Ribavirin, usp capsules

  • Ribavirin monotherapy is not effective for the treatment of chronic hepatitis C virus infection and should not be used alone for this indication. (See WARNINGS .)
  • The primary toxicity of ribavirin is hemolytic anemia. The anemia associated with ribavirin therapy may result in worsening of cardiac disease that has led to fatal and nonfatal myocardial infarctions. Patients with a history of significant or unstable cardiac disease should not be treated with ribavirin. (See WARNINGS , ADVERSE REACTIONS , and DOSAGE AND ADMINISTRATION .)
  • Significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin. In addition, ribavirin has a multiple-dose half-life of 12 days, and so it may persist in nonplasma compartments for as long as 6 months. Therefore, ribavirin therapy is contraindicated in women who are pregnant and in the male partners of women who are pregnant. Extreme care must be taken to avoid pregnancy during therapy and for 6 months after completion of treatment in both female patients and in female partners of male patients who are taking ribavirin therapy. At least two reliable forms of effective contraception must be utilized during treatment and during the 6-month posttreatment follow-up period. (See CONTRAINDICATIONS , WARNINGS , PRECAUTIONS - Information for Patients and Pregnancy Category X .)

Description

Ribavirin is a nucleoside analog. The chemical name of ribavirin is 1-(beta)-D-ribofuranosyl-1 H -1,2,4-triazole-3-carboxamide and has the following structural formula:

images/17/40057001.jpg

Ribavirin is a white, crystalline powder. It is freely soluble in water and slightly soluble in anhydrous alcohol. The empirical formula is C 8 H 12 N 4 O 5 and the molecular weight is 244.21.

Ribavirin Capsules consist of a white powder in a white, opaque, gelatin capsule. Each capsule contains 200 mg ribavirin and the inactive ingredients microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, and magnesium stearate. The capsule shell consists of gelatin, sodium lauryl sulfate, silicon dioxide, and titanium dioxide. The capsule is printed with edible blue pharmaceutical ink which is made of shellac, anhydrous ethyl alcohol, isopropyl alcohol, n-butyl alcohol, propylene glycol, ammonium hydroxide, and FD&C Blue #2 aluminum lake.

Mechanism of Action

The mechanism of inhibition of hepatitis C virus (HCV) RNA by combination therapy with interferon products has not been established.

Clinical Pharmacology

Pharmacokinetics

Ribavirin   Single- and multiple-dose pharmacokinetic properties in adults with chronic hepatitis C are summarized in TABLE 1 . Ribavirin was rapidly and extensively absorbed following oral administration. However, due to first-pass metabolism, the absolute bioavailability averaged 64% (44%). There was a linear relationship between dose and AUC tf (AUC from time zero to last measurable concentration) following single doses of 200-1200 mg ribavirin. The relationship between dose and C max was curvilinear, tending to asymptote above single doses of 400-600 mg.

Upon multiple oral dosing, based on AUC12 hr , a sixfold accumulation of ribavirin was observed in plasma. Following oral dosing with 600 mg BID, steady-state was reached by approximately 4 weeks, with mean steady-state plasma concentrations of 2200 (37%) ng/mL. Upon discontinuation of dosing, the mean half-life was 298 (30%) hours, which probably reflects slow elimination from nonplasma compartments.

Effect of Food on Absorption of Ribavirin   Both AUC tf and C max increased by 70% when Ribavirin Capsules were administered with a high-fat meal (841 kcal, 53.8 g fat, 31.6 g protein, and 57.4 g carbohydrate) in a single-dose pharmacokinetic study. There are insufficient data to address the clinical relevance of these results. Clinical efficacy studies with Ribavirin/INTRON A were conducted without instructions with respect to food consumption. During clinical studies with Ribavirin/PEG-INTRON, all subjects were instructed to take Ribavirin Capsules with food. (See DOSAGE AND ADMINISTRATION .)

Effect of Antacid on Absorption of Ribavirin   Coadministration with an antacid containing magnesium, aluminum, and simethicone (Mylanta 1 ) resulted in a 14% decrease in mean ribavirin AUC tf . The clinical relevance of results from this single-dose study is unknown.

TABLE 1. Mean (% CV) Pharmacokinetic Parameters
for Ribavirin When Administered Individually to Adults
with Chronic Hepatitis C
Parameter
Ribavirin (N=12)
Single Dose
600 mg
Multiple Dose
600 mg BID
T max (hr)
1.7 (46) *** 3 (60)
C max *
782 (37) 3680 (85)
AUC tf **
13400 (48) 228000 (25)
T 1/2 (hr)
43.6 (47) 298 (30)
Apparent Volume of Distribution (L)
2825 (9) **/*    
Apparent Clearance (L/hr)
38.2 (40)     
Absolute Bioavailability
64% (44) #    
*ng/mL
**ng.hr/mL
***N = 11
**/* data obtained from a single-dose pharmacokinetic study using 14 C labeled ribavirin; N = 5
# N = 6

Ribavirin transport into nonplasma compartments has been most extensively studied in red blood cells, and has been identified to be primarily via an e s -type equilibrative nucleoside transporter. This type of transporter is present on virtually all cell types and may account for the extensive volume of distribution. Ribavirin does not bind to plasma proteins.

Ribavirin has two pathways of metabolism: (i) a reversible phosphorylation pathway in nucleated cells; and (ii) a degradative pathway involving deribosylation and amide hydrolysis to yield a triazole carboxylic acid metabolite. Ribavirin and its triazole carboxamide and triazole carboxylic acid metabolites are excreted renally. After oral administration of 600 mg of 14 C-ribavirin, approximately 61% and 12% of the radioactivity was eliminated in the urine and feces, respectively, in 336 hours. Unchanged ribavirin accounted for 17% of the administered dose.

Results of in vitro studies using both human and rat liver microsome preparations indicated little or no cytochrome P450 enzyme-mediated metabolism of ribavirin, with minimal potential for P450 enzyme-based drug interactions.

No pharmacokinetic interactions were noted between INTRON A Injection and Ribavirin Capsules in a multiple-dose pharmacokinetic study.

1. Trademark of Johnson & Johnson-Merck Consumer Pharmaceuticals Co.

Special Populations

Renal Dysfunction   The pharmacokinetics of ribavirin were assessed after administration of a single oral dose (400 mg) of ribavirin to non HCV-infected subjects with varying degrees of renal dysfunction. The mean AUC tf value was threefold greater in subjects with creatinine clearance values between 10 to 30 mL/min when compared to control subjects (creatinine clearance >90 mL/min). In subjects with creatinine clearance values between 30 to 60 mL/min, AUC tf was twofold greater when compared to control subjects. The increased AUC tf appears to be due to reduction of renal and non-renal clearance in these patients. Phase III efficacy trials included subjects with creatinine clearance values >50 mL/min. The multiple dose pharmacokinetics of ribavirin cannot be accurately predicted in patients with renal dysfunction. Ribavirin is not effectively removed by hemodialysis. Patients with creatinine clearance <50 mL/min should not be treated with ribavirin (See WARNINGS .)

Hepatic Dysfunction   The effect of hepatic dysfunction was assessed after a single oral dose of ribavirin (600 mg). The mean AUC tf values were not significantly different in subjects with mild, moderate, or severe hepatic dysfunction (Child-Pugh Classification A, B, or C) when compared to control subjects. However, the mean C max values increased with severity of hepatic dysfunction and was twofold greater in subjects with severe hepatic dysfunction when compared to control subjects.

Pediatric Patients   Pharmacokinetic evaluations in pediatric subjects have not been performed.

Elderly Patients   Pharmacokinetic evaluations in elderly subjects have not been performed.

Gender   There were no clinically significant pharmacokinetic differences noted in a single-dose study of eighteen male and eighteen female subjects.

*In this section of the label, numbers in parenthesis indicate % coefficient of variation.

Indications and Usage

Ribavirin, USP Capsules are indicated in combination with INTRON A (interferon alfa-2b, recombinant) Injection for the treatment of chronic hepatitis C in patients with compensated liver disease previously untreated with alpha interferon or who have relapsed following alpha interferon therapy.

Ribavirin Capsules are indicated in combination with PEG-INTRON (peg-interferon alfa-2b, recombinant) Injection for the treatment of chronic hepatitis C in patients with compensated liver disease who have not been previously treated with interferon alpha and are at least 18 years of age.

The safety and efficacy of Ribavirin Capsules with interferons other than INTRON A or PEG-INTRON products have not been established.

Description of Clinical Studies

Ribavirin/INTRON A Combination Therapy

Previously Untreated Patients

Adults with compensated chronic hepatitis C and detectable HCV RNA (assessed by a central laboratory using a research-based RT-PCR assay) who were previously untreated with alpha interferon therapy were enrolled into two multicenter, double-blind trials (US and International) and randomized to receive Ribavirin Capsules 1200 mg/day (1000 mg/day for patients weighing </=75 kg) plus INTRON A Injection 3 MIU TIW or INTRON A Injection plus placebo for 24 or 48 weeks followed by 24 weeks of off-therapy follow-up. The International study did not contain a 24-week INTRON A plus placebo treatment arm. The US study enrolled 912 patients who, at baseline, were 67% male, 89% Caucasian with a mean Knodell HAI score (I+II+III) of 7.5, and 72% genotype 1. The International study, conducted in Europe, Israel, Canada, and Australia, enrolled 799 patients (65% male, 95% Caucasian, mean Knodell score 6.8, and 58% genotype 1).

Study results are summarized in TABLE 2 .

TABLE 2. Virologic and Histologic Responses:
Previously Untreated Patients *
US Study
24 weeks
of treatment
48 weeks
of treatment
INTRON A
plus
Ribavirin
(N=228)
INTRON A
plus
Placebo
(N=231)
INTRON A
plus
Ribavirin
(N=228)
INTRON A
plus
Placebo
(N=225)
Virologic Response
-Responder 1
65 (29) 13 (6) 85 (37) 27 (12)
-Nonresponder
147 (64) 194 (84) 110 (48) 168 (75)
-Missing Data
16 (7) 24 (10) 33 (14) 30 (13)
Histologic Response
-Improvement 2
102 (45) 77 (33) 96 (42) 65 (29)
-No improvement
77 (34) 99 (43) 61 (27) 93 (41)
-Missing Data
49 (21) 55 (24) 71 (31) 67 (30)
International Study
24 weeks
of treatment
48 weeks
of treatment
INTRON A
plus
Ribavirin
(N=265)
INTRON A
plus
Ribavirin
(N=268)
INTRON A
plus
Placebo
(N=266)
Virologic Response
-Responder 1
 86 (32) 113 (42) 46 (17)
-Nonresponder
158 (60) 120 (45) 196 (74)
-Missing Data
21 (8) 35 (13) 24 (9)
Histologic Response
-Improvement 2
103 (39) 102 (38) 69 (26)
-No improvement
 85 (32) 58 (22) 111 (41)
-Missing Data
 77 (29) 108 (40) 86 (32)
* Number (%) of patients.
1. Defined as HCV RNA below limit of detection using a research based RT-PCR assay at end of treatment and during follow-up period.
2. Defined as posttreatment (end of follow-up) minus pretreatment liver biopsy Knodell HAI score (I+II+III) improvement of >/=2 points.

Of patients who had not achieved HCV RNA below the limit of detection of the research based assay by week 24 of Ribavirin/INTRON A treatment, less than 5% responded to an additional 24 weeks of combination treatment.

Among patients with HCV Genotype 1 treated with Ribavirin/INTRON A therapy who achieved HCV RNA below the detection limit of the research-based assay by 24 weeks, those randomized to 48 weeks of treatment had higher virologic responses compared to those in the 24 week treatment group. There was no observed increase in response rates for patients with HCV nongenotype 1 randomized to Ribavirin/INTRON A therapy for 48 weeks compared to 24 weeks.

Relapse Patients

Patients with compensated chronic hepatitis C and detectable HCV RNA (assessed by a central laboratory using a research-based RT-PCR assay) who had relapsed following one or two courses of interferon therapy (defined as abnormal serum ALT levels) were enrolled into two multicenter, double-blind trials (US and International) and randomized to receive ribavirin 1200 mg/day (1000 mg/day for patients weighing </=75 kg) plus INTRON A 3 MIU TIW or INTRON A plus placebo for 24 weeks followed by 24 weeks of off-therapy follow-up. The US study enrolled 153 patients who, at baseline, were 67% male, 92% Caucasian with a mean Knodell HAI score (I+II+III) of 6.8, and 58% genotype 1. The International study, conducted in Europe, Israel, Canada, and Australia, enrolled 192 patients (64% male, 95% Caucasian, mean Knodell score 6.6, and 56% genotype 1).

Study results are summarized in TABLE 3 .

TABLE 3. Virologic and Histologic Responses:
Relapse Patients *
US Study International Study
INTRON A
plus
Ribavirin
(N=77)
INTRON A
plus
Placebo
(N=76)
INTRON A
plus
Ribavirin
(N=96)
INTRON A
plus
Placebo
(N=96)
Virologic Response
-Responder 1
33 (43) 3 (4) 46 (48) 5 (5)
-Nonresponder
36 (47) 66 (87) 45 (47) 91 (95)
-Missing Data
8 (10) 7 (9) 5 (5) 0 (0)
Histologic Response
-Improvement 2
38 (49) 27 (36) 49 (51) 30 (31)
-No improvement
23 (30) 37 (49) 29 (30) 44 (46)
-Missing Data
16 (21) 12 (16) 18 (19) 22 (23)
* Number (%) of patients.
1. Defined as HCV RNA below limit of detection using a research based RT-PCR assay at end of treatment and during follow-up period.
2. Defined as posttreatment (end of follow-up) minus pretreatment liver biopsy Knodell HAI score (I+II+III) improvement of >/=2 points.

Virologic and histologic responses were similar among male and female patients in both the previously untreated and relapse studies.

Ribavirin/PEG-INTRON Combination Therapy

A randomized study compared treatment with two PEG-INTRON/Ribavirin regimens [PEG-INTRON 1.5 µg/kg SC once weekly (QW)/Ribavirin 800 mg PO daily (in divided doses); PEG-INTRON 1.5 µg/kg SC QW for 4 weeks then 0.5 µg/kg SC QW for 44 weeks/ Ribavirin 1000/1200 mg PO daily (in divided doses)] with INTRON A [3 MIU SC thrice weekly (TIW)/Ribavirin 1000/1200 mg PO daily (in divided doses)] in 1530 adults with chronic hepatitis C. Interferon na[iuml ]ve patients were treated for 48 weeks and followed for 24 weeks post-treatment. Eligible patients had compensated liver disease, detectable HCV RNA, elevated ALT, and liver histopathology consistent with chronic hepatitis.

Response to treatment was defined as undetectable HCV RNA at 24 weeks posttreatment (See Table 4 ).

TABLE 4. Rates of Response to Combination Treatment
PEG-INTRON 1.5µg/kg QW Ribavirin 800 mg QD INTRON A 3 MIU TIW
Ribavirin 1000/1200 mg QD
Overall 1 , 2 response
52% (264/511) 46% (231/505)
Genotype 1
41% (141/348) 33% (112/343)
Genotype 2-6
75% (123/163) 73% (119/162)
1. Serum HCV RNA was measured with a research-based quantitative polymerase chain reaction assay by a central laboratory.
2. Difference in overall treatment response (PEG-INTRON/Ribavirin vs. INTRON A/Ribavirin) is 6% with 95% confidence interval of (0.18, 11.63) adjusted for viral genotype and presence of cirrhosis at baseline.

The response rate to PEG-INTRON 1.5->0.5µg/kg/Ribavirin was essentially the same as the response to INTRON A/Ribavirin (data not shown).

Patients with viral genotype 1, regardless of viral load, had a lower response rate to PEG-INTRON (1.5 µg/kg)/Ribavirin combination therapy compared to patients with other viral genotypes. Patients with both poor prognostic factors (genotype 1 and high viral load) had a response rate of 30% (78/256) compared to a response rate of 29% (71/247) with INTRON A/Ribavirin combination therapy.

Patients with lower body weight tended to have higher adverse event rates (see ADVERSE REACTIONS ) and higher response rates than patients with higher body weights. Differences in response rates between treatment arms did not substantially vary with body weight.

Treatment response rates with PEG-INTRON/Ribavirin combination therapy were 49% in men and 56% in women. Response rates were lower in African American and Hispanic patients and higher in Asians compared to Caucasians. Although African Americans had a higher proportion of poor prognostic factors compared to Caucasians the number of non-Caucasians studied (11% of the total) was insufficient to allow meaningful conclusions about differences in response rates after adjusting for prognostic factors.

Liver biopsies were obtained before and after treatment in 68% of patients. Compared to baseline approximately 2 / 3 of patients in all treatment groups were observed to have a modest reduction in inflammation.

Contraindications

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 WARNINGS , PRECAUTIONS - Information for Patients and Pregnancy Category X .) 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 (eg, thalassemia major, sickle-cell anemia) should not be treated with Ribavirin Capsules.

Warnings

Based on results of clinical trials ribavirin monotherapy is not effective for the treatment of chronic hepatitis C virus infection; therefore, Ribavirin Capsules must not be used alone. The safety and efficacy of Ribavirin Capsules have only been established when used together with INTRON A (interferon alfa-2b, recombinant) as REBETRON Combination Therapy or with PEG-INTRON Injection.

There are significant adverse events caused by Ribavirin/INTRON A or PEG-INTRON therapy, including severe depression and suicidal ideation, hemolytic anemia, suppression of bone marrow function, autoimmune and infectious disorders, pulmonary dysfunction, pancreatitis, and diabetes. The REBETRON Combination Therapy and PEG-INTRON package inserts should be reviewed in their entirety prior to initiation of combination treatment for additional safety information.

Pregnancy

Ribavirin Capsules 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. Ribavirin has demonstrated significant teratogenic and/or embryocidal effects 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. RIBAVIRIN THERAPY SHOULD NOT BE STARTED UNTIL A REPORT OF A NEGATIVE PREGNANCY TEST HAS BEEN OBTAINED IMMEDIATELY PRIOR TO PLANNED INITIATION OF THERAPY. Patients should be instructed to use at least two forms of effective contraception during treatment and during the six month period after treatment has been stopped based on multiple dose half-life of ribavirin of 12 days. Pregnancy testing should occur monthly during ribavirin therapy and for six months after therapy has stopped (see CONTRAINDICATIONS and PRECAUTIONS : Information for Patients and Pregnancy Category X ).

Anemia

The primary toxicity of ribavirin is hemolytic anemia, which was observed in approximately 10% of Ribavirin/INTRON A-treated patients in clinical trials (See ADVERSE REACTIONS : Laboratory Values - Hemoglobin ). The anemia associated with ribavirin capsules occurs within 1-2 weeks of initiation of therapy. BECAUSE THE INITIAL DROP IN HEMOGLOBIN MAY BE SIGNIFICANT, IT IS ADVISED THAT HEMOGLOBIN OR HEMATOCRIT 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.

Fatal and nonfatal myocardial infarctions have been reported in patients with anemia caused by Ribavirin. Patients should be assessed for underlying cardiac disease before initiation of ribavirin therapy. Patients with pre-existing cardiac disease should have electrocardiograms administered before treatment, and should be appropriately monitored during therapy. If there is any deterioration of cardiovascular status, therapy should be suspended or discontinued. (See DOSAGE AND ADMINISTRATION : Guidelines for Dose Modification .) Because cardiac disease may be worsened by drug induced anemia, patients with a history of significant or unstable cardiac disease should not use ribavirin. (See ADVERSE REACTIONS .)

Ribavirin and INTRON A or PEG-INTRON therapy should be suspended in patients with signs and symptoms of pancreatitis and discontinued in patients with confirmed pancreatitis.

Ribavirin should not be used in patients with creatinine clearance <50 mL/min. (See Clinical Pharmacology , Special Populations .)

Pulmonary

Pulmonary symptoms, including dyspnea, pulmonary infiltrates, pneumonitis and pneumonia, have been reported during therapy with Ribavirin/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/INTRON A treatment should be discontinued.

Precautions

The safety and efficacy of Ribavirin/INTRON A and PEG-INTRON therapy for the treatment of HIV infection, adenovirus, RSV, parainfluenza, or influenza infections have not been established. Ribavirin Capsules should not be used for these indications. Ribavirin for inhalation has a separate package insert, which should be consulted if ribavirin inhalation therapy is being considered.

The safety and efficacy of Ribavirin/INTRON A therapy has not been established in liver or other organ transplant patients, patients with decompensated liver disease due to hepatitis C infection, patients who are nonresponders to interferon therapy, or patients coinfected with HBV or HIV.

Information for Patients

Patients must be informed that Ribavirin Capsules may cause birth defects and/or death of the exposed fetus. Ribavirin must not be used by women who are pregnant or by men whose female partners are pregnant. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients taking ribavirin. Ribavirin 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. Women 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 ribavirin and for 6 months posttherapy. Patients (male and female) should be advised to notify the physician immediately in the event of a pregnancy. (See CONTRAINDICATIONS and WARNINGS .)

If pregnancy does occur during treatment or during 6 months post-therapy, the patient must be advised of the teratogenic risk of ribavirin 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 should report such cases by calling 1-800-727-7064.

Patients receiving Ribavirin Capsules should be informed of the benefits and risks associated with treatment, directed in its appropriate use, and referred to the patient MEDICATION GUIDE . Patients should be informed that the effect of treatment of hepatitis C infection on transmission is not known, and that appropriate precautions to prevent transmission of the hepatitis C virus should be taken.

The most common adverse experience occurring with Ribavirin Capsules is anemia, which may be severe. (See ADVERSE REACTIONS .) Patients should be advised that laboratory evaluations are required prior to starting therapy and periodically thereafter. (See Laboratory Tests .) 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 treated with Ribavirin Capsules, prior to beginning treatment and then periodically thereafter.

  • Standard hematologic tests - including hemoglobin (pretreatment, week 2 and week 4 of therapy, and as clinically appropriate [see WARNINGS ]), complete and differential white blood cell counts, and platelet count.
  • Blood chemistries - liver function tests and TSH.
  • Pregnancy - including monthly monitoring for women of childbearing potential.
  • ECG (See WARNINGS )

Carcinogenesis and Mutagenesis   Adequate studies to assess the carcinogenic potential of ribavirin in animals have not been conducted. However, ribavirin is a nucleoside analogue that has produced positive findings in multiple in vitro and animal in vivo genotoxicity assays, and should be considered a potential carcinogen. Further studies to assess the carcinogenic potential of ribavirin in animals are ongoing.

Ribavirin demonstrated increased incidences of mutation and cell transformation in multiple genotoxicity assays. Ribavirin was active in the Balb/3T3 In Vitro Cell Transformation Assay. Mutagenic activity was observed in the mouse lymphoma assay, and at doses of 20-200 mg/kg (estimated human equivalent of 1.67-16.7 mg/kg, based on body surface area adjustment for a 60 kg adult; 0.1-1 × 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   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 women and partners of fertile women should not receive ribavirin unless the patient and his/her partner are using effective contraception (two reliable forms). Based on a multiple dose half-life (t 1/2 ) of ribavirin of 12 days, effective contraception must be utilized for 6 months posttherapy (eg, 15 half-lives of clearance for ribavirin).

Ribavirin should be used with caution in fertile men. 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 1.25-12.5 mg/kg/day, based on body surface area adjustment for a 60 kg adult; 0.1-0.8 × 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 (18-24 months; doses of 20-75 and 10-40 mg/kg/day, respectively {estimated human equivalent doses of 1.67-6.25 and 1.43-5.71 mg/ kg/day, respectively, based on body surface area adjustment for a 60 kg adult; approximately 0.1-0.4 × 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 CONTRAINDICATIONS )

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 × 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 × 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 7.14-28.6 mg/kg, based on body surface area adjustment for a 60 kg adult; up to 1.7 × 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.

Women of childbearing potential should not receive ribavirin 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 1/2 ) of ribavirin of 12 days. Male patients and their female partners must practice effective contraception (two reliable forms) during treatment with ribavirin and for the 6-month posttherapy period (eg, 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 should report such cases by calling 1-800-727-7064.

Nursing Mothers   It is not known whether the ribavirin product is excreted in human milk. Because of the potential for serious adverse reactions from the drug in nursing infants, a decision should be made whether to discontinue nursing or to delay or discontinue ribavirin.

Geriatric Use   Clinical studies of Ribavirin/INTRON A or PEG-INTRON therapy did not include sufficient numbers of subjects aged 65 and over to determine if they respond differently from younger subjects.

Ribavirin is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug 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 should be made accordingly. Ribavirin should not be used in patients with creatinine clearance <50 mL/min. (See WARNINGS .)

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 hepatic and/or cardiac function, and of concomitant disease or other drug therapy. In clinical trials, elderly subjects had a higher frequency of anemia (67%) than did younger patients (28%). (See WARNINGS .)

Pediatric Use   Safety and effectiveness in pediatric patients have not been established.

Adverse Reactions

The primary toxicity of ribavirin is hemolytic anemia. Reductions in hemoglobin levels occurred within the first 1-2 weeks of oral therapy. (See WARNINGS .) Cardiac and pulmonary events associated with anemia occurred in approximately 10% of patients. (See WARNINGS .)

Ribavirin/INTRON A Combination Therapy

In clinical trials, 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. Selected treatment-emergent adverse events that occurred in the US studies with >/=5% incidence are provided in TABLE 5 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.

TABLE 5. Selected Treatment-Emergent Adverse Events:
Previously Untreated and Relapse Patients
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 *
INTRON A plus
Ribavirin (N=228)
INTRON A plus
Placebo (N=231)
INTRON A plus
Ribavirin (N=228)
INTRON A plus
Placebo (N=225)
INTRON A plus
Ribavirin (N=77)
INTRON A plus
Placebo (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
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
*Patients reporting one or more adverse events. A patient may have reported more than one adverse event within a body system/organ class category.

In addition, the following spontaneous adverse events have been reported during the marketing surveillance of Ribavirin/INTRON A therapy: hearing disorder and vertigo.

Ribavirin/PEG-INTRON Combination Therapy

Overall, in clinical trials, 14% of patients receiving ribavirin in combination with PEG-INTRON, discontinued therapy compared with 13% treated with ribavirin in combination with INTRON A. The most common reasons for discontinuation of therapy were related to psychiatric, systemic (eg, fatigue, headache), or gastrointestinal adverse events. Adverse events that occurred in clinical trial at >5% incidence are provided in Table 6 by treatment group.

TABLE 6. Adverse Events Occurring in > 5% of Patients
Percentage of Patients
Reporting Adverse Events *
Adverse
Events
PEG-INTRON
1.5 µg/kg/Ribavirin
(N=511)
INTRON A/
Ribavirin
(N=505)
Application Site
  Injection Site
    Inflammation
25 18
  Injection Site Reaction
58 36
Autonomic Nervous
System
  Mouth Dry
12 8
  Sweating Increased
11 7
  Flushing
4 3
Body as a Whole
  Fatigue/Asthenia
66 63
  Headache
62 58
  Rigors
48 41
  Fever
46 33
  Weight Decrease
29 20
  RUO Pain
12 6
  Chest Pain
8 7
  Malaise
4 6
Central/Peripheral Nervous
System
  Dizziness
21 17
Endocrine
  Hypothyroidism
5 4
Gastrointestinal
  Nausea
43 33
  Anorexia
32 27
  Diarrhea
22 17
  Vomiting
14 12
  Abdominal Pain
13 13
  Dyspepsia
9 8
  Constipation
5 5
Hematologic Disorders
  Neutropenia
26 14
  Anemia
12 17
  Leukopenia
6 5
  Thrombocytopenia
5 2
Liver and Biliary System
  Hepatomegaly
4 4
Musculoskeletal
  Myalgia
56 50
  Arthralgia
34 28
  Musculoskeletal Pain
21 19
Psychiatric
  Insomnia
40 41
  Depression
31 34
  Anxiety/Emotional
    Lability/Irritability
47 47
  Concentration Impaired
17 21
  Agitation
8 5
  Nervousness
6 6
Reproductive, Female
  Menstrual Disorder
7 6
Resistance Mechanism
  Infection Viral
12 12
  Infection Fungal
6 1
Respiratory System
  Dyspnea
26 24
  Coughing
23 16
  Pharyngitis
12 13
  Rhinitis
8 6
  Sinusitis
6 5
Skin and Appendages
  Alopecia
36 32
  Pruritus
29 28
  Rash
24 23
  Skin Dry
24 23
Special Senses, Other
  Taste Perversion
9 4
Vision Disorders
  Vision Blurred
5 6
  Conjunctivitis
4 5
*Patients reporting one or more adverse events. A patient may have reported more than one adverse event within a body system/organ class category.

Laboratory Values

Ribavirin/INTRON A Combination Therapy

Changes in selected hematologic values (hemoglobin, white blood cells, neutrophils, and platelets) during therapy are described below. (See TABLE 7 .)

Hemoglobin   Hemoglobin decreases among patients receiving ribavirin 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 4-8 weeks of cessation of therapy in most patients.

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.

TABLE 7. Selected Hematologic Values During Treatment with
Ribavirin plus INTRON A:

Previously Untreated and Relapse Patients
     Percentage of Patients
US Previously
Untreated Study
US Relapse
Study
24 weeks
of treatment
48 weeks
of treatment
24 weeks
of treatment
INTRON A
plus
Ribavirin
(N=228)
INTRON A
plus
Placebo
(N=231)
INTRON A
plus
Ribavirin
(N=228)
INTRON A
plus
Placebo
(N=225)
INTRON A
plus
Ribavirin
(N=77)
INTRON A
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 ( × 10 9 /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 ( × 10 9 /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 ( × 10 9 /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

Ribavirin/PEG-INTRON Combination Therapy

Changes in selected hematologic values (hemoglobin, white blood cells, neutrophils, and platelets) during therapy are described below. (See TABLE 8 .)

Hemoglobin

Ribavirin induced a decrease in hemoglobin levels in approximately two thirds of patients. Hemoglobin levels decreased to <11g/dL in about 30% of patients. Severe anemia (<8 g/dL) occurred in <1% of patients. Dose modification was required in 9 and 13% of patients in the PEG-INTRON/Ribavirin and INTRON A/Ribavirin groups.

Bilirubin and Uric

In the Ribavirin/PEG-INTRON combination trial 10-14% of patients developed hyperbilirubenemia and 33-38% developed hyperuricemia in association with hemolysis. Six patients developed mild to moderate gout.

TABLE 8. Selected Hematologic Values During
Treatment with Ribavirin plus PEG-INTRON
    Number (%) of Subjects
PEG-INTRON
plus
Ribavirin
(N=511)
INTRON A
plus
Ribavirin
(N=505)
Hemoglobin (g/dL)
  9.5-10.9 26 27
  8.0-9.4 3 3
  6.5-7.9 0.2 0.2
  <6.5 0 0
Leukocytes ( × 10 9 /L)
  2.0-2.9 46 41
  1.5-1.9 24 8
  1.0-1.4 5 1
  <1.0 0 0
Neutrophils ( × 10 9 /L)
  1.0-1.49 33 37
  0.75-0.99 25 13
  0.5-0.74 18 7
  <0.5 4 2
Platelets ( × 10 9 /L)
  70-99 15 5
  50-69 3 0.8
  30-49 0.2 0.2
  <30 0 0
Total Bilirubin (mg/dL)
  1.5-3.0 10 13
  3.1-6.0 0.6 0.2
  6.1-12.0 0 0.2
  >12.0 0 0
ALT (SGPT)
  2 × Baseline 0.6 0.2
  2.1-5 × Baseline 3 1
  5.1-10 × Baseline 0 0
  >10 × Baseline 0 0

Overdosage

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. 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, and hemodialysis and peritoneal dialysis are not effective for treatment of overdose of either agent.

DOSAGE AND ADMINISTRATION (see CLINICAL PHARMACOLOGY , Special Populations ; see WARNINGS )

Ribavirin/INTRON A Combination Therapy

The recommended dose of Ribavirin Capsules depends on the patient's body weight. The recommended dose of ribavirin is provided in TABLE 9 .

The recommended duration of treatment for patients previously untreated with interferon is 24 to 48 weeks. The duration of treatment should be individualized to the patient depending on baseline disease characteristics, response to therapy, and tolerability of the regimen. (See Description of Clinical Studies and ADVERSE REACTIONS .) After 24 weeks of treatment virologic response should be assessed. Treatment discontinuation should be considered in any patient who has not achieved an HCV RNA below the limit of detection of the assay by 24 weeks. There are no safety and efficacy data on treatment for longer than 48 weeks in the previously untreated patient population.

In patients who relapse following interferon therapy, the recommended duration of treatment is 24 weeks. There are no safety and efficacy data on treatment for longer than 24 weeks in the relapse patient population.

TABLE 9. Recommended Dosing
Body weight Ribavirin Capsules
</= 75 kg 2 × 200-mg capsules AM,
3 × 200-mg capsules PM daily p.o.
> 75 kg 3 × 200-mg capsules AM,
3 × 200-mg capsules PM daily p.o.

Ribavirin may be administered without regard to food, but should be administered in a consistent manner with respect to food intake. (See CLINICAL PHARMACOLOGY .)

Ribavirin/PEG-INTRON Combination Therapy

The recommended dose of Ribavirin Capsules is 800 mg/day in 2 divided doses: two capsules (400 mg) in the morning with food and two capsules (400 mg) in the evening with food.

Dose Modifications (TABLE 10)

If severe adverse reactions or laboratory abnormalities develop during combination Ribavirin/INTRON A therapy the dose should be modified, or discontinued if appropriate, until the adverse reactions abate. If intolerance persists after dose adjustment, Ribavirin/INTRON A therapy should be discontinued.

Ribavirin should not be used in patients with creatinine clearance <50 mL/min. (See WARNINGS and CLINICAL PHARMACOLOGY , Special Populations .)

Ribavirin should be administered with caution to patients with preexisting cardiac disease. Patients should be assessed before commencement of therapy and should be appropriately monitored during therapy. If there is any deterioration of cardiovascular status, therapy should be stopped. (See WARNINGS .)

For patients with a history of stable cardiovascular disease, a permanent dose reduction is required if the hemoglobin decreases by >/=2 g/dL during any 4-week period. In addition, for these cardiac history patients, if the hemoglobin remains <12 g/dL after 4 weeks on a reduced dose, the patient should discontinue combination Ribavirin/INTRON A therapy.

It is recommended that a patient whose hemoglobin level falls below 10 g/dL have his/her ribavirin dose reduced to 600 mg daily (1 × 200-mg capsule AM, 2 × 200 mg capsules PM). A patient whose hemoglobin level falls below 8.5 g/dL should be permanently discontinued from ribavirin therapy. (See WARNINGS .)

TABLE 10. Guidelines for Dose Modifications
and Discontinuation for Anemia
Hemoglobin
Dose Reduction*
Ribavirin-600 mg daily
Permanent Discontinuation
of Ribavirin Treatment
No Cardiac History
<10 g/dL <8.5 g/dL
Cardiac History Patients
>/=2 g/dL decrease during any
4-week period during treatment
<12 g/dL after 4 weeks
of dose reduction

How Supplied

Ribavirin 200-mg Capsules are white, opaque capsules with 200 mg and W-1523 imprinted on the capsule shell; the capsules are packaged in a bottle containing 42 capsules (NDC-59930-1523-4), 56 capsules (NDC 59930-1523-3), 70 capsules (NDC 59930-1523-2), and 84 capsules (NDC 59930-1523-1).

Storage Conditions

The bottle of Ribavirin Capsules should be stored at 25°C (77°F); excursions are permitted between 15° and 30°C (59° and 86°F).

Warrick Pharmaceuticals Corporation

Reno, NV 89506 USA

B-26964210  3/03

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