Ribavirin

Ribavirin is an antiviral medication.

Ribavirin must be used together with an interferon alfa product (such as Pegasys, PegIntron, Sylatron, or Intron A) to treat chronic hepatitis C.

Ribavirin may also be used for purposes not listed in this medication guide.

You should not use ribavirin if you have autoimmune hepatitis, severe kidney disease, or a hemoglobin blood cell disorder.

Ribavirin is not effective when used alone. It must be used together with an interferon alfa product. You should not take ribavirin with didanosine.

Ribavirin can cause birth defects or death in an unborn baby. Do not use this medicine if you are pregnant, or if you are a man and your sexual partner is pregnant. Use 2 forms of birth control to prevent pregnancy while either sexual partner is taking ribavirin, and for at least 6 months after treatment ends.

In rare cases, ribavirin can cause fatal heart problems. Get emergency medical attention if you have chest pain.

You should not take ribavirin if you are allergic to it, or if you have:

• a hemoglobin blood cell disorder such as sickle-cell anemia or thalassemia;
• autoimmune hepatitis;
• severe kidney disease;
• if you are also taking didanosine (Videx); or
• if you are pregnant, or if you are a man whose sexual partner is pregnant.

You should not take ribavirin with peginterferon alfa-2a if you have:

• autoimmune hepatitis; or
• severe liver disease (especially cirrhosis).

To make sure ribavirin is safe for you, tell your doctor if you have:

• heart disease;
• a blood cell disorder such as anemia (low red blood cells);
• breathing problems;
• vision problems;
• liver problems other than hepatitis C;
• a thyroid disorder;
• kidney disease;
• human immunodeficiency virus (HIV or AIDS);
• diabetes;
• a history of depression, mental illness, or suicide attempt;
• a history of organ transplant; or
• if you have ever received treatment for hepatitis C that did not work well.

Ribavirin can cause birth defects or death in an unborn baby. You may need to have a negative pregnancy test before taking this medicine and every month during your treatment.

• If you are a woman, do not take ribavirin if you are pregnant.
• If you are a man, do not take ribavirin if your sexual partner is pregnant. An unborn baby could also be harmed if a man fathers the child while he is taking ribavirin.
• Use at least 2 effective forms of birth control to prevent pregnancy while either sexual partner is taking ribavirin. Keep using 2 forms of birth control for at least 6 months after treatment ends.
• Tell your doctor right away if a pregnancy occurs while either the mother or the father is taking ribavirin.

If a pregnancy occurs, your name may be listed on a pregnancy registry. This is to track the outcome of the pregnancy and to evaluate any effects of ribavirin on the baby.

It is not known whether ribavirin passes into breast milk or if it could harm a nursing baby. You should not breast-feed while using this medicine.

Ribavirin is not approved for use by anyone younger than 3 years old.

Ribavirin can affect growth in children. Tell your doctor if your child is not growing at a normal rate while using this medicine.

COPEGUS in combination with PEGASYS (peginterferon alfa-2a) is indicated for the treatment of patients 5 years of age and older with chronic hepatitis C (CHC) virus infection who have compensated liver disease and have not been previously treated with interferon alpha.

The following points should be considered when initiating COPEGUS combination therapy with PEGASYS:

• This indication is based on clinical trials of combination therapy in patients with CHC and compensated liver disease, some of whom had histological evidence of cirrhosis (Child-Pugh class A), and in adult patients with clinically stable HIV disease and CD4 count greater than 100 cells/mm³ .
• This indication is based on achieving undetectable HCV RNA after treatment for 24 or 48 weeks, based on HCV genotype, and maintaining a Sustained Virologic Response (SVR) 24 weeks after the last dose.
• Safety and efficacy data are not available for treatment longer than 48 weeks.
• The safety and efficacy of COPEGUS and PEGASYS therapy have not been established in liver or other organ transplant recipients, patients with decompensated liver disease, or previous non-responders to interferon therapy.
• The safety and efficacy of COPEGUS therapy for the treatment of adenovirus, RSV, parainfluenza or influenza infections have not been established. COPEGUS 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.

Dosage Forms And Strengths

COPEGUS (ribavirin) is available as a light pink to pink colored, flat, oval-shaped, film-coated tablet for oral administration. Each tablet contains 200 mg of ribavirin.

COPEGUS® (ribavirin) is available as tablets for oral administration. Each tablet contains 200 mg of ribavirin and is light pink to pink colored, flat, oval-shaped, film-coated, and engraved with RIB 200 on one side and ROCHE on the other side. They are packaged as bottle of 168 tablets (NDC 0004-0086-94).

Storage And Handling

Store the COPEGUS®Tablets bottle at 25°C (77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature]. Keep bottle tightly closed.

Manufactured by: Hoffmann-La Roche, Inc. c/o Genentech, Inc. A Member of the Roche Group, 1 DNA Way, South San Francisco, CA 94080-4990. Revised: Aug 2015

Mechanism Of Action

Ribavirin is an antiviral agent [see Microbiology].

Pharmacokinetics

Single- and multiple-dose pharmacokinetic properties in adults are summarized in Table 11. 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 AUCtf (AUC from time zero to last measurable concentration) following single doses of 200 to 1200 mg ribavirin. The relationship between dose and Cmax was curvilinear, tending to asymptote above single doses of 400 to 600 mg.

Upon multiple oral dosing, based on AUC12hr, a 6-fold accumulation of ribavirin was observed in plasma. Following oral dosing with 600 mg twice daily, steady-state was reached by approximately 4 weeks, with mean steady-state plasma concentrations of 2200 ng/mL (37%). Upon discontinuation of dosing, the mean half-life was 298 (30%) hours, which probably reflects slow elimination from nonplasma compartments.

Effect of Antacid on Absorption of Ribavirin

Coadministration of REBETOL capsules with an antacid containing magnesium, aluminum, and simethicone resulted in a 14% decrease in mean ribavirin AUCtf. The clinical relevance of results from this single-dose study is unknown.

Table 11: Mean (% CV) Pharmacokinetic Parameters for REBETOL When Administered Individually to Adults

Parameter	REBETOL
	Single-Dose 600 mg Oral Solution (N=14)	Single-Dose 600 mg Capsules (N=12)	Multiple-Dose 600 mg Capsules twice daily (N=12)
Tmax (hr)	1.00 (34)	1.7 (46)*	3 (60)
Cmax (ng/mL)	872 (42)	782 (37)	3680 (85)
AUCtf (ng•hr/mL)	14,098 (38)	13,400 (48)	228,000 (25)
T½ (hr)		43.6 (47)	298 (30)
Apparent Volume of Distribution (L)		2825 (9)1
Apparent Clearance (L/hr)		38.2 (40)
Absolute Bioavailability		64% (44)*
* N=11. † Data obtained from a single-dose pharmacokinetic study using 14C labeled ribavirin; N=5. † N=6.

Tissue Distribution

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

Metabolism and Excretion

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 14C-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.

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 AUCtf value was threefold greater in subjects with creatinine clearance values between 10 to 30 mL/min when compared to control subjects (creatinine clearance greater than 90 mL/min). In subjects with creatinine clearance values between 30 to 60 mL/min, AUCtf was twofold greater when compared to control subjects. The increased AUCtf appears to be due to reduction of renal and nonrenal clearance in these subjects. Phase 3 efficacy trials included subjects with creatinine clearance values greater than 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 less than 50 mL/min should not be treated with REBETOL [see CONTRAINDICATIONS].

Hepatic Dysfunction

The effect of hepatic dysfunction was assessed after a single oral dose of ribavirin (600 mg). The mean AUCtf 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 Cmax values increased with severity of hepatic dysfunction and was twofold greater in subjects with severe hepatic dysfunction when compared to control subjects.

Elderly Patients

Pharmacokinetic evaluations in elderly subjects have not been performed.

Gender

There were no clinically significant pharmacokinetic differences noted in a single-dose trial of 18 male and 18 female subjects.

Pediatric Patients

Multiple-dose pharmacokinetic properties for REBETOL capsules and INTRON A in pediatric subjects with chronic hepatitis C between 5 and 16 years of age are summarized in Table 12. The pharmacokinetics of REBETOL and INTRON A (dose-normalized) are similar in adults and pediatric subjects.

Complete pharmacokinetic characteristics of REBETOL oral solution have not been determined in pediatric subjects. Ribavirin Cmin values were similar following administration of REBETOL oral solution or REBETOL capsules during 48 weeks of therapy in pediatric subjects (3 to 16 years of age).

Table 12: Mean (% CV) Multiple-dose Pharmacokinetic Parameters for INTRON A and REBETOL Capsules When Administered to Pediatric Subjects with Chronic Hepatitis C

Parameter	REBETOL 15 mg/kg/day as 2 divided doses (N=17)	INTRON A 3 MIU/m² three times weekly (N=54)
Tmax (hr)	1.9 (83)	5.9 (36)
Cmax (ng/mL)	3275 (25)	51 (48)
AUC*	29,774 (26)	622 (48)
Apparent Clearance L/hr/kg	0.27 (27)	ND†
* AUC12 (ng·hr/mL) for REBETOL; AUC0-24 (IU·hr/mL) for INTRON A. † ND=not done. Note: numbers in parenthesis indicate % coefficient of variation.

A clinical trial in pediatric subjects with chronic hepatitis C between 3 and 17 years of age was conducted in which pharmacokinetics for PegIntron and REBETOL (capsules and oral solution) were evaluated. In pediatric subjects receiving body surface area-adjusted dosing of PegIntron at 60 mcg/m²/week, the log transformed ratio estimate of exposure during the dosing interval was predicted to be 58% [90% CI: 141%, 177%] higher than observed in adults receiving 1.5 mcg/kg/week. The pharmacokinetics of REBETOL (dose-normalized) in this trial were similar to those reported in a prior study of REBETOL in combination with INTRON A in pediatric subjects and in adults.

Effect of Food on Absorption of Ribavirin

Both AUCtf and Cmax increased by 70% when REBETOL 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 [see DOSAGE AND ADMINISTRATION].

Microbiology

Mechanism of Action

The mechanism by which ribavirin contributes to its antiviral efficacy in the clinic is not fully understood. Ribavirin has direct antiviral activity in tissue culture against many RNA viruses. Ribavirin increases the mutation frequency in the genomes of several viruses and ribavirin triphosphate inhibits HCV polymerase in a biochemical reaction.

Antiviral Activity in Cell Culture

The antiviral activity of ribavirin in the HCV-replicon is not well understood and has not been defined because of the cellular toxicity of ribavirin. Direct antiviral activity has been observed in tissue culture of other RNA viruses. The anti-HCV activity of interferon was demonstrated in cell containing self-replicating HCV-RNS (HCV replicon cells) or HCV infection.

Resistance

HCV genotypes show wide variability in their response to pegylated recombinant human interferon/ribavirin therapy. Genetic changes associated with the variable response have not been identified.

Cross-resistance

There is no reported cross-resistance between pegylated/non-pegylated interferons and ribavirin.

Animal Toxicology And Pharmacology

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 ribavirintreated rats.

In a study in which rat pups were dosed postnatally with ribavirin at doses of 10, 25, and 50 mg/kg/day, drug-related deaths occurred at 50 mg/kg (at rat pup plasma concentrations below human plasma concentrations at the human therapeutic dose) between study Days 13 and 48. Rat pups dosed from postnatal Days 7 through 63 demonstrated a minor, dose-related decrease in overall growth at all doses, which was subsequently manifested as slight decreases in body weight, crown-rump length, and bone length. These effects showed evidence of reversibility, and no histopathological effects on bone were observed. No ribavirin effects were observed regarding neurobehavioral or reproductive development.

Clinical Studies

Clinical Study 1 evaluated PegIntron monotherapy. See PegIntron labeling for information about this trial.

REBETOL/PegIntron Combination Therapy

Adult Subjects

Study 2

A randomized trial compared treatment with two PegIntron/REBETOL regimens [PegIntron 1.5 mcg/kg subcutaneously once weekly/REBETOL 800 mg orally daily (in divided doses); PegIntron 1.5 mcg/kg subcutaneously once weekly for 4 weeks then 0.5 mcg/kg subcutaneously once weekly for 44 weeks/REBETOL 1000 or 1200 mg orally daily (in divided doses)] with INTRON A [3 MIU subcutaneously three times weekly/REBETOL 1000 or 1200 mg orally daily (in divided doses)] in 1530 adults with chronic hepatitis C. Interferon-naïve subjects were treated for 48 weeks and followed for 24 weeks post-treatment. Eligible subjects 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 post-treatment (see Table 13). The response rate to the PegIntron 1.5 mcg/kg and ribavirin 800 mg dose was higher than the response rate to INTRON A/REBETOL (see Table 13).The response rate to PegIntron 1.5→0.5 mcg/kg/REBETOL was essentially the same as the response to INTRON A/REBETOL (data not shown).

Table 13: Rates of Response to Combination Treatment – Study 2

	PegIntron 1.5 mcg/kg once weekly REBETOL 800 mg once daily	INTRON A 3 MIU three times weekly REBETOL 1000/1200 mg once daily
Overall response*†	52% (264/511)	46% (231/505)
Genotype 1	41% (141/348)	33% (112/343)
Genotype 2-6	75% (123/163)	73% (119/162)
* Serum HCV-RNA was measured with a research-based quantitative polymerase chain reaction assay by a central laboratory. † Difference in overall treatment response (PegIntron/REBETOL vs. INTRON A/REBETOL) is 6% with 95% confidence interval of (0.18, 11.63) adjusted for viral genotype and presence of cirrhosis at baseline. Response to treatment was defined as undetectable HCV-RNA at 24 weeks post-treatment.

Subjects with viral genotype 1, regardless of viral load, had a lower response rate to PegIntron (1.5 mcg/kg)/REBETOL (800 mg) compared to subjects with other viral genotypes. Subjects 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/REBETOL combination therapy.

Subjects with lower body weight tended to have higher adverse-reaction rates [see ADVERSE REACTIONS] and higher response rates than subjects with higher body weights. Differences in response rates between treatment arms did not substantially vary with body weight.

Treatment response rates with PegIntron/REBETOL combination therapy were 49% in men and 56% in women. Response rates were lower in African American and Hispanic subjects 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 in this trial.

Liver biopsies were obtained before and after treatment in 68% of subjects. Compared to baseline, approximately two-thirds of subjects in all treatment groups were observed to have a modest reduction in inflammation.

Study 3

In a large United States community-based trial, 4913 subjects with chronic hepatitis C were randomized to receive PegIntron 1.5 mcg/kg subcutaneously once weekly in combination with a REBETOL dose of 800 to 1400 mg (weight-based dosing [WBD]) or 800 mg (flat) orally daily (in divided doses) for 24 or 48 weeks based on genotype. Response to treatment was defined as undetectable HCV-RNA (based on an assay with a lower limit of detection of 125 IU/mL) at 24 weeks post-treatment.

Treatment with PegIntron 1.5 mcg/kg and REBETOL 800 to 1400 mg resulted in a higher sustained virologic response compared to PegIntron in combination with a flat 800 mg daily dose of REBETOL. Subjects weighing greater than 105 kg obtained the greatest benefit with WBD, although a modest benefit was also observed in subjects weighing greater than 85 to 105 kg (see Table 14). The benefit of WBD in subjects weighing greater than 85 kg was observed with HCV genotypes 1-3. Insufficient data were available to reach conclusions regarding other genotypes. Use of WBD resulted in an increased incidence of anemia [see ADVERSE REACTIONS].

Table 14: SVR Rate by Treatment and Baseline Weight - Study 3

Treatment Group	Subject Baseline Weight
	< 65 kg ( < 143 lb)	65-85 kg (143-188 lb)	> 85-105 kg ( > 188-231 lb)	> 105 kg ( > 231 lb)
WBD*	50% (173/348)	45% (449/994)	42% (351/835)	47% (138/292)
Flat	51% (173/342)	44% (443/1011)	39% (318/819)	33% (91/272)
* P=0.01, primary efficacy comparison (based on data from subjects weighing 65 kg or higher at baseline and utilizing a logistic regression analysis that includes treatment [WBD or Flat], genotype and presence/absence of advanced fibrosis, in the model).

A total of 1552 subjects weighing greater than 65 kg in Study 3 had genotype 2 or 3 and were randomized to 24 or 48 weeks of therapy. No additional benefit was observed with the longer treatment duration.

Study 4

A large randomized trial compared the safety and efficacy of treatment for 48 weeks with two PegIntron/REBETOL regimens [PegIntron 1.5 mcg/kg and 1 mcg/kg subcutaneously once weekly both in combination with REBETOL 800 to 1400 mg PO daily (in two divided doses)] and Pegasys 180 mcg subcutaneously once weekly in combination with Copegus 1000 to 1200 mg PO daily (in two divided doses) in 3070 treatment-naïve adults with chronic hepatitis C genotype 1. In this trial, lack of early virologic response (undetectable HCV-RNA or greater than or equal to 2 log10 reduction from baseline) by treatment Week 12 was the criterion for discontinuation of treatment. SVR was defined as undetectable HCV-RNA (Roche COBAS TaqMan assay, a lower limit of quantitation of 27 IU/mL) at 24 weeks post-treatment (see Table 15).

Table 15: SVR Rate by Treatment – Study 4

% (number) of Subjects
PegIntron 1.5 mcg/kg/REBETOL	PegIntron 1 mcg/kg/REBETOL	Pegasys 180 mcg/Copegus
40 (406/1019)	38 (386/1016)	41 (423/1035)

Overall SVR rates were similar among the three treatment groups. Regardless of treatment group, SVR rates were lower in subjects with poor prognostic factors. Subjects with poor prognostic factors randomized to PegIntron (1.5 mcg/kg)/REBETOL or Pegasys/Copegus, however, achieved higher SVR rates compared to similar subjects randomized to PegIntron 1 mcg/kg/REBETOL. For the PegIntron 1.5 mcg/kg and REBETOL dose, SVR rates for subjects with and without the following prognostic factors were as follows: cirrhosis (10% vs. 42%), normal ALT levels (32% vs. 42%), baseline viral load greater than 600,000 IU/mL (35% vs. 61%), 40 years of age and older (38% vs. 50%), and African American race (23% vs. 44%). In subjects with undetectable HCV-RNA at treatment Week 12 who received PegIntron (1.5 mcg/kg)/REBETOL, the SVR rate was 81% (328/407).

Study 5 - REBETOL/PegIntron Combination Therapy in Prior Treatment Failures

In a noncomparative trial, 2293 subjects with moderate to severe fibrosis who failed previous treatment with combination alpha interferon/ribavirin were re-treated with PegIntron, 1.5 mcg/kg subcutaneously, once weekly, in combination with weight adjusted ribavirin. Eligible subjects included prior nonresponders (subjects who were HCV-RNA positive at the end of a minimum 12 weeks of treatment) and prior relapsers (subjects who were HCVRNA negative at the end of a minimum 12 weeks of treatment and subsequently relapsed after post-treatment follow-up). Subjects who were negative at Week 12 were treated for 48 weeks and followed for 24 weeks post-treatment. Response to treatment was defined as undetectable HCV-RNA at 24 weeks post-treatment (measured using a research-based test, limit of detection 125 IU/mL). The overall response rate was 22% (497/2293) (99% CI: 19.5, 23.9). Subjects with the following characteristics were less likely to benefit from re-treatment: previous nonresponse, previous pegylated interferon treatment, significant bridging fibrosis or cirrhosis, and genotype 1 infection.

The re-treatment sustained virologic response rates by baseline characteristics are summarized in Table 16.

Table 16: SVR Rates by Baseline Characteristics of Prior Treatment Failures - Study 5

HCV Genotype/ Metavir Fibrosis Score	Overall SVR by Previous Response and Treatment
	Nonresponder		Relapser
	interferon alfa/ribavirin % (number of subjects)	peginterferon (2a and 2b combined)/ribavirin % (number of subjects)	interferon alfa/ribavirin % (number of subjects)	peginterferon (2a and 2b combined)/ribavirin % (number of subjects)
Overall	18 (158/903)	6 (30/476)	43 (130/300)	35 (113/344)
HCV 1	13 (98/761)	4 (19/431)	32 (67/208)	23 (56/243)
F2	18 (36/202)	6 (7/117)	42 (33/79)	32 (23/72)
F3	16 (38/233)	4 (4/112)	28 (16/58)	21 (14/67)
F4	7 (24/325)	4 (8/202)	26 (18/70)	18 (19/104)
HCV 2/3	49 (53/109)	36 (10/28)	67 (54/81)	57 (52/92)
F2	68 (23/34)	56 (5/9)	76 (19/25)	61 (11/18)
F3	39 (11/28)	38 (3/8)	67 (18/27)	62 (18/29)
F4	40 (19/47)	18 (2/11)	59 (17/29)	51 (23/45)
HCV 4	17 (5/29)	7 (1/15)	88 (7/8)	50 (4/8)

Achievement of an undetectable HCV-RNA at treatment Week 12 was a strong predictor of SVR. In this trial, 1470 (64%) subjects did not achieve an undetectable HCV-RNA at treatment Week 12, and were offered enrollment into long-term treatment trials, due to an inadequate treatment response. Of the 823 (36%) subjects who were HCV-RNA undetectable at treatment Week 12, those infected with genotype 1 had an SVR of 48% (245/507), with a range of responses by fibrosis scores (F4-F2) of 39-55%. Subjects infected with genotype 2/3 who were HCV-RNA undetectable at treatment Week 12 had an overall SVR of 70% (196/281), with a range of responses by fibrosis scores (F4-F2) of 60-83%. For all genotypes, higher fibrosis scores were associated with a decreased likelihood of achieving SVR.

Pediatric Subjects

Previously untreated pediatric subjects 3 to 17 years of age with compensated chronic hepatitis C and detectable HCV-RNA were treated with REBETOL 15 mg/kg per day and PegIntron 60 mcg/m² once weekly for 24 or 48 weeks based on HCV genotype and baseline viral load. All subjects were to be followed for 24 weeks post-treatment. A total of 107 subjects received treatment, of which 52% were female, 89% were Caucasian, and 67% were infected with HCV Genotype 1. Subjects infected with Genotypes 1, 4 or Genotype 3 with HCV-RNA greater than or equal to 600,000 IU/mL received 48 weeks of therapy while those infected with Genotype 2 or Genotype 3 with HCV-RNA less than 600,000 IU/mL received 24 weeks of therapy. The trial results are summarized in Table 17.

Table 17: Sustained Virologic Response Rates by Genotype and Assigned Treatment Duration – Pediatric Trial

Genotype	All Subjects N=107
	24 Weeks	48 Weeks
	Virologic Response N*† (%)	Virologic Response N*† (%)
All	26/27 (96.3)	44/80 (55.0)
1	-	38/72 (52.8)
2	14/15 (93.3)	-
3‡	12/12 (100)	2/3 (66.7)
4	-	4/5 (80.0)
* Response to treatment was defined as undetectable HCV-RNA at 24 weeks post-treatment. † N=number of responders/number of subjects with given genotype, and assigned treatment duration. ‡ Subjects with genotype 3 low viral load (less than 600,000 IU/mL) were to receive 24 weeks of treatment while those with genotype 3 and high viral load were to receive 48 weeks of treatment

REBETOL/INTRON A Combination Therapy

Adult Subjects

Previously Untreated Subjects

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 REBETOL capsules 1200 mg/day (1000 mg/day for subjects weighing less than or equal to 75 kg) and INTRON A 3 MIU three times weekly or INTRON A and placebo for 24 or 48 weeks followed by 24 weeks of off-therapy follow-up. The international trial did not contain a 24-week INTRON A and placebo treatment arm. The US trial enrolled 912 subjects 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 trial, conducted in Europe, Israel, Canada, and Australia, enrolled 799 subjects (65% male, 95% Caucasian, mean Knodell score 6.8, and 58% genotype 1).

Trial results are summarized in Table 18.

Table 18: Virologic and Histologic Responses: Previously Untreated Subjects*

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

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

Among subjects with HCV Genotype 1 treated with REBETOL/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 subjects with HCV non-genotype 1 randomized to REBETOL/INTRON A therapy for 48 weeks compared to 24 weeks.

Relapse Subjects

Subjects 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 REBETOL 1200 mg/day (1000 mg/day for subjects weighing ≤ 75 kg) and INTRON A 3 MIU three times weekly or INTRON A and placebo for 24 weeks followed by 24 weeks of off-therapy follow-up. The US trial enrolled 153 subjects 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 trial, conducted in Europe, Israel, Canada, and Australia, enrolled 192 subjects (64% male, 95% Caucasian, mean Knodell score 6.6, and 56% genotype 1).  Trial results are summarized in Table 19.

Table 19: Virologic and Histologic Responses: Relapse Subjects*

	US Trial		International Trial
	INTRON A/ REBETOL (N=77)	INTRON A/ Placebo (N=76)	INTRON A/ REBETOL (N=96)	INTRON A/ Placebo (N=96)
Virologic Response
Responder†	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‡	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 subjects. † Defined as HCV-RNA below limit of detection using a research-based RT-PCR assay at end of treatment and during follow-up period. ‡ Defined as post-treatment (end of follow-up) minus pretreatment liver biopsy Knodell HAI score (I+II+III) improvement of greater than or equal to 2 points.

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

Pediatric Subjects

Pediatric subjects 3 to 16 years of age with compensated chronic hepatitis C and detectable HCV-RNA (assessed by a central laboratory using a research-based RT-PCR assay) were treated with REBETOL 15 mg/kg per day and INTRON A 3 MIU/m² three times weekly for 48 weeks followed by 24 weeks of off-therapy follow-up. A total of 118 subjects received treatment, of which 57% were male, 80% Caucasian, and 78% genotype 1. Subjects less than 5 years of age received REBETOL oral solution and those 5 years of age or older received either REBETOL oral solution or capsules.

Trial results are summarized in Table 20.

Table 20: Virologic Response: Previously Untreated Pediatric Subjects*

	INTRON A 3 MIU/m² three times weekly/ REBETOL 15 mg/kg/day
Overall Response† (N=118)	54 (46)
Genotype 1 (N=92)	33 (36)
Genotype non-1 (N=26)	21 (81)
* Number (%) of subjects. † Defined as HCV-RNA below limit of detection using a research-based RTPCR assay at end of treatment and during follow-up period.

Subjects with viral genotype 1, regardless of viral load, had a lower response rate to INTRON A/REBETOL combination therapy compared to subjects with genotype non-1, 36% vs. 81%. Subjects with both poor prognostic factors (genotype 1 and high viral load) had a response rate of 26% (13/50).

Ribavirin is a prescription medication used to treat hepatitis C infection in adults and children.   Ribavirin is also used to treat respiratory syncitial virus in children.  Ribavirin belongs to a group of antiviral drugs called nucleoside analogues, which stop the spread of hepatitis C virus in the body.

This medication comes in capsule, tablet, inhalation and liquid forms. 

Common side effects of ribavirin include flu-like symptoms, mood changes, difficulty breathing, low blood pressure, and decreased appetite.

Ribavirin is a prescription medicine used with either interferon alfa-2b (Intron A) or peginterferon alfa-2b (PegIntron) to treat chronic (lasting a long time) hepatitis C infection in people 3 years and older with liver disease.

The inhalation form of this medication, Virazole, can also be used to treat Respiratory Syncytial Virus (RSV) in children. 

This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.

Ribavirin may be found in some form under the following brand names:

• Copegus

• Rebetol

• Ribasphere

• Ribasphere RibaPak

• RibaTab

• Virazole

Tell your doctor if you are pregnant or plan to become pregnant. The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X, are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy. Ribavirin falls into category X.

It has been shown that women taking ribavirin during pregnancy may have babies born with problems. There are no situations where the benefits of the medication for the mother outweigh the risks of harm to the baby. These medicines should never be used by pregnant women. Do not take ribavirin if you or your sexual partner is pregnant or plan to be come pregnant. Do not become pregnant within 6 months after discontinuing ribavirin therapy. You must use 2 forms of birth control when you take ribavirin and for the 6 months after treatment.

Ribavirin may cause birth defects or the death of your unborn baby. Do not take ribavirin if you or your sexual partner is pregnant or plan to be come pregnant. Do not become pregnant within 6 months after discontinuing ribavirin therapy. You must use 2 forms of birth control when you take ribavirin and for the 6 months after treatment.

• Females must have a pregnancy test before starting ribavirin, every month while taking ribavirin, and every month for the 6 months after the last dose of ribavirin.
• If you or your female sexual partner becomes pregnant while taking ribavirin, tell your healthcare provider right away. You or your healthcare provider should contact the ribavirin pregnancy registry by calling 1-800-593-2214. The ribavirin pregnancy registry collects information about what happens to mothers and their babies if the mother takes ribavirin while she is pregnant.
• For those taking ribavirin inhalation, it is not known when it is safe to become pregnant after taking ribavirin inhalation.

Chronic HCV Infection

Treatment of chronic HCV infection in adults and pediatric patients with compensated liver disease.119 342 349 362 377 402 403 419 420 421 422

Used in conjunction with other drugs in multiple-drug regimens for treatment of chronic HCV infection; do not use alone.119 349 377 402 403

Has been used in conjunction with peginterferon alfa (peginterferon alfa-2a, peginterferon alfa-2b).20 119 342 349 362 377 388 402 403 419 420 421 422 423 Although used in conjunction with nonconjugated interferon alfa-2b in the past,323 324 325 326 331 332 333 338 339 340 349 362 403 428 such regimens no longer included in recommendations for treatment of chronic HCV infection.119

Usually used in multiple-drug regimens that include one or more HCV direct-acting antivirals (DAAs) with or without peginterferon alfa.119 179 180 187 188 Has been used in regimens that include simeprevir (an HCV protease inhibitor), ribavirin, and peginterferon alfa;187 regimens that include sofosbuvir (an HCV polymerase inhibitor) and ribavirin with or without peginterferon alfa;119 188 regimens that include simeprevir (an HCV protease inhibitor), sofosbuvir (an HCV polymerase inhibitor), and ribavirin;119 regimens that include the fixed combination of ombitasvir (an HCV replication complex inhibitor), paritaprevir (an HCV protease inhibitor), and ritonavir (ombitasvir/paritaprevir/ritonavir) and ribavirin;119 179 or regimens that include the fixed combination ombitasvir/paritaprevir/ritonavir with dasabuvir and with ribavirin.119 180

Safety and efficacy of oral ribavirin in conjunction with peginterferon alfa not established for treatment of chronic HCV infection in patients with decompensated liver disease,349 377 402 403 HBV coinfection,349 403 or liver or other organ transplants.20 349 377 402 403

Most appropriate multiple-drug regimen depends on specific HCV genotype and patient population involved.119

Treatment of chronic HCV infection is complex and rapidly evolving; consult a specialist to obtain the most up-to-date information.119 Information from the American Association for the Study of Liver Diseases (AASLD), Infectious Diseases Society of America (IDSA), and International Antiviral Society–USA (IAS–USA) regarding diagnosis and management of HCV infection, including recommendations for initial treatment, is available at .119

Acute HCV Infection

Treatment of acute HCV infection† in an attempt to prevent progression to chronic HCV infection; used in conjunction with peginterferon alfa (alfa-2a, alfa-2b).96 121 126 128 129 190

Approximately 10–50% of patients with acute HCV infection have self-limited disease and spontaneous clearance of the virus without treatment;120 optimum regimen (including dosage and duration of therapy) and optimum time to initiate treatment in patients with acute HCV infection not established.120 190

To allow for spontaneous resolution, some experts suggest delaying initiation of treatment of acute HCV infection (especially in asymptomatic individuals) for 8–12 weeks after acute onset of hepatitis, unless HCV RNA levels are high and not declining.120

Consult a specialist to obtain the most up-to-date information regarding treatment of acute HCV infection.120 121

Hepatitis E Virus (HEV) Infection

Treatment of chronic HEV infection†;430 431 432 433 has been used alone or in conjunction with peginterferon alfa.430 431 432 433

Chronic HEV infection reported almost exclusively among immunocompromised individuals, including solid organ transplant recipients, patients receiving cancer chemotherapy, and HIV patients.430 431 432 433 Optimal treatment of chronic HEV infection not identified.431 432

Respiratory Syncytial Virus (RSV) Infection

Ribavirin nasal and oral inhalation used for treatment of severe lower respiratory tract infections (i.e., bronchiolitis, pneumonia) caused by RSV in hospitalized infants and young children.1 16 41 45 75 76 89 90 91 100 101 105 196 197 202 277 278 405 410 411 412 413 414 415 416 417 418

Manufacturer states consider use only in infants and small children with severe RSV lower respiratory tract infections; use in mechanically ventilated patients only if clinicians and support staff are familiar with the mode of administration and specific ventilator being used.1

AAP states ribavirin nasal and oral inhalation therapy may be considered for selected patients with documented life-threatening RSV infection, but routine use not recommended.105

Ribavirin nasal and oral inhalation has been used for treatment of RSV infection in immunocompromised adults†, including bone marrow or hematopoietic cell transplant recipients;213 407 409 429 434 manufacturer states not indicated for treatment of RSV infection in adults.1

Viral Hemorrhagic Fevers

Treatment of certain viral hemorrhagic fevers†, including Lassa fever, hemorrhagic fever with renal syndrome (HFRS) caused by Hantavirus infection, infections caused by New World arenaviruses, and Crimean-Congo hemorrhagic fever.105 337 343 344 351 389 392

Inactive against and not used for treatment of infections caused by Filoviridae (including Ebola hemorrhagic fever and Marburg hemorrhagic fever).343 344 351 Also inactive against and not used for infections by caused most Flaviviridae (including dengue hemorrhagic fever).343 344 351

Treatment of Lassa fever†; considered the drug of choice.59 104 105 146 177 219 257 258 343 351 Previously recommended for postexposure prophylaxis of Lassa fever in high-risk contacts,219 but CDC recommends the strategy of placing exposed individuals or contacts under medical surveillance for 21 days and treating presumptively with ribavirin if clinical evidence of viral hemorrhagic fever develops.397

Treatment of hemorrhagic fever with renal syndrome† (HFRS);105 270 271 272 276 designated an orphan drug by FDA for this use.273 When administered IV† within 4–7 days after onset of fever, has decreased viremia, renal dysfunction, vascular instability, and mortality of HFRS.105 270 271 272 276

Treatment of Crimean-Congo hemorrhagic fever† (CCHF).105 347 389 392 Although experience limited, CDC states use of ribavirin to treat the disease and prevent infection in high-risk contacts is reasonable based on in vitro susceptibility data for this and other Bunyaviridae.219

Treatment of clinically evident viral hemorrhagic fever in the context of biologic warfare or bioterrorism† when the disease is caused by Arenavirus (e.g., Lassa fever, New World hemorrhagic fever) or Bunyavirus (e.g., Rift Valley fever) or is of unknown etiology.343 351 357 Preemptive administration of ribavirin or postexposure prophylaxis with ribavirin not recommended following known or presumed exposure to hemorrhagic fever virus in the context of biologic warfare or bioterrorism.351 Those with known or presumed exposure, including high-risk contacts (i.e., individuals with mucous membrane contact with infected patient) and close contacts (i.e., individuals who live with, shake hands or hug, process laboratory specimens from, or care for infected patients [prior to initiation of appropriate precautions]) should be placed under medical surveillance for 21 days and treated presumptively with ribavirin if fever ≥38.3°C develops.351

Information on diagnosis and management of viral hemorrhagic fevers is available from Special Pathogens Branch of CDC at or at 404-639-1115.345 Any suspected cases of viral hemorrhagic fever occurring in individuals residing in or requiring evacuation to the US should immediately be reported to local health authorities and the CDC Viral Special Pathogens Branch at 404-639-1115 or CDC Emergency Operations Center at 770-488-7100.337

Adenovirus Infections

Has been used for treatment of infections caused by adenovirus† in immunocompromised adults and children, including bone marrow or stem cell transplant recipients, solid organ transplant recipients (e.g., liver, kidney), and patients with leukemia or severe combined immunodeficiency.393 394 395 396

Safety and efficacy not established;349 377 only limited experience to date.393 394 395 396

Generally has been used in critically ill patients with severe adenovirus infections (e.g., hemorrhagic cystitis, nephritis, respiratory tract infections, GI infections, disseminated disease) who received multiple treatment modalities.393 395 396 Not all patients respond;393 394 396 unlikely to be of benefit if initiated late in the course of severe infections.393

Has been used for preemptive therapy in immunocompromised patients who were asymptomatic but had clinical cultures positive for adenovirus.395 Possible benefits and risks in such patients not determined; asymptomatic adenovirus infections often resolve spontaneously.395

Coronavirus Infections

Has been used alone or in conjunction with systemic corticosteroids for treatment of severe acute respiratory syndrome† (SARS) caused by the SARS coronavirus (SARS-CoV). 367 368 369 370 371 373 380 381 382 Clinical benefits of various anti-infective regimens used for empiric treatment of SARS, including oral ribavirin, have been disappointing.368 369 373 SARS first reported in Asia during early 2003 and then spread to many areas of the world, including North America, South America, and Europe.346 367 368 369 370 371 372 373 376 380 381 Person-to-person transmission of SARS-CoV not currently occurring anywhere in the world, but could recur and future outbreaks are possible.386

Has been used in conjunction with an interferon (e.g., peginterferon alfa-2a, interferon alfa-2b) for treatment of Middle East respiratory syndrome† (MERS) caused by the Middle East respiratory syndrome coronavirus (MERS-CoV).440 441 442 443 445 No specific treatment for MERS has been identified;436 444 445 some evidence that regimen of oral ribavirin and peginterferon alfa-2a may improve 14-day survival rate when used in addition to usual supportive care, but 28-day survival rate not significantly improved.443 MERS-CoV infections first reported in September 2012 in Saudi Arabia;435 436 439 441 444 as of August 28, 2015, 1,474 laboratory-confirmed cases (including 515 deaths) reported worldwide.444 Most reported cases to date (including 2 in the US and an outbreak in Republic of Korea) directly or indirectly linked through travel or residence to the Middle East.436 444 446 Information regarding evaluation, diagnosis, and management of MERS-CoV infection and guidance for individuals traveling to areas where MERS reported (e.g., the Middle East) is available at CDC website at .436

Administration

Administer orally349 377 402 403 or by nasal and oral inhalation.1 Also has been administered IV†.105 270 271 272 276 389 393 394 395 396 397

Oral Administration

Administer ribavirin capsules,349 403 tablets,377 402 and oral solution349 with food.

Do not open, crush, or break capsules.349 403

Oral solution containing 40 mg of ribavirin per mL recommended (instead of capsules) in children ≥3 years of age weighing <47 kg.349 The oral solution may be used in any patient ≥3 years of age, regardless of weight.349

Patients should be well hydrated, especially during initial treatment.349 377 402 403

Nasal and Oral Inhalation

Ribavirin sterile powder (Virazole) must be reconstituted and diluted and administered as a solution only via nasal and oral inhalation using the Valeant small-particle aerosol generator (SPAG) Model SPAG-2 available from the manufacturer.1 162 Do not administer using any other aerosol generator and do not administer concomitantly with other drug solutions for nebulization.1

Consult the SPAG-2 manual for detailed administration instructions.1 162

In patients not requiring mechanical ventilation, ribavirin solution for nebulization should be administered from the SPAG-2 aerosol generator via an oxygen hood.1 162 If an oxygen hood cannot be used, the solution may be administered from the SPAG-2 aerosol generator via a face mask or oxygen tent;1 162 because the volume and condensation area of the solution for nebulization are larger in an oxygen tent, this may alter delivery dynamics of the drug.1

When ribavirin inhalation therapy is used in patients who require assisted ventilation, constantly monitor the patient and apparatus (e.g., in an intensive care setting).182 183 Use either a pressure or volume cycle ventilator in conjunction with the SPAG-2.1 For pressure or volume cycle ventilators, heated wire connective tubing and bacterial filters in series in the expiratory limb of the system must be used to minimize the risk of ribavirin precipitation in the system and risk of ventilator dysfunction; the filters should be changed frequently (e.g., every 4 hours).1 Water column pressure release valves should be used in the ventilator circuit for pressure cycle ventilators and may be used in the ventilator circuit for volume cycle ventilators.1 The endotracheal tube should be suctioned every 1–2 hours; monitor pulmonary pressure frequently (every 2–4 hours).1

Reconstitution and Dilution

Add a minimum of 75 mL of sterile water for injection or inhalation (additive free) to the vial containing 6 g of ribavirin; shake well.1 162 Transfer reconstituted solution to the sterile 500-mL reservoir of the SPAG-2 aerosol generator; further dilute with sterile water for injection or inhalation (additive free) to a final volume of 300 mL to provide a solution containing 20 mg/mL.1 162

Solutions that have been placed into the SPAG-2 reservoir should be discarded at least every 24 hours and prior to the addition of freshly reconstituted solution whenever the amount of solution remaining in the reservoir is low.1 162

Rate of Administration

When 20-mg/mL solution is delivered using the SPAG-2 aerosol generator according to the manufacturer's instructions, the average aerosol concentration for a 12-hour delivery period is 190 mcg/L.1

Administer the 20-mg/mL solution via the SPAG-2 aerosol generator at a rate of about 15 L/minute when using an oxygen hood or tent or about 12 L/minute when using a face mask.162

Parenteral Administration

Although not commercially available, parenteral ribavirin is available for compassionate use protocols for treatment of viral hemorrhagic fevers† such as Lassa fever†, Hantavirus infections†, and Congo-Crimean hemorrhagic fever†.337 To obtain IV ribavirin for emergency use, contact FDA at 301-736-3400 for compassionate use authorization and also contact the manufacturer (Valeant Pharmaceuticals) at 800-548-5100.337

Dosage

Pediatric Patients

Treatment of Chronic HCV Infection

Must be used in conjunction with other drugs as part of a multiple-drug regimen.349 377 403 May be used in conjunction with peginterferon alfa;349 377 403 although no longer recommended,119 has been used in conjunction with nonconjugated interferon alfa.349 403

Concomitant Ribavirin Capsules (Rebetol, Ribasphere) or Oral Solution (Rebetol) and Peginterferon Alfa-2b (PegIntron) or Interferon Alfa-2b (Intron A) Oral

Children 3–17 years of age: 15 mg/kg daily in 2 divided doses in conjunction with sub-Q peginterferon alfa-2b or interferon alfa-2b.349 403 (See Table 1.) Use oral solution in those weighing <47 kg.349 If patient reaches 18th birthday during treatment, complete treatment using pediatric dosage.349 403

Recommended treatment duration is 24 weeks for HCV genotype 2 or 3 and 48 weeks for genotype 1.349 403

With the exception of HCV genotypes 2 and 3, consider discontinuing HCV treatment if HCV RNA levels have not decreased ≥2 log10 from baseline at week 12 or remain detectable after 24 weeks of treatment.349 403

Table 1. Pediatric Dosage of Ribavirin Capsules (Rebetol, Ribasphere) or Oral Solution (Rebetol) for Concomitant Use with Peginterferon Alfa-2b (PegIntron) or Nonconjugated Interferon Alfa-2b (Intron A)349403

Weight	Ribavirin Dosage (Capsules, Oral Solution)
<47 kg	15 mg/kg daily, given as oral solution in 2 divided doses
47–59 kg	400 mg in morning and 400 mg in evening
60–73 kg	400 mg in morning and 600 mg in evening
>73 kg	600 mg in morning and 600 mg in evening

Concomitant Ribavirin Tablets (Copegus) and Peginterferon Alfa-2a (Pegasys) Oral

Children ≥5 years of age: Approximately 15 mg/kg daily in 2 divided doses in conjunction with sub-Q peginterferon alfa-2a.377 (See Table 2.) If patient reaches 18th birthday during treatment, complete treatment using pediatric dosage.377

Recommended treatment duration is 24 weeks for HCV genotype 2 or 3 and 48 weeks for other HCV genotypes.377

Table 2. Pediatric Dosage of Ribavirin Tablets (Copegus) for Concomitant Use with Peginterferon Alfa-2a (Pegasys)377

Weight	Copegus Dosage (Tablets)
23–33 kg	200 mg in morning and 200 mg in evening
34–46 kg	200 mg in morning and 400 mg in evening
47–59 kg	400 mg in morning and 400 mg in evening
60–74 kg	400 mg in morning and 600 mg in evening
>75 kg	600 mg in morning and 600 mg in evening

Dosage Modification for Toxicity Oral

If serious adverse effects or laboratory changes occur when oral ribavirin used in conjunction with peginterferon alfa or nonconjugated interferon alfa, modify dosage of one or both drugs, if appropriate, until adverse effects abate.349 377 403 If intolerance persists after dosage adjustment, discontinue both drugs.349 377 403

Concomitant ribavirin capsules or oral solution (Rebetol, Ribasphere) and peginterferon alfa-2b or nonconjugated interferon alfa-2b in children 3–17 years of age: If hemoglobin <10 g/dL, decrease ribavirin dosage from 15 mg/kg daily to 12 mg/kg daily and, if needed, to 8 mg/kg daily.349 403 If hemoglobin <8.5 g/dL, leukocyte count <1000/mm3, neutrophil count <500/mm3, or platelet count <50,000/mm3, permanently discontinue both drugs.349 403 In pediatric patients with preexisting cardiac conditions, closely monitor with weekly hematology evaluations if hemoglobin decreases by ≥2 g/dL during any 4-week period; discontinue if hemoglobin concentration <8.5 g/dL (or <12 g/dL after 4 weeks of reduced dosage).349

Concomitant ribavirin tablets (Copegus) and peginterferon alfa-2a in children ≥5 years of age without cardiac disease: If hemoglobin <10 g/dL, decrease ribavirin dosage to 200 mg daily (200 mg in morning) in those weighing 23–33 kg, 400 mg daily (200 mg in morning and 200 mg in evening) in those weighing 34–59 kg, or 600 mg daily (200 mg in morning and 400 mg in evening) in those weighing ≥60 kg.377 If hemoglobin <8.5 g/dL, discontinue both drugs.377

Concomitant ribavirin tablets (Copegus) and peginterferon alfa-2a in children ≥5 years of age with history of stable cardiac disease: If hemoglobin decreases by ≥2 g/dL during any 4-week period, decrease ribavirin dosage to 200 mg daily (200 mg in morning) in those weighing 23–33 kg, 400 mg daily (200 mg in morning and 200 mg in evening) in those weighing 34–59 kg, or 600 mg daily (200 mg in morning and 400 mg in evening) in those weighing ≥60 kg.377 If hemoglobin <12 g/dL after 4 weeks of reduced dosage, discontinue both drugs.377

Consult manufacturer's information for more specific recommendations regarding dosage modification for hematologic or other adverse effects.349 377 403

Treatment of Respiratory Syncytial Virus (RSV) Infection Inhalation

Using a solution containing 20 mg/mL and SPAG-2 aerosol generator with an oxygen hood, face mask, or oxygen tent, deliver mist continuously for 12–18 hours daily for 3–7 days.1 162 Manufacturer recommends mist be delivered at a rate of about 15 L/minute when using an oxygen hood or tent or about 12 L/minute when using a face mask.162 The average aerosol concentration for a 12-hour delivery period is 190 mcg/L.1

Dose and administration schedule for infants requiring mechanical ventilation is the same as that for infants not requiring assisted ventilation.1

Viral Hemorrhagic Fevers† Treatment of Viral Hemorrhagic Fevers in Context of Biologic Warfare or Bioterrorism† Oral

US Army Medical Research Institute of Infectious Diseases (USAMRIID) and US Working Group on Civilian Biodefense recommend initial loading dose of 30 mg/kg, followed by 15 mg/kg daily given in 2 divided doses.343 351 Duration of treatment is 10 days.343 351

IV regimen usually preferred.343 351 Oral regimen may be used when parenteral preparation cannot be obtained or would be impractical (e.g., when large numbers of individuals require treatment in a mass casualty setting).343 351

IV†

USAMRIID and US Working Group on Civilian Biodefense recommend initial loading dose of 30 mg/kg (maximum 2 g), followed by 16 mg/kg (maximum 1 g) every 6 hours for 4 days and then 8 mg/kg (maximum 500 mg) every 8 hours for 6 days.343 351

IV regimen recommended for contained casualty settings if parenteral preparation can be obtained.351

Treatment of Adenovirus Infections† IV†

Severe infections in immunocompromised children: 25 mg/kg daily in 3 divided doses on day 1 followed by 15 mg/kg daily in 3 divided doses on days 2–10 has been used.393 Alternatively, 15 mg/kg daily for 10 days has been used.396

Adults

Treatment of Chronic HCV Infection

Must be used in conjunction with other drugs as part of a multiple-drug regimen.119 349 377 402 403 May be used in conjunction with peginterferon alfa;119 349 377 402 403 although no longer recommended,119 has been used in conjunction with nonconjugated interferon alfa.349 403

Usually used in multiple-drug regimens that include one or more HCV DAAs with or without peginterferon alfa.119 179 180 187 188 Most appropriate multiple-drug regimen depends on specific HCV genotype and patient population involved.119

Concomitant Ribavirin Capsules (Rebetol, Ribasphere) and Peginterferon Alfa-2b (PegIntron) Oral

800–1400 mg daily (based on body weight) in 2 divided doses in conjunction with sub-Q peginterferon alfa-2b.349 403 (See Table 3.) Duration of treatment depends on history of prior treatment, HCV genotype, and treatment response.349 403 (See Table 4.)

Table 3. Adult Dosage of Ribavirin Capsules (Rebetol, Ribasphere) for Concomitant Use with Peginterferon Alfa-2b (PegIntron) for Chronic HCV Infection.349403

Weight	Total Daily Dosage of Ribavirin (Capsules)	Recommended Ribavirin Dosage Regimen (Capsules)
≤65 kg	800 mg	400 mg in morning and 400 mg in evening
66–80 kg	1 g	400 mg in morning and 600 mg in evening
81–105 kg	1.2 g	600 mg in morning and 600 mg in evening
>105 kg	1.4 g	600 mg in morning and 800 mg in evening

Table 4. Duration of Treatment with Ribavirin Capsules (Rebetol, Ribasphere) and Peginterferon Alfa-2b (PegIntron) in Adults for Chronic HCV Infection.349403

Patient Type and Response	HCV Genotype	Duration	Considerations
Treatment-naive	1	48 weeks	Consider discontinuing HCV treatment if HCV RNA has not decreased ≥2 log10 by week 12 or remains detectable after 24 weeks of treatment349 403
Treatment-naive	2,3	24 weeks
Prior failure	Any	48 weeks	Consider discontinuing HCV treatment if HCV RNA still detectable at week 12 or remains detectable after 24 weeks of treatment349 403

Concomitant Ribavirin Capsules (Rebetol, Ribasphere) and Interferon Alfa-2b (Intron A) Oral

Adults weighing ≤75 kg: 1 g daily (400 mg in morning and 600 mg in evening) in conjunction with sub-Q interferon alfa-2b.349 403

Adults weighing >75 kg: 1.2 g daily (600 mg in morning and 600 mg in evening) in conjunction with sub-Q interferon alfa-2b.349 403

Duration of treatment depends on history of prior treatment, HCV genotype, and treatment response.349 403 In treatment-naive adults, usual duration is 24–48 weeks; consider discontinuing if HCV RNA levels are not below the limit of detection at 24 weeks.349 403 If used in adults who relapsed after prior nonconjugated interferon monotherapy, manufacturers recommend treatment duration of 24 weeks.349 403

Concomitant Ribavirin Tablets (Copegus, generic) and Peginterferon Alfa-2a (Pegasys) Oral

Adults with HCV monoinfection (without coexisting HIV infection): 800–1200 mg daily in 2 divided doses in conjunction with sub-Q peginterferon alfa-2a.377 402 Treatment duration depends on HCV genotype.377 402 (See Table 5.)

Table 5. Adult Dosage of Ribavirin Tablets (Copegus, generic) for Concomitant Use with Peginterferon Alfa-2a (Pegasys) for Chronic HCV Monoinfection377402

HCV Genotype	Ribavirin Dosage (Tablets)	Duration
1,4	1 g daily (500 mg twice daily) in those weighing <75 kg	48 weeks
	1.2 g daily (600 mg twice daily) in those weighing ≥75 kg
2,3	800 mg daily (400 mg twice daily)	24 weeks
5,6	Data insufficient to make dosage recommendations	–

Adults with HCV and HIV coinfection: 800 mg daily in 2 divided doses in conjunction with sub-Q peginterferon alfa-2a for 48 weeks, regardless of HCV genotype.377 402 Some experts suggest HIV-infected adults with HCV coinfection types 1, 4, 5, or 6 receive weight-based ribavirin dosage: 1 g daily (600 mg in morning and 400 mg in evening) for those weighing <75 kg or 1.2 g daily (600 mg in morning and 600 mg in evening) for those weighing ≥75 kg.190

Consider discontinuing HCV treatment if HCV RNA levels have not decreased ≥2 log10 from baseline at week 12 or are still detectable after 24 weeks of treatment.377 402

Manufacturer states safety and efficacy beyond 48 weeks of therapy not established.377 402

Dosage Modification for Toxicity Oral

If serious adverse effects or laboratory changes occur when oral ribavirin used in conjunction with peginterferon alfa or nonconjugated interferon alfa, modify dosage of one or both drugs, if appropriate, until adverse effects abate.349 377 402 403 If intolerance persists after dosage adjustment, discontinue both drugs.349 377 402 403

Ribavirin capsules (Rebetol, Ribasphere) and peginterferon alfa-2b or interferon alfa-2b in adults: If hemoglobin decreases to <10 g/dL, decrease ribavirin dosage by 200 mg daily (or by 400 mg daily in those originally receiving 1.4 g daily); an additional dosage reduction of 200 mg daily may be used if needed.349 403 If hemoglobin <8.5 g/dL, leukocyte count <1000/mm3, neutrophil count <500/mm3, or platelet count <25,000/mm3, permanently discontinue both drugs.349 403 In those with history of stable cardiovascular disease, decrease ribavirin dosage by 200 mg daily if hemoglobin decreases by ≥2 g/dL during any 4-week period; discontinue if hemoglobin <8.5 g/dL (or <12 g/dL after 4 weeks of reduced dosage).349

Ribavirin tablets (Copegus, generic) and peginterferon alfa-2a in adults: In those without cardiac disease, decrease ribavirin dosage to 600 mg daily (200 mg in morning and 400 mg in evening) if hemoglobin decreases to <10 g/dL; discontinue the drug if hemoglobin decreases to <8.5 g/dL.377 402 In those with history of stable cardiac disease, decrease ribavirin dosage to 600 mg daily (200 mg in morning and 400 mg in evening) if hemoglobin decreases by ≥2 g/dL during any 4-week period; discontinue the drug if hemoglobin decreases to <12 g/dL after 4 weeks of reduced dosage.377 402 If ribavirin tablets have been withheld and toxicity resolves or decreases in severity, may attempt reinitiation using ribavirin dosage of 600 mg daily; may then increase ribavirin dosage to 800 mg daily if tolerated.377 402 Do not resume usual maximum recommended adult dosage of 1–1.2 g daily (see Table 5).377 402

Consult manufacturer's information for more specific recommendations regarding dosage modification for hematologic or other adverse effects.349 377 402 403

Viral Hemorrhagic Fevers† Treatment of Lassa Fever† IV†

CDC and USAMRIID recommend initial loading dose of 30 mg/kg (up to 2 g), followed by 16 mg/kg (up to 1 g) every 6 hours for 4 days and then 8 mg/kg (up to 500 mg) every 8 hours for 6 days for total treatment duration of 10 days.219 343

Treatment of Hantavirus Infections† IV†

Hemorrhagic fever with renal syndrome† (HFRS): Initial loading dose of 33 mg/kg, followed by 16 mg/kg every 6 hours for 4 days and then 8 mg/kg every 8 hours for 3 days for a total treatment duration of 7 days has been used.270 271 276

Treatment of Crimean-Congo Hemorrhagic Fever† Oral

Initial loading dose of 30 mg/kg, followed by 15 mg/kg every 6 hours for 4 days and then 7.5 mg/kg every 8 hours for 6 days has been used.392

IV†

CDC and USAMRIID recommend initial loading dose of 30 mg/kg (up to 2 g), followed by 16 mg/kg (up to 1 g) every 6 hours for 4 days and then 8 mg/kg (up to 500 mg) every 8 hours for 6 days for a total treatment duration of 10 days.219 343

Treatment of Viral Hemorrhagic Fevers in Context of Biologic Warfare or Bioterrorism† Oral

USAMRIID and US Working Group on Civilian Biodefense recommend initial loading dose of 2 g, followed by 1.2 daily given in 2 divided doses for those weighing >75 kg or 1 g daily (400 mg in morning and 600 mg in evening) for those weighing ≤75 kg.343 351 Duration of treatment is 10 days.343 351

IV regimen usually preferred.343 351 Oral regimen may be used when parenteral preparation cannot be obtained or would be impractical (e.g., when large numbers of individuals require treatment in a mass casualty setting).343 351

IV†

USAMRIID and US Working Group on Civilian Biodefense recommend initial loading dose of 30 mg/kg (maximum 2 g), followed by 16 mg/kg (maximum 1 g) every 6 hours for 4 days and then 8 mg/kg (maximum 500 mg) every 8 hours for 6 days.343 351

IV regimen recommended for contained casualty settings if parenteral preparation can be obtained.343 351

Treatment of Adenovirus Infections† IV†

Severe infections in immunocompromised adults: Initial 33-mg/kg loading dose followed by 16 mg/kg every 6 hours for 4 days and then 8 mg/kg every 8 hours for another 3 days or longer until relevant cultures are negative for adenovirus.394 396

Special Populations

Hepatic Impairment

Effect of hepatic impairment on pharmacokinetics of oral ribavirin not fully evaluated;349 377 402 403 peak concentrations are increased depending on severity of hepatic impairment.349 403 (See Pharmacokinetics.)

Renal Impairment

Ribavirin tablets (Copegus): Reduce dosage in adults with Clcr ≤50 mL/minute.377 For treatment of chronic HCV infection, use alternating doses of 200 mg and 400 mg every other day in adults with Clcr 30–50 mL/minute and use 200 mg daily in adults with Clcr <30 mL/minute or undergoing hemodialysis.377 Do not reduce dosage any further; if severe adverse effects or laboratory abnormalities occur, discontinue drug.377 Data insufficient to make dosage recommendations for pediatric patients with renal impairment.377

Ribavirin capsules (Rebetol, Ribasphere),349 403 tablets (generic),402 oral solution (Rebetol) and peginterferon alfa-2b or interferon alfa-2b therapy:349 Contraindicated in adults with Clcr <50 mL/minute.349 402 403

Pediatric patients with renal impairment: Discontinue ribavirin capsules or oral solution (Rebetol) and peginterferon alfa-2b or interferon alfa-2b if Scr concentrations >2 mg/dL.349

Geriatric Patients

Cautious dosage selection because of age-related decreases in renal, hepatic, and/or cardiac function.349 403 Initiate therapy at the lower end of the dosing range.349 403 (See Geriatric Precautions under Cautions.)

Does not inhibit and is not a substrate for CYP450 isoenzymes.349 377 Interactions with drugs affecting or metabolized by CYP enzymes unlikely.349 377

Specific Drugs

Drug	Interaction	Comments
Antacids containing magnesium, aluminum, and simethicone (Mylanta)	Decreased ribavirin concentrations349	Clinical importance unknown349
Antiretrovirals, HIV nucleoside reverse transcriptase inhibitors (NRTIs)	Possible increased risk of potentially fatal hepatic decompensation in cirrhotic patients with chronic HCV coinfected with HIV who are receiving peginterferon alfa (with or without ribavirin) and antiretroviral regimens that include NRTIs20 377 Didanosine: Fatal hepatic failure, peripheral neuropathy, pancreatitis, symptomatic hyperlactatemia/lactic acidosis reported349 377 Zidovudine: Possible increased risk of severe neutropenia (ANC <500/mm3) and severe anemia (hemoglobin <8 g/dL) if used concomitantly with peginterferon alfa and ribavirin20 377 Ribavirin can reduce phosphorylation of lamivudine, stavudine, and zidovudine; no evidence of pharmacokinetic or pharmacodynamic interaction when ribavirin used concomitantly with these drugs in patients coinfected with HCV and HIV349 377 Stavudine and zidovudine: In vitro evidence of antagonistic antiretroviral effects; possibility of increased risk of adverse effects173 222 279 349 352 353 354 377	If used in patients coinfected with HIV who are receiving NRTIs, closely monitor for toxicities;20 377 if worsening toxicities are observed, consider discontinuing or reducing dosage of peginterferon and/or ribavirin;20 377 if decompensation occurs (Child-Pugh score ≥6), discontinue20 Didanosine: Concomitant use contraindicated200 349 377 402 403 Stavudine: Use concomitantly with caution220 349 377 402 403 Zidovudine: Concomitant use not recommended;200 use concomitantly with caution and increased monitoring200 222 349 377 402 403
Azathioprine	Severe pancytopenia and bone marrow suppression reported in patients receiving peginterferon alfa and oral ribavirin;349 377 402 403 may be due to interaction with ribavirin which may increase accumulation of azathioprine metabolite associated with myelotoxicity349 377 402 403	If used concomitantly with oral ribavirin and peginterferon alfa, perform CBCs (including platelet counts) weekly for first month, twice monthly during second and third months, and then monthly or more frequently if necessary349 377 402 403 If pancytopenia develops, discontinue all 3 drugs (azathioprine, ribavirin, peginterferon alfa) and do not reinitiate peginterferon alfa and ribavirin concomitantly with azathioprine349 377 402 403
Daclatasvir	Clinically important interactions not expected178
Interferons (interferon alfa, peginterferon alfa)	Hepatic decompensation, including some fatalities, reported in cirrhotic HCV patients coinfected with HIV receiving ribavirin, peginterferon alfa, and NRTIs349 377 402 403 Ribavirin may potentiate hematologic effects of interferons (anemia, neutropenia, lymphocytopenia);20 388 no evidence of pharmacokinetic interaction377
Ombitasvir, paritaprevir, dasabuvir fixed combination	Ombitasvir/paritaprevir/ritonavir: No in vitro evidence of antagonistic anti-HCV effects180
Simeprevir	No effect on simeprevir concentrations or AUC when used with ribavirin and peginterferon alfa187 In vitro evidence of additive effects against HCV;114 no in vitro evidence of antagonistic anti-HCV effects114 187
Sofosbuvir	No in vitro evidence of antagonistic anti-HCV effects188

Absorption

Bioavailability

Absorbed rapidly from GI tract; peak plasma concentrations achieved within 1–3 hours.349 377 Bioavailability is 64%.349

Following nasal and oral inhalation, absorbed systemically from the respiratory tract.1 Concentrations achieved in respiratory tract secretions are likely to be substantially greater than those achieved in plasma.1 4 16

Food

Administration with a high-fat meal increases oral bioavailability.349 377

Special Populations

Mean peak plasma concentrations increased with severity of hepatic impairment; mean AUCs in individuals with mild, moderate, or severe hepatic impairment similar to AUCs in controls.349

Following a single oral dose of ribavirin, AUC increased twofold or threefold in non-HCV-infected individuals with Clcr 30–60 or 10–30 mL/minute, respectively.349

In HCV-infected individuals with end-stage renal disease requiring hemodialysis, ribavirin 200 mg daily (Copegus tablets) produced plasma exposures about 20% lower than exposures achieved with 1–1.2 g daily in individuals with normal renal function.377

Distribution

Extent

Ribavirin and/or its metabolites accumulate in erythrocytes.1 4 16 22 61 132 133 138 149 193

Distributes slowly into CSF.78 169 CSF concentrations approximately 70% of concurrent plasma concentrations reported in HIV-infected patients.78

Not known whether ribavirin crosses the placenta158 or distributes into milk in humans.1

Plasma Protein Binding

Not bound.349

Elimination

Metabolism

Undergoes reversible phosphorylation in nucleated cells and deribosylation and amide hydrolysis.349

Elimination Route

Following oral administration, eliminated in urine (61%) and feces (12%) as metabolites and unchanged drug (17%).349

Half-life

Rebetol capsules: 43.6 hours (single dose) and 298 hours (multiple doses).349

Copegus tablets: 120–170 hours (single dose).377

Special Populations

Clearance reduced in patients with renal impairment.349

Significant adverse reactions associated with Ribavirin/peginterferon alfa-2a combination therapy include severe depression and suicidal ideation, hemolytic anemia, suppression of bone marrow function, autoimmune and infectious disorders, ophthalmologic disorders, cerebrovascular disorders, pulmonary dysfunction, colitis, pancreatitis, and diabetes.

The Peginterferon alfa-2a Package Insert should be reviewed in its entirety for additional safety information prior to initiation of combination treatment.

Pregnancy

Ribavirin may cause birth defects and/or death of the exposed fetus. 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 unless a report of a negative pregnancy test has been obtained immediately prior to planned initiation of therapy. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients. Patients should be instructed to use at least two forms of effective contraception during treatment and for 6 months after treatment has been stopped. Pregnancy testing should occur monthly during Ribavirin therapy and for 6 months after therapy has stopped [see BOXED WARNING, CONTRAINDICATIONS (4), USE IN SPECIFIC POPULATIONS (8.1), and PATIENT COUNSELING INFORMATION (17)].

Anemia

The primary toxicity of Ribavirin is hemolytic anemia, which was observed in approximately 13% of all Ribavirin/peginterferon alfa-2a- treated subjects in clinical trials. Anemia associated with Ribavirin occurs within 1 to 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. Caution should be exercised in initiating treatment in any patient with baseline risk of severe anemia (e.g., spherocytosis, history of gastrointestinal bleeding) [see DOSAGE AND ADMINISTRATION (2.3)].

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 (2.3)]. 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 BOXED WARNING, and DOSAGE AND ADMINISTRATION (2.3)].

Hepatic Failure

Chronic hepatitis C (CHC) patients with cirrhosis may be at risk of hepatic decompensation and death when treated with alpha interferons, including peginterferon alfa-2a. Cirrhotic CHC patients coinfected with HIV receiving highly active antiretroviral therapy (HAART) and interferon alfa-2a with or without Ribavirin appear to be at increased risk for the development of hepatic decompensation compared to patients not receiving HAART. In Study NR15961 [see CLINICAL STUDIES (14.3)], among 129 CHC/HIV cirrhotic patients receiving HAART, 14 (11%) of these patients across all treatment arms developed hepatic decompensation resulting in 6 deaths. All 14 patients were on NRTIs, including stavudine, didanosine, abacavir, zidovudine, and lamivudine. These small numbers of patients do not permit discrimination between specific NRTIs or the associated risk. During treatment, patients’ clinical status and hepatic function should be closely monitored for signs and symptoms of hepatic decompensation. Treatment with peginterferon alfa-2a/ Ribavirin should be discontinued immediately in patients with hepatic decompensation [see CONTRAINDICATIONS (4)]

Hypersensitivity

Severe acute hypersensitivity reactions (e.g., urticaria, angioedema, bronchoconstriction, and anaphylaxis) have been observed during alpha interferon and Ribavirin therapy. If such a reaction occurs, therapy with peginterferon alfa-2a and Ribavirin should be discontinued immediately and appropriate medical therapy instituted. Serious skin reactions including vesiculobullous eruptions, reactions in the spectrum of Stevens-Johnson Syndrome (erythema multiforme major) with varying degrees of skin and mucosal involvement and exfoliative dermatitis (erythroderma) have been reported in patients receiving peginterferon alfa-2a with and without Ribavirin. Patients developing signs or symptoms of severe skin reactions must discontinue therapy [see ADVERSE REACTIONS (6.2)].

Pulmonary Disorders

Dyspnea, pulmonary infiltrates, pneumonitis, pulmonary hypertension, and pneumonia have been reported during therapy with Ribavirin and interferon. 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, patients should be closely monitored and, if appropriate, combination Ribavirin/peginterferon alfa-2a treatment should be discontinued.

Bone Marrow Suppression

Pancytopenia (marked decreases in RBCs, neutrophils and platelets) and bone marrow suppression have been reported in the literature to occur within 3 to 7 weeks after the concomitant administration of pegylated interferon/Ribavirin and azathioprine. In this limited number of patients (n=8), myelotoxicity was reversible within 4 to 6 weeks upon withdrawal of both HCV antiviral therapy and concomitant azathioprine and did not recur upon reintroduction of either treatment alone. peginterferon alfa-2a, Ribavirin, and azathioprine should be discontinued for pancytopenia, and pegylated interferon/Ribavirin should not be re-introduced with concomitant azathioprine [see Drug Interactions (7.3)].

Pancreatitis

Ribavirin and peginterferon alfa-2a therapy should be suspended in patients with signs and symptoms of pancreatitis, and discontinued in patients with confirmed pancreatitis.

Impact on Growth in Pediatric Patients

During combination therapy for up to 48 weeks with peginterferon alfa-2a  plus Ribavirin, growth inhibition was observed in pediatric subjects 5 to 17 years of age. Decreases in weight for age z-score and height for age z-score up to 48 weeks of therapy compared with baseline were observed. At 2 years post-treatment, 16% of pediatric subjects were more than 15 percentiles below their baseline weight curve and 11% were more than 15 percentiles below their baseline height curve.

The available longer term data on subjects who were followed up to 6 years post-treatment are too limited to determine the risk of reduced adult height in some patients [see Clinical Studies Experience (6.1)].

Laboratory Tests

Before beginning Ribavirin/peginterferon alfa-2a combination therapy, standard hematological and biochemical laboratory tests are recommended for all patients. Pregnancy screening for women of childbearing potential must be performed. Patients who have pre-existing cardiac abnormalities should have electrocardiograms administered before treatment with Ribavirin/peginterferon alfa-2a.

 

After initiation of therapy, hematological tests should be performed at 2 weeks and 4 weeks and biochemical tests should be performed at 4 weeks. Additional testing should be performed periodically during therapy. In adult clinical studies, the CBC (including hemoglobin level and white blood cell and platelet counts) and chemistries (including liver function tests and uric acid) were measured at 1, 2, 4, 6, and 8 weeks, and then every 4 to 6 weeks or more frequently if abnormalities were found. In the pediatric clinical trial, hematological and chemistry assessments were at 1, 3, 5, and 8 weeks, then every 4 weeks. Thyroid stimulating hormone (TSH) was measured every 12 weeks. Monthly pregnancy testing should be performed during combination therapy and for 6 months after discontinuing therapy.

The entrance criteria used for the clinical studies of Ribavirin and peginterferon alfa-2a may be considered as a guideline to acceptable baseline values for initiation of treatment:

• Platelet count greater than or equal to 90,000 cells/mm3 (as low as 75,000 cells/mm3 in HCV patients with cirrhosis or 70,000 cells/mm3 in patients with CHC and HIV)
• Absolute neutrophil count (ANC) greater than or equal to 1500 cells/mm3
• TSH and T4 within normal limits or adequately controlled thyroid function
• CD4+ cell count greater than or equal to 200 cells/mm3or CD4+ cell count greater than or equal to 100 cells/mm3 but less than 200 cells/mm3 and HIV-1 RNA less than 5,000 copies/mL in patients coinfected with HIV
• Hemoglobin greater than or equal to 12 g/dL for women and greater than or equal to 13 g/dL for men in CHC monoinfected patients
• Hemoglobin greater than or equal to 11 g/dL for women and greater than or equal to 12 g/dL for men in patients with CHC and HIV

Peginterferon alfa-2a in combination with Ribavirin causes a broad variety of serious adverse reactions [see BOXED WARNING and WARNINGS AND PRECAUTIONS (5)]. The most common serious or life-threatening adverse reactions induced or aggravated by Ribavirin/peginterferon alfa-2a include depression, suicide, relapse of drug abuse/overdose, and bacterial infections each occurring at a frequency of less than 1%. Hepatic decompensation occurred in 2% (10/574) CHC/HIV patients [see WARNINGS AND PRECAUTIONS (5.3)].

Clinical Studies Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Adult Patients

In the pivotal registration trials NV15801 and NV15942, 886 patients received Ribavirin for 48 weeks at doses of 1000/1200 mg based on body weight. In these trials, one or more serious adverse reactions occurred in 10% of CHC monoinfected subjects and in 19% of CHC/HIV subjects receiving peginterferon alfa-2a alone or in combination with Ribavirin. The most common serious adverse event (3% in CHC and 5% in CHC/HIV) was bacterial infection (e.g., sepsis, osteomyelitis, endocarditis, pyelonephritis, pneumonia).

Other serious adverse reactions occurred at a frequency of less than 1% and included: suicide, suicidal ideation, psychosis, aggression, anxiety, drug abuse and drug overdose, angina, hepatic dysfunction, fatty liver, cholangitis, arrhythmia, diabetes mellitus, autoimmune phenomena (e.g., hyperthyroidism, hypothyroidism, sarcoidosis, systemic lupus erythematosus, rheumatoid arthritis), peripheral neuropathy, aplastic anemia, peptic ulcer, gastrointestinal bleeding, pancreatitis, colitis, corneal ulcer, pulmonary embolism, coma, myositis, cerebral hemorrhage, thrombotic thrombocytopenic purpura, psychotic disorder, and hallucination.

The percentage of patients in clinical trials who experienced one or more adverse events was 98%. The most commonly reported adverse reactions were psychiatric reactions, including depression, insomnia, irritability, anxiety, and flu-like symptoms such as fatigue, pyrexia, myalgia, headache and rigors. Other common reactions were anorexia, nausea and vomiting, diarrhea, arthralgias, injection site reactions, alopecia, and pruritus. Table 5 shows rates of adverse events occurring in greater than or equal to 5% of subjects receiving pegylated interferon and Ribavirin combination therapy in the CHC Clinical Trial, NV15801.

Ten percent of CHC monoinfected patients receiving 48 weeks of therapy with peginterferon alfa-2a in combination with Ribavirin discontinued therapy; 16% of CHC/HIV coinfected patients discontinued therapy. The most common reasons for discontinuation of therapy were psychiatric, flu-like syndrome (e.g., lethargy, fatigue, headache), dermatologic and gastrointestinal disorders, and laboratory abnormalities (thrombocytopenia, neutropenia, and anemia).

Overall 39% of patients with CHC or CHC/HIV required modification of peginterferon alfa-2a and/or Ribavirin therapy. The most common reason for dose modification of peginterferon alfa-2a in CHC and CHC/HIV patients was for laboratory abnormalities; neutropenia (20% and 27%, respectively) and thrombocytopenia (4% and 6%, respectively). The most common reason for dose modification of Ribavirin in CHC and CHC/HIV patients was anemia (22% and 16%, respectively).

Peginterferon alfa-2a dose was reduced in 12% of patients receiving 1000 mg to 1200 mg Ribavirin for 48 weeks and in 7% of patients receiving 800 mg Ribavirin for 24 weeks. Ribavirin dose was reduced in 21% of patients receiving 1000 mg to 1200 mg Ribavirin for 48 weeks and in 12% of patients receiving 800 mg Ribavirin for 24 weeks.

Chronic hepatitis C monoinfected patients treated for 24 weeks with peginterferon alfa-2a and 800 mg Ribavirin were observed to have lower incidence of serious adverse events (3% vs. 10%), hemoglobin less than 10g/dL (3% vs. 15%), dose modification of peginterferon alfa-2a (30% vs. 36%) and Ribavirin (19% vs. 38%), and of withdrawal from treatment (5% vs. 15%) compared to patients treated for 48 weeks with peginterferon alfa-2a and 1000 mg or 1200 mg Ribavirin. On the other hand, the overall incidence of adverse events appeared to be similar in the two treatment groups.

Table 5Adverse Reactions Occurring in greater than or equal to 5% of Patients in Chronic Hepatitis C Clinical Trials (Study NV15801)

	CHC Combination Therapy Study NV15801
*Severe hematologic abnormalities (lymphocyte less than 500 cells/mm3; hemoglobin less than 10 g/dL; neutrophil less than 750 cells/mm3; platelet less than 50,000 cells/mm3).
Body System	Peginterferon Alfa-2a 180 mcg + 1000 mg or 1200 mg Ribavirin Tablets 48 weeks	Interferon alfa-2b + 1000 mg or 1200 mg Ribavirin Capsules 48 weeks
	N=451	N=443
	%	%
Application Site Disorders
Injection site reaction	23	16
Endocrine Disorders
Hypothyroidism	4	5
Flu-like Symptoms and Signs
Fatigue/Asthenia	65	68
Pyrexia	41	55
Rigors	25	37
Pain	10	9
Gastrointestinal
Nausea/Vomiting	25	29
Diarrhea	11	10
Abdominal pain	8	9
Dry mouth	4	7
Dyspepsia	6	5
Hematologic*
Lymphopenia	14	12
Anemia	11	11
Neutropenia	27	8
Thrombocytopenia	5	< 1
Metabolic and Nutritional
Anorexia	24	26
Weight decrease	10	10
Musculoskeletal, Connective Tissue and Bone
Myalgia	40	49
Arthralgia	22	23
Back pain	5	5
Neurological
Headache	43	49
Dizziness (excluding vertigo)	14	14
Memory impairment	6	5
Psychiatric
Irritability/Anxiety/Nervousness	33	38
Insomnia	30	37
Depression	20	28
Concentration impairment	10	13
Mood alteration	5	6
Resistance Mechanism Disorders
Overall	12	10
Respiratory, Thoracic and Mediastinal
Dyspnea	13	14
Cough	10	7
Dyspnea exertional	4	7
Skin and Subcutaneous Tissue
Alopecia	28	33
Pruritus	19	18
Dermatitis	16	13
Dry skin	10	13
Rash	8	5
Sweating increased	6	5
Eczema	5	4
Visual Disorders
Vision blurred	5	2

Pediatric Patients

In a clinical trial with 114 pediatric subjects (5 to 17 years of age) treated with peginterferon alfa-2a alone or in combination with Ribavirin, dose modifications were required in approximately one-third of subjects, most commonly for neutropenia and anemia. In general, the safety profile observed in pediatric subjects was similar to that seen in adults. In the pediatric study, the most common adverse events in subjects treated with combination therapy peginterferon alfa-2a and Ribavirin for up to 48 weeks were influenza-like illness (91%), upper respiratory tract infection (60%), headache (64%), gastrointestinal disorder (56%), skin disorder (47%), and injection-site reaction (45%). Seven subjects receiving combination peginterferon alfa-2a and Ribavirin treatment for 48 weeks discontinued therapy for safety reasons (depression, psychiatric evaluation abnormal, transient blindness, retinal exudates, hyperglycemia, type 1 diabetes mellitus, and anemia). Severe adverse events were reported in 2 subjects in the peginterferon alfa-2a plus Ribavirin combination therapy group (hyperglycemia and cholecystectomy).

Table 6 Percentage of Pediatric Subjects with Adverse Reactions* During First 24 Weeks of Treatment by Treatment Group and for 24 Weeks Post-treatment (in at Least 10% of Subjects)

* Displayed adverse drug reactions include all grades of reported adverse clinical events considered possibly, probably, or definitely related to study drug.
**Subjects in the peginterferon alfa-2a plus placebo arm who did not achieve undetectable viral load at week 24 switched to combination treatment thereafter. Therefore, only the first 24 weeks are presented for the comparison of combination therapy with monotherapy.
	Study NV17424
System Organ Class	Peginterferon Alfa-2a 180 mcg/1.73 m² x BSA + Ribavirin 15 mg/kg  (N=55)	Peginterferon Alfa-2a 180 mcg/1.73 m² x BSA + Placebo**  (N=59)
	%	%
General disorders and administration site conditions
Influenza like illness	91	81
Injection site reaction	44	42
Fatigue	25	20
Irritability	24	14
Gastrointestinal disorders
Gastrointestinal disorder	49	44
Nervous system disorders
Headache	51	39
Skin and subcutaneous tissue disorders
Rash	15	10
Pruritus	11	12
Musculoskeletal, connective tissue and bone disorders
Musculoskeletal pain	35	29
Psychiatric disorders
Insomnia	9	12
Metabolism and nutrition disorders
Decreased appetite	11	14

In pediatric subjects randomized to combination therapy, the incidence of most adverse reactions was similar for the entire treatment period (up to 48 weeks plus 24 weeks follow-up) in comparison to the first 24 weeks, and increased only slightly for headache, gastrointestinal disorder, irritability and rash. The majority of adverse reactions occurred in the first 24 weeks of treatment.

Growth Inhibition in Pediatric Subjects [see Warnings and Precautions (5.8)].

Pediatric subjects treated with PEGASYS plus Ribavirin combination therapy showed a delay in weight and height increases with up to 48 weeks of therapy compared with baseline. Both weight for age and height for age z-scores as well as the percentiles of the normative population for subject weight and height decreased during treatment. At the end of 2 years follow-up after treatment, most subjects had returned to baseline normative curve percentiles for weight (64th mean percentile at baseline, 60th mean percentile at 2 years post-treatment) and height (54th mean percentile at baseline, 56th mean percentile at 2 years post-treatment). At the end of treatment, 43% (23 of 53) of subjects experienced a weight percentile decrease of more than 15 percentiles, and 25% (13 of 53) experienced a height percentile decrease of more than 15 percentiles on the normative growth curves. At 2 years post-treatment, 16% (6 of 38) of subjects were more than 15 percentiles below their baseline weight curve and 11% (4 of 38) were more than 15 percentiles below their baseline height curve.

Thirty-eight of the 114 subjects enrolled in the long-term follow-up study, extending up to 6 years posttreatment. For most subjects, post-treatment recovery in growth at 2 years post-treatment was maintained to 6 years post-treatment.

Common Adverse Reactions in CHC with HIV Coinfection (Adults)

The adverse event profile of coinfected patients treated with peginterferon alfa-2a/Ribavirin in Study NR15961 was generally similar to that shown for monoinfected patients in Study NV15801 (Table 5). Events occurring more frequently in coinfected patients were neutropenia (40%), anemia (14%), thrombocytopenia (8%), weight decrease (16%), and mood alteration (9%).

Laboratory Test Abnormalities

Adult Patients 

Anemia due to hemolysis is the most significant toxicity of Ribavirin therapy. Anemia (hemoglobin less than 10 g/dL) was observed in 13% of all Ribavirin and peginterferon alfa-2a combination-treated patients in clinical trials. The maximum drop in hemoglobin occurred during the first 8 weeks of initiation of Ribavirin therapy [see DOSAGE AND ADMINISTRATION (2.3)].

Table 7Selected Laboratory Abnormalities During Treatment with Ribavirin in Combination With Either Peginterferon Alfa-2a or Interferon alfa-2b

Laboratory Parameter	Peginterferon Alfa-2a  +  Ribavirin  1000/1200 mg  48 wks	Interferon alfa-2b  +  Ribavirin  1000/1200 mg  48 wks
	(N=887)	(N=443)
Neutrophils (cells/mm3)
1,000 <1,500	34%	38%
500 <1,000	49%	21%
<500	5%	1%
Platelets (cells/mm3)
50,000 - <75,000	11%	4%
20,000 - <50,000	5%	< 1%
<20,000	0	0
Hemoglobin (g/dL)
8.5 - 9.9	11%	11%
<8.5	2%	< 1%

Pediatric Patients

Decreases in hemoglobin, neutrophils and platelets may require dose reduction or permanent discontinuation from treatment [see DOSAGE AND ADMINISTRATION (2.4)]. Most laboratory abnormalities noted during the clinical trial returned to baseline levels shortly after discontinuation of treatment.

Table 8 Selected Hematologic Abnormalities During First 24 Weeks of Treatment by Treatment Group in Previously Untreated Pediatric Subjects

* Subjects in the peginterferon alfa-2a plus placebo arm who did not achieve undetectable viral load at week 24 switched to combination treatment thereafter. Therefore, only the first 24 weeks are presented for the comparison of combination therapy with monotherapy.
Laboratory Parameter	Peginterferon Alfa-2a 180 mcg/1.73 m² x BSA + Ribavirin 15 mg/kg  (N=55)	Peginterferon Alfa-2a 180 mcg/1.73 m² x BSA + Placebo* (N=59)
Neutrophils (cells/mm3)
1,000 to < 1,500	31%	39%
750 to < 1,000	27%	17%
500 to < 750	25%	15%
< 500	7%	5%
Platelets (cells/mm3)
75,000 to < 100,000	4%	2%
50,000 to < 75,000	0%	2%
< 50,000	0%	0%
Hemoglobin (g/dL)
8.5 to < 10	7%	3%
< 8.5	0%	0%

In patients randomized to combination therapy, the incidence of abnormalities during the entire treatment phase (up to 48 weeks plus 24 weeks follow-up) in comparison to the first 24 weeks increased slightly for neutrophils between 500 and 1,000 cells/mm  and hemoglobin values between 8.5 and 10 g/dL. The majority of hematologic abnormalities occurred in the first 24 weeks of treatment.

Postmarketing Experience

The following adverse reactions have been identified and reported during post-approval use of peginterferon alfa-2a/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)