Moderiba: Indications, Dosage, Precautions, Adverse Effects
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Moderiba - Product Information

Manufacture: Abbvie
Country: Canada
Condition: Hepatitis C
Class: Purine nucleosides
Form: Tablets
Ingredients: ribavirin, carnauba wax, croscarmellose sodium, indigo carmine aluminum lake lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, povidone, talc, titanium dioxide

MODERIBA

ribavirin

Summary Product Information

Route of
Administration
Dosage Form /
Strength
Clinically Relevant Nonmedicinal Ingredients
Oral Tablet/ 200 mg,
400 mg, 600 mg
Lactose monohydrate
For a complete listing see Dosage Forms,
Composition and Packaging Section

Indications and Clinical Use

MODERIBA (ribavirin tablets) is indicated in combination with other agents for the treatment of chronic hepatitis C virus (HCV) infection in adults including patients with compensated cirrhosis.

Treatment with MODERIBA should be initiated and monitored by a physician experienced in the management of chronic hepatitis C (CHC).

Geriatrics (> 65 years of age)

In general, caution should be exercised when administering MODERIBA in elderly patients, reflecting the greater frequency of anemia, decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy (see WARNINGS AND PRECAUTIONS).

Pediatrics (< 18 years of age)

Safety and effectiveness of MODERIBA in children less than 18 years of age have not been established (see WARNINGS AND PRECAUTIONS, Special Populations, Pediatrics).

Contraindications

MODERIBA (ribavirin tablets) must be used in combination with other therapeutic agents for the treatment of CHC. The contraindications applicable to those agents are therefore also applicable to the combination ribavirin therapy. The Product Monograph(s) of other agent(s) used in combination with ribavirin should be consulted before starting treatment with MODERIBA.

MODERIBA is contraindicated in:

  • Patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. For a complete listing, see the DOSAGE FORMS, COMPOSITION AND PACKAGING section.
  • Women who are pregnant or in men whose female partners are pregnant because of the associated risk of birth defects and fetal death (see WARNINGS AND PRECAUTIONS, Special Populations, Pregnant Women).
  • Patients with hemoglobinopathies (e.g., thalassemia or sickle-cell anemia).
  • Patients taking didanosine because exposures of the active metabolite of didanosine (dideoxyadenosine 5′-triphosphate) are increased. Fatal hepatic failure, as well as peripheral neuropathy, pancreatitis, and symptomatic hyperlactatemia/lactic acidosis have been reported in patients receiving both didanosine and ribavirin.

Warnings and Precautions

Serious Warnings and Precautions

  • Ribavirin monotherapy is not effective for treatment of chronic hepatitis C infection.
  • Hemolytic anemia associated with ribavirin therapy may result in worsening of cardiac disease and lead to fatal and nonfatal myocardial infarctions. Patients with a history of significant or unstable cardiac disease should not be treated with MODERIBA (see WARNINGS AND PRECAUTIONS, Hematologic).
  • Significant teratogenic and embryocidal effects have been demonstrated in all animal species exposed to ribavirin. Therefore, MODERIBATM is contraindicated in women who are pregnant, and in the male partners of women who are pregnant. Extreme care must be taken to avoid pregnancy during therapy and for six months after completion of treatment in both female patients and in female partners of male patients who are taking MODERIBA (see WARNINGS AND PRECAUTIONS, Sexual Function/Reproduction).

General

The Product Monograph(s) of agent(s) used in combination with ribavirin should be consulted before starting treatment with MODERIBA.

Cardiovascular

Although ribavirin has no direct cardiovascular effects, the anemia associated with ribavirin may result in worsening of cardiac disease and lead to fatal and nonfatal myocardial infarctions. Therefore, MODERIBA should be administered with caution to patients with pre-existing cardiac disease. Patients should be assessed before initiation of therapy and should be appropriately monitored during therapy. If there is any deterioration of cardiovascular status associated with anemia, MODERIBA therapy should be suspended or discontinued (see DOSAGE AND ADMINISTRATION, Recommended Dose and Dosage Adjustment, Dose Modifications).

MODERIBA should not be used in patients with pre-existing severe, unstable or uncontrolled cardiac disease.

Hematologic

The primary toxicity of ribavirin is hemolytic anemia. The anemia associated with MODERIBA occurs within 1 to 2 weeks of initiation of therapy. Because the initial acute drop in hemoglobin may be significant, it is advised that hemoglobin or hematocrit be obtained pre-treatment and at Week 2 and Week 4 of therapy, or more frequently if clinically indicated. Patients should then be followed as appropriate.

Caution should be exercised in initiating treatment in any patient with baseline risk of severe anemia (e.g., spherocytosis, history of gastrointestinal bleeding). MODERIBA should be used with extreme caution in patients with baseline hemoglobin < 100 g/L.

Deterioration of blood hemoglobin concentration during treatment may require MODERIBA dose adjustments (see DOSAGE AND ADMINISTRATION, Recommended Dose and Dosage Adjustment, Dose Modifications).

Pancytopenia (marked decreases in red blood counts (RBC), neutrophils and platelets) and bone marrow suppression have been reported to occur within 3 to 7 weeks after the concomitant administration of ribavirin and 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 (see DRUG INTERACTIONS).

Hepatic/Biliary/Pancreatic

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. Safety and efficacy of ribavirin have not been established in patients with decompensated cirrhosis.

Renal

MODERIBA should not be used in patients with a creatinine clearance < 50 mL/min. Clearance of ribavirin is substantially reduced in patients with serum creatinine > 177 μmol/L or creatinine clearance < 50 mL/min. Hemodialysis has negligible effects on the plasma concentration of ribavirin.

Sexual Function/Reproduction

Significant teratogenic and/or embryocidal potential have been demonstrated for ribavirin in all animal species in which adequate studies have been conducted, occurring at doses well below the recommended human dose. Malformations of the skull, palate, eye, jaw, limbs, skeleton, central nervous system and gastrointestinal tract were noted. The incidence and severity of teratogenic effects increased with escalation of the ribavirin dose. Survival of fetuses and offspring was reduced.

Ribavirin accumulates intracellularly and is cleared from the body very slowly. In animal studies, ribavirin produced changes in sperm at doses approximating the clinical dose. It is unknown whether the ribavirin that is contained in sperm will exert its known teratogenic effects upon fertilisation of the ova. Because of the potential risk of teratogenicity, it is recommended that both male and female patients must practice effective contraception (at least 2 reliable forms, one for each partner) during ribavirin therapy and for six months after completion of therapy (see WARNINGS AND PRECAUTIONS, Special Populations, Pregnant Women).

Special Populations

Pregnant Women

Prior to initiation of treatment with ribavirin, the physician must comprehensively inform the patient of the teratogenic risk of MODERIBA the necessity of two forms 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 see WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests section.

Female Patients

MODERIBA must not be used by women who are pregnant (see CONTRAINDICATIONS). Ribavirin may cause birth defects and/or death of the exposed fetus. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients as significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin. MODERIBA therapy should not be started unless a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy. Female patients of childbearing potential and their male partners as well as male patients and their female partners must use at least two effective forms of contraception during treatment and for at least six months (i.e., 15 half-lives for ribavirin clearance from the body) after treatment has concluded. If pregnancy does occur during treatment or within six months from stopping treatment the patient must be advised of the significant teratogenic risk of MODERIBA to the fetus. Routine monthly pregnancy tests must be performed during this time (see WARNINGS AND PRECAUTIONS, Special Populations, Pregnant Women and WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests).

Male Patients and their Female Partners

Extreme care must be taken to avoid pregnancy in partners of male patients taking MODERIBA. In animal studies, ribavirin produced changes in sperm at doses below the clinical dose. It is unknown whether the ribavirin that is contained in sperm will exert its known teratogenic effects upon fertilisation of the ova. Male patients and their female partners of childbearing age must, therefore, be counselled to use two types of effective contraception simultaneously during treatment with MODERIBA and for six months after treatment has been concluded. A pregnancy test must be performed before therapy is started.

Nursing Women

It is not known whether ribavirin is excreted in human milk. Because many drugs are excreted in human milk and to avoid any potential for adverse reactions in nursing infants from MODERIBA, a decision must be made whether to discontinue nursing or discontinue treatment with MODERIBA, taking into account the importance of the therapy to the mother.

Pediatrics (< 18 years of age)

Safety and effectiveness of MODERIBA in children less than 18 years of age have not been established. Therefore,MODERIBA is not recommended for use in children and adolescents under the age of 18 years.

Geriatrics (> 65 years of age)

Caution should be exercised when administering MODERIBA in elderly patients, reflecting the greater frequency of anemia, decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy in this population. The risk of toxic reactions to this drug may be greater in patients with impaired renal function.

HIV or HBV Co-infection

The safety and efficacy of MODERIBA combination therapy has not been established in patients co-infected with HIV or hepatitis B virus infection.

Post-Liver Transplant

The safety and efficacy of MODERIBA combination therapy has not been established in post liver transplant patients.

Monitoring and Laboratory Tests

Standard hematologic 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 and as clinically appropriate during treatment.

Pregnancy screening in women of childbearing potential must be performed. Monthly pregnancy testing must be performed during MODERIBA combination therapy, and for 6 months after discontinuation of therapy, both in female patients and the female partners of male patients.

Patients who have pre-existing cardiac abnormalities should have electrocardiograms administered before treatment with MODERIBA and should be monitored during therapy.

Adverse Reactions

Adverse Drug Reaction Overview

The Adverse Reactions section(s) of the Product Monograph(s) of agents used in combination with MODERIBA should also be consulted.

For detailed information on the adverse reactions reported in patients treated with MODERIBA (ribavirin) in combination with HOLKIRA PAK, consult the HOLKIRA PAK Product Monograph.

In subjects receiving MODERIBATM in combination with HOLKIRA PAK, the most commonly reported adverse reactions considered related to study drug by site investigator (greater than 10% of subjects) were fatigue, headache, nausea, pruritus and insomnia. The proportion of subjects who permanently discontinued treatment due to related adverse events was 0.8% (17/2,044). 0.5% (11/2,044) of subjects interrupted treatment due to related adverse events. 3.5% (72/2,044) of subjects had ribavirin dose reductions due to related adverse events.

The safety profile of MODERIBATM and HOLKIRA PAK in subjects with cirrhosis was similar to that of subjects without cirrhosis.

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Ribavirin is used in combination with other agents. Please refer to the appropriate Product Monograph(s) for a complete list of clinical trial adverse reactions.

Ribavirin in Combination with HOLKIRA PAK

Table 1 lists adverse drug reactions (Grades 2 to 4) observed in ≥ 3% of patients in the Phase 3 trials.

The majority of adverse events in the Phase 3 clinical trials were of grade 1 severity. The safety profile of HOLKIRA PAK with ribavirin was consistent with the known safety profile of ribavirin. The daily dose of MODERIBA used in these Phase 3 clinical trials was 1000 mg, for patients weighing less than 75 kg, and 1200 mg, for patients weighing more than or equal to 75 kg, administered orally in two divided doses.

Table 1. Side-by-Side Tabulation of Adverse Reactions (Grade 2 – 4) Rates in ≥ 3% of Subjects in Phase 3 Trials*
SAPPHIRE I and II PEARL II, III and IV TURQUOISE II
(subjects with
cirrhosis)
Adverse
Reaction
HOLKIRA PAK
+ RBV
12 Weeks
N = 770
n (%)
Placebo
12 Weeks
N = 255
n (%)
HOLKIRA PAK
+ RBV
12 Weeks
N = 401
n (%)
HOLKIRA PAK
12 Weeks
N = 509
n (%)
HOLKIRA PAK
+ RBV
12 or 24 Weeks
N = 380
n (%)
Fatigue 29 (3.8) 4 (1.6) 26 (6.5) 22 (4.3) 15 (3.9)
Nausea 26 (3.4) 2 (0.8) 2 (0.5) 2 (0.4) 8 (2.1)
Asthenia 22 (2.9) 3 (1.2) 6 (1.5) 1 (0.2) 12 (3.2)
Headache 35 (4.5) 6 (2.3) 10 (2.5) 12 (2.4) 12 (3.2)

* Frequencies of adverse events are based on treatment-emergent adverse events considered at least possibly related to study drug by site investigators.

Less Common Clinical Trial Adverse Drug Reactions (<3%)

Treatment emergent adverse events (Grades 2 to 4) considered at least possibly related to study drug by site investigators which occurred in less than 3% of subjects in Phase 3 trials are listed below by system organ class (Table 2).

Table 2. Adverse Events (Grade 2 – 4) in < 3% of Subjects in Phase 3 Trials
Body System Adverse Events
Age (years)
Median (range)52 (18 – 70)50 (19 – 70)54 (19 – 70)
Gender, n (%)
Male344 (54.5)192 (45.8)199 (65.2)
Female287 (45.5)227 (54.2)106 (34.8)
Race, n (%)
White572 (90.6)394 (94.3)257 (84.3)
Black or African American34 (5.4)20 (4.8)36 (11.8)
Asian14 (2.2)2 (0.5)4 (1.3)
Other11 (1.7)2 (0.5)8 (2.6)
Ethnicity, n (%)
Hispanic or Latino32 (5.1)7 (1.7)28 (9.2)
None of the above599 (94.9)412 (98.3)277 (90.8)
Body mass index, n (%)
< 30 kg/m2529 (83.8)350 (83.5)245 (80.3)
≥ 30 kg/m2102 (16.2)69 (16.5)60 (19.7)
HCV genotype, n (%)
1a427 (67.7)N/A304 (99.7)
1b204 (32.3)419 (100)1 (0.3)
Baseline HCV RNA
Mean ± SD (log10 IU/mL)6.42 ± 0.636.31 ± 0.726.57 ± 0.63
< 800000 IU/mL, n (%)132 (20.9)112 (26.7)41 (13.4)
≥ 800000 IU/mL, n (%)499 (79.1)307 (73.3)264 (86.6)
IL28B, n (%)
CC194 (30.7)88 (21.0)94 (30.8)
Non-CC437 (69.3)331 (79.0)211 (69.2)
Baseline fibrosis stage, n (%)
F0-F1479 (75.9)291 (69.6)195 (63.9)
F297 (15.4)85 (20.3)56 (18.4)
≥ F355 (8.7)42 (10.0)54 (17.7)
History of depression or bipolar disorder, n (%)
No535 (84.8)380 (90.7)242 (79.3)
Yes96 (15.2)39 (9.3)63 (20.7)

Abnormal Hematologic and Clinical Chemistry Findings

Laboratory Abnormalities

Changes in selected laboratory parameters are described in Table 3. A side-by-side tabulation is provided to simplify presentation; direct comparisons should not be made across trials that differ in design.

Table 3. Selected Treatment Emergent Laboratory Abnormalities
Laboratory
Parameters
SAPPHIRE I and II PEARL II, III and IV TURQUOISE II
(subjects with
cirrhosis)
HOLKIRA
PAK + RBV
12 Weeks
N = 770
n (%)
Placebo
12 Weeks
N = 255
n (%)
HOLKIRA
PAK + RBV
12 Weeks
N = 401
n (%)
HOLKIRA PAK
12 Weeks
N = 509
n (%)
HOLKIRA
PAK + RBV
12 or 24 Weeks
N = 380
n (%)
ALT
> 5-20 × ULN* (Grade 3) 6/765 (0.8%) 10/254 (3.9%) 3/401 (0.7%) 1/509 (0.2%) 4/380 (1.1%)
> 20 × ULN (Grade 4) 3/765 (0.4%) 0 0 0 2/380 (0.5%)
Hemoglobin
< 10-8 g/dL (Grade 2) 41/765 (5.4%) 0 23/401 (5.7%) 0 30/380 (7.9%)
< 8-6.5 g/dL (Grade 3) 1/765 (0.1%) 0 2/401 (0.5%) 0 3/380 (0.8%)
< 6.5 g/dL (Grade 4) 0 0 0 0 1/380 (0.3%)
Total Bilirubin
> 3-10 × ULN (Grade 3) 19/765 (2.5%) 0 23/401 (5.7%) 2/509 (0.4%) 37/380 (9.7%)
> 10 × ULN (Grade 4) 1/765 (0.1%) 0 0 0 0

* ULN: Upper Limit of Normal according to testing laboratory

Serum ALT Elevations

Refer to the HOLKIRA PAK Product Monograph.

Hemoglobin

Treatment with ribavirin in combination with HOLKIRA PAK for HCV was associated with a gradual decrease in hemoglobin. Anemia due to hemolysis is the most significant toxicity of ribavirin therapy. The most rapid decrease in hemoglobin occurred during the first 4 weeks of therapy (see Table 3 and DOSAGE AND ADMINISTRATION, Recommended Dose and Dosage Adjustment, Dose Modifications).

Serum Bilirubin Elevations

Transient elevations in bilirubin (predominantly indirect) were observed in subjects receiving HOLKIRA PAK with ribavirin, related to the inhibition of the bilirubin transporters OATP1B1/1B3 by paritaprevir and ribavirin-induced hemolysis. Bilirubin elevations occurred after initiation of treatment, peaked by study Week 1, and generally resolved with ongoing therapy. Bilirubin elevations were not associated with aminotransferase elevations.

Post-Market Adverse Reactions

The post-marketing adverse reactions for combination therapies including ribavirin + HOLKIRA PAK are not yet available.

The following adverse reactions have been identified and reported during post-approval use of peginterferon alfa2a + ribavirin combination therapy. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and Lymphatic System
disorders:
Pure red cell aplasia
Ear and Labyrinth disorders: Hearing impairment, hearing loss
Eye disorders: Serous retinal detachment
Immune disorders: Liver and renal graft rejection
Metabolism and Nutrition
disorders:
Dehydration
Skin and Subcutaneous Tissue
Disorders:
Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN)

Drug Interactions

Overview

MODERIBA is to be used in combination with other products. Refer to the appropriate Product Monograph(s) for a detailed list of their drug interactions.

MODERIBA is not a substrate, inhibitor or inducer of cytochrome P450 enzymes. There is minimal potential for P450 enzyme-based interactions.

Co-administration of ribavirin with an antacid containing magnesium, aluminium and methicone reduced the bioavailability of ribavirin (AUCtf decreased 14 %). This change is not considered to be of clinical relevance.

No pharmacokinetic interactions between interferon alfa products and ribavirin have been observed in clinical trials in which the two agents were used in combination therapy. MODERIBA does not share common disposition pathways with HOLKIRA PAK and does not interact with HOLKIRA PAK or contribute to HOLKIRA PAK drug interactions.

There is no evidence that ribavirin interacts with non-nucleoside reverse transcriptase inhibitors (NNRTIs) or protease inhibitors (i.e., HIV protease inhibitors).

Due to the long half-life of ribavirin (approximately 300 h following multiple doses) any potential drug interactions may persist for up to 2 months (5 half-lives for ribavirin) following the end of treatment.

Drug-Drug Interactions

Table 4. Established or Potential Drug Interactions
Concomitant Drug Class:
Drug Name
Clinical comment
HIV-Antiviral Agents
Nucleoside analog reverse-
transcriptase inhibitor:
stavudine In vitro data indicate that the phosphorylation of stavudine is inhibited at relevant concentrations by ribavirin; therefore coadministration of stavudine with MODERIBA should be undertaken with caution.
zidovudine Ribavirin levels could be increased by zidovudine leading to increased risk of anemia. The use of MODERIBA concomitantly with zidovudine in the treatment of HIV/HCV co-infected patients is not advised.
lamivudine In a 12 week study pharmacokinetic substudy in 47 HCV/HIV co-infected patients to determine the effects of ribavirin on the intracellular phosphorykation of some nucleoside reverse transcriptase inhibitors including lamivudine, stavudine or zidovudine, no evidence of drug interaction was seen.
Nucleoside Reverse-
Transcriptase Inhibitor:

didanosine
Based on in vitro data, ribavirin increases the intracellular triphosphate levels of didanosine. Fatal hepatic failure, as well as peripheral neuropathy, pancreatitis, and symptomatic hyperlactatemia/lactic acidosis have been reported in patients receiving didanosine and ribavirin with or without stavudine. Ribavirin is contraindicated with didanosine.
Other Agents
Immunosuppressive
Agents:

azathioprine
Ribavirin has an inhibitory effect on azathioprine metabolism, possibly leading to an accumulation of 6-methylthioinosine monophosphate which has been associated with myelotoxicity.
In individual cases where the benefit of administering MODERIBA concomitantly with azathioprine warrants the potential risk, it is recommended that close hematologic monitoring be done during concomitant azathioprine use to identify signs of myelotoxicity, at which time treatment with these drugs should be stopped.

Drug-Food Interactions

Bioavailability of MODERIBA was increased with food. MODERIBA should be taken with food (see ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics, Absorption, Effects of Food on Oral Absorption and DOSAGE AND ADMINISTRATION, Administration).

Drug-Herb Interactions

Interactions of MODERIBA with herbs have not been established.

Drug-Laboratory Interactions

Interactions or interferences of MODERIBA with laboratory tests have not been established.

Drug-Lifestyle Interactions

Patients who develop dizziness, confusion, somnolence, and fatigue should be cautioned to avoid driving or operating machinery.

Drug-Alcohol Interactions

Patients should be advised not to drink alcohol, as alcohol may exacerbate chronic hepatitis C infection.

Dosage and Administration

Dosing Considerations

Ribavirin monotherapy is not effective and MODERIBA (ribavirin tablet) must only be used in combination with other agents for the treatment of CHC.

For detailed dosage and administration instructions pertaining to the use of MODERIBA in combination with HOLKIRA PAK, consult the HOLKIRA PAK Product Monograph.

Recommended Dose and Dosage adjustment

The recommended dose and treatment durations of MODERIBA should be individualized to the patient depending on body weight, baseline disease characteristics (e.g., genotype), response to therapy and underlying conditions. Depending on the agent(s) it is combined with, the usual MODERIBA dose varies between 800 mg and 1200 mg daily (and up to 1400 mg in certain situations). For information on dosage and treatment duration of ribavirin in combination with other agents in patients with CHC, please refer to the appropriate Product Monograph(s).

The daily dose of MODERIBA in combination with HOLKIRA PAK is 1000 mg for patients weighing less than 75 kg, and 1200 mg, for patients weighing more than or equal to 75 kg, administered orally in two divided doses.

To maximize absorption, MODERIBA in combination with HOLKIRA PAK should be taken with food without regard to fat or calorie content (see ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics, Absorption, Effects of Food on Oral Absorption).

Table 5 shows the recommended treatment regimen and duration based on patient population.

Table 5. MODERIBA Combination Therapy with HOLKIRA PAK: Treatment Regimen and Duration by Patient Population
Patient Population Treatment Duration
Genotype 1a, without cirrhosis MODERIBA* + HOLKIRA PAK 12 weeks
Genotypes 1a and 1b, with cirrhosis MODERIBA* + HOLKIRA PAK 12 weeks†

* HOLKIRA PAK without ribavirin can be considered as a therapeutic option for treatment-naïve patients with genotype 1a infection without cirrhosis who are intolerant of or ineligible for ribavirin (see CLINICAL TRIALS). Treatment decision should be guided by an assessment of the potential benefits and risks for the individual patient.

† 24 weeks of MODERIBA + HOLKIRA PAK is recommended for patients with genotype 1a-infection with compensated cirrhosis who have had a previous null response to pegylated interferon (pegIFN) and ribavirin (see CLINICAL TRIALS).

Note: MODERIBA + HOLKIRA PAK is recommended in patients with an unknown genotype 1 subtype or with mixed genotype 1 infection.

Dose Modifications

In general the MODERIBA dose should be adjusted according to the patient’s tolerance to medication. If severe adverse reactions or laboratory abnormalities develop, the dose should be modified or therapy temporarily discontinued until the adverse reactions abate or decrease in severity. If intolerance persists after dose adjustment, discontinuation of ribavirin therapy may be needed.

Guidelines were developed for MODERIBA dose modification (see Table 6).

Table 6. MODERIBA Tablets Dosage Modification Guidelines for Management of Treatment- Emergent Anemia
Laboratory Values Reduce Only MODERIBA Dose to
600 mg/Daya if:
Discontinue MODERIBA if:b
Hemoglobin in Patients with
No Cardiac Disease
< 10 g/dL < 8.5 g/dL
Hemoglobin: Patients with
History of Stable Cardiac
Disease
≥ 2 g/dL decrease in hemoglobin during any 4
week period during treatment (permanent dose
reduction)
< 12 g/dL despite 4 weeks at
reduced dose

a Patients whose dose of ribavirin is reduced to 600 mg daily receive one 200 mg tablet in the morning and two 200 mg tablets or one 400 mg tablet in the evening.

b If the abnormality is reversed, ribavirin 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.

Pediatrics (< 18 Years of Age)

The safety and effectiveness of MODERIBA in children less 18 years of age have not been established (see WARNINGS AND PRECAUTIONS, Special Populations, Pediatrics).

Geriatrics (≥ 65 years)

No dose adjustment of MODERIBA is warranted in geriatric patients based upon age alone. In Phase 3 clinical trials, 8.5% (174/2053) of subjects were age 65 or over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger subjects. However, caution should be exercised when administering ribavirin to elderly patients. This is due to the greater frequency of anemia, decreased hepatic, renal and cardiac function, and the greater frequency of concomitant disease and other drug therapy in the geriatric population.

Hepatic Impairment

Hepatic function does not affect the pharmacokinetics of ribavirin. Therefore, no dose adjustment of MODERIBA is required in patients with hepatic impairment. Safety and efficacy of ribavirin has not been established in patients with decompensated cirrhosis.

Renal Impairment

No dose adjustment of MODERIBA is required in patients with creatinine clearance > 50 mL/min. MODERIBA should not be used in patients with a creatinine clearance < 50 mL/min.

Gender

No dose adjustment is necessary for MODERIBA based on gender.

Race

No dose adjustment is necessary for MODERIBA based on race.

Discontinuation of Dosing

If the other agents used in combination with MODERIBA are permanently discontinued, MODERIBA should also be discontinued.

Missed Dose

If a MODERIBA dose is missed but remembered within 6 hours, it should be taken as soon as possible. If more than 6 hours has passed since MODERIBA is usually taken, the missed dose should NOT be taken and the patient should take the next dose as per the usual dosing schedule. Two doses should not be taken at the same time.

Administration

MODERIBA is 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.

Overdosage

For management of a suspected drug overdose, contact your regional Poison Control Centre.

No cases of overdose of ribavirin have been reported in clinical trials. Hypocalcemia and hypomagnesemia have been observed in persons administered greater than recommended dosage of ribavirin. In most of these cases, ribavirin was administered intravenously at dosages up to and in some cases exceeding four times the recommended maximum oral daily dose. Treatment of overdose with ribavirin should consist of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. There is no specific antidote for overdose with ribavirin. Due to the large volume of distribution of ribavirin, significant amounts of ribavirin are not effectively removed by hemodialysis.

Action and Clinical Pharmacology

Mechanism of Action

Ribavirin is a synthetic nucleoside analog that shows in vitro activity against some Ribonucleic acid (RNA) and Deoxyribonucleic acid (DNA) viruses. Ribavirin combined with HOLKIRA PAK demonstrated additive to synergistic inhibition of the HCV genotype 1 replicon at the majority of drug concentrations studied in short term cell culture assays.

The mechanism of action by which ribavirin contributes to its antiviral efficacy is not fully understood. It likely involves the direct inhibition of HCV replication, the inhibition of inosine monophosphate dehydrogenase, the induction of mutagenesis and immunomodulation.

Pharmacodynamics

The oral form of ribavirin is used in combination with other agents for the treatment of CHC. Ribavirin alone has limited effect on HCV RNA levels and on improving hepatic histology, as demonstrated in randomized placebo controlled trials in patients with confirmed CHC.

Pharmacokinetics

Absorption

Ribavirin is rapidly absorbed with Tmax occurring between 1 and 2 hours. Following multiple twice-daily dosing, ribavirin showed extensive accumulation with steady state exposure significantly higher than single dose values. Observed ribavirin exposure in HCV genotype 1-infected subjects in Phase 3 studies who received 1000 or 1200 mg/day ribavirin in combination with HOLKIRA PAK showed steady state AUC24 of 47800 ng·hr/mL, Cmax of 2120 ng/mL and Cmin of 1870 ng/mL.

Effects of Food on Oral Absorption

Ribavirin absorption is enhanced by food or fatty meal. In order to achieve optimal ribavirin plasma concentrations, it is recommended to take ribavirin with food.

Distribution

Ribavirin demonstrated multiphasic disposition. Ribavirin is extensively distributed with a high volume of distribution reported as approximately 4500 litres, which reflect the mechanism of cellular uptake of the drug across membranes, primarily via an es-type equilibrative nucleoside transporter found on almost all cell types. As a result ribavirin accumulates in erythrocytes, ova and spermatozoa. Ribavirin nucleotides are sequestered in erythrocytes; ribavirin concentration in whole blood is about 60 times that in plasma. Ribavirin does not bind to plasma proteins.

Metabolism

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.

Excretion

Ribavirin and its triazole carboxamide and diphosphate metabolites are primarily excreted in the urine with the majority of the dose eliminated as metabolites. In HCV infected patients, ribavirin mean terminal phase half-life is reported to be approximately 300 hours.

Special Populations and Conditions

Pediatrics

The pharmacokinetics of MODERIBA in pediatric patients has not been established [see WARNINGS AND PRECAUTIONS, Special Populations, Pediatrics (< 18 years of age)].

Geriatrics

Specific pharmacokinetic evaluations for elderly patients have not been performed. Population pharmacokinetic analyses showed that renal function and not age is the determining factor in the pharmacokinetics of ribavirin.

Hepatic Insufficiency

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.

Population pharmacokinetic analyses of HOLKIRA PAK Phase 3 studies indicated that exposures of ribavirin were comparable (< 6% difference) in HCV-infected subjects with Child-Pugh A cirrhosis compared to subjects who did not have cirrhosis. Ribavirin exposure in patients with mild, moderate and severe hepatic dysfunction was also shown to be similar to those observed in normal control subjects. No dose adjustment of MODERIBA is required in patients with hepatic impairment. Safety and efficacy of ribavirin have not been established in patients with decompensated cirrhosis.

Renal Insufficiency

Subjects with creatinine clearance > 50 mL/min showed minimal ribavirin exposure difference (8%) compared to normal renal function. The pharmacokinetics of single-dose ribavirin were altered in patients with renal dysfunction. Substantial increases in ribavirin plasma concentrations are seen at the recommended dosing regimen in patients with serum creatinine > 2 mg/dL (> 177 micromol/L) or with creatinine clearance < 50 mL/min (0.83 mL/sec). MODERIBA should not be used in patients with a creatinine clearance < 50 mL/min. (see DOSAGE AND ADMINISTRATION, Recommended Dose and Dosage Adjustment, Dose Modifications, Renal Impairment and WARNINGS AND PRECAUTIONS, Renal).

Storage and Stability

Store MODERIBA (ribavirin) at room temperature between 15 and 30ºC. Keep the bottle tightly closed in order to protect from moisture.

Special Handling Instructions

There are no special handling instructions.

Dosage Forms, Composition and Packaging

MODERIBA (ribavirin) tablets are available in three strengths: 200 mg, 400 mg, and 600 mg.

MODERIBA 200 mg tablets are supplied as light blue coloured, capsule-shaped, film-coated tablet, debossed with “200” on one side and the logo “3RP” on the other side. Each bottle contains 168 tablets.

MODERIBA 400 mg tablets are supplied as medium blue coloured, capsule-shaped, film-coated tablet, debossed with “400” on one side and the logo “3RP” on the other side. Each bottle contains 56 tablets.

MODERIBA 600 mg tablets are supplied as dark blue coloured, capsule-shaped, film-coated tablet, debossed with “600” on one side and the logo “3RP” on the other side. Each bottle contains 56 tablets.

Listing of Non-Medicinal Ingredients

Each MODERIBA 200 mg tablet contains 200 mg of ribavirin with the following non-medicinal ingredients: carnauba wax, croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, partially hydrolyzed polyvinyl alcohol, polyethylene glycol 3350, povidone, talc, titanium dioxide, and indigo carmine aluminum lake.

Each MODERIBA 400 mg tablet contains 400 mg of ribavirin with the following non-medicinal ingredients: carnauba wax, croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, partially hydrolyzed polyvinyl alcohol, polyethylene glycol 3350, povidone, talc, titanium dioxide, and brilliant blue FCF aluminum lake.

Each MODERIBA 600 mg tablet contains 600 mg of ribavirin with the following non-medicinal ingredients: carnauba wax, croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, partially hydrolyzed polyvinyl alcohol, polyethylene glycol 3350, povidone, talc, titanium dioxide, and brilliant blue FCF aluminum lake.