Indications & Usage Section

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Ribavirin tablets are a nucleoside analogue indicated for the treatment of chronic hepatitis C (CHC) virus infection in combination with PEGASYS® in patients 5 years of age and older with compensated liver disease not previously treated with interferon alpha, and in adult CHC patients coinfected with HIV (1)

1 INDICATIONS AND USAGE

Ribavirin tablets in combination with PEGASYS® (peginterferon alfa-2a) are 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 ribavirin tablets 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 ribavirin tablets 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 ribavirin tablets therapy for the treatment of adenovirus, RSV, parainfluenza or influenza infections have not been established. Ribavirin tablets 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 & Administration Section

Highlight: * CHC: Ribavirin tablets are administered according to body weight and genotype (2.1)

• CHC with HIV coinfection: 800 mg by mouth daily for a total of 48 weeks, regardless of genotype (2.2)
• Dose reduction or discontinuation is recommended in patients experiencing certain adverse reactions or renal impairment (2.3, 2.4)

2 DOSAGE AND ADMINISTRATION

Ribavirin tablets should be taken with food. Ribavirin tablets should be given in combination with PEGASYS®; it is important to note that ribavirin tablets should never be given as monotherapy. See PEGASYS® Package Insert for all instructions regarding PEGASYS® dosing and administration.

2.1 Chronic Hepatitis C Monoinfection

Adult Patients

The recommended dose of ribavirin tablets is provided inTable 1. The recommended duration of treatment for patients previously untreated with ribavirin and interferon is 24 to 48 weeks.

The daily dose of ribavirin tablets is 800 mg to 1200 mg administered orally in two divided doses. The dose should be individualized to the patient depending on baseline disease characteristics (e.g., genotype), response to therapy, and tolerability of the regimen (seeTable 1).

Table 1 PEGASYS® and Ribavirin Tablets Dosing Recommendations

Pediatric Patients

PEGASYS® is administered as 180 mcg/1.73m2 x BSA once weekly subcutaneously, to a maximum dose of 180 mcg, and should be given in combination with ribavirin. The recommended treatment duration for patients with genotype 2 or 3 is 24 weeks and for other genotypes is 48 weeks.

Ribavirin tablets should be given in combination with PEGASYS®. Ribavirin tablets are available only as a 200 mg tablet and therefore the healthcare provider should determine if this sized tablet can be swallowed by the pediatric patient. The recommended doses for ribavirin tablets are provided in Table 2. Patients who initiate treatment prior to their 18th birthday should maintain pediatric dosing through the completion of therapy.

Table 2 Ribavirin Tablets Dosing Recommendations for Pediatric Patients

2.2 Chronic Hepatitis C with HIV Coinfection

Adult Patients

The recommended dose for treatment of chronic hepatitis C in patients coinfected with HIV is PEGASYS® 180 mcg subcutaneous once weekly and ribavirin tablets 800 mg by mouth daily for a total duration of 48 weeks, regardless of HCV genotype.

2.3 Dose Modifications

Adult and Pediatric Patients

If severe adverse reactions or laboratory abnormalities develop during combination ribavirin tablets/PEGASYS® therapy, the dose should be modified or discontinued, if appropriate, until the adverse reactions abate or decrease in severity. If intolerance persists after dose adjustment, ribavirin tablets/PEGASYS® therapy should be discontinued.Table 3 provides guidelines for dose modifications and discontinuation based on the patient’s hemoglobin concentration and cardiac status.

Ribavirin tablets should be administered with caution to patients with pre- existing cardiac disease. Patients should be assessed before commencement of therapy and should be appropriately monitored during therapy. If there is any deterioration of cardiovascular status, therapy should be stopped [see Warnings and Precautions (5.2)].

Table 3 Ribavirin Tablets Dose Modification Guidelines in Adults and Pediatrics

The guidelines for ribavirin tablets dose modifications outlined in this table also apply to laboratory abnormalities or adverse reactions other than decreases in hemoglobin values.

Adult Patients

Once ribavirin tablets have been withheld due to either a laboratory abnormality or clinical adverse reaction, an attempt may be made to restart ribavirin tablets at 600 mg daily and further increase the dose to 800 mg daily. However, it is not recommended that ribavirin tablets be increased to the original assigned dose (1000 mg to 1200 mg).

Pediatric Patients

Upon resolution of a laboratory abnormality or clinical adverse reaction, an increase in ribavirin tablets dose to the original dose may be attempted depending upon the physician’s judgment. If ribavirin tablets have been withheld due to a laboratory abnormality or clinical adverse reaction, an attempt may be made to restart ribavirin tablets at one-half the full dose.

2.4 Renal Impairment

The total daily dose of ribavirin tablets should be reduced for patients with creatinine clearance less than or equal to 50 mL/min; and the weekly dose of PEGASYS® should be reduced for creatinine clearance less than 30 mL/min as follows inTable 4[see Use in Specific Populations (8.7), Pharmacokinetics (12.3), and PEGASYS® Package Insert].

Table 4 Dosage Modification for Renal Impairment

The dose of ribavirin tablets should not be further modified in patients with renal impairment. If severe adverse reactions or laboratory abnormalities develop, ribavirin tablets should be discontinued, if appropriate, until the adverse reactions abate or decrease in severity. If intolerance persists after restarting ribavirin tablets, ribavirin tablets/PEGASYS® therapy should be discontinued.

No data are available for pediatric subjects with renal impairment.

2.5 Discontinuation of Dosing

Discontinuation of PEGASYS®/ribavirin tablets therapy should be considered if the patient has failed to demonstrate at least a 2 log10 reduction from baseline in HCV RNA by 12 weeks of therapy, or undetectable HCV RNA levels after 24 weeks of therapy.

PEGASYS®/Ribavirin tablets therapy should be discontinued in patients who develop hepatic decompensation during treatment [see Warnings and Precautions (5.3)].

Dosage Forms & Strengths Section

Highlight: * Ribavirin tablets, USP 200 mg (3)

3 DOSAGE FORMS AND STRENGTHS

Ribavirin is available as a light pink colored, capsule shaped, film-coated tablet for oral administration. Each tablet contains 200 mg of ribavirin.

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Contraindications Section

Highlight: * Pregnant women and men whose female partners are pregnant (4, 5.1, 8.1)

• Hemoglobinopathies (4)
• Coadministration with didanosine (4, 7.1)

Ribavirin tablets in combination with PEGASYS® are contraindicated in patients with:

• Autoimmune hepatitis (4)
• Hepatic decompensation in cirrhotic patients (4, 5.3)

4 CONTRAINDICATIONS

Ribavirin tablets are contraindicated in:

• Women who are pregnant. Ribavirin tablets may cause fetal harm when administered to a pregnant woman. Ribavirin tablets are contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus [see Warnings and Precautions (5.1), Use in Specific Populations (8.1), and Patient Counseling Information (17)].
• Men whose female partners are pregnant.
• Patients with hemoglobinopathies (e.g., thalassemia major or sickle-cell anemia).
• In combination with didanosine. Reports of fatal hepatic failure, as well as peripheral neuropathy, pancreatitis, and symptomatic hyperlactatemia/lactic acidosis have been reported in clinical trials [see Drug Interactions (7.1)].

Ribavirin tablets and PEGASYS® combination therapy are contraindicated in patients with:

• Autoimmune hepatitis.
• Hepatic decompensation (Child-Pugh score greater than 6; class B and C) in cirrhotic CHC monoinfected patients before treatment [see Warnings and Precautions (5.3)].
• Hepatic decompensation (Child-Pugh score greater than or equal to 6) in cirrhotic CHC patients coinfected with HIV before treatment [see Warnings and Precautions (5.3)].

Boxed Warning Section

WARNING: RISK OF SERIOUS DISORDERS AND RIBAVIRIN-ASSOCIATED EFFECTS

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Overdosage Section

10 OVERDOSAGE

No cases of overdose with ribavirin have been reported in clinical trials. Hypocalcemia and hypomagnesemia have been observed in persons administered greater than the recommended dosage of ribavirin. In most of these cases, ribavirin was administered intravenously at dosages up to and in some cases exceeding four times the recommended maximum oral daily dose.

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Nonclinical Toxicology Section

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.****

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** Mutagenesis**

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****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.

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** Impairment of Fertility**

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****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 ribavirin unless the patient and his/her partner are using effective contraception (two reliable forms). Based on a multiple dose half-life (t1/2) 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 PEGASYS® 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

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.

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SPL MEDGUIDE SECTION

MEDICATION GUIDE

Ribavirin Tablets, USP
****(rye" ba vye' rin)

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Read this Medication Guide carefully before you start taking ribavirin tablets and read the Medication Guide each time you get more ribavirin tablets. 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 PEGASYS® (peginterferon alfa-2a).

What is the most important information I should know about ribavirin tablets?

**1. You should not take ribavirin tablets alone to treat chronic hepatitis C infection.**Ribavirin tablets should be used with PEGASYS® to treat chronic hepatitis C infection.

** 2. Ribavirin tablets 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. Ribavirin tablets may not be right for you. If you have chest pain while you take ribavirin tablets, get emergency medical attention right away.

3. Ribavirin tablets may cause birth defects or death of your unborn baby. If you are pregnant or your sexual partner is pregnant, do not take ribavirin tablets. You or your sexual partner should not become pregnant while you take ribavirin tablets and for 6 months after treatment is over. You must use two forms of birth control when you take ribavirin tablets and for the 6 months after treatment.

• Females must have a pregnancy test before starting ribavirin tablets, every month while treated with ribavirin tablets, and every month for the 6 months after treatment with ribavirin tablets. *If you or your female sexual partner becomes pregnant while taking ribavirin tablets or within 6 months after you stop taking ribavirin tablets, tell your healthcare provider right away.

What are ribavirin tablets?

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Ribavirin tablets are a prescription medicine used with another medicine called PEGASYS® (peginterferon alfa-2a) to treat chronic (lasting a long time) hepatitis C infection in people 5 years and older whose liver still works normally, and who have not been treated before with a medicine called an interferon alpha. It is not known if ribavirin tablets are safe and will work in children under 5 years of age.

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** Who should not take ribavirin tablets?**

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** See “What is the most important information I should know about ribavirin tablets?”**

Do not take ribavirin tablets if you:

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

Talk to your healthcare provider before starting treatment with ribavirin tablets if you have any of these medical conditions.

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** What should I tell my healthcare provider before taking ribavirin tablets?**

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****Before you take ribavirin tablets, tell your healthcare provider if you have or have had:

*treatment for hepatitis C that did not work for you *serious allergic reactions to ribavirin tablets or to any of the ingredients in ribavirin tablets. See the end of this Medication Guide for a list of ingredients. ***breathing problems.**Ribavirin tablets may cause or worsen your breathing problems you already have. *vision problems. Ribavirin tablets may cause eye problems or worsen eye problems you already have. You should have an eye exam before you start treatment with ribavirin tablets. *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 ribavirin tablets. *thyroid problems ***diabetes.**Ribavirin tablets and PEGASYS® 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 ribavirin passes into your breast milk. You and your healthcare provider should decide if you will take ribavirin tablets or breastfeed.

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 ribavirin tablets. Some medicines may affect how ribavirin tablets work or ribavirin tablets 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 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 ribavirin tablets?

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• Take ribavirin tablets exactly as your healthcare provider tells you. Your healthcare provider will tell you how much ribavirin tablets to take and when to take them. For children 5 years of age and older your healthcare provider will prescribe the dose of ribavirin tablets based on weight.
• Take ribavirin tablets with food.
• If you miss a dose of ribavirin tablets, 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 ribavirin tablets, call your healthcare provider or local Poison Control Center right away, or go the nearest hospital emergency room right away.
• Your healthcare provider should do blood tests before you start treatment with ribavirin tablets, 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 ribavirin tablets 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 ribavirin tablets, and if needed during treatment.

What should I avoid while taking ribavirin tablets?

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*Ribavirin tablets 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 ribavirin tablets?

Ribavirin tablets may cause serious side effects including:

See “What is the most important information I should know about ribavirin tablets?”

*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 problemsthat 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 *Effect on growth in children. Children can experience a delay in weight gain and height increase while being treated with PEGASYS® and ribavirin tablets. Catch-up in growth happens after treatment stops, but some children may not reach the height that they were expected to have before treatment. Talk to your healthcare provider if you are concerned about your child’s growth during treatment with PEGASYS® and ribavirin tablets.

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**** Call your healthcare provider or get medical help right away if you have any of the symptoms listed above. These may be signs of a serious side effect of ribavirin tablets treatment******.**

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** Common side effects of ribavirin tablets taken with PEGASYS****®**** 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 ribavirin tablets 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 Aurobindo Pharma USA, Inc. at 1-866-850-2876.

How should I store****ribavirin tablets?

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• Store ribavirin tablets at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].
• Keep the bottle tightly closed.

** Keep ribavirin tablets and all medicines out of the reach of children.**

General information about the safe and effective use of ribavirin tablets

It is not known if treatment with ribavirin tablets in combination with PEGASYS® will prevent an infected person from spreading the hepatitis C virus to another person while on treatment.

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

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

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** What are the ingredients in ribavirin tablets?**

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****Active Ingredient: ribavirin

Inactive Ingredients: microcrystalline cellulose, pregelatinised starch (maize), sodium starch glycolate, povidone (Kollidon 30), colloidal silicon dioxide, magnesium stearate, ethyl cellulose, triacetin, hypromellose, iron oxide red, titanium dioxide, and yellow iron oxide.

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

Trademarks are the property of their respective owners.

Distributed by:
Aurobindo Pharma USA, Inc.
****279 Princeton-Hightstown Road
East Windsor, NJ 08520

Manufactured by:
Aurobindo Pharma Limited
****Hyderabad–500 032, India

Revised: 05/2023

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How Supplied Section

16 HOW SUPPLIED/STORAGE AND HANDLING

Ribavirin Tablets USP, 200 mg are light pink colored, capsule shaped, film-coated tablets debossed with ‘F’ on one side and ‘10’ on the other side.

Bottles of 168 NDC 65862-207-68
Bottles of 500 NDC 65862-207-05

Storage and Handling

Store at20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Keep bottle tightly closed.

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