Product Monograph - Moderiba
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
MODERIBATM (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 MODERIBATM.
MODERIBATM 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 |
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General
The Product Monograph(s) of agent(s) used in combination with ribavirin should be consulted before starting treatment with MODERIBATM.
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, MODERIBATM 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, MODERIBATM therapy should be suspended or discontinued (see DOSAGE AND ADMINISTRATION, Recommended Dose and Dosage Adjustment, Dose Modifications).
MODERIBATM 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 MODERIBATM 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). MODERIBATM should be used with extreme caution in patients with baseline hemoglobin < 100 g/L.
Deterioration of blood hemoglobin concentration during treatment may require MODERIBATM 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
MODERIBATM 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, MODERIBATM 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 MODERIBATM 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 MODERIBATM 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 MODERIBATM 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 MODERIBATM 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 MODERIBATM should also be consulted.
For detailed information on the adverse reactions reported in patients treated with MODERIBATM (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 MODERIBATM 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 |
|---|---|
| Blood and lymphatic system disorders: | anemia, leukopenia, neutropenia |
| Cardiac disorders: | extrasystoles, palpitations, sinus tachycardia, tachycardia, ventricular extrasystoles |
| Body System |
|---|
Adverse Events
| Ear and labyrinth disorders: | tinnitus |
| Endocrine disorders: | goitre, hypothyroidism, thyroiditis, adrenal insufficiency |
| Eye disorders | blepharitis: ulcerative keratitis, visual impairment |
| Gastrointestinal disorders: | abdominal discomfort, abdominal pain, abdominal pain upper, anorectal discomfort, constipation, dental caries, diarrhoea, dry mouth, dyspepsia, dysphagia, frequent bowel movements, gastrointestinal disorder, gastrooesophageal reflux disease, haemorrhoids, hyperchlorhydria, lip ulceration, pancreatitis, retching, vomiting |
| General disorders and administration site conditions: | chest discomfort, chills, energy increased, exercise tolerance decreased, hunger, inflammation, influenza like illness, irritability, malaise, oedema peripheral, pain, pre-existing condition improved, product taste abnormal, pyrexia, swelling |
| Hepatobiliary disorders: | hyperbilirubinemia, jaundice |
| Immune system disorders: | seasonal allergy |
| Infections and infestations: | abscess, bronchitis, cellulitis, ear infection, gastroenteritis, gingival infection, herpes simplex, lower respiratory tract infection, nasopharyngitis, oral herpes, sinusitis, skin infection, upper respiratory tract infection, tooth abscess |
| Investigations: | alanine aminotransferase increased, blood bilirubin increased, blood bilirubin unconjugated increased, irritability, malaise, electrocardiogram abnormal, haemoglobin decreased, neutrophil count increased, reticulocyte count increased, transaminases increased, weight decreased, white blood cell count decreased |
| Metabolism and nutrition disorders: | decreased appetite, diabetes mellitus, gout, hyperphosphataemia, hypertriglyceridaemia, hypophosphataemia, increased appetite, lactic acidosis |
| Musculoskeletal and connective tissue disorders: | arthralgia, arthritis, axillary mass, back pain, bone pain, bursitis, muscle spasms, musculoskeletal chest pain, musculoskeletal stiffness, myalgia, neck pain, pain in extremity, sensation of heaviness, tendonitis |
| Nervous system disorders: | ataxia, cerebrovascular accident, disturbance in attention, dizziness, dysgeusia, hyperesthesia, intention tremor, lethargy, memory impairment, migraine, neuralgia, paraesthesia, presyncope, restless legs syndrome, somnolence, syncope, tension headache, tremor |
| Psychiatric disorders: | abnormal dreams, affect lability, agitation, anger, anxiety, anxiety disorder, depressed mood, depression, emotional disorder, euphoric mood, insomnia, libido decreased, mental status changes, mood altered, mood swings, nervousness, nightmare, sleep disorder, suicidal ideation, tearfulness, terminal insomnia |
| Reproductive system and breast disorders: | amenorrhoea, menorrhagia, metrorrhagia |
| Respiratory thoracic and mediastinal disorders: | acute respiratory failure, chronic obstructive pulmonary disease, cough, dyspnoea, dyspnoea exertional, hypoxia, respiratory depression, sleep apnoea syndrome. |
| Skin and subcutaneous tissue disorders: | alopecia, blister, cold sweat, dandruff, dry skin, erythema, night sweats, photodermatosis, photosensitivity reaction, pruritus, pruritus generalised, rash, rash erythematous, rash generalised, rash papular, rash pruritic, skin odour abnormal, skin reaction |
| Vascular disorders: | flushing, hot flush, hypertension, hypotension |
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 HOLKIRATM 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
MODERIBATM is to be used in combination with other products. Refer to the appropriate Product Monograph(s) for a detailed list of their drug interactions.
MODERIBATM 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. MODERIBATM 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 MODERIBATM should be undertaken with caution. | |
| zidovudine | Ribavirin levels could be increased by zidovudine leading to increased risk of anemia. The use of MODERIBATM 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. | |
| Concomitant Drug Class: Drug Name | Clinical comment | |
|---|---|---|
| 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 MODERIBATM 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 MODERIBATM was increased with food. MODERIBATM 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 MODERIBATM with herbs have not been established.
Drug-Laboratory Interactions
Interactions or interferences of MODERIBATM 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 MODERIBATM (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 MODERIBATM in combination with HOLKIRA™ PAK, consult the HOLKIRA™ PAK Product Monograph.
Recommended Dose and Dosage Adjustment
The recommended dose and treatment durations of MODERIBATM 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 MODERIBATM 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 MODERIBATM 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, MODERIBATM 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. MODERIBATM Combination Therapy with HOLKIRATM PAK: Treatment Regimen and Duration by Patient Population
| Patient Population | Treatment | Duration |
| Genotype 1a, without cirrhosis | MODERIBATM* + HOLKIRA™ PAK | 12 weeks |
| Genotypes 1a and 1b, with cirrhosis | MODERIBATM* + 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 MODERIBATM + 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: MODERIBATM + HOLKIRA™ PAK is recommended in patients with an unknown genotype 1 subtype or with mixed genotype 1 infection. | ||
Dose Modifications
In general the MODERIBATM 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 MODERIBATM dose modification (see Table 6).
Table 6. MODERIBATM Tablets Dosage Modification Guidelines for Management of Treatment- Emergent Anemia
| Laboratory Values | Reduce Only MODERIBATM Dose to 600 mg/Daya if: | Discontinue MODERIBATM 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 MODERIBATM 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 MODERIBATM 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 MODERIBATM 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 MODERIBATM is required in patients with creatinine clearance > 50 mL/min. MODERIBATM 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 MODERIBATM are permanently discontinued, MODERIBATM should also be discontinued.
Missed Dose
If a MODERIBATM dose is missed but remembered within 6 hours, it should be taken as soon as possible. If more than 6 hours has passed since MODERIBATM 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
MODERIBATM 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 HOLKIRATM 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 HOLKIRATM 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 MODERIBATM 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). MODERIBATM 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.
PART II: SCIENTIFIC INFORMATION
PHARMACEUTICAL INFORMATION
| Proper name: | ribavirin | |
| Chemical name: | 1- -D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide | |
| Molecular formula and molecular mass: | C8H12N4O5 244.21 | |
| Structural formula: | N N N CONH2 O OH OH OH | |
| Physicochemical properties: | Ribavirin is a white to off-white powder. It is freely soluble in water and slightly soluble in anhydrous alcohol. | |
CLINICAL TRIALS
Consult the respective Product Monograph(s) of products used in combination with MODERIBA™ (ribavirin) for information on the relevant clinical studies.
Clinical Trials: Ribavirin in Combination Therapy with HOLKIRA™ PAK
Trial Design
The efficacy and safety of ribavirin in combination with HOLKIRA™ PAK was evaluated in six randomized Phase 3 clinical trials, including one trial exclusively in subjects with cirrhosis (Child-Pugh A), in over 2300 subjects with genotype 1 chronic hepatitis C infection, as summarized in Table 7.
Table 7. Summary of Clinical Trial Designs in Treatment of Genotype 1 Chronic Hepatitis C Infection
| Study # | Number of Subjects Treateda | HCV Genotype (GT) | Trial Design | Dosage, Route of Administration and Durationb |
|---|---|---|---|---|
| Treatment-Naïvec, without Cirrhosis | ||||
SAPPHIRE-I (M11-646) | 631 | GT1 | Double-blind, randomized, placebo controlled | ombitasvir/paritaprevir /ritonavir tablet: 25/150/100 mg or placebo QD; dasabuvir tablet: 250 mg or placebo BID; RBV tablet: 1000 or 1200 mg or placebo QD (divided BID); Oral 12 weeks |
PEARL-III (M13-961) | 419 | GT1b | Double-blind, randomized (RBV or RBV placebo) | ombitasvir/ paritaprevir /ritonavir tablet: 25/150/100 mg QD; dasabuvir tablet: 250 mg BID; RBV tablet: 1000 to 1200 mg or placebo QD (divided BID); Oral 12 weeks |
| Study # | Number of Subjects Treateda | HCV Genotype (GT) | Trial Design | Dosage, Route of Administration and Durationb |
|---|---|---|---|---|
PEARL-IV (M14-002) | 305 | GT1a | Double-blind, randomized (RBV or RBV placebo) | ombitasvir/ paritaprevir /ritonavir tablet: 25/150/100 mg QD; dasabuvir tablet: 250 mg BID; RBV tablet: 1000 to 1200 mg or placebo QD (divided BID) Oral 12 weeks |
| Treatment-Experiencedd, without Cirrhosis | ||||
SAPPHIRE-II (M13-098) | 394 | GT1 | Double-blind, randomized, placebo controlled | ombitasvir/ paritaprevir /ritonavir tablet: 25/150/100 mg or placebo QD; dasabuvir tablet: 250 mg or placebo BID; RBV tablet: 1000 or 1200 mg or placebo QD (divided BID) Oral 12 weeks |
PEARL-II (M13-389) | 179 | GT1b | Open-label, randomized (with or without RBV) | ombitasvir/ paritaprevir /ritonavir tablet: 25/150/100 mg QD; dasabuvir tablet: 250 mg BID; RBV tablet: 1000 or 1200 mg QD (divided BID) Oral 12 weeks |
| Treatment-Naïve and Treatment-Experienced, with Cirrhosis | ||||
TURQUOISE -II (M13-099) | 380 | GT1 | Open-label, randomized to 12 or 24 weeks | ombitasvir/ paritaprevir /ritonavir tablet: 25/150/100 mg QD; dasabuvir tablet: 250 mg BID; RBV tablet: 1000 to 1200 mg or placebo QD (divided BID) Oral 12 or 24 weeks |
| Study # | Number of Subjects Treateda | HCV Genotype (GT) | Trial Design | Dosage, Route of Administration and Durationb |
|---|---|---|---|---|
BID = twice daily, QD = daily, pegIFN = pegylated interferon, RBV = ribavirin
| ||||
Sustained virologic response (SVR) (virologic cure) was defined as unquantifiable or undetectable HCV RNA 12 weeks after the end of treatment (SVR12) in the Phase 3 trials. Treatment duration was fixed in each trial and was not guided by subjects’ HCV RNA levels (no response guided algorithm). Plasma HCV RNA values were measured during the clinical trials using the COBAS TaqMan HCV test (version 2.0), for use with the High Pure System. The assay had a lower limit of quantification (LLOQ) of 25 IU per Ml.
Clinical Trials in Treatment-Naïve Adults
SAPPHIRE-I was a randomized, global multicenter, double-blind, placebo-controlled trial conducted in 631 treatment-naïve adults with genotype 1 chronic hepatitis C virus infection without cirrhosis. HOLKIRA™ PAK was given for 12 weeks of treatment in combination with ribavirin (RBV). Subjects randomized to the placebo arm received placebo for 12 weeks, after which they received open-label HOLKIRA™ PAK in combination with ribavirin for 12 weeks.
PEARL-III and PEARL-IV were randomized, global, multicenter, double-blind, controlled trials conducted in 419 treatment-naïve adults with genotype 1b chronic hepatitis C virus infection without cirrhosis (PEARL-III) and 305 treatment-naïve adults with genotype 1a chronic hepatitis C virus infection without cirrhosis (PEARL-IV). Subjects were randomized, in a 1:1 ratio (PEARL-III) or a 1:2 ratio (PEARL-IV), to receive HOLKIRA™ PAK with or without ribavirin for 12 weeks of treatment.
Demographic and baseline characteristics for treatment-naïve subjects in SAPPHIRE-I, PEARL-III and PEARL-IV are provided in Table 8.
Table 8. Demographic and Baseline Characteristics of Treatment-Naïve Subjects without Cirrhosis in SAPPHIRE-I, PEARL-III and PEARL-IV
| Characteristics | SAPPHIRE-I N=631 | PEARL-III N=419 | PEARL-IV N=305 |
|---|---|---|---|
| Age (years) | |||
| Median (range) | 52 (18 – 70) | 50 (19 – 70) | 54 (19 – 70) |
| Gender, n (%) | |||
| Male | 344 (54.5) | 192 (45.8) | 199 (65.2) |
| Female | 287 (45.5) | 227 (54.2) | 106 (34.8) |
| Race, n (%) | |||
| White | 572 (90.6) | 394 (94.3) | 257 (84.3) |
| Black or African American | 34 (5.4) | 20 (4.8) | 36 (11.8) |
| Asian | 14 (2.2) | 2 (0.5) | 4 (1.3) |
| Other | 11 (1.7) | 2 (0.5) | 8 (2.6) |
| Ethnicity, n (%) | |||
| Hispanic or Latino | 32 (5.1) | 7 (1.7) | 28 (9.2) |
| None of the above | 599 (94.9) | 412 (98.3) | 277 (90.8) |
| Body mass index, n (%) | |||
| < 30 kg/m2 | 529 (83.8) | 350 (83.5) | 245 (80.3) |
| ≥ 30 kg/m2 | 102 (16.2) | 69 (16.5) | 60 (19.7) |
| HCV genotype, n (%) | |||
| 1a | 427 (67.7) | N/A | 304 (99.7) |
| 1b | 204 (32.3) | 419 (100) | 1 (0.3) |
| Characteristics | SAPPHIRE-I N=631 | PEARL-III N=419 | PEARL-IV N=305 |
|---|---|---|---|
| Baseline HCV RNA | |||
| Mean ± SD (log10 IU/mL) | 6.42 ± 0.63 | 6.31 ± 0.72 | 6.57 ± 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 (%) | |||
| CC | 194 (30.7) | 88 (21.0) | 94 (30.8) |
| Non-CC | 437 (69.3) | 331 (79.0) | 211 (69.2) |
| Baseline fibrosis stage, n (%) | |||
| F0-F1 | 479 (75.9) | 291 (69.6) | 195 (63.9) |
| F2 | 97 (15.4) | 85 (20.3) | 56 (18.4) |
| ≥ F3 | 55 (8.7) | 42 (10.0) | 54 (17.7) |
| History of depression or bipolar disorder, n (%) | |||
| No | 535 (84.8) | 380 (90.7) | 242 (79.3) |
| Yes | 96 (15.2) | 39 (9.3) | 63 (20.7) |
| N/A = Not Applicable. | |||
Study Results
Table 9 shows the SVR12 rates for genotype 1-infected, treatment-naïve subjects receiving HOLKIRA™ PAK with or without ribavirin for 12 weeks in SAPPHIRE-I, PEARL-III and PEARL-IV. All treatment groups met the primary efficacy endpoint. In study PEARL-III, HOLKIRA™ PAK without ribavirin had similar SVR12 rates (99.0%) compared to HOLKIRA™ PAK with ribavirin (99.5%). In study PEARL-IV, HOLKIRA™ PAK without ribavirin did not meet the pre-specified criteria for non-inferiority to HOLKIRA™ PAK with ribavirin.
Table 9. SVR12 for Genotype 1-Infected Treatment-Naïve Subjects without Cirrhosis in SAPPHIRE-I, PEARL-III and PEARL-IV
| Treatment Outcome | SAPPHIRE-I Genotype 1 | PEARL-III Genotype 1b | PEARL-IV Genotype 1a | ||
|---|---|---|---|---|---|
HOLKIRA™ PAK + RBV N=473 % (n/N) | HOLKIRA™ PAK + RBV N=210 % (n/N) | HOLKIRA™ PAK N=209 % (n/N) | HOLKIRA™ PAK + RBV N=100 % (n/N) | HOLKIRA™ PAK N=205 % (n/N) | |
| Overall SVR12 | 96 (455/473) | 99 (209/210) | 99 (207/209) | 97 (97/100) | 90 (185/205) |
| 95% CI | 94.5 to 97.9 | 98.6 to 100 | 97.7 to 100 | 93.7 to 100 | 86.2 to 94.3 |
| HCV genotype 1a | 95 (307/322) | N/A | N/A | 97 (97/100) | 90 (184/204) |
| HCV genotype 1b | 98 (148/151) | 99 (209/210) | 99 (207/209) | N/A | |
| Outcome for subjects without SVR12 | |||||
| On-treatment VFa | <1 (1/473)d | <1 (1/210) | 0 | 1 (1/100) | 3 (6/205) |
| Relapseb | 2 (7/463)d | 0 | 0 | 1 (1/98) | 5 (10/194) |
| Otherc | 2 (10/473) | 0 | 1 (2/209) | 1 (1/100) | 2 (4/205) |
CI = confidence interval, VF = virologic failure, N/A = Not Applicable
| |||||
Table 10 presents the SVR12 rates by selected subgroups for genotype 1-infected, treatment-naïve subjects in studies SAPPHIRE-I, PEARL-III and PEARL-IV.
Table 10. SVR12 rates for Selected Subgroups of Genotype 1-infected, Treatment-Naïve Subjects without Cirrhosis in SAPPHIRE-I, PEARL-III and PEARL-IV
| Treatment Outcome | SAPPHIRE-I Genotype 1 | PEARL-III Genotype 1b | PEARL-IV Genotype 1a | ||
|---|---|---|---|---|---|
HOLKIRA™ PAK + RBV N=473 % (n/N) | HOLKIRA™ PAK + RBV N=210 % (n/N) | HOLKIRA™ PAK N=209* % (n/N) | HOLKIRA™ PAK + RBV N=100** % (n/N) | HOLKIRA™ PAK N=205 % (n/N) | |
| IL28B | |||||
| CC | 97 (139/144) | 100 (44/44) | 98 (43/44) | 100 (31/31) | 97 (61/63) |
| Non-CC | 96 (316/329) | 99 (165/166) | 99 (164/165) | 96 (66/69) | 87 (124/142) |
| Sex | |||||
| Female | 98 (197/202) | 99 (103/104) | 100 (123/123) | 100 (30/30) | 95 (72/76) |
| Male | 95 (258/271) | 100 (106/106) | 98 (84/86) | 96 (67/70) | 88 (113/129) |
| Age | |||||
| < 65 years | 96 (437/454) | 99 (195/196) | 99 (188/190) | 97 (87/90) | 90 (172/192) |
| ≥ 65 years | 95 (18/19) | 100 (14/14) | 100 (19/19) | 100 (10/10) | 100 (13/13) |
| Race | |||||
| 96 (27/28) | 100 (11/11) | 100 (11/11) | 100 (10/10) | 85 (23/27) | |
| Non-black | 96 (428/445) | 99 (198/199) | 99 (196/197) | 97 (87/90) | 91 (162/178) |
| Ethnicity | |||||
| Hispanic or Latino | 93 (25/27) | 100 (2/2) | 80 (4/5) | 90 (9/10) | 89 (16/18) |
| None of the above | 430/446 (96.4) | 99 (207/208) | 99 (203/204) | 98 (88/90) | 90 (169/187) |
| Body mass index | |||||
| < 30 kg/m2 | 97 (390/402) | 100 (182/182) | 100 (168/168) | 99 (78/79) | 92 (153/166) |
| ≥ 30 kg/m2 | 92 (65/71) | 96 (27/28) | 95 (39/41) | 90 (19/21) | 82 (32/39) |
| Baseline HCV RNA | |||||
| < 800000 IU/mL | 98 (102/104) | 100 (51/51) | 100 (61/61) | 100 (8/8) | 91 (30/33) |
| ≥ 800000 IU/mL | 96 (353/369) | 99 (158/159) | 99 (146/148) | 97 (89/92) | 90 (155/172) |
| Baseline fibrosis stage | |||||
| F0-F1 | 97 (352/363) | 99 (149/150) | 100 (141/141) | 97 (61/63) | 92 (122/132) |
| F2 | 94 (66/70) | 100 (38/38) | 100 (47/47) | 95 (20/21) | 83 (29/35) |
| ≥ F3 | 93 (37/40) | 100 (22/22) | 90 (18/20) | 100 (16/16) | 89 (34/38) |
| History of depression or bipolar disorder | |||||
| No | 97 (389/403) | 99 (189/190) | 99 (189/190) | 96 (80/83) | 89 (142/159) |
| Yes | 94 (66/70) | 100 (20/20) | 95 (18/19) | 100 (17/17) |
|
* For subjects with GT1b infection without cirrhosis, HOLKIRA™ PAK alone for 12 weeks is the recommended regimen. ** For subjects with GT1a infection without cirrhosis, HOLKIRA™ PAK with RBV for 12 weeks is the recommended regimen. | |||||
These baseline viral (genotype 1 subtype, baseline viral load) and host factors (gender, race, ethnicity, age, IL28B allele, baseline body mass index, history of depression or bipolar disorder, fibrosis stage) were not associated with lower SVR12 rates across subgroups.
In addition, subjects who underwent ribavirin dose modifications did not have lower SVR12 rates.
Clinical Trials in Treatment-Experienced Adults
SAPPHIRE-II was a randomized, global multicenter, double-blind, placebo-controlled trial conducted in 394 subjects with genotype 1 chronic hepatitis C virus infection without cirrhosis who did not achieve SVR with prior treatment with peginterferon and ribavirin (pegIFN/RBV). HOLKIRA™ PAK in combination with ribavirin was given for 12 weeks of treatment. Subjects randomized to the placebo arm received placebo for 12 weeks, after which they received HOLKIRA™ PAK in combination with ribavirin for 12 weeks.
PEARL-II was a randomized, global, multicenter, open-label trial conducted in 179 adults with chronic genotype 1b hepatitis C virus infection without cirrhosis who did not achieve SVR with prior treatment with pegIFN/RBV. Subjects were randomized, in a 1:1 ratio, to receive HOLKIRA™ PAK with or without ribavirin for 12 weeks of treatment.
Demographic and baseline characteristics for treatment-experienced subjects in SAPPHIRE-II and PEARL-II are provided in Table 11.
Table 11. Demographic and Baseline Characteristics of Treatment-Experienced Subjects without Cirrhosis in SAPPHIRE-II and PEARL-II
| Characteristics | SAPPHIRE-II N=394 | PEARL-II N=179 |
|---|---|---|
| Age (years) | ||
| Median (range) | 54 (19 – 71) | 57 (26 – 70) |
| Gender, n (%) | ||
| Male | 227 (57.6) | 97 (54.2) |
| Female | 167 (42.4) | 82 (45.8) |
| Race, n (%) | ||
| White | 355 (90.1) | 165 (92.2) |
| Black or African American | 32 (8.1) | 7 (3.9) |
| Asian | 6 (1.5) | 3 (1.7) |
| Other | 1 (0.3) | 4 (2.3) |
| Ethnicity, n (%) | ||
| Hispanic or Latino | 25 (6.3) | 3 (1.7) |
| None of the above | 369 (93.7) | 176 (98.3) |
| Characteristics | SAPPHIRE-II N=394 | PEARL-II N=179 |
|---|---|---|
| Body mass index, n (%) | ||
| < 30 kg/m2 | 316 (80.2) | 140 (78.2) |
| ≥ 30 kg/m2 | 78 (19.8) | 39 (21.8) |
| HCV genotype, n (%) | ||
| 1a | 230 (58.4) | N/A |
| 1b | 163 (41.4) | 179 (100) |
| Baseline HCV RNA | ||
| Mean ± SD (log10 IU/mL) | 6.55 ± 0.52 | 6.51 ± 0.55 |
| < 800000 IU/mL, n (%) | 51 (12.9) | 22 (12.3) |
| ≥ 800000 IU/mL, n (%) | 343 (87.1) | 157 (87.7) |
| IL28B, n (%) | ||
| CC | 41 (10.4) | 17 (9.5) |
| Non-CC | 353 (89.6) | 162 (90.5) |
| Type of response to previous pegIFN/RBV treatment, n (%) | ||
| Null responder | 193 (49.0) | 63 (35.2) |
| Nonresponder/partial responder | 86 (21,8) | 51 (28.5) |
| Relapser | 115 (29.2) | 65 (36.3) |
| Baseline fibrosis stage, n (%) | ||
| F0-F1 | 267 (67.8) | 122 (68.2) |
| F2 | 70 (17.8) | 32 (17.9) |
| ≥ F3 | 57 (14.5) | 25 (14.0) |
| History of depression or bipolar disorder, n (%) | ||
| No | 313 (79.4) | 156 (87.2) |
| Yes | 81 (20.6) | 23 (12.8) |
| N/A = Not Applicable | ||
Study Results
Table 12 shows the SVR12 rates for treatment-experienced subjects with genotype 1-infection receiving HOLKIRA™ PAK in combination with ribavirin for 12 weeks in SAPPHIRE-II and PEARL-II and HOLKIRA™ PAK alone in PEARL-II. All the treatment groups met the primary efficacy endpoint.
Table 12. SVR12 for Genotype 1-Infected Treatment-Experienced Subjects without Cirrhosis in SAPPHIRE-II and PEARL-II
| Treatment Outcome | SAPPHIRE-II Genotype 1 | PEARL-II Genotype 1b | |
|---|---|---|---|
HOLKIRA™ PAK + RBV N=297 % (n/N) | HOLKIRA™ PAK + RBV N=88 % (n/N) | HOLKIRA™ PAK* N=91 % (n/N) | |
| Overall SVR12 | 96 (286/297) | 97 (85/88) | 100 (91/91) |
| 95% CI | 94.1 to 98.4 | 92.8 to 100 | 95.9 to 100 |
| HCV genotype 1a | 96 (166/173) | N/A | N/A |
| Prior pegIFN/RBV null responder | 95 (83/87) | N/A | N/A |
| Prior pegIFN/RBV partial responder | 100 (36/36) | N/A | N/A |
| Prior pegIFN/RBV relapser | 94 (47/50) | N/A | N/A |
| HCV genotype 1b | 97 (119/123) | 97 (85/88) | 100 (91/91) |
| Prior pegIFN/RBV null responder | 95 (56/59) | 94 (29/31) | 100 (32/32) |
| Prior pegIFN/RBV partial responder | 100 (28/28) | 96 (24/25) | 100 (26/26) |
| Prior pegIFN/RBV relapser | 97 (35/36) | 100 (32/32) | 100 (33/33) |
| Outcome for subjects without SVR12 | |||
| On-treatment VFa | 0 | 0 | 0 |
| Relapseb | 2 (7/293) | 0 | 0 |
| Otherc | 1 (4/297) | 3 (3/88) | 0 |
CI = confidence interval, VF = virologic failure, N/A = Not Applicable * For subjects with GT1b infection without cirrhosis, HOLKIRA™ PAK alone for 12 weeks is the recommended regimen.
| |||
Table 13 presents the SVR12 rates by selected subgroups for genotype 1-infected, treatment-experienced subjects in studies SAPPHIRE-II and PEARL-II.
Table 13. SVR12 rates for Selected Subgroups of Genotype 1-infected, Treatment-Experienced Subjects without Cirrhosis in SAPPHIRE-II and PEARL-II
| Treatment Outcome | SAPPHIRE-II Genotype 1 | PEARL-II Genotype 1b | |
|---|---|---|---|
HOLKIRA™ PAK + RBV N=297 % (n/N) | HOLKIRA™ PAK + RBV N=88 % (n/N) | HOLKIRA™ PAK* N=91 % (n/N) | |
| IL28B | |||
| CC | 91 (31/34) | 100 (10/10) | 100 (7/7) |
| Non-CC | 97 (255/263) | 96 (75/78) | 100 (84/84) |
| Sex | |||
| Female | 97 (126/130) | 98 (44/45) | 100 (37/37) |
| Male | 96 (160/167) | 95 (41/43) | 100 (54/54) |
| Age | |||
| < 65 years | 97 (269/277) | 96 (70/73) | 100 (76/76) |
| ≥ 65 years | 85 (17/20) | 100 (15/15) | 100 (15/15) |
| Race | |||
| 95 (21/22) | 100 (3/3) | 100 (5/5) | |
| Non-black | 96 (265/275) | 96 (82/85) | 100 (86/86) |
| Ethnicity | |||
| Hispanic or Latino | 95 (21/22) | 50 (1/ 2) | 100 (1/ 1) |
| None of the above | 96 (265/275) | 98 (84/86) | 100 (90/90) |
| Body mass index | |||
| < 30 kg/m2 | 97 (231/238) | 96 (68/71) | 100 (69/69) |
| ≥ 30 kg/m2 | 93 (55/59) | 100 (17/17) | 100 (22/22) |
| Baseline HCV RNA | |||
| < 800000 IU/mL | 100 (42/42) | 100 (13/13) | 100 (9/9) |
| ≥ 800000 IU/mL | 96 (244/255) | 96 (72/75) | 100 (82/82) |
| Baseline fibrosis stage | |||
| F0-F1 | 98 (197/202) | 97 (61/63) | 100 (59/59) |
| F2 | 94 (50/53) | 100 (13/13) | 100 (19/19) |
| ≥ F3 | 93 (39/42) | 92 (11/12) | 100 (13/13) |
| History of depression or bipolar disorder | |||
| No | 96 (220/229) | 97 (71/73) | 100 (83/83) |
| Yes | 97 (66/68) | 93 (14/15) | 100 (8/8) |
| * For subjects with GT1b infection without cirrhosis, HOLKIRA™ PAK alone for 12 weeks is the recommended regimen. | |||
These baseline viral (genotype 1 subtype, baseline viral load) and host factors (prior treatment response, sex, race, ethnicity, age, IL28B allele, baseline body mass index, history of depression or bipolar disorder, fibrosis stage) were not associated with lower SVR12 rates across subgroups.
In addition, subjects who underwent ribavirin dose modifications did not have lower SVR12 rates.
Clinical Trial in Subjects with Cirrhosis
TURQUOISE-II was a randomized, global multicenter, open-label trial conducted exclusively in 380 genotype 1-infected subjects with cirrhosis (Child-Pugh A) who were either treatment-naïve or did not achieve SVR with prior treatment with pegIFN/RBV. HOLKIRA™ PAK in combination with ribavirin was administered for either 12 or 24 weeks of treatment.
Demographic and baseline characteristics for genotype 1-infected subjects with cirrhosis in study TURQUOISE-II are provided in Table 14.
Table 14. Demographic and Baseline Characteristics of Subjects with Cirrhosis in TURQUOISE-II
| Characteristics | TURQUOISE-II HOLKIRA™ PAK + RBV N = 380 |
|---|---|
| Age (years) | |
| Median (range) | 58 (21 – 71) |
| Gender, n (%) | |
| Male | 267 (70.3) |
| Female | 113 (29.7) |
| Race, n (%) | |
| White | 360 (94.7) |
| Black or African American | 12 (3.2) |
| Asian | 8 (2.1) |
| Ethnicity | |
| Hispanic or Latino | 45 (11.8) |
| None of the above | 335 (88.2) |
| Body mass index | |
| < 30 kg/m2 | 272 (71.6) |
| ≥ 30 kg/m2 | 108 (28.4) |
| HCV genotype, n (%) | |
| 1a | 261 (68.7) |
| 1b | 119 (31.3) |
| Characteristics | TURQUOISE-II HOLKIRA™ PAK + RBV N = 380 |
|---|---|
| Baseline HCV RNA | |
| Mean ± SD (log10 IU/mL) | 6.47 ± 0.58 |
| < 800000 IU/mL, n (%) | 53 (13.9) |
| ≥ 800000 IU/mL, n (%) | 327 (86.1) |
| Prior HCV Therapy | |
| Treatment-Naive | 160 (42.1) |
| Treatment-experienced with pegIFN/RBV, n (%) | 220 (57.9) |
| Null responder | 137 (36.1) |
| Partial responder | 31 (8.2) |
| Relapser | 52 (13.7) |
| IL28B, n (%) | |
| CC | 69 (18.2) |
| CT | 237 (62.4) |
| TT | 74 (19.5) |
| Baseline platelet count, n (%) | |
| < 90 x109/L | 56 (14.7) |
| ≥ 90 x109/L | 324 (85.3) |
| Baseline albumin, n (%) | |
| < 35 g/L | 43 (11.3) |
| ≥ 35 g/L | 337 (88.7) |
| History of depression or bipolar disorder, n (%) | |
| No | 286 (75.3) |
| Yes | 94 (24.7) |
Study Results
Table 15 shows the SVR12 rates for genotype 1-infected subjects with cirrhosis who were treatment-naïve or previously treated with pegIFN/RBV. Both treatment groups met the primary efficacy endpoint.
Table 15. SVR12 for Genotype 1-Infected Subjects with Cirrhosis who were Treatment-Naïve or Previously Treated with pegIFN/RBV in TURQUOISE-II
| Treatment Outcome | HOLKIRA™ PAK with RBV | |
|---|---|---|
| 12 Weeks* | 24 Weeks | |
| % (n/N) | % (n/N) | |
| Overall SVR12 | 92 (191/208)d | 96 (165/172)d |
| 97.5% CI | 87.6 to 96.1 | 92.6 to 99.3 |
| HCV genotype 1a | 89 (124/140) | 94 (114/121) |
| Treatment naïve | 92 (59/64) | 93 (52/56) |
| Prior pegIFN/RBV null responders | 80 (40/50) | 93 (39/42)** |
| Prior pegIFN/RBV partial responders | 100 (11/11) | 100 (10/10) |
| Prior pegIFN/RBV prior relapsers | 93 (14/15) | 100 (13/13) |
| HCV genotype 1b | 99 (67/68) | 100 (51/51) |
| Treatment naïve | 100 (22/22) | 100 (18/18) |
| Prior pegIFN/RBV null responders | 100 (25/25) | 100 (20/20) |
| Prior pegIFN/RBV partial responders | 86 (6/7) | 100 (3/3) |
| Prior pegIFN/RBV prior relapsers | 100 (14/14) | 100 (10/10) |
| Outcome for subjects without SVR12 | ||
| On-treatment VFa | <1 (1/208) | 2 (3/172) |
| Relapseb | 6 (12/203) | <1 (1/164) |
| Otherc | 2 (4/208) | 2 (3/172) |
CI = confidence interval, VF = virologic failure * 12 weeks of HOLKIRA™ PAK with RBV is the recommended regimen for all subjects with cirrhosis,except those with genotype 1a infection and prior null response to pegIFN/RBV. ** 24 weeks of HOLKIRA™ PAK + ribavirin is recommended for patients with genotype 1a-infection with cirrhosis who have had a previous null response to pegIFN/RBV.
| ||
Table 16 presents the SVR12 rates by selected subgroups for genotype 1-infected subjects with cirrhosis who were treatment-naïve or previously treated with pegIFN/RBV.
Table 16. SVR12 rates for Selected Subgroups of Genotype 1-infected Subjects with Cirrhosis who were Treatment-Naïve or Previously Treated with pegIFN/RBV in TURQUOISE-II
| Subgroup | TURQUOISE-II | |
|---|---|---|
| HOLKIRA™ PAK + RBV | ||
12 Weeks N = 208 | 24 Weeks N = 172 | |
| n/N (%) | n/N (%) | |
| IL28B | ||
| CC | 94 (33/35) | 97 (33/34) |
| Non-CC | 91 (158/173) | 96 (132/138) |
| Sex | ||
| Female | 94 (58/62) | 96 (49/51) |
| Male | 91 (133/146) | 96 (116/121) |
| Age | ||
| < 65 years | 91 (166/182) | 95 (142/149) |
| ≥ 65 years | 96 (25/26) | 100 (23/23) |
| Race | ||
| 100 (6/6 ) | 83 (5/6) | |
| Nonblack | 92 (185/202) | 96 (160/166) |
| Ethnicity | ||
| Hispanic or Latino | 84 (21/25) | 95 (19/20) |
| None of the above | 93 (170/183) | 96 (146/152) |
| Body mass index | ||
| < 30 kg/m2 | 92 (135/146) | 97 (122/126) |
| ≥ 30 kg/m2 | 90 (56/62) | 93 (43/46) |
| Baseline HCV RNA | ||
| < 800000 IU/mL | 91 (31/34) | 89 (17/19) |
| ≥ 800000 IU/mL | 92 (160/174) | 97 (148/153) |
| Baseline platelet count | ||
| < 90 x 109/L | 83 (25/30) | 96 (25/26) |
| ≥ 90 x 109/L | 93 (166/178) | 96 (140/146) |
| Baseline albumin | ||
| < 35 g/L | 84 (21/25) | 89 (16/18) |
| ≥ 35 g/L | 93 (170/183) | 97 (149/154) |
| History of depression or bipolar disorder | ||
| No | 91 (143/157) | 96 (124/129) |
| Yes | 94 (48/51) | 95 (41/43) |
Subjects who underwent ribavirin dose modifications did not have lower SVR12 rates.
Pooled Analyses of Clinical Trials
Durability of Response
Overall, 660 subjects in Phase 2 and 3 clinical trials had HCV RNA results for both the SVR12 and SVR24 time points. Among these subjects, the positive predictive value of SVR12 on SVR24 was 99.8%.
Pooled Efficacy Analysis
In Phase 3 clinical trials, 1096 subjects (including 202 with cirrhosis) received the recommended regimen for their HCV subtype, cirrhosis status and previous treatment. Table 17 shows SVR rates for these subjects. Among subjects who received the recommended regimen in Phase 3 clinical trials, 97% achieved SVR (95% with cirrhosis and 97% without cirrhosis), while 0.5% demonstrated virologic breakthrough and 1.6% experienced post-treatment relapse.
Table 17. SVR12 Rates for Recommended Treatment Regimens
| Genotype 1a | Genotype 1b | |||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| No Cirrhosis HOLKIRA ™ PAK with RBV | With Cirrhosis HOLKIRA ™ PAK with RBV | No Cirrhosis HOLKIRA ™ PAK | With Cirrhosis HOLKIRA ™ PAK with RBV | |||||||||||||||
| 12 weeks | 12 weeks* | 12 weeks | 12 weeks | |||||||||||||||
| Treatment-naïve | 96% (402/420) | 92% (61/66) | 99% (208/210) | 100% (22/22) | ||||||||||||||
| Treatment-experienced | 96% (166/173) | 94% (64/68)* | 100% (91/91) | 98% (45/46) | ||||||||||||||
| Prior pegIFN/RBV relapser | 94% (47/50) | 93% (14/15) | 100% (33/33) | 100% (14/14) | ||||||||||||||
| Prior pegIFN/RBV partial responder | 100% (36/36) | 100% (11/11) | 100% (26/26) | 86% (6/7) | ||||||||||||||
| Prior pegIFN/RBV null responder | 95% (83/87) | 93% (39/42) (24 weeks) | 100% (32/32) | 100% (25/25) | ||||||||||||||
| TOTAL | 96% (568/593) | 93% (125/134)* | 99% (299/301) | 99% (67/68) | ||||||||||||||
RBV = ribavirin * All subjects received 12 weeks of therapy except for genotype 1a infected prior null responders with cirrhosis who received 24 weeks of therapy. | ||||||||||||||||||
Impact of Ribavirin Dose Adjustment on Probability of SVR
In Phase 3 clinical trials, 91.5% of subjects did not require ribavirin dose adjustments during therapy. In the 8.5% of subjects who had ribavirin dose adjustments during therapy, the SVR rate (98.5%) was comparable to subjects who maintained their starting ribavirin dose throughout treatment.
DETAILED PHARMACOLOGY
Pharmacodynamics
Ribavirin is a synthetic nucleoside analogue which has shown in vitro activity against some Deoxyribonucleic acid (DNA) and Ribonucleic acid (RNA) viruses. It is not incorporated into RNA or DNA. Inhibition of Hepatitis C Virus (HCV)-specific enzymes or HCV replication is also not seen with ribavirin or its intracellular nucleotide metabolites at physiologic concentrations.
TOXICOLOGY
Acute Toxicity
Single dose studies were conducted. The oral lethal dose (LD50) was ≥5000 mg/kg in rodents, >480 mg/kg in dogs and > 10,000 mg/kg in monkeys. When administered parenterally (intramuscular, intraperitoneal or intravenous), the LD50 was ≥800 mg/kg for those species evaluated.
Long-Term Toxicity
General toxicology studies were conducted in mice, rats, dogs and monkeys. The longest term studies along with the high dose and relationship to maximal recommended human dose (1400 mg) on a mg/m2 basis are listed in tabular format below.
| Species and Duration | High Dose (mg/kg/day) | Multiple Compared to 1400 mg Clinical Dose (Based on mg/m2) |
|---|---|---|
| Mouse (13 weeks) | 600 | 2 |
| Rat (26 weeks) | 75 | 0.5 |
| Dog (26 weeks) | 20 | 0.5 |
| Monkey (39 weeks) | 60 | 0.8 |
Primary toxicities included effects on the erythron and testes. Erythroid effects (reduced red blood cell counts, hemoglobin, and/or hematocrit) were observed in the repeat-dose rodent studies. Anemia was indicated at the higher doses. The observed erythroid effects are similar to those reported in the literature for monkeys and patients following administration of ribavirin although it has been suggested that these erythroid effects are both dose- and duration-dependent, reversible upon dose reduction or withdrawal, and interspecies differences exist. In repeat dose studies in mice, abnormalities in sperm occurred at doses approximating human therapeutic doses. Upon cessation of treatment, essentially total recovery from ribavirin-induced testicular toxicity occurred within one or two spermatogenic cycles. Effects on erythroid parameters and testes occurred at dosages similar to below the maximal human dose of ribavirin.
Mutagenicity and Carcinogenicity
Mutagenicity
Genotoxic activity has been observed in Balb/3T3 in vitro cell transformation assays, the in vitro mouse lymphoma assay and in vivo mouse micronucleus assays. The high dose in the in vivo micronucleus assay was 2000 mg/kg. The estimated human equivalent of this dose was 167 mg/kg, based on a body surface area adjustment for a 60 kg adult, approximately 7 times the maximum recommended dose of ribavirin on a mg/m2 basis. Ribavirin was negative in the reverse bacterial mutation assay (Ames assay). In a study in rats, it was concluded that dominant lethality was not induced by ribavirin at doses up to 200 mg/kg. The estimated human equivalent of this dose was 33 mg/kg, based on a body surface area adjustment for a 60 kg adult, approximately 1.4 times the maximum recommended human daily dose of ribavirin.
Carcinogenicity
Ribavirin was not carcinogenic in a two-year study in rats at doses up to 60 mg/kg/day or in a 6-month study in p53 knockout mice at doses up to 100 mg/kg/day. The estimated human equivalents of these doses were 10 and 8.3 mg/kg, respectively, based on a body surface area adjustment for a 60 kg adult, approximately 0.4 times the maximum recommended human daily dose of ribavirin.
Reproduction and Teratology
Fertility has been assessed in a study in which males were administered ribavirin orally for 8 weeks, females for 2 weeks, prior to mating, during mating (males) and until gestation day 14 (females). Males in the 60 and 90 mg/kg/day groups exhibited paternal toxicity which consisted of decreased body weight gain; there was no evidence of maternal toxicity. There were no effects on male or female fertility in terms of mating parameters and the number of animals becoming pregnant at ribavirin doses as high as 90 mg/kg/day. Resorptions were increased at 90 mg/kg/day as evaluated on gestation day 14. The no observed adverse effect levels (NOAELs) for paternal and maternal toxicity were 30 and 90 mg/kg/day, respectively. The adult male and female NOAEL in rats for mating and fertility parameters was 90 mg/kg/day.
Ribavirin produces embryolethality and/or teratogenicity in most species tested and the dose levels at which such effects are seen are below the recommended human dose. Malformations observed in more than one rodent species included cleft palate, skeletal anomalies and CNS anomalies. The incidence and severity of teratogenic effects increased with escalation of the dose. The no observed adverse effect level (NOAEL) for embryo-fetal developmental toxicity in rats was 1 mg/kg/day.
While no effects on parturition or on lactation have been reported in terms of maternal responses in a study with prenatal and postnatal development endpoints, there was an increase in stillbirths and postnatal loss from birth to weaning on postnatal day 21 at 60 and 90 mg/kg/day. These are consistent with the findings in the developmental toxicity studies and are just later manifestations of the same activity. The NOAEL for viability and growth in the offspring in this study was 30 mg/kg/day.
REFERENCES
- 1. Poordad F, Hezode C, Trinh R, et al. ABT-450/r-Ombitasvir and Dasabuvir with Ribavirin for Hepatitis C with Cirrhosis. N Engl J Med 2014 Apr 11. [Epub ahead of print]
- 2. Feld JJ, Kowdley KV, Coakley E, et al. Treatment of HCV with ABT-450/r-ombitasvir and dasabuvir with ribavirin. N Engl J Med 2014 Apr 24;370(17):1594-603.
- 3. Zeuzem S, Jacobson IM, Baykal T, et al. Retreatment of HCV with ABT-450/r-ombitasvir and dasabuvir with ribavirin. N Engl J Med 2014 Apr 24;370(17):1604-14.