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Ribavirin
Overview
What is Ribavirin?
What does Ribavirin look like?
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What are the available doses of Ribavirin?
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What should I talk to my health care provider before I take Ribavirin?
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How should I use Ribavirin?
Ribavirin capsules are indicated in combination with INTRON A (interferon alfa-2b, recombinant) Injection for the treatment of chronic hepatitis C in patients 18 years of age and older with compensated liver disease previously untreated with alpha interferon or in patients 18 years of age and older who have relapsed following alpha interferon therapy.
The safety and efficacy of ribavirin capsules with non-pegylated interferons other than the INTRON A product have not been established.
INTRON A Injection should be administered subcutaneously and ribavirin capsules should be administered orally. Ribavirin capsules may be administered without regard to food, but should be administered in a consistent manner. (See .)
What interacts with Ribavirin?
Pregnancy
Ribavirin capsules may cause birth defects and/or death of the exposed fetus. Ribavirin therapy is contraindicated for use in women who are pregnant or in men whose female partners are pregnant. (See and ).
Ribavirin capsules are contraindicated in patients with a history of hypersensitivity to ribavirin or any component of the capsule.
Patients with autoimmune hepatitis must not be treated with combination ribavirin/INTRON A therapy because using these medicines can make the hepatitis worse.
Patients with hemoglobinopathies (e.g., thalassemia major, sickle-cell anemia) should not be treated with ribavirin capsules.
What are the warnings of Ribavirin?
Pregnancy
Category X, may cause birth defects. See boxed CONTRAINDICATIONS AND WARNINGS. See .
Anemia
HEMOLYTIC ANEMIA (HEMOGLOBIN <10 G/DL) WAS OBSERVED IN APPROXIMATELY 10% OF RIBAVIRIN CAPSULES/INTRON A-TREATED PATIENTS IN CLINICAL TRIALS (See : :
). ANEMIA OCCURRED WITHIN 1 TO 2 WEEKS OF INITIATION OF RIBAVIRIN THERAPY. BECAUSE OF THIS INITIAL ACUTE DROP IN HEMOGLOBIN, IT IS ADVISED THAT COMPLETE BLOOD COUNTS (CBC) SHOULD BE OBTAINED PRETREATMENT AND AT WEEK 2 AND WEEK 4 OF THERAPY OR MORE FREQUENTLY IF CLINICALLY INDICATED. PATIENTS SHOULD THEN BE FOLLOWED AS CLINICALLY APPROPRIATE.
The anemia associated with ribavirin capsules/INTRON A therapy may result in deterioration of cardiac function and/or exacerbation of the symptoms of coronary disease. Patients should be assessed before initiation of therapy and should be appropriately monitored during therapy. If there is any deterioration of cardiovascular status, therapy should be suspended or discontinued. (See .) Because cardiac disease may be worsened by drug induced anemia, patients with a history of significant or unstable cardiac disease should not use combination ribavirin capsules/INTRON A therapy. (See .)
Similarly, patients with hemoglobinopathies (e.g., thalassemia, sickle-cell anemia) should not be treated with combination ribavirin capsules/INTRON A therapy.
Psychiatric
Severe psychiatric adverse events, including depression, psychoses, aggressive behavior, hallucinations, violent behavior (suicidal ideation, suicidal attempts, suicides) and rare instances of homicidal ideation have occurred during combination ribavirin capsules/Intron A therapy, both in patients with and without a previous psychiatric disorder. Ribavirin capsules/Intron A therapy should be used with extreme caution in patients with a history of pre-existing psychiatric disorders, and all patients should be carefully monitored for evidence of depression and other psychiatric symptoms.
Suspension of ribavirin capsules/Intron A therapy should be considered if psychiatric intervention and/or dose reduction is unsuccessful in controlling psychiatric symptoms. In severe cases, therapy should be stopped immediately and psychiatric intervention sought. (See .)
Bone Marrow Toxicity
INTRON A therapy suppresses bone marrow function and may result in severe cytopenias including very rare events of aplastic anemia. It is advised that complete blood counts (CBC) be obtained pretreatment and monitored routinely during therapy (see ). INTRON A therapy should be discontinued in patients who develop severe decreases in neutrophil (<0.5 x 10/L) or platelet counts (<25 x 10/L) (see ).
Pulmonary
Pulmonary symptoms, including dyspnea, pulmonary infiltrates, pneumonitis and pneumonia, have been reported during therapy with ribavirin capsules/INTRON A; occasional cases of fatal pneumonia have occurred. In addition, sarcoidosis or the exacerbation of sarcoidosis has been reported. If there is evidence of pulmonary infiltrates or pulmonary function impairment, the patient should be closely monitored, and if appropriate, combination ribavirin capsules/INTRON A treatment should be discontinued.
Other
What are the precautions of Ribavirin?
Exacerbation of autoimmune disease has been reported in patients receiving alpha interferon therapy (including INTRON A therapy). Ribavirin capsules/INTRON A therapy should be used with caution in patients with other autoimmune disorders.
There have been reports of interferon, including INTRON A (interferon alfa-2b, recombinant) exacerbating pre-existing psoriasis; therefore, combination ribavirin capsules/INTRON A therapy should be used in these patients only if the potential benefit justifies the potential risk.
The safety and efficacy of ribavirin capsules/INTRON A therapy has not been established in liver or other organ transplant patients, decompensated hepatitis C patients, patients who are nonresponders to interferon therapy, or patients coinfected with HBV or HIV.
The safety and efficacy of ribavirin capsules monotherapy for the treatment of HIV infection, adenovirus, early RSV infection, parainfluenza, or influenza have not been established and ribavirin capsules should not be used for these indications.
There is no information regarding the use of ribavirin capsules with other interferons.
Triglycerides
Elevated triglyceride levels have been observed in patients treated with interferon including ribavirin capsules/INTRON A therapy. Elevated triglyceride levels should be managed as clinically appropriate. Severe hypertriglyceridemia (triglycerides >1000 mg/dL) may result in pancreatitis. Discontinuation of ribavirin capsules/INTRON A therapy should be considered for patients with persistently elevated triglycerides (triglycerides >1000 mg/dL) associated with symptoms of potential pancreatitis, such as abdominal pain, nausea, or vomiting (see ).
Drug Interactions
Nucleoside Analogs
Administration of nucleoside analogues has resulted in fatal and nonfatal lactic acidosis. Coadministration of ribavirin and nucleoside analogues should be undertaken with caution and only if the potential benefit outweighs the potential risks.
Information for Patients
Combination ribavirin capsules/INTRON A therapy must not be used by females who are pregnant or by males whose female partners are pregnant. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients taking combination ribavirin capsules/INTRON A therapy. Combination ribavirin capsules/INTRON A therapy should not be initiated until a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy. Patients must perform a pregnancy test monthly during therapy and for 6 months posttherapy. Females of childbearing potential must be counseled about use of effective contraception (two reliable forms) prior to initiating therapy. Patients (male and female) must be advised of the teratogenic/embryocidal risks and must be instructed to practice effective contraception during combination ribavirin capsules/INTRON A therapy and for 6 months posttherapy. Patients (male and female) should be advised to notify the physician immediately in the event of a pregnancy. (See ).
If pregnancy does occur during treatment or during 6 months posttherapy, the patient must be advised of the significant teratogenic risk of ribavirin capsules therapy to the fetus. Patients, or partners of patients, should immediately report any pregnancy that occurs during treatment or within 6 months after treatment cessation to their physician. Physicians are encouraged to report such cases by calling the Ribavirin Pregnancy Registry at 1-800-593-2214.
Patients receiving combination ribavirin capsules/INTRON A treatment should be directed in its appropriate use, informed of the benefits and risks associated with treatment, and referred to the Appendix of the Medication Guide on ribavirin capsules. There are no data evaluating whether ribavirin capsules/INTRON A therapy will prevent transmission of infection to others. Also, it is not known if treatment with ribavirin capsules/INTRON A therapy will cure hepatitis C or prevent cirrhosis, liver failure, or liver cancer that may be the result of infection with the hepatitis C virus.
If home use is prescribed, a puncture-resistant container for the disposal of used syringes and needles should be supplied to the patient. Patients should be thoroughly instructed in the importance of proper disposal and cautioned against any reuse of needles and syringes. The full container should be disposed of according to the directions provided by the physician. [see Appendix to the Medication Guide on ribavirin capsules.] To avoid possible transmission of disease, do not share your multidose pen with anyone; it is for you and you alone.
The most common adverse experiences occurring with combination ribavirin capsules/INTRON A therapy are “flu-like” symptoms, such as headache, fatigue, myalgia, and fever (see ) and appear to decrease in severity as treatment continues. Some of these “flu-like” symptoms may be minimized by bedtime administration of INTRON A therapy. Antipyretics should be considered to prevent or partially alleviate the fever and headache. Another common adverse experience associated with INTRON A therapy is thinning of the hair.
Patients should be advised that laboratory evaluations are required prior to starting therapy and periodically thereafter (see ). It is advised that patients be well hydrated, especially during the initial stages of treatment.
Laboratory Tests
The following laboratory tests are recommended for all patients on combination ribavirin capsules/INTRON A therapy, prior to beginning treatment and then periodically thereafter.
Carcinogenesis and Mutagenesis
Carcinogenicity studies with interferon alfa-2b, recombinant have not been performed because neutralizing activity appears in the serum after multiple dosing in all of the animal species tested.
Ribavirin did not cause an increase in any tumor type when administered for 6 months in the transgenic p53 deficient mouse model at doses up to 300 mg/kg (estimated human equivalent of 25 mg/kg based on body surface area adjustment for a 60 kg adult; approximately 1.9 times the maximum recommended human daily dose). Ribavirin was non-carcinogenic when administered for 2 years to rats at doses up to 40 mg/kg (estimated human equivalent of 5.71 mg/kg based on body surface area adjustment for a 60 kg adult). However, this dose was less than the maximum tolerated dose, and therefore the study was not adequate to fully characterize the carcinogenic potential of ribavirin.
Mutagenicity studies have demonstrated that interferon alfa-2b, recombinant is not mutagenic. Ribavirin demonstrated increased incidences of mutation and cell transformation in multiple genotoxicity assays. Ribavirin was active in the Balb/3T3 Cell Transformation Assay. Mutagenic activity was observed in the mouse lymphoma assay, and at doses of 20 to 200 mg/kg (estimated human equivalent of 1.67 to 16.7 mg/kg, based on body surface area adjustment for a 60 kg adult; 0.1 to 1 times the maximum recommended human 24-hour dose of ribavirin) in a mouse micronucleus assay. A dominant lethal assay in rats was negative, indicating that if mutations occurred in rats they were not transmitted through male gametes.
Impairment of Fertility
No reproductive toxicology studies have been performed using interferon alfa-2b, recombinant in combination with ribavirin. However, evidence provided below for interferon alfa-2b, recombinant and ribavirin when administered alone indicate that both agents have adverse effects on reproduction. It should be assumed that the effects produced by either agent alone will also be caused by the combination of the two agents. Interferons may impair human fertility. In studies of interferon alfa-2b recombinant administration in nonhuman primates, menstrual cycle abnormalities have been observed. Decreases in serum estradiol and progesterone concentrations have been reported in females treated with human leukocyte interferon. In addition, ribavirin demonstrated significant embryocidal and/or teratogenic effects at doses well below the recommended human dose in all animal species in which adequate studies have been conducted.
Fertile females and partners of fertile females should not receive combination ribavirin capsules/INTRON A therapy unless the patient and his/her partner are using effective contraception (two reliable forms). Based on a multiple dose half-life (t) of ribavirin of 12 days, effective contraception must be utilized for 6 months posttherapy (e.g., 15 half-lives of clearance for ribavirin).
Combination ribavirin capsules/INTRON A therapy should be used with caution in fertile males. In studies in mice to evaluate the time course and reversibility of ribavirin-induced testicular degeneration at doses of 15 to 150 mg/kg/day (estimated human equivalent of 1.25 to 12.5 mg/kg/day, based on body surface area adjustment for a 60 kg adult; 0.1 to 0.8 times the maximum human 24-hour dose of ribavirin) administered for 3 or 6 months, abnormalities in sperm occurred. Upon cessation of treatment, essentially total recovery from ribavirin-induced testicular toxicity was apparent within 1 or 2 spermatogenesis cycles.
Animal Toxicology
Long-term studies in the mouse and rat (18 to 24 months; doses of 20 to 75 and 10 to 40 mg/kg/day, respectively [estimated human equivalent doses of 1.67 to 6.25 and 1.43 to 5.71 mg/kg/day, respectively, based on body surface area adjustment for a 60 kg adult; approximately 0.1 to 0.4 times the maximum human 24-hour dose of ribavirin]) have demonstrated a relationship between chronic ribavirin exposure and increased incidences of vascular lesions (microscopic hemorrhages) in mice. In rats, retinal degeneration occurred in controls, but the incidence was increased in ribavirin-treated rats.
Pregnancy Category X:
(See .)
Interferon alfa-2b, recombinant has been shown to have abortifacient effects in (rhesus monkeys) at 15 and 30 million IU/kg (estimated human equivalent of 5 and 10 million IU/kg, based on body surface area adjustment for a 60 kg adult). There are no adequate and well-controlled studies in pregnant females.
Ribavirin produced significant embryocidal and/or teratogenic effects in all animal species in which adequate studies have been conducted. Malformations of the skull, palate, eye, jaw, limbs, skeleton, and gastrointestinal tract were noted. The incidence and severity of teratogenic effects increased with escalation of the drug dose. Survival of fetuses and offspring was reduced. In conventional embryotoxicity/teratogenicity studies in rats and rabbits, observed no effect dose levels were well below those for proposed clinical use (0.3 mg/kg/day for both the rat and rabbit; approximately 0.06 times the recommended human 24-hour dose of ribavirin). No maternal toxicity or effects on offspring were observed in a peri/postnatal toxicity study in rats dosed orally at up to 1 mg/kg/day (estimated human equivalent dose of 0.17 mg/kg based on body surface area adjustment for a 60 kg adult; approximately 0.01 times the maximum recommended human 24-hour dose of ribavirin).
Treatment and Posttreatment
Potential Risk to the Fetus
Ribavirin is known to accumulate in intracellular components from where it is cleared very slowly. It is not known whether ribavirin contained in sperm will exert a potential teratogenic effect upon fertilization of the ova. In a study in rats, it was concluded that dominant lethality was not induced by ribavirin at doses up to 200 mg/kg for 5 days (estimated human equivalent doses of 7.14 to 28.6 mg/kg, based on body surface area adjustment for a 60 kg adult; up to 1.7 times the maximum recommended human dose of ribavirin). However, because of the potential human teratogenic effects of ribavirin, male patients should be advised to take every precaution to avoid risk of pregnancy for their female partners.
Females of childbearing potential should not receive combination ribavirin capsules/INTRON A therapy unless they are using effective contraception (two reliable forms) during the therapy period. In addition, effective contraception should be utilized for 6 months posttherapy based on a multiple dose half-life (t) of ribavirin of 12 days.
Male patients and their female partners must practice effective contraception (two reliable forms) during treatment with combination ribavirin capsules/INTRON A therapy and for the 6-month posttherapy period (e.g., 15 half-lives for ribavirin clearance from the body).
If pregnancy occurs in a patient or partner of a patient during treatment or during the 6 months after treatment cessation, physicians are encouraged to report such cases by calling the Ribavirin Pregnancy Registry at (800) 593-2214.
Ribavirin Pregnancy Registry
A Ribavirin Pregnancy Registry has been established to monitor maternal-fetal outcomes of pregnancies in female patients and female partners of male patients exposed to ribavirin during treatment and for six months following cessation of treatment. Physicians and patients are encouraged to report such cases by calling the Ribavirin Pregnancy Registry at 1-800-593-2214.
Nursing Mothers
It is not known whether ribavirin capsules and INTRON A are excreted in human milk. However, studies in mice have shown that mouse interferons are excreted into the milk. Because of the potential for serious adverse reactions from the drugs in nursing infants, a decision should be made whether to discontinue nursing or to discontinue combination ribavirin capsules/INTRON A therapy, taking into account the importance of the therapy to the mother.
Pediatric Use
Suicidal ideation or attempts occurred more frequently among pediatric patients compared to adult patients (2.4% versus 1%) during treatment and off therapy follow-up (see ).
Injection site disorders, fever, anorexia, vomiting, and emotional lability occurred more frequently in pediatric patients compared to adult patients. Conversely, pediatric patients experienced less fatigue, dyspepsia, arthralgia, insomnia, irritability, impaired concentration, dyspnea, and pruritis compared to adult patients.
Geriatric Use
Clinical studies of combination therapy of ribavirin capsules taken together with INTRON A did not include sufficient numbers of subjects aged 65 and over to determine if they respond differently from younger subjects. In clinical trials, elderly subjects had a higher frequency of anemia (67%) than did younger patients (28%) (see ).
In general, ribavirin capsules should be administered to elderly patients cautiously, starting at the lower end of the dosing range, reflecting the greater frequency of decreased renal, hepatic and/or cardiac function, and of concomitant disease or other drug therapy.
Ribavirin capsules are known to be substantially excreted by the kidney, and the risk of adverse reactions to ribavirin may be greater in patients with impaired renal function. Because elderly patients often have decreased renal function, care should be taken in dose selection. Renal function should be monitored and dosage adjustments of ribavirin should be made accordingly (see ). Ribavirin capsules should not be used in elderly patients with creatinine clearance <50 mL/min (see ).
Ribavirin capsules taken together with INTRON A should be used very cautiously in elderly patients with a history of psychiatric disorders (see ).
What are the side effects of Ribavirin?
The safety of combination ribavirin capsules/INTRON A therapy was evaluated in controlled trials of 1010 HCV-infected adults who were previously untreated with interferon therapy and were subsequently treated for 24 or 48 weeks with combination ribavirin capsules/INTRON A therapy and in 173 HCV-infected patients who had relapsed after interferon therapy and were subsequently treated for 24 weeks with combination ribavirin capsules/INTRON A therapy. (See .) Overall, 19% and 6% of previously untreated and relapse patients, respectively, discontinued therapy due to adverse events in the combination arms compared to 13% and 3% in the interferon arms.
The primary toxicity of ribavirin is hemolytic anemia. Reductions in hemoglobin levels occurred within the first 1 to 2 weeks of therapy (see ). Cardiac and pulmonary events associated with anemia occurred in approximately 10% of patients treated with ribavirin capsules/INTRON A therapy. (See .)
The most common psychiatric events occurring in US studies of previously untreated and relapse patients treated with ribavirin capsules/INTRON A therapy, respectively, were insomnia (39%, 26%), depression (34%, 23%), and irritability (27%, 25%). Suicidal behavior (ideation, attempts, and suicides) occurred in 1% of patients. (See .) In addition, the following spontaneous adverse events have been reported during the marketing surveillance of ribavirin capsules/INTRON A therapy: hearing disorder and vertigo. Very rarely, combination ribavirin capsules/INTRON A therapy may be associated with aplastic anemia.
Selected treatment-emergent adverse events that occurred in the US studies with ≥5% incidence are provided in by treatment group. In general, the selected treatment-emergent adverse events reported with lower incidence in the international studies as compared to the US studies with the exception of asthenia, influenza-like symptoms, nervousness, and pruritus.
| Percentage of Patients | ||||||||
| US Previously Untreated Study | US Relapse Study | |||||||
| 24 weeks of treatment | 48 weeks of treatment | 24 weeks of treatment | ||||||
| Patients Reporting | Adverse Events | (N=228) | (N=231) | (N=228) | (N=225) | (N=77) | (N=76) | |
| Application Site Disorders | ||||||||
| Injection site inflammation | 13 | 10 | 12 | 14 | 6 | 8 | ||
| Injection site reaction | 7 | 9 | 8 | 9 | 5 | 3 | ||
| Body as a Whole – | General Disorders | |||||||
| Headache | 63 | 63 | 66 | 67 | 66 | 68 | ||
| Fatigue | 68 | 62 | 70 | 72 | 60 | 53 | ||
| Rigors | 40 | 32 | 42 | 39 | 43 | 37 | ||
| Fever | 37 | 35 | 41 | 40 | 32 | 36 | ||
| Influenza-like symptoms | 14 | 18 | 18 | 20 | 13 | 13 | ||
| Asthenia | 9 | 4 | 9 | 9 | 10 | 4 | ||
| Chest pain | 5 | 4 | 9 | 8 | 6 | 7 | ||
| Central & Peripheral | Nervous System Disorders | |||||||
| Dizziness | 17 | 15 | 23 | 19 | 26 | 21 | ||
| Gastrointestinal System Disorders | ||||||||
| Nausea | 38 | 35 | 46 | 33 | 47 | 33 | ||
| Anorexia | 27 | 16 | 25 | 19 | 21 | 14 | ||
| Dyspepsia | 14 | 6 | 16 | 9 | 16 | 9 | ||
| Vomiting | 11 | 10 | 9 | 13 | 12 | 8 | ||
| Percentage of Patients | ||||||||
| US Previously Untreated Study | US Relapse Study | |||||||
| 24 weeks of treatment | 48 weeks of treatment | 24 weeks of treatment | ||||||
| Patients Reporting | Adverse Events | Patients reporting one or more adverse events. A patient may have reported more than one adverse event within a body system/organ class category. | (N=228) | (N=231) | (N=228) | (N=225) | (N=77) | (N=76) |
| Musculoskeletal System Disorders | ||||||||
| Myalgia | 61 | 57 | 64 | 63 | 61 | 58 | ||
| Arthralgia | 30 | 27 | 33 | 36 | 29 | 29 | ||
| Musculoskeletal pain | 20 | 26 | 28 | 32 | 22 | 28 | ||
| Psychiatric Disorders | ||||||||
| Insomnia | 39 | 27 | 39 | 30 | 26 | 25 | ||
| Irritability | 23 | 19 | 32 | 27 | 25 | 20 | ||
| Depression | 32 | 25 | 36 | 37 | 23 | 14 | ||
| Emotional lability | 7 | 6 | 11 | 8 | 12 | 8 | ||
| Concentration impaired | 11 | 14 | 14 | 14 | 10 | 12 | ||
| Nervousness | 4 | 2 | 4 | 4 | 5 | 4 | ||
| Respiratory System Disorders | ||||||||
| Dyspnea | 19 | 9 | 18 | 10 | 17 | 12 | ||
| Sinusitis | 9 | 7 | 10 | 14 | 12 | 7 | ||
| Skin and Appendages Disorders | ||||||||
| Alopecia | 28 | 27 | 32 | 28 | 27 | 26 | ||
| Rash | 20 | 9 | 28 | 8 | 21 | 5 | ||
| Pruritus | 21 | 9 | 19 | 8 | 13 | 4 | ||
| Special Senses, Other Disorders | ||||||||
| Taste perversion | 7 | 4 | 8 | 4 | 6 | 5 |
Laboratory Values
Changes in selected hematologic values (hemoglobin, white blood cells, neutrophils, and platelets) during combination ribavirin capsules/INTRON A treatment are described below (see ).
Hemoglobin
Hemoglobin decreases among patients on combination therapy began at Week 1, with stabilization by Week 4. In previously untreated patients treated for 48 weeks the mean maximum decrease from baseline was 3.1 g/dL in the US study and 2.9 g/dL in the International study. In relapse patients the mean maximum decrease from baseline was 2.8 g/dL in the US study and 2.6 g/dL in the International study. Hemoglobin values returned to pretreatment levels within 4 to 8 weeks of cessation of therapy in most patients.
Neutrophils
There were decreases in neutrophil counts in both the combination ribavirin capsules/INTRON A and INTRON A plus placebo dose groups. In previously untreated patients treated for 48 weeks the mean maximum decrease in neutrophil count in the US study was 1.3x 10/L and in the International study was 1.5 x 10/L. In relapse patients the mean maximum decrease in neutrophil count in the US study was 1.3 x 10/L and in the International study was 1.6 x 10/L. Neutrophil counts returned to pretreatment levels within 4 weeks of cessation of therapy in most patients.
Platelets
In both previously untreated and relapse patients mean platelet counts generally remained in the normal range in all treatment groups, however, mean platelet counts were 10% to 15% lower in the INTRON A plus placebo group than the ribavirin capsules/INTRON A group. Mean platelet counts returned to baseline levels within 4 weeks after treatment discontinuation.
Thyroid Function
Of patients who entered the previously untreated (24 and 48 week treatment) and relapse (24 week treatment) studies without thyroid abnormalities, approximately 3% to 6% and 1% to 2%, respectively, developed thyroid abnormalities requiring clinical intervention.
Bilirubin and Uric Acid
Increases in both bilirubin and uric acid, associated with hemolysis, were noted in clinical trials. Most were moderate biochemical changes and were reversed within 4 weeks after treatment discontinuation. This observation occurs most frequently in patients with a previous diagnosis of Gilbert’s syndrome. This has not been associated with hepatic dysfunction or clinical morbidity.
| Percentage of Patients | ||||||
| US Previously Untreated Study | US Relapse Study | |||||
| 24 weeks of treatment | 48 weeks of treatment | 24 weeks of treatment | ||||
| plus Ribavirin (N=228) | plus Placebo (N=231) | plus Ribavirin (N=228) | plus Placebo (N=225) | plus Ribavirin (N=77) | plus Placebo (N=76) | |
| Hemoglobin (g/dL) | ||||||
| 9.5-10.9 | 24 | 1 | 32 | 1 | 21 | 3 |
| 8.0-9.4 | 5 | 0 | 4 | 0 | 4 | 0 |
| 6.5-7.9 | 0 | 0 | 0 | 0.4 | 0 | 0 |
| <6.5 | 0 | 0 | 0 | 0 | 0 | 0 |
| Leukocytes (x10/L) | ||||||
| 2.0-2.9 | 40 | 20 | 38 | 23 | 45 | 26 |
| 1.5-1.9 | 4 | 1 | 9 | 2 | 5 | 3 |
| 1.0-1.4 | 0.9 | 0 | 2 | 0 | 0 | 0 |
| <1.0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Neutrophils (x10/L) | ||||||
| 1.0-1.49 | 30 | 32 | 31 | 44 | 42 | 34 |
| 0.75-0.99 | 14 | 15 | 14 | 11 | 16 | 18 |
| 0.5-0.74 | 9 | 9 | 14 | 7 | 8 | 4 |
| <0.5 | 11 | 8 | 11 | 5 | 5 | 8 |
| Platelets (x10/L) | ||||||
| 70-99 | 9 | 11 | 11 | 14 | 6 | 12 |
| 50-69 | 2 | 3 | 2 | 3 | 0 | 5 |
| 30-49 | 0 | 0.4 | 0 | 0.4 | 0 | 0 |
| <30 | 0.9 | 0 | 1 | 0.9 | 0 | 0 |
| Total Bilirubin (mg/dL) | ||||||
| 1.5-3.0 | 27 | 13 | 32 | 13 | 21 | 7 |
| 3.1-6.0 | 0.9 | 0.4 | 2 | 0 | 3 | 0 |
| 6.1-12.0 | 0 | 0 | 0.4 | 0 | 0 | 0 |
| >12.0 | 0 | 0 | 0 | 0 | 0 | 0 |
What should I look out for while using Ribavirin?
Combination ribavirin capsules/INTRON A therapy must not be used by females who are pregnant or by males whose female partners are pregnant. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients taking combination ribavirin capsules/INTRON A therapy. Combination ribavirin capsules/INTRON A therapy should not be initiated until a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy. Females of childbearing potential and males must use two forms of effective contraception during treatment and during the 6 months after treatment has been concluded. Significant teratogenic and/or embryocidal effects have been demonstrated for ribavirin in all animal species in which adequate studies have been conducted. These effects occurred at doses as low as one twentieth of the recommended human dose of ribavirin capsules. If pregnancy occurs in a patient or partner of a patient during treatment or during the 6 months after treatment stops, physicians are encouraged to report such cases by calling the Ribavirin Pregnancy Registry at 1-800-593-2214.
Ribavirin capsules in combination with INTRON A Injection is contraindicated in patients with a history of hypersensitivity to ribavirin and/or alpha interferon or any component of the capsule and/or injection.
Patients with autoimmune hepatitis must not be treated with combination ribavirin capsules/INTRON A therapy.
What might happen if I take too much Ribavirin?
There is limited experience with overdosage. Acute ingestion of up to 20 grams of ribavirin capsules, INTRON A ingestion of up to 120 million units, and subcutaneous doses of INTRON A up to 10 times the recommended doses have been reported. Primary effects that have been observed are increased incidence and severity of the adverse events related to the therapeutic use of INTRON A and ribavirin capsules. However, hepatic enzyme abnormalities, renal failure, hemorrhage, and myocardial infarction have been reported with administration of single subcutaneous doses of INTRON A that exceed dosing recommendations.
There is no specific antidote for INTRON A or ribavirin capsules, and hemodialysis and peritoneal dialysis are not effective for treatment of overdose of either agent.
How should I store and handle Ribavirin?
Store at 25°C (77°F); excursions permitted to 15°C-30°C (59°F-86°F) [see USP Controlled Room Temperature].Ribavirin capsules, 200 mg are white, opaque, hard gelatin capsules imprinted (in blue) RIBAVIRIN over 200 mg on cap and GG 608 on body.They are supplied by as follows:Dispense in a tight container as defined in the USP.Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled Room Temperature].INTRON A Injection is a clear, colorless solution packaged in single dose and multidose vials, and a multidose pen.INTRON A Injection and the INTRON A Multidose Pen should be stored refrigerated between 2° and 8°C (36° and 46°F).INTRON® A is a registered trademark of Schering Corporation.Mylanta® is a registered trademark of Johnson & Johnson-Merck Consumer Pharmaceuticals Co.REBETOL® is a registered trademark of Schering Corporation.REBETRON® is a registered trademark of Schering Corporation.Ribavirin capsules, 200 mg are white, opaque, hard gelatin capsules imprinted (in blue) RIBAVIRIN over 200 mg on cap and GG 608 on body.They are supplied by as follows:Dispense in a tight container as defined in the USP.Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled Room Temperature].INTRON A Injection is a clear, colorless solution packaged in single dose and multidose vials, and a multidose pen.INTRON A Injection and the INTRON A Multidose Pen should be stored refrigerated between 2° and 8°C (36° and 46°F).INTRON® A is a registered trademark of Schering Corporation.Mylanta® is a registered trademark of Johnson & Johnson-Merck Consumer Pharmaceuticals Co.REBETOL® is a registered trademark of Schering Corporation.REBETRON® is a registered trademark of Schering Corporation.Ribavirin capsules, 200 mg are white, opaque, hard gelatin capsules imprinted (in blue) RIBAVIRIN over 200 mg on cap and GG 608 on body.They are supplied by as follows:Dispense in a tight container as defined in the USP.Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled Room Temperature].INTRON A Injection is a clear, colorless solution packaged in single dose and multidose vials, and a multidose pen.INTRON A Injection and the INTRON A Multidose Pen should be stored refrigerated between 2° and 8°C (36° and 46°F).INTRON® A is a registered trademark of Schering Corporation.Mylanta® is a registered trademark of Johnson & Johnson-Merck Consumer Pharmaceuticals Co.REBETOL® is a registered trademark of Schering Corporation.REBETRON® is a registered trademark of Schering Corporation.Ribavirin capsules, 200 mg are white, opaque, hard gelatin capsules imprinted (in blue) RIBAVIRIN over 200 mg on cap and GG 608 on body.They are supplied by as follows:Dispense in a tight container as defined in the USP.Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled Room Temperature].INTRON A Injection is a clear, colorless solution packaged in single dose and multidose vials, and a multidose pen.INTRON A Injection and the INTRON A Multidose Pen should be stored refrigerated between 2° and 8°C (36° and 46°F).INTRON® A is a registered trademark of Schering Corporation.Mylanta® is a registered trademark of Johnson & Johnson-Merck Consumer Pharmaceuticals Co.REBETOL® is a registered trademark of Schering Corporation.REBETRON® is a registered trademark of Schering Corporation.Ribavirin capsules, 200 mg are white, opaque, hard gelatin capsules imprinted (in blue) RIBAVIRIN over 200 mg on cap and GG 608 on body.They are supplied by as follows:Dispense in a tight container as defined in the USP.Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled Room Temperature].INTRON A Injection is a clear, colorless solution packaged in single dose and multidose vials, and a multidose pen.INTRON A Injection and the INTRON A Multidose Pen should be stored refrigerated between 2° and 8°C (36° and 46°F).INTRON® A is a registered trademark of Schering Corporation.Mylanta® is a registered trademark of Johnson & Johnson-Merck Consumer Pharmaceuticals Co.REBETOL® is a registered trademark of Schering Corporation.REBETRON® is a registered trademark of Schering Corporation.Ribavirin capsules, 200 mg are white, opaque, hard gelatin capsules imprinted (in blue) RIBAVIRIN over 200 mg on cap and GG 608 on body.They are supplied by as follows:Dispense in a tight container as defined in the USP.Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled Room Temperature].INTRON A Injection is a clear, colorless solution packaged in single dose and multidose vials, and a multidose pen.INTRON A Injection and the INTRON A Multidose Pen should be stored refrigerated between 2° and 8°C (36° and 46°F).INTRON® A is a registered trademark of Schering Corporation.Mylanta® is a registered trademark of Johnson & Johnson-Merck Consumer Pharmaceuticals Co.REBETOL® is a registered trademark of Schering Corporation.REBETRON® is a registered trademark of Schering Corporation.Ribavirin capsules, 200 mg are white, opaque, hard gelatin capsules imprinted (in blue) RIBAVIRIN over 200 mg on cap and GG 608 on body.They are supplied by as follows:Dispense in a tight container as defined in the USP.Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled Room Temperature].INTRON A Injection is a clear, colorless solution packaged in single dose and multidose vials, and a multidose pen.INTRON A Injection and the INTRON A Multidose Pen should be stored refrigerated between 2° and 8°C (36° and 46°F).INTRON® A is a registered trademark of Schering Corporation.Mylanta® is a registered trademark of Johnson & Johnson-Merck Consumer Pharmaceuticals Co.REBETOL® is a registered trademark of Schering Corporation.REBETRON® is a registered trademark of Schering Corporation.Ribavirin capsules, 200 mg are white, opaque, hard gelatin capsules imprinted (in blue) RIBAVIRIN over 200 mg on cap and GG 608 on body.They are supplied by as follows:Dispense in a tight container as defined in the USP.Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled Room Temperature].INTRON A Injection is a clear, colorless solution packaged in single dose and multidose vials, and a multidose pen.INTRON A Injection and the INTRON A Multidose Pen should be stored refrigerated between 2° and 8°C (36° and 46°F).INTRON® A is a registered trademark of Schering Corporation.Mylanta® is a registered trademark of Johnson & Johnson-Merck Consumer Pharmaceuticals Co.REBETOL® is a registered trademark of Schering Corporation.REBETRON® is a registered trademark of Schering Corporation.Ribavirin capsules, 200 mg are white, opaque, hard gelatin capsules imprinted (in blue) RIBAVIRIN over 200 mg on cap and GG 608 on body.They are supplied by as follows:Dispense in a tight container as defined in the USP.Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled Room Temperature].INTRON A Injection is a clear, colorless solution packaged in single dose and multidose vials, and a multidose pen.INTRON A Injection and the INTRON A Multidose Pen should be stored refrigerated between 2° and 8°C (36° and 46°F).INTRON® A is a registered trademark of Schering Corporation.Mylanta® is a registered trademark of Johnson & Johnson-Merck Consumer Pharmaceuticals Co.REBETOL® is a registered trademark of Schering Corporation.REBETRON® is a registered trademark of Schering Corporation.Ribavirin capsules, 200 mg are white, opaque, hard gelatin capsules imprinted (in blue) RIBAVIRIN over 200 mg on cap and GG 608 on body.They are supplied by as follows:Dispense in a tight container as defined in the USP.Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled Room Temperature].INTRON A Injection is a clear, colorless solution packaged in single dose and multidose vials, and a multidose pen.INTRON A Injection and the INTRON A Multidose Pen should be stored refrigerated between 2° and 8°C (36° and 46°F).INTRON® A is a registered trademark of Schering Corporation.Mylanta® is a registered trademark of Johnson & Johnson-Merck Consumer Pharmaceuticals Co.REBETOL® is a registered trademark of Schering Corporation.REBETRON® is a registered trademark of Schering Corporation.
Clinical Information
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Non-Clinical Toxicology
Combination ribavirin capsules/INTRON A therapy must not be used by females who are pregnant or by males whose female partners are pregnant. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients taking combination ribavirin capsules/INTRON A therapy. Combination ribavirin capsules/INTRON A therapy should not be initiated until a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy. Females of childbearing potential and males must use two forms of effective contraception during treatment and during the 6 months after treatment has been concluded. Significant teratogenic and/or embryocidal effects have been demonstrated for ribavirin in all animal species in which adequate studies have been conducted. These effects occurred at doses as low as one twentieth of the recommended human dose of ribavirin capsules. If pregnancy occurs in a patient or partner of a patient during treatment or during the 6 months after treatment stops, physicians are encouraged to report such cases by calling the Ribavirin Pregnancy Registry at 1-800-593-2214.Ribavirin capsules in combination with INTRON A Injection is contraindicated in patients with a history of hypersensitivity to ribavirin and/or alpha interferon or any component of the capsule and/or injection.
Patients with autoimmune hepatitis must not be treated with combination ribavirin capsules/INTRON A therapy.
Exacerbation of autoimmune disease has been reported in patients receiving alpha interferon therapy (including INTRON A therapy). Ribavirin capsules/INTRON A therapy should be used with caution in patients with other autoimmune disorders.
There have been reports of interferon, including INTRON A (interferon alfa-2b, recombinant) exacerbating pre-existing psoriasis; therefore, combination ribavirin capsules/INTRON A therapy should be used in these patients only if the potential benefit justifies the potential risk.
The safety and efficacy of ribavirin capsules/INTRON A therapy has not been established in liver or other organ transplant patients, decompensated hepatitis C patients, patients who are nonresponders to interferon therapy, or patients coinfected with HBV or HIV.
The safety and efficacy of ribavirin capsules monotherapy for the treatment of HIV infection, adenovirus, early RSV infection, parainfluenza, or influenza have not been established and ribavirin capsules should not be used for these indications.
There is no information regarding the use of ribavirin capsules with other interferons.
The safety of combination ribavirin capsules/INTRON A therapy was evaluated in controlled trials of 1010 HCV-infected adults who were previously untreated with interferon therapy and were subsequently treated for 24 or 48 weeks with combination ribavirin capsules/INTRON A therapy and in 173 HCV-infected patients who had relapsed after interferon therapy and were subsequently treated for 24 weeks with combination ribavirin capsules/INTRON A therapy. (See .) Overall, 19% and 6% of previously untreated and relapse patients, respectively, discontinued therapy due to adverse events in the combination arms compared to 13% and 3% in the interferon arms.
The primary toxicity of ribavirin is hemolytic anemia. Reductions in hemoglobin levels occurred within the first 1 to 2 weeks of therapy (see ). Cardiac and pulmonary events associated with anemia occurred in approximately 10% of patients treated with ribavirin capsules/INTRON A therapy. (See .)
The most common psychiatric events occurring in US studies of previously untreated and relapse patients treated with ribavirin capsules/INTRON A therapy, respectively, were insomnia (39%, 26%), depression (34%, 23%), and irritability (27%, 25%). Suicidal behavior (ideation, attempts, and suicides) occurred in 1% of patients. (See .) In addition, the following spontaneous adverse events have been reported during the marketing surveillance of ribavirin capsules/INTRON A therapy: hearing disorder and vertigo. Very rarely, combination ribavirin capsules/INTRON A therapy may be associated with aplastic anemia.
Selected treatment-emergent adverse events that occurred in the US studies with ≥5% incidence are provided in by treatment group. In general, the selected treatment-emergent adverse events reported with lower incidence in the international studies as compared to the US studies with the exception of asthenia, influenza-like symptoms, nervousness, and pruritus.
Reference
This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
"https://dailymed.nlm.nih.gov/dailymed/"
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