening) or 2 x 400 mg (1 morning, 1 evening) |
| Genotype 1/4 Genotype 2/3 treatment-experienced Genotype 1 HIV-coinfection <75kg=1000mg
=>75 kg = 1200 mg |
5 x 200 mg (2 morning, 3 evening) 6 x 200 mg (3 morning, 3 evening) | |
| IFN alfa-2a without DAA | <75kg=1000mg
=>75 kg = 1200 mg | 5 x 200 mg (2 morning, 3 evening) 6 x 200 mg (3 morning, 3 evening) |
| PegIFN alfa-2b with or without DAA | <65kg= 800 mg | 4 x 200mg (2 morning, 2 evening) or 2 x 400(1 morning, 1 evening) |
| 65-80kg= 1,000 mg | 5 (2 morning, 3 evening) | |
| 81-105kg= 1,200 mg | 6 (3 morning, 3 evening) | |
| >105kg= 1,400 mg | 7 (3 morning, 4 evening) | |
Duration of treatment
Duration of treatment depends on medicinal products that it is being combined with and may depend on several patients or virus characteristics including genotype, co-infection status, previous history of treatment, on-treatment response.
Refer to the SPC of the medicinal product that is used in combination with Ribavirin Mylan.
Dosage modification for adverse reactions
Dose modification of Ribavirin Mylan depends on medicinal products that it is being combined with.
If a patient has a severe adverse reaction potentially related to ribavirin, the ribavirin dose should be modified or discontinued, if appropriate, until the adverse reaction abates or decreases in severity. Table 2 provides guidelines for dose modifications and discontinuation based on the patient's haemoglobin concentration and cardiac status.
| Table 2 Dosage Modification Guidelines for Management of Treatment-Emergent Anaemia | ||
| Laboratory Values | Reduce Ribavirin Mylan dose to [1] [2] if: | Discontinue Ribavirin Mylan if |
| Haemoglobin in Patients with No Cardiac Disease | <10 g/dl | <8.5 g/dl |
| Haemoglobin: Patients with History of Stable Cardiac Disease | >2 g/dl decrease in haemoglobin during any 4 week period during treatment (permanent dose reduction) | <12 g/dl despite 4 weeks at reduced dose |
[1] For patients receiving a 1000mg (<75kg) or 1200mg (>75kg) dose, Ribavirin Mylan dose should be reduced to 600mg/day (administered as one 200 mg tablet in the morning and two 200 mg tablets or one 400 mg tablet in the evening). If the abnormality is reversed, Ribavirin Mylan may be restarted at 600 mg daily, and further increased to 800 mg daily at the discretion of the treating physician. However, a return to higher doses is not recommended.
[2]For patients receiving an 800mg (<65kg)-1000mg (65-80kg)-1200mg (81-105kg) or 1400mg (>105kg) dose, 1st dose reduction of Ribavirin Mylan is by 200 mg/day (except in patients receiving the 1400 mg, dose reduction should be by 400 mg/day). If needed, 2nd dose reduction of Ribavirin Mylan is by an additional 200 mg/day. Patients whose dose of Ribavirin Mylan is reduced to 600 mg daily receive one 200 mg capsule in the morning and two 200 mg capsules in the evening.
Refer to the SmPCs of peginterferon alfa or interferon alfa for dose modification and/or discontinuation in case of serious adverse reaction potentially related to these drugs.â€
Special populations
Use in renal impairment: The recommended dose regimens (adjusted by the body weight cutoff of 75 kg) of ribavirin give rise to substantial increases in plasma concentrations of ribavirin in patients with renal impairment.).
| Table 3 Dosage Modification for Renal Impairment | |
| Creatinine Clearance | Ribavirin Mylan Dose (daily) |
| 30 to 50 ml/min | Alternating doses, 200 mg and 400 mg every other day |
| Less than 30 ml/min | 200 mg daily |
| Hemodialysis | 200 mg daily |
Therapy should be initiated (or continued if renal impairment develops while on therapy) with extreme caution and intensive monitoring of haemoglobin concentrations, with corrective action as may be necessary, should be employed throughout the treatment period.
If severe adverse reactions or laboratory abnormalities develop, Ribavirin Mylan should be discontinued, if appropriate, until the adverse reactions abate or decrease in severity. If intolerance persists after restarting Ribavirin Mylan, Ribavirin Mylan therapy should be discontinued. No data are available for pediatric subjects with renal impairment.
Use in hepatic impairment: Hepatic function does not affect the pharmacokinetics of ribavirin. Therefore, no dose adjustment of Ribavirin Mylan is required in patients with hepatic impairment. Use in elderly patients over the age of 65: There does not appear to be a significant age-related effect on the pharmacokinetics of ribavirin. However, as in younger patients, renal function must be determined prior to administration of Ribavirin Mylan.
Use in patients under the age of 18 years: Treatment with Ribavirin Mylan is not recommended for use in children and adolescents (<18 years) due to insufficient data on safety and efficacy in combination with other medicinal products for the treatment of hepatitis C. Only limited safety and efficacy data are available in children and adolescents (6-18 years) in combination with peginterferon alfa-2a. A case by case benefit/risk assessment with respect to the use of Ribavirin Mylan in children is needed .
No special requirements.
Any unused product or waste material should be disposed of in accordance with local requirements.
