RIBASPHERE RibaPak

The molecular formula of ribavirin is C₈H₁₂N₄O₅ and the molecular weight is 244.2. Ribavirin is a white to off-white powder. It is freely soluble in water and slightly soluble in anhydrous alcohol.

Ribasphere (ribavirin, USP) is available as a blue-colored (shade depending on strength), capsule-shaped, film-coated tablet for oral administration. Each tablet contains 200 mg, 400 mg, or 600 mg of ribavirin and the following inactive ingredients: microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, povidone K27-33, magnesium stearate, and purified water. The coating of the 200 mg tablet contains partially hydrolyzed polyvinyl alcohol, titanium dioxide, polyethylene glycol 3350, talc, FD&C blue #2 [indigo carmine aluminum lake], and carnauba wax. The coating of the 400 mg and 600 mg tablet contains partially hydrolyzed polyvinyl alcohol, titanium dioxide, polyethylene glycol 3350, talc, FD&C blue #1 [brilliant blue FCF aluminum lake], and carnauba wax.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Ribavirin is an antiviral drug [see Clinical Pharmacology (12.4)].

12.3 Pharmacokinetics

Multiple dose ribavirin pharmacokinetic data are available for HCV patients who received ribavirin in combination with peginterferon alfa-2a. Following administration of 1200 mg/day with food for 12 weeks mean±SD (n=39; body weight >75 kg) AUC_0-12hr was 25,361±7110 ng∙hr/mL and C_max was 2748±818 ng/mL. The average time to reach C_max was 2 hours. Trough ribavirin plasma concentrations following 12 weeks of dosing with food were 1662±545 ng/mL in HCV infected patients who received 800 mg/day (n=89), and 2112±810 ng/mL in patients who received 1200 mg/day (n=75; body weight >75 kg).

The terminal half-life of ribavirin following administration of a single oral dose of ribavirin is about 120 to 170 hours. The total apparent clearance following administration of a single oral dose of ribavirin is about 26 L/h. There is extensive accumulation of ribavirin after multiple dosing (twice daily) such that the C_max at steady state was four-fold higher than that of a single dose.

Effect of Food on Absorption of Ribavirin

Bioavailability of a single oral dose of ribavirin was increased by co-administration with a high-fat meal. The absorption was slowed (T_max was doubled) and the AUC_0-192h and C_max increased by 42% and 66%, respectively, when ribavirin was taken with a high-fat meal compared with fasting conditions [see Dosage and Administration (2.1) and Patient Counseling Information (17)].

Elimination and Metabolism

The contribution of renal and hepatic pathways to ribavirin elimination after administration of ribavirin is not known. In vitro studies indicate that ribavirin is not a substrate of CYP450 enzymes.

12.4 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 RNA viruses and ribavirin triphosphate inhibits HCV polymerase in a biochemical reaction.

Antiviral Activity in Cell Culture

In the stable HCV cell culture model system (HCV replicon), ribavirin inhibited autonomous HCV RNA replication with a 50% effective concentration (EC₅₀) value of 11-21 mcM. In the same model, PEG-IFN α-2a also inhibited HCV RNA replication, with an EC₅₀ value of 0.1-3 ng/mL. The combination of PEG-IFN α-2a and ribavirin was more effective at inhibiting HCV RNA replication than either agent alone.

Resistance

Different HCV genotypes display considerable clinical variability in their response to PEG-IFN-α and ribavirin therapy. Viral genetic determinants associated with the variable response have not been definitively identified.

Cross-resistance

Cross-resistance between IFN α and ribavirin has not been observed.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

In a p53 (+/-) mouse carcinogenicity study up to the maximum tolerated dose of 100 mg/kg/day, ribavirin was not oncogenic. Ribavirin was also not oncogenic in a rat 2-year carcinogenicity study at doses up to the maximum tolerated dose of 60 mg/kg/day. On a body surface area basis, these doses are approximately 0.5 and 0.6 times the maximum recommended daily human dose of ribavirin, respectively.

Mutagenesis

Ribavirin demonstrated mutagenic activity in the in vitro mouse lymphoma assay. No clastogenic activity was observed in an in vivo mouse micronucleus assay at doses up to 2000 mg/kg. However, results from studies published in the literature show clastogenic activity in the in vivo mouse micronucleus assay at oral doses up to 2000 mg/kg. A dominant lethal assay in rats was negative, indicating that if mutations occurred in rats they were not transmitted through male gametes. However, potential carcinogenic risk to humans cannot be excluded.

Impairment of Fertility

In a fertility study in rats, ribavirin showed a marginal reduction in sperm counts at the dose of 100 mg/kg/day with no effect on fertility. Upon cessation of treatment, total recovery occurred after 1 spermatogenesis cycle. Abnormalities in sperm were observed in studies in mice designed to evaluate the time course and reversibility of ribavirin-induced testicular degeneration at doses of 15 to 150 mg/kg/day (approximately 0.1 to 0.8 times the maximum recommended daily human dose of ribavirin) administered for 3 to 6 months. Upon cessation of treatment, essentially total recovery from ribavirin-induced testicular toxicity was apparent within 1 or 2 spermatogenic cycles.

Female patients of childbearing potential and male patients with female partners of childbearing potential should not receive Ribasphere (ribavirin, USP) unless the patient and his/her partner are using effective contraception (two reliable forms). Based on a multiple dose half-life (t_1/2) of ribavirin of 12 days, effective contraception must be utilized for 6 months post therapy (i.e., 15 half-lives of clearance for ribavirin).

No reproductive toxicology studies have been performed using peginterferon alfa-2a in combination with ribavirin. However, peginterferon alfa-2a and ribavirin when administered separately, each has adverse effects on reproduction. It should be assumed that the effects produced by either agent alone would also be caused by the combination of the two agents.

13.2 Animal Toxicology and/or Pharmacology

In a study in rats, it was concluded that dominant lethality was not induced by ribavirin at doses up to 200 mg/kg for 5 days (up to 1.7 times the maximum recommended human dose of ribavirin).

Long-term studies in the mouse and rat (18 to 24 months; dose 20 to 75, and 10 to 40 mg/kg/day, respectively, approximately 0.1 to 0.4 times the maximum daily human dose of ribavirin) have demonstrated a relationship between chronic ribavirin exposure and an increased incidence of vascular lesions (microscopic hemorrhages) in mice. In rats, retinal degeneration occurred in controls, but the incidence was increased in ribavirin-treated rats.

14 CLINICAL STUDIES

14.1 Chronic Hepatitis C Patients

The safety and effectiveness of peginterferon alfa-2a in combination with ribavirin for the treatment of hepatitis C virus infection were assessed in two randomized controlled clinical trials. All patients were adults, had compensated liver disease, detectable hepatitis C virus, liver biopsy diagnosis of chronic hepatitis, and were previously untreated with interferon. Approximately 20% of patients in both studies had compensated cirrhosis (Child-Pugh class A). Patients coinfected with HIV were excluded from these studies.

In Study NV15801, patients were randomized to receive either peginterferon alfa-2a 180 mcg subcutaneous once weekly with an oral placebo, peginterferon alfa-2a 180 mcg once weekly with ribavirin 1000 mg by mouth (body weight <75 kg) or 1200 mg by mouth (body weight ≥75 kg) or interferon alfa-2b 3 MIU subcutaneous three times a week plus ribavirin 1000 mg or 1200 mg by mouth. All patients received 48 weeks of therapy followed by 24 weeks of treatment-free follow-up. Ribavirin or placebo treatment assignment was blinded. Sustained virological response was defined as undetectable (<50 IU/mL) HCV RNA on or after study week 68. Peginterferon alfa-2a in combination with ribavirin resulted in a higher SVR compared to peginterferon alfa-2a alone or interferon alfa-2b and ribavirin (Table 5 ). In all treatment arms, patients with viral genotype 1, regardless of viral load, had a lower response rate to peginterferon alfa-2a in combination with ribavirin compared to patients with other viral genotypes.

In Study NV15942, all patients received peginterferon alfa-2a 180 mcg subcutaneous once weekly and were randomized to treatment for either 24 or 48 weeks and to a ribavirin dose of either 800 mg or 1000 mg/1200 mg (for body weight <75 kg/≥75 kg). Assignment to the four treatment arms was stratified by viral genotype and baseline HCV viral titer. Patients with genotype 1 and high viral titer (defined as >2 x 10⁶ HCV RNA copies/mL serum) were preferentially assigned to treatment for 48 weeks.

Sustained Virologic Response (SVR) and HCV Genotype

HCV 1 and 4- Irrespective of baseline viral titer, treatment for 48 weeks with peginterferon alfa-2a and 1000 mg or 1200 mg of ribavirin resulted in higher SVR (defined as undetectable HCV RNA at the end of the 24-week treatment-free follow-up period) compared to shorter treatment (24 weeks) and/or 800 mg ribavirin.

HCV 2 and 3- Irrespective of baseline viral titer, treatment for 24 weeks with peginterferon alfa-2a and 800 mg of ribavirin resulted in a similar SVR compared to longer treatment (48 weeks) and/or 1000 mg or 1200 mg of ribavirin (see Table 6 ).

The numbers of patients with genotype 5 and 6 were too few to allow for meaningful assessment.

Table 6 Sustained Virologic Response as a Function of Genotype (Study NV15942)

	24 Weeks Treatment		48 Weeks Treatment
	Peginterferon alfa-2a +    Ribavirin 800 mg    (N=207)	Peginterferon alfa-2a + Ribavirin    1000 mg or 1200 mg 1000 mg for body weight <75 kg; 1200 mg for body weight ≥75 kg.     (N=280)	Peginterferon alfa-2a +    Ribavirin 800 mg    (N=361)	Peginterferon alfa-2a + Ribavirin    1000 mg or 1200 mg 1000 mg for body weight <75 kg; 1200 mg for body weight ≥75 kg.     (N=436)
Genotype 1	29/101 (29%)	48/118 (41%)	99/250 (40%)	138/271 (51%)
Genotypes 2,3	79/96 (82%)	116/144 (81%)	75/99 (76%)	117/153 (76%)
Genotype 4	0/5 (0%)	7/12 (58%)	5/8 (63%)	9/11 (82%)

14.2 Other Treatment Response Predictors

Treatment response rates are lower in patients with poor prognostic factors receiving pegylated interferon alpha therapy. In studies NV15801 and NV15942, treatment response rates were lower in patients older than 40 years (50% vs. 66%), in patients with cirrhosis (47% vs. 59%), in patients weighing over 85 kg (49% vs. 60%), and in patients with genotype 1 with high vs. low viral load (43% vs. 56%). African-American patients had lower response rates compared to Caucasians.

In studies NV15801 and NV15942, lack of early virologic response by 12 weeks (defined as HCV RNA undetectable or >2log₁₀ lower than baseline) was grounds for discontinuation of treatment. Of patients who lacked an early viral response by 12 weeks and completed a recommended course of therapy despite a protocol-defined option to discontinue therapy, 5/39 (13%) achieved an SVR. Of patients who lacked an early viral response by 24 weeks, 19 completed a full course of therapy and none achieved an SVR.

14.3 Chronic Hepatitis C/HIV Coinfected Patients

In Study NR15961, patients with CHC/HIV were randomized to receive either peginterferon alfa-2a 180 mcg subcutaneous once weekly plus an oral placebo, peginterferon alfa-2a 180 mcg once weekly plus ribavirin 800 mg by mouth daily or interferon alfa-2a, 3 MIU subcutaneous three times a week plus ribavirin 800 mg by mouth daily. All patients received 48 weeks of therapy and sustained virologic response (SVR) was assessed at 24 weeks of treatment-free follow-up. Ribavirin or placebo treatment assignment was blinded in the peginterferon alfa-2a treatment arms. All patients were adults, had compensated liver disease, detectable hepatitis C virus, liver biopsy diagnosis of chronic hepatitis C, and were previously untreated with interferon. Patients also had CD4+ cell count ≥200 cells/mcL or CD4+ cell count ≥100 cells/mcL but <200 cells/mcL and HIV-1 RNA <5000 copies/mL, and stable status of HIV. Approximately 15% of patients in the study had cirrhosis. Results are shown in Table 7 .

Treatment response rates were lower in CHC/HIV patients with poor prognostic factors (including HCV genotype 1, HCV RNA >800,000 IU/mL, and cirrhosis) receiving pegylated interferon alpha therapy.

Of the patients who did not demonstrate either undetectable HCV RNA or at least a 2 log₁₀ reduction from baseline in HCV RNA titer by 12 weeks of peginterferon alfa-2a and ribavirin combination therapy, 2% (2/85) achieved an SVR.

In CHC patients with HIV coinfection who received 48 weeks of peginterferon alfa-2a alone or in combination with ribavirin treatment, mean and median HIV RNA titers did not increase above baseline during treatment or 24 weeks post treatment.

16 HOW SUPPLIED/STORAGE AND HANDLING

Ribasphere (ribavirin, USP) is available as tablets for oral administration.

Each Ribasphere (ribavirin, USP) 200-mg tablet contains 200 mg of ribavirin and is a capsule-shaped, light blue colored, film-coated tablet, debossed with “200” on one side and the logo “3RP” on the other side.

Each Ribasphere (ribavirin, USP) 400-mg tablet contains 400 mg of ribavirin and is a capsule-shaped, medium blue colored, film-coated tablet, debossed with “400” on one side and the logo “3RP” on the other side.

Each Ribasphere (ribavirin, USP) 600-mg tablet contains 600 mg of ribavirin and is a capsule-shaped, dark blue colored, film-coated tablet, debossed with “600” on one side and the logo “3RP” on the other side.

They are packaged as follows:

200 mg    Bottles of 168   NDC 66435-102-16
200 mg    Bottles of 500   NDC 66435-102-95

400 mg    Bottles of 56     NDC 66435-103-56
400 mg    Bottles of 500   NDC 66435-103-95

600 mg    Bottles of 56     NDC 66435-104-56
600 mg    Bottles of 250   NDC 66435-104-92

Ribasphere^® is also available in blister packs with the tradename Ribasphere^® RibaPak^®.
Ribasphere^® RibaPak^® is available as follows:

Ribasphere ^® RibaPak^® 600 Dose Pack Carton contains a total of 28 - 200 mg Ribasphere (ribavirin, USP) tablets and 28 - 400 mg Ribasphere (ribavirin, USP) tablets. Each carton contains 4 individual Ribasphere^® RibaPak^® 600 Dose Packs. Each individual Ribasphere^®RibaPak^® 600 Dose Pack contains 7 (seven) - 200 mg Ribasphere (ribavirin, USP) tablets and 7 (seven) - 400 mg Ribasphere (ribavirin, USP) tablets.

Each 200 mg Ribasphere (ribavirin, USP) tablet contains 200 mg of ribavirin and is a capsule-shaped, light blue colored, film-coated tablet, debossed with “200” on one side and the logo “3RP” on the other side. Each 400 mg Ribasphere (ribavirin, USP) tablet contains 400 mg of ribavirin and is a capsule-shaped, medium blue colored, film-coated tablet, debossed with “400” on one side and the logo “3RP” on the other side.

Ribasphere^® RibaPak^® 600 Dose Pack Carton

NDC: 66435-108-99

Ribasphere^® RibaPak^® 600 Dose Pack

NDC: 66435-108-56

Ribasphere^® RibaPak^® 800 Dose Pack Carton contains a total of 56 - 400 mg Ribasphere (ribavirin, USP) tablets. Each carton contains 4 individual Ribasphere RibaPak 800 Dose Packs. Each individual Ribasphere RibaPak 800 Dose Pack contains 14 (fourteen) - 400 mg Ribasphere (ribavirin, USP) tablets.
Each 400 mg Ribasphere (ribavirin, USP) tablet contains 400 mg of ribavirin and is a capsule-shaped, medium blue colored, film-coated tablet, debossed with “400” on one side and the logo “3RP” on the other side.
Ribasphere^® RibaPak^® 800 Dose Pack Carton

NDC:  66435-105-99
Ribasphere^® RibaPak^® 800 Dose Pack

NDC:  66435-105-56

Ribasphere^® RibaPak^® 1000 Dose Pack Carton contains a total of 28 - 400 mg Ribasphere (ribavirin, USP) tablets and 28 - 600 mg Ribasphere (ribavirin, USP) tablets. Each carton contains 4 individual Ribasphere RibaPak 1000 Dose Packs. Each individual Ribasphere RibaPak 1000 Dose Pack contains 7 (seven) - 400 mg Ribasphere (ribavirin, USP) tablets and 7 (seven) - 600 mg Ribasphere (ribavirin, USP) tablets. Each 400 mg Ribasphere (ribavirin, USP) tablet contains 400 mg of ribavirin and is a capsule-shaped, medium blue colored, film-coated tablet, debossed with “400” on one side and the logo “3RP” on the other side. Each 600 mg Ribasphere (ribavirin, USP) tablet contains 600 mg of ribavirin and is a capsule-shaped, dark blue colored, film-coated tablet, debossed with “600” on one side and the logo “3RP” on the other side.
Ribasphere^® RibaPak^® 1000 Dose Pack Carton

NDC: 66435-106-99
Ribasphere^® RibaPak^® 1000 Dose Pack

NDC: 66435-106-56

Ribasphere^® RibaPak^® 1200 Dose Pack Carton contains a total of 56 - 600 mg Ribasphere (ribavirin, USP) tablets. Each carton contains 4 individual Ribasphere RibaPak 1200 Dose Packs. Each individual Ribasphere RibaPak 1200 Dose Pack contains 14 (fourteen) - 600 mg Ribasphere (ribavirin, USP) tablets.
Each 600 mg Ribasphere (ribavirin, USP) tablet contains 600 mg of ribavirin and is a capsule-shaped, dark blue colored, film-coated tablet, debossed with “600” on one side and the logo “3RP” on the other side.
Ribasphere^® RibaPak^® 1200 Dose Pack Carton

NDC: 66435-107-99
Ribasphere^® RibaPak^® 1200 mg Dose Pack

NDC: 66435-107-56

Storage and Handling

Store the Ribasphere^® 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.

17 PATIENT COUNSELING INFORMATION

See FDA-approved Medication Guide

Pregnancy

Patients must be informed that ribavirin may cause birth defects and/or death of the exposed fetus. Ribasphere (ribavirin, USP) therapy must not be used by women who are pregnant or by men whose female partners are pregnant. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients taking Ribasphere (ribavirin, USP) therapy and for 6 months post therapy. Ribasphere (ribavirin, USP) therapy should not be initiated until a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy. Patients must perform a pregnancy test monthly during therapy and for 6 months post therapy.

Female patients of childbearing potential and male patients with female partners of childbearing potential must be advised of the teratogenic/embryocidal risks and must be instructed to practice effective contraception during Ribasphere (ribavirin, USP) therapy and for 6 months post therapy. Patients should be advised to notify the healthcare provider immediately in the event of a pregnancy [see Contraindications (4) and Warnings and Precautions (5.1)].

Anemia

The most common adverse event associated with ribavirin is anemia, which may be severe [see Boxed Warning, Warnings and Precautions (5.2) and Adverse Reactions (6.1)]. Patients should be advised that laboratory evaluations are required prior to starting Ribasphere (ribavirin, USP) therapy and periodically thereafter [see Warnings and Precautions (5.9)]. It is advised that patients be well hydrated, especially during the initial stages of treatment.

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

Patients should be advised to take Ribasphere (ribavirin, USP) with food.

Patients should be questioned about prior history of drug abuse before initiating Ribasphere (ribavirin, USP)/peginterferon alfa-2a, as relapse of drug addiction and drug overdoses have been reported in patients treated with interferons.

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

Patient should be informed about what to do in the event they miss a dose of Ribasphere (ribavirin, USP). The missed doses should be taken as soon as possible during the same day. Patients should not double the next dose. Patients should be advised to call their healthcare provider if they have questions.

Patients should be informed that the effect of peginterferon alfa-2a/ Ribasphere (ribavirin, USP) treatment of hepatitis C infection on transmission is not known, and that appropriate precautions to prevent transmission of hepatitis C virus should be taken.

Patients should be informed regarding the potential benefits and risks attendant to the use of Ribasphere (ribavirin, USP). Instructions on appropriate use should be given, including review of the contents of the enclosed MEDICATION GUIDE, which is not a disclosure of all or possible adverse effects.

U.S. Patent No. 7,723,310

C108.00011-04/11

Issued: 02/2012

MEDICATION GUIDE

FDA-approved Medication Guide
RIBASPHERE^®(Rīb-ă-sphere)
(ribavirin, USP)
Tablets

Read this Medication Guide carefully before you start taking Ribasphere (ribavirin, USP) and read the Medication Guide each time you get more Ribasphere (ribavirin, USP). There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment.

Also read the Medication Guide for PEGASYS¹ (peginterferon alfa-2a).

What is the most important information I should know about Ribasphere (ribavirin, USP)?

• 1. You should not take Ribasphere (ribavirin, USP) alone to treat chronic hepatitis C infection. Ribasphere (ribavirin, USP) should be used with peginterferon alfa-2a to treat chronic hepatitis C infection.
• 2. Ribasphere (ribavirin, USP) may cause you to have a blood problem (hemolytic anemia) that can worsen any heart problems you have, and cause you to have a heart attack or die. Tell your healthcare provider if you have ever had any heart problems. Ribasphere (ribavirin, USP) may not be right for you. If you have chest pain while you take Ribasphere (ribavirin, USP), get emergency medical attention right away.
• 3. Ribasphere (ribavirin, USP) may cause birth defects or death of your unborn baby. If you are pregnant or your sexual partner is pregnant, do not take Ribasphere (ribavirin, USP). You or your sexual partner should not become pregnant while you take Ribasphere (ribavirin, USP) and for 6 months after treatment is over. You must use two forms of birth control when you take Ribasphere (ribavirin, USP) and for the 6 months after treatment.

• •Females must have a pregnancy test before starting Ribasphere (ribavirin, USP), every month while treated with Ribasphere (ribavirin, USP), and every month for the 6 months after treatment with Ribasphere (ribavirin, USP).
• • If you or your female sexual partner becomes pregnant while taking Ribasphere (ribavirin, USP) or within 6 months after you stop taking Ribasphere (ribavirin, USP), 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 Ribasphere (ribavirin, USP) while she is pregnant.

What is Ribasphere (ribavirin, USP)?

Ribasphere (ribavirin, USP) is a medicine used with another medicine called peginterferon alfa-2a to treat chronic (lasting a long time) hepatitis C infection in people whose liver still works normally, and who have not been treated before with a medicine called an interferon alpha. It is not known if Ribasphere (ribavirin, USP) is safe and will work in children under 18 years of age.

Who should not take Ribasphere (ribavirin, USP)?

See “What is the most important information I should know about Ribasphere (ribavirin, USP)?”

Do not take Ribasphere (ribavirin, USP) if you:

• • have certain types of hepatitis caused by your immune system attacking your liver (autoimmune hepatitis)
• • have certain blood disorders, such as thalassemia major or sickle-cell anemia (hemoglobinopathies)
• • have severe kidney disease
• • take didanosine (Videx or Videx EC)

Talk to your healthcare provider before starting treatment with Ribasphere (ribavirin, USP) if you have any of these medical conditions.

What should I tell my healthcare provider before taking Ribasphere (ribavirin, USP)?

Before you take Ribasphere (ribavirin, USP), tell your healthcare provider if you have or have had:

• • treatment for hepatitis C that did not work for you
• • serious allergic reactions to Ribasphere (ribavirin, USP) or to any of the ingredients in Ribasphere (ribavirin, USP). See the end of this Medication Guide for a list of ingredients.
• • breathing problems. Ribasphere (ribavirin, USP) may cause or worsen your breathing problems you already have.
• • vision problems. Ribasphere (ribavirin, USP) may cause eye problems or worsen eye problems you already have. You should have an eye exam before you start treatment with Ribasphere (ribavirin, USP).
• • certain blood disorders such as anemia
• • high blood pressure, heart problems or have had a heart attack. Your healthcare provider should test your blood and heart before you start treatment with Ribasphere (ribavirin, USP).
• • thyroid problems
• • diabetes. Ribasphere (ribavirin, USP) and peginterferon alfa-2a combination therapy may make your diabetes worse or harder to treat.
• • liver problems other than hepatitis C virus infection
• • human immunodeficiency virus (HIV) or other immunity problems
• • mental health problems, including depression or thoughts of suicide
• • kidney problems
• • an organ transplant
• • drug addiction or abuse
• • infection with hepatitis B virus
• • any other medical condition
• • are breast-feeding. It is not known if Ribasphere (ribavirin, USP) passes into your breast milk. You and your healthcare provider should decide if you will take Ribasphere (ribavirin, USP) or breast-feed.

Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements. Some medicines can cause serious side effects if taken while you also take Ribasphere (ribavirin, USP). Some medicines may affect how Ribasphere (ribavirin, USP) works or Ribasphere (ribavirin, USP) may affect how your other medicines work.

Especially tell your healthcare provider if you take any medicines to treat HIV, including didanosine (Videx or Videx EC), or if you take azathioprine (Imuran^®2 or Azasan).

Know the medicines you take. Keep a list of them to show your healthcare provider or pharmacist when you get a new medicine.

How should I take Ribasphere (ribavirin, USP)?

• •Take Ribasphere (ribavirin, USP) exactly as your healthcare provider tells you. Your healthcare provider will tell you how much Ribasphere (ribavirin, USP) to take and when to take it.
• •Take Ribasphere (ribavirin, USP) with food.
• •If you miss a dose of Ribasphere (ribavirin, USP), take the missed dose as soon as possible during the same day. Do not double the next dose. If you have questions about what to do, call your healthcare provider.
• •If you take too much Ribasphere (ribavirin, USP), call your healthcare provider or local Poison Control Center right away, or go to the nearest hospital emergency room right away.
• •Your healthcare provider should do blood tests before you start treatment with Ribasphere (ribavirin, USP), at weeks 2 and 4 of treatment, and then as needed to see how well you are tolerating treatment and to check for side effects. Your healthcare provider may change your dose of Ribasphere (ribavirin, USP) based on blood test results or side effects you may have.
• •If you have heart problems, your healthcare provider should check your heart by doing an electrocardiogram before you start treatment with Ribasphere (ribavirin, USP), and if needed during treatment.

What should I avoid while taking Ribasphere (ribavirin, USP)?

• • Ribasphere (ribavirin, USP) can make you feel tired, dizzy, or confused. You should not drive or operate machinery if you have any of these symptoms.
• • Do not drink alcohol, including beer, wine, and liquor. This may make your liver disease worse.

 What are the possible side effects of Ribasphere (ribavirin, USP)?

Ribasphere (ribavirin, USP) may cause serious side effects including:

See “What is the most important information I should know about Ribasphere (ribavirin, USP)?”

• • Swelling and irritation of your pancreas (pancreatitis). You may have stomach pain, nausea, vomiting or diarrhea.
• • Severe allergic reactions. Symptoms may include hives, wheezing, trouble breathing, chest pain, swelling of your mouth, tongue, or lips, or severe rash.
• • Serious breathing problems. Difficulty breathing may be a sign of a serious lung infection (pneumonia) that can lead to death.
• • Serious eye problems that may lead to vision loss or blindness.
• • Liver problems. Some people may get worsening of liver function. Tell your healthcare provider right away if you have any of these symptoms: stomach bloating, confusion, brown urine, and yellow eyes.
• • Severe depression
• • Suicidal thoughts and attempts

Call your healthcare provider or get medical help right away if you have any of the symptoms listed above. These may be signs of serious side effects of Ribasphere (ribavirin, USP) treatment.

Common side effects of Ribasphere (ribavirin, USP) taken with peginterferon alfa-2a include:

• •flu-like symptoms-feeling tired, headache, shaking along with high temperature (fever), and muscle or joint aches
• •mood changes, feeling irritable, anxiety, and difficulty sleeping
• •loss of appetite, nausea, vomiting, and diarrhea
• •hair loss
• •itching

Tell your healthcare provider about any side effect that bothers you or that does not go away.

These are not all the possible side effects of Ribasphere (ribavirin, USP) treatment. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

You may also report side effects to Kadmon Pharmaceuticals, LLC at 1-877-377-7862.

How should I store Ribasphere (ribavirin, USP)?

• •Store Ribasphere (ribavirin, USP) tablets between 59°F and 86°F (15°C and 30°C).
• •Keep the bottle tightly closed.

Keep Ribasphere (ribavirin, USP) and all medicines out of the reach of children.

General information about the safe and effective use of Ribasphere (ribavirin, USP)

It is not known if treatment with Ribasphere (ribavirin, USP) can cure hepatitis C or if it can prevent liver damage (cirrhosis), liver failure or liver cancer that is caused by hepatitis C virus infections. It is not known if treatment with Ribasphere (ribavirin, USP) will prevent an infected person from spreading the hepatitis C virus to another person.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Ribasphere (ribavirin, USP) for a condition for which it was not prescribed. Do not give Ribasphere (ribavirin, USP) to other people, even if they have the same symptoms that you have. It may harm them.

This Medication Guide summarizes the most important information about Ribasphere (ribavirin, USP). If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about Ribasphere (ribavirin, USP) that is written for healthcare professionals.

What are the ingredients in Ribasphere (ribavirin, USP) ?

Active Ingredient: ribavirin

Inactive Ingredients: microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, povidone K27-33, magnesium stearate, and purified water. The tablet is coated with partially hydrolyzed polyvinyl alcohol, polyethylene glycol 3350, talc, titanium dioxide, FD&C blue #2 [indigo carmine aluminum lake] (200 mg tablet only), FD&C blue #1 [brilliant blue FCF aluminum lake] (400 mg and 600 mg tablets only), and carnauba wax.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

¹ PEGASYS is a trademark of Hoffmann-La Roche Inc.

² Imuran is a registered trademark of Prometheus Laboratories, Inc.

Manufactured by
DSM PHARMACEUTICALS, INC.
Greenville, NC  27834

for

KADMON PHARMACEUTICALS, LLC
Warrendale, PA 15086

C108.00002-04/11

Issued: 02/2012

Printed in USA

U.S. Patent No. 7,723,310

Copyright © 2012 by Kadmon Pharmaceuticals, LLC. All rights reserved.

PRINCIPAL DISPLAY PANEL - DOSE PACK 600

Rx only          NDC 66435-108-56

Ribasphere^® Ribapak^® 600
(ribavirin, USP) Tablets Dose Pack

AM Dose: 200 mg
PM Dose: 400 mg

Contains 7 Ribavirin Tablets, 200 mg each
and 7 Ribavirin Tablets, 400 mg each

Patient instructions for each daily dose:
AM- In the morning, push one Ribavirin Tablet, 200 mg through the cardboard backing.
PM- In the evening, push one Ribavirin Tablet, 400 mg through the cardboard backing.

Kadmon
Pharmaceuticals, LLC

AVOID PREGNANCY WHILE TAKING THIS
MEDICATION. READ THE MEDICATION
GUIDE FOR IMPORTANT INFORMATION.

Please Read
the Enclosed
Medication
Guide

Each 200 mg film-coated tablet
contains 200 mg of ribavirin.
Each 400 mg film-coated tablet
contains 400 mg of ribavirin.

USUAL DOSAGE:
See package insert.

KEEP THIS AND ALL DRUGS
OUT OF REACH OF CHILDREN

Store at 25°C (77°F);
excursions permitted between
15° and 30°C (59° and 86°F)
[see USP Controlled Room
Temperature].

C001.00116

Manufactured by
DSM PHARMACEUTICALS, INC.
Greenville, NC 27834, USA

Distributed by
KADMON PHARMACEUTICALS, LLC
Warrendale, PA 15086, USA
U.S. Patent No. 7,723,310

AVOID PREGNANCY WHILE
TAKING THIS MEDICATION.
READ THE MEDICATION GUIDE
FOR IMPORTANT INFORMATION.

PRINCIPAL DISPLAY PANEL - DOSE PACK 800

Rx only          NDC 66435-105-56

Ribasphere^® Ribapak^® 800
(ribavirin, USP) Tablets Dose Pack

AM Dose: 400 mg
PM Dose: 400 mg

Contains 14 Ribavirin Tablets, 400 mg each

Patient instructions for each daily dose:
AM- In the morning, push one Ribavirin Tablet, 400 mg through the cardboard backing.
PM- In the evening, push one Ribavirin Tablet, 400 mg through the cardboard backing.

Kadmon
Pharmaceuticals, LLC

AVOID PREGNANCY WHILE TAKING THIS
MEDICATION. READ THE MEDICATION
GUIDE FOR IMPORTANT INFORMATION.

Please Read
the Enclosed
Medication
Guide

Each 400 mg film-coated tablet
contains 400 mg of ribavirin.

USUAL DOSAGE:
See package insert.

KEEP THIS AND ALL DRUGS
OUT OF REACH OF CHILDREN

Store at 25°C (77°F);
excursions permitted between
15° and 30°C (59° and 86°F)
[see USP Controlled Room
Temperature].

C001.00094

Manufactured by
DSM PHARMACEUTICALS, INC.
Greenville, NC 27834, USA

Distributed by
KADMON PHARMACEUTICALS, LLC
Warrendale, PA 15086, USA
U.S. Patent No. 7,723,310

AVOID PREGNANCY WHILE
TAKING THIS MEDICATION.
READ THE MEDICATION GUIDE
FOR IMPORTANT INFORMATION.

PRINCIPAL DISPLAY PANEL - DOSE PACK 1000

Rx only          NDC 66435-106-56

Ribasphere^® Ribapak^® 1000
(ribavirin, USP) Tablets Dose Pack

AM Dose: 600 mg
PM Dose: 400 mg

Contains 7 Ribavirin Tablets, 600 mg each
and 7 Ribavirin Tablets, 400 mg each

Patient instructions for each daily dose:
AM- In the morning, push one Ribavirin Tablet, 600 mg through the cardboard backing.
PM- In the evening, push one Ribavirin Tablet, 400 mg through the cardboard backing.

Kadmon
Pharmaceuticals, LLC

AVOID PREGNANCY WHILE TAKING THIS
MEDICATION. READ THE MEDICATION
GUIDE FOR IMPORTANT INFORMATION.

Please Read
the Enclosed
Medication
Guide

Each 600 mg film-coated tablet
contains 600 mg of ribavirin.
Each 400 mg film-coated tablet
contains 400 mg of ribavirin.

USUAL DOSAGE:
See package insert.

KEEP THIS AND ALL DRUGS
OUT OF REACH OF CHILDREN

Store at 25°C (77°F);
excursions permitted between
15° and 30°C (59° and 86°F)
[see USP Controlled Room
Temperature].

C001.00097

Manufactured by
DSM PHARMACEUTICALS, INC.
Greenville, NC 27834, USA

Distributed by
KADMON PHARMACEUTICALS, LLC
Warrendale, PA 15086, USA
U.S. Patent No. 7,723,310

AVOID PREGNANCY WHILE
TAKING THIS MEDICATION.
READ THE MEDICATION GUIDE
FOR IMPORTANT INFORMATION.

PRINCIPAL DISPLAY PANEL - DOSE PACK 1200

Rx only          NDC 66435-107-56

Ribasphere^® Ribapak^® 1200
(ribavirin, USP) Tablets Dose Pack

AM Dose: 600 mg
PM Dose: 600 mg

Contains 14 Ribavirin Tablets, 600 mg each

Patient instructions for each daily dose:
AM- In the morning, push one Ribavirin Tablet, 600 mg through the cardboard backing.
PM- In the evening, push one Ribavirin Tablet, 600 mg through the cardboard backing.

Kadmon
Pharmaceuticals, LLC

AVOID PREGNANCY WHILE TAKING THIS
MEDICATION. READ THE MEDICATION
GUIDE FOR IMPORTANT INFORMATION.

Please Read
the Enclosed
Medication
Guide

Each 600 mg film-coated tablet
contains 600 mg of ribavirin.

USUAL DOSAGE:
See package insert.

KEEP THIS AND ALL DRUGS
OUT OF REACH OF CHILDREN

Store at 25°C (77°F);
excursions permitted between
15° and 30°C (59° and 86°F)
[see USP Controlled Room
Temperature].

C001.00100

Manufactured by
DSM PHARMACEUTICALS, INC.
Greenville, NC 27834, USA

Distributed by
KADMON PHARMACEUTICALS, LLC
Warrendale, PA 15086, USA
U.S. Patent No. 7,723,310

AVOID PREGNANCY WHILE
TAKING THIS MEDICATION.
READ THE MEDICATION GUIDE
FOR IMPORTANT INFORMATION.

PRINCIPAL DISPLAY PANEL - BOTTLE 200 mg

Kadmon
Pharmaceuticals, LLC

NDC 66435-102-16

Ribasphere^®
(ribavirin, USP) Tablets

200 mg
Each coated tablet contains
200 mg, ribavirin

Rx only

AVOID PREGNANCY WHILE TAKING THIS
MEDICATION. READ THE MEDICATION
GUIDE FOR IMPORTANT INFORMATION.

168 Tablets

ATTENTION PHARMACIST: Each patient
is required to receive a medication guide.

Store RIBASPHERE tablets at 25°C (77°F); Excursions
permitted to 15° and 30°C (59° and 86°F) [see USP
Controlled Room Temperature]. Keep bottle tightly closed.

Usual Dosage: See package insert.

Manufactured by
DSM Pharmaceuticals, Inc.
Greenville, NC 27834, USA
for
Kadmon Pharmaceuticals, LLC,
Warrendale, PA 15086, USA

C001.00102

PRINCIPAL DISPLAY PANEL - BOTTLE 400 mg

Kadmon
Pharmaceuticals, LLC

NDC 66435-103-56

Ribasphere^®
(ribavirin, USP) Tablets

400 mg
Each coated tablet contains
400 mg, ribavirin

Rx only

AVOID PREGNANCY WHILE TAKING THIS
MEDICATION. READ THE MEDICATION
GUIDE FOR IMPORTANT INFORMATION.

56 Tablets

ATTENTION PHARMACIST: Each patient
is required to receive a medication guide.

Store RIBASPHERE tablets at 25°C (77°F); Excursions
permitted to 15° and 30°C (59° and 86°F) [see USP
Controlled Room Temperature]. Keep bottle tightly closed.

Usual Dosage: See package insert.

Manufactured by
DSM Pharmaceuticals, Inc.
Greenville, NC 27834, USA
for
Kadmon Pharmaceuticals, LLC,
Warrendale, PA 15086, USA

C001.00103

PRINCIPAL DISPLAY PANEL - BOTTLE 600 mg

Kadmon
Pharmaceuticals, LLC

NDC 66435-104-56

Ribasphere^®
(ribavirin, USP) Tablets

600 mg
Each coated tablet contains
600 mg, ribavirin

Rx only

AVOID PREGNANCY WHILE TAKING THIS
MEDICATION. READ THE MEDICATION
GUIDE FOR IMPORTANT INFORMATION.

56 Tablets

ATTENTION PHARMACIST: Each patient
is required to receive a medication guide.

Store RIBASPHERE tablets at 25°C (77°F); Excursions
permitted to 15° and 30°C (59° and 86°F) [see USP
Controlled Room Temperature]. Keep bottle tightly closed.

Usual Dosage: See package insert.

Manufactured by
DSM Pharmaceuticals, Inc.
Greenville, NC 27834, USA
for
Kadmon Pharmaceuticals, LLC,
Warrendale, PA 15086, USA

C001.00104