Moderiba

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 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.

Follow all directions on your prescription label. Do not take this medicine in larger or smaller amounts or for longer than recommended.

Ribavirin is not effective when used alone to treat hepatitis C. It must be used together with an interferon alfa product.

Take ribavirin with food.

Do not crush, chew, break, or open a ribavirin capsule. Swallow it whole. Tell your doctor if you have trouble swallowing the capsule.

Measure liquid medicine with the dosing syringe provided, or with a special dose-measuring spoon or medicine cup. If you do not have a dose-measuring device, ask your pharmacist for one.

Use ribavirin regularly to get the most benefit. Get your prescription refilled before you run out of medicine completely.

Drink extra fluids while you are taking ribavirin to keep from getting dehydrated, especially during exercise or in hot weather.

Ribavirin can cause dry mouth, which could lead to tooth decay or gum disease. If you vomit while taking ribavirin, rinse your mouth out with water to prevent damage to your teeth or gums. Be sure to have regular dental exams while you are taking this medication.

Store ribavirin tablets or capsules at room temperature away from moisture, heat, and light.

Store ribavirin liquid (oral solution) in the refrigerator. Do not allow it to freeze.

Avoid drinking alcohol. It may increase your risk of liver damage.

Using this medicine will not prevent you from passing hepatitis to other people. Follow your doctor's instructions about how to prevent passing the disease to another person.

Get emergency medical help if you have signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Ribavirin can cause anemia. In rare cases, this can lead to fatal heart problems. Get emergency medical attention if you have chest pain.

Call your doctor at once if you have:

• problems with your vision;

• severe pain in your upper stomach spreading to your back, nausea, vomiting, diarrhea;

• stabbing chest pain, wheezing, feeling short of breath;

• severe depression, thoughts about suicide, or thoughts about hurting someone else;

• signs of serious anemia--pale or yellowed skin, dark colored urine, confusion or weakness; or

• other signs of low blood cell counts--fever, chills, flu-like symptoms, swollen gums, mouth sores, skin sores, easy bruising, unusual bleeding, feeling light-headed.

Common side effects may include:

• nausea, flu-like symptoms, tiredness;

• fever, chills or shaking;

• headache;

• mood changes, feeling irritable;

• muscle pain; or

• stomach pain, vomiting, loss of appetite.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

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

Each Moderiba 200-mg tablet contains 200 mg of ribavirin, USP 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 Moderiba 400-mg tablet contains 400 mg of ribavirin, USP 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 Moderiba 600-mg tablet contains 600 mg of ribavirin, USP 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.

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.

• “See FDA-approved patient labeling (Medication Guide)”

Pregnancy

Patients must be informed that ribavirin may cause birth defects and/or death of the exposed fetus. Moderiba 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 Moderiba therapy and for 6 months post therapy. Patients should use two reliable methods of birth control while taking Moderiba therapy and for 6 months post therapy. Moderiba 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 Moderiba 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 Moderiba 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 Moderiba with food.

Patients should be questioned about prior history of drug abuse before initiating Moderiba/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.

Patients should be informed about what to do in the event they miss a dose of Moderiba. 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/Moderiba treatment of hepatitis C infection on transmission is not known, and that appropriate precautions to prevent transmission of hepatitis C virus during treatment or in the event of treatment failure should be taken.

Patients should be informed regarding the potential benefits and risks attendant to the use of Moderiba. 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

C139.00015

MEDICATION GUIDE

Moderiba™ (Mah-duh-RYE-bah)
(ribavirin, USP)
Tablets

Read this Medication Guide carefully before you start taking Moderiba and read the Medication Guide each time you get more Moderiba. 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 Moderiba?

1. You should not take Moderiba alone to treat chronic hepatitis C infection. Moderiba should be used with peginterferon alfa-2a to treat chronic hepatitis C infection.
2. Moderiba 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. Moderiba may not be right for you. If you have chest pain while you take Moderiba, get emergency medical attention right away.
3. Moderiba may cause birth defects or death of your unborn baby. If you are pregnant or your sexual partner is pregnant, do not take Moderiba. You or your sexual partner should not become pregnant while you take Moderiba and for 6 months after treatment is over. You must use two forms of birth control when you take Moderiba and for the 6 months after treatment.

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

What is Moderiba?

Moderiba is a prescription medicine used with another medicine called 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 Moderiba is safe and will work in children under 5 years of age.

Who should not take Moderiba?

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

Do not take Moderiba 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)
• take didanosine (Videx®2 or Videx EC®2)

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

What should I tell my healthcare provider before taking Moderiba?

Before you take Moderiba, tell your healthcare provider if you have or have had:

• treatment for hepatitis C that did not work for you
• serious allergic reactions to Moderiba or to any of the ingredients in Moderiba. See the end of this Medication Guide for a list of ingredients.
• breathing problems. Moderiba may cause or worsen your breathing problems you already have.
• vision problems. Moderiba may cause eye problems or worsen eye problems you already have. You should have an eye exam before you start treatment with Moderiba.
• 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 Moderiba.
• thyroid problems
• diabetes. Moderiba 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 Moderiba passes into your breast milk. You and your healthcare provider should decide if you will take Moderiba 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 Moderiba. Some medicines may affect how Moderiba works or Moderiba may affect how your other medicines work.

Especially tell your healthcare provider if you take any medicines to treat HIV, including didanosine (Videx®2 or Videx EC®2), or if you take azathioprine (Imuran®3 or Azasan®4).

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 Moderiba?

• Take Moderiba exactly as your healthcare provider tells you. Your healthcare provider will tell you how much Moderiba to take and when to take it. For children 5 years of age and older your healthcare provider will prescribe the dose of Moderiba based on weight.
• Take Moderiba with food.
• If you miss a dose of Moderiba, 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 Moderiba, 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 Moderiba, 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 Moderiba 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 Moderiba, and if needed during treatment.

What should I avoid while taking Moderiba?

• Moderiba 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 Moderiba?

Moderiba may cause serious side effects including:

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

• 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
• Effect on growth in children. Children can experience a delay in weight gain and height increase while being treated with peginterferon alfa-2a and Moderiba. 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 peginterferon alfa-2a and Moderiba.

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 Moderiba treatment.

Common side effects of Moderiba 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 Moderiba 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 AbbVie Inc. at 1-800-633-9110.

How should I store Moderiba?

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

Keep Moderiba and all medicines out of the reach of children.

General information about the safe and effective use of Moderiba

It is not known if treatment with Moderiba in combination with peginterferon alfa-2a 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 Moderiba for a condition for which it was not prescribed. Do not give Moderiba 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 Moderiba. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about Moderiba that is written for healthcare professionals.

What are the ingredients in Moderiba?

Active Ingredient: ribavirin

Inactive Ingredients: microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, povidone, 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 Videx and Videx EC is a registered trademark of Bristol-Myers Squibb Company

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

4 Azasan is a registered trademark of Salix Pharmaceuticals, Inc.

Distributed by

AbbVie Inc.

North Chicago, IL 60064 USA

C139.00016 – Revised February, 2015

Printed in USA

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

Copyright © 2015 by Kadmon Pharmaceuticals, LLC. All rights reserved.

NDC 0074-3197-16

Moderiba™

(ribavirin, USP) Tablets

200 mg

168 Tablets

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

Rx only abbvie

NDC 0074-3224-14

Moderiba™ 600 Dose Pack

(ribavirin, USP) Tablets

200 mg / 400 mg

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

Contains 7 ribavirin tablets (200 mg each) and 7 ribavirin tablets (400 mg each)

AM Dose: 200 mg / PM Dose: 400 mg

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.

Please read the enclosed Medication Guide

Rx only abbvie

NDC 0074-3224-56

Moderiba™ 600 Dose Pack

(ribavirin, USP) Tablets

200 mg / 400 mg

56 Tablets in 4 Unit Dose Packs

Each Unit Dose Pack contains

7 ribavirin tablets (200 mg each) and

7 ribavirin tablets (400 mg each)

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

NDC 0074-3239-14

Moderiba™ 800 Dose Pack

(ribavirin, USP) Tablets

400 mg / 400 mg

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

Contains 14 ribavirin tablets (400 mg each)

AM Dose: 400 mg / PM Dose: 400 mg

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.

Please read the enclosed Medication Guide

Rx only abbvie

NDC 0074-3239-56

Moderiba™ 800 Dose Pack

(ribavirin, USP) Tablets

400 mg / 400 mg

56 Tablets in 4 Unit Dose Packs

Each Unit Dose Pack contains

14 ribavirin tablets (400 mg each)

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

NDC 0074-3271-14

Moderiba™ 1000 Dose Pack

(ribavirin, USP) Tablets

600 mg / 400 mg

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

Contains 7 ribavirin tablets (600 mg each) and 7 ribavirin tablets (400 mg each)

AM Dose: 600 mg / PM Dose: 400 mg

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.

Please read the enclosed Medication Guide

Rx only abbvie

NDC 0074-3271-56

Moderiba™ 1000 Dose Pack

(ribavirin, USP) Tablets

600 mg / 400 mg

56 Tablets in 4 Unit Dose Packs

Each Unit Dose Pack contains

7 ribavirin tablets (600 mg each) and

7 ribavirin tablets (400 mg each)

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

NDC 0074-3282-14

Moderiba™ 1200 Dose Pack

(ribavirin, USP) Tablets

600 mg / 600 mg

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

Contains 14 ribavirin tablets (600 mg each)

AM Dose: 600 mg / PM Dose: 600 mg

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.

Please read the enclosed Medication Guide

Rx only abbvie

NDC 0074-3282-56

Moderiba™ 1200 Dose Pack

(ribavirin, USP) Tablets

600 mg / 600 mg

56 Tablets in 4 Unit Dose Packs

Each Unit Dose Pack contains

14 ribavirin tablets (600 mg each)

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

Common side effects of Moderiba include: hemolytic anemia, decreased hemoglobin, insomnia, dyspnea, lack of concentration, emotional lability, and irritability. Other side effects include: nervousness. See below for a comprehensive list of adverse effects.

Applies to ribavirin: compounding powder, inhalation powder for reconstitution, oral capsule, oral solution, oral tablet

General

The most common serious or life-threatening side effects induced or aggravated by ribavirin (the active ingredient contained in Moderiba) tablets in combination with peginterferon alfa-2a have included depression, suicide, relapse of drug abuse/overdose, and bacterial infections in less than 1% of patients and hepatic decompensation in 2% of chronic hepatitis C (CHC)-HIV coinfected patients. The most common serious side effect in CHC monoinfected (3%) and CHC-HIV coinfected (5%) patients receiving peginterferon alfa-2a alone or in combination with ribavirin tablets was bacterial infection (e.g., sepsis, osteomyelitis, endocarditis, pyelonephritis, pneumonia). Common side effects reported in CHC-HIV coinfected patients receiving ribavirin tablets in combination with peginterferon alfa-2a have included neutropenia, anemia, thrombocytopenia, weight decrease, and mood alteration.

The most common side effects reported in patients receiving ribavirin capsules/oral solution in combination with peginterferon alfa-2b or interferon alfa-2b were injection site inflammation/reaction, fatigue/asthenia, headache, rigors, fevers, nausea, myalgia, and anxiety/emotional lability/irritability. The most common serious side effects associated with peginterferon alfa-2b in combination with ribavirin capsules/oral solution were depression and suicidal ideation in less than 1% of patients. The most common fatal side effects reported in patients receiving peginterferon alfa-2b in combination with ribavirin capsules/oral solution were cardiac arrest, suicidal ideation, and suicide attempt in less than 1% of patients.[Ref]

Respiratory

Mechanically ventilated patients may be predisposed to respiratory deterioration.

Severe hypoxia was described in a case report of a previously healthy infant who experienced a dramatic drop in transcutaneous oxygen within 1 minute of receiving ribavirin (the active ingredient contained in Moderiba) Oxygen levels returned to normal promptly following discontinuation of therapy. However, the infant later died, and postmortem examination revealed a high pulmonary arterial pressure and a patent ductus arteriosus. A definitive causal relationship was not established, and equipment failure was not specifically ruled out by the authors.

Most signs and symptoms reported in exposed health care workers resolved within minutes to hours of stopping close exposure to aerosolized ribavirin.[Ref]

Respiratory side effects associated with oral ribavirin in combination with peginterferon alfa-2a, peginterferon alfa-2b, or interferon alfa-2b have included dyspnea (up to 26%), cough (up to 23%), and exertional dyspnea (up to 7%). Pharyngitis (up to 13%), rhinitis (up to 8%), and sinusitis (up to 12%) have been reported with ribavirin capsules/oral solution in combination with peginterferon alfa-2b or interferon alfa-2b. Pulmonary symptoms (including dyspnea, pulmonary infiltrates, pneumonitis, pulmonary hypertension, pneumonia, and fatal pneumonia), sarcoidosis, and exacerbation of sarcoidosis have been reported with oral ribavirin in combination with alpha interferon. Pulmonary hypertension has been reported during postmarketing experience with ribavirin capsules/oral solution in combination with interferon alfa-2b or peginterferon alfa-2b. Significant deterioration of pulmonary function in patients with chronic obstructive pulmonary disease or asthma and minor pulmonary function abnormalities in healthy volunteers have been reported with aerosolized ribavirin. Asthmatic patients have also reported dyspnea and chest soreness with aerosolized ribavirin. Worsening of respiratory status, bronchospasm, hypoventilation, cyanosis, dyspnea, bronchoconstriction, bacterial pneumonia, cough, pneumothorax, pulmonary edema, apnea, atelectasis, hypoxia, and ventilator dependence have been reported with aerosolized ribavirin. Rhinitis and pharyngitis, as well as several cases of bronchospasm and/or chest pain (usually in individuals with underlying reactive airway disease), have been reported in health care workers exposed to aerosolized ribavirin.[Ref]

Hypersensitivity

Hypersensitivity side effects have included reactions such as urticaria, angioedema, bronchoconstriction, and anaphylaxis in patients treated with alfa interferon and ribavirin (the active ingredient contained in Moderiba) Severe skin reactions (including vesiculobullous eruptions, Stevens-Johnson syndrome, erythema multiforme, and exfoliative dermatitis/erythroderma) have been reported in patients treated with peginterferon alfa-2a alone or in combination with ribavirin tablets. Serious skin reactions have been reported during postmarketing experience in patients treated with peginterferon alfa-2a.[Ref]

Dermatologic

Dermatologic side effects have included rash and skin irritation from prolonged drug contact. Alopecia (up to 36%), pruritus (up to 29%), dermatitis (up to 16%), dry skin (up to 24%), increased sweating (up to 11%), rash (up to 34%), and eczema (up to 5%) have been associated with oral ribavirin (the active ingredient contained in Moderiba) in combination with peginterferon alfa-2a, peginterferon alfa-2b, or interferon alfa-2b. Grover's disease has been reported in a 55-year-old man 2 weeks after the start of ribavirin therapy. A photoallergic skin reaction was reported to occur 4 months after initiation of ribavirin treatment, and recurred approximately 24 hours after reexposure to ribavirin. Skin disorders associated with ribavirin tablets in combination with peginterferon alfa-2a have included lichenoid eruptions and maculopapular rashes. Rash has been reported in patients treated with and health care workers exposed to aerosolized ribavirin. Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported during postmarketing experience with ribavirin tablets in combination with peginterferon alfa-2a.[Ref]

Grover's disease (suprabasal transient acantholytic dermatosis) secondary to ribavirin use was confirmed upon drug rechallenge in a 55-year-old man with chronic active hepatitis C.

Rash associated with aerosolized ribavirin usually resolved within hours of stopping treatment in patients and within minutes to hours of stopping close exposure in health care workers.[Ref]

Cardiovascular

Cardiovascular side effects have included angina, arrhythmia, and pulmonary embolism in less than 1% of patients treated with peginterferon alfa-2a alone or in combination with ribavirin (the active ingredient contained in Moderiba) tablets. Fatal and nonfatal myocardial infarctions have been reported in patients with anemia due to ribavirin capsules/oral solution. Cardiac arrest, hypotension, bradycardia, bigeminy, tachycardia, hypertension (usually slight increases in blood pressure), and digitalis toxicity have been reported with aerosolized ribavirin.[Ref]

Bigeminy, bradycardia, and tachycardia have been reported in patients with underlying congenital heart disease.[Ref]

Hematologic

Hematologic side effects associated with oral ribavirin (the active ingredient contained in Moderiba) in combination with peginterferon alfa-2a, peginterferon alfa-2b, or interferon alfa-2b have included anemia (up to 35%), lymphopenia (up to 14%), neutropenia (up to 40%), thrombocytopenia (up to 8%), and leukopenia (up to 10%). Hemolytic anemia is the most significant toxicity of ribavirin. Aplastic anemia and thrombotic thrombocytopenic purpura have been reported in less than 1% of patients treated with peginterferon alfa-2a alone or in combination with ribavirin tablets. Pancytopenia (marked decreases in red blood cells, neutrophils, and platelets) and bone marrow suppression have been reported following concomitant administration of pegylated interferon plus oral ribavirin and azathioprine. Aplastic anemia has been reported during postmarketing experience with ribavirin capsules/oral solution in combination with interferon alfa-2b or peginterferon alfa-2b. Pure red cell aplasia has been reported during postmarketing experience with oral ribavirin in combination with peginterferon alfa-2a, peginterferon alfa-2b, or interferon alfa-2b. Cases of anemia (type unspecified), reticulocytosis, and hemolytic anemia associated with aerosolized ribavirin have been reported during postmarketing experience and have been reversible with drug discontinuation.[Ref]

Hemolytic anemia is the primary toxicity of ribavirin therapy. Hemoglobin levels generally declined within the first 1 to 2 weeks of oral therapy. Cardiac and pulmonary adverse effects associated with anemia have been reported in 10% of patients.

Hemoglobin less than 10 g/dL was reported in 13% of patients receiving ribavirin tablets in combination with peginterferon alfa-2a. Additional laboratory abnormalities during treatment with ribavirin tablets in combination with peginterferon alfa-2a or interferon alfa-2b have included decreased neutrophils (1000 to less than 1500 cells/mm3: up to 38%; 500 to less than 1000 cells/mm3: up to 49%; less than 500 cells/mm3: up to 5%), platelets (50,000 to less than 75,000 cells/mm3: up to 11%; 20,000 to less than 50,000 cells/mm3: up to 5%), and hemoglobin (8.5 to 9.9 g/dL: 11%; less than 8.5 g/dL: up to 2%).

Changes in laboratory values during treatment with ribavirin capsules/oral solution in combination with peginterferon alfa-2b or interferon alfa-2b have included decreased hemoglobin (9.5 to 10.9 g/dL: up to 32%; 8 to 9.4 g/dL: up to 5%; 6.5 to 7.9 g/dL: up to 0.2%), leukocytes [2 to 2.9 x 10(9)/L: up to 46%; 1.5 to 1.9 x 10(9)/L: up to 24%; 1 to 1.4 x 10(9)/L: up to 5%], neutrophils [1 to 1.49 x 10(9)/L: up to 42%; 0.75 to 0.99 x 10(9)/L: up to 25%; 0.5 to 0.74 x 10(9)/L: up to 18%; less than 0.5 x 10(9)/L: up to 11%], and platelets [70 to 99 x 10(9)/L: up to 15%; 50 to 69 x 10(9)/L: up to 3%; 30 to 49 x 10(9)/L: up to 0.2%; less than 30 x 10(9)/L: up to 1%].[Ref]

Ocular

Ocular side effects associated with oral ribavirin (the active ingredient contained in Moderiba) in combination with peginterferon alfa-2a, peginterferon alfa-2b, or interferon alfa-2b have included blurred vision (up to 6%). Corneal ulcer has been reported in less than 1% of patients treated with peginterferon alfa-2a alone or in combination with ribavirin tablets. Conjunctivitis (up to 5%) has been reported with ribavirin capsules/oral solution in combination with peginterferon alfa-2b or interferon alfa-2b. Serous retinal detachment has been reported during postmarketing experience with oral ribavirin in combination with peginterferon alfa-2a, interferon alfa-2b, or peginterferon alfa-2b. Eye irritation and conjunctivitis have been reported in patients treated with and health care workers exposed to aerosolized ribavirin. Lacrimation has been reported in health care workers exposed to aerosolized ribavirin. Damage to contact lenses after prolonged close exposure to aerosolized ribavirin has also been reported.[Ref]

Conjunctivitis associated with aerosolized ribavirin usually resolved within hours of stopping treatment in patients. Most signs and symptoms reported in exposed health care workers resolved within minutes to hours of stopping close exposure to aerosolized ribavirin.

Eye and conjunctival irritation resolved spontaneously when the caregivers left the hospital. In five of six cases, the caregivers were wearing contact lenses. After the staff stopped wearing contact lenses while caring for patients receiving aerosolized ribavirin, the reactions did not occur.[Ref]

Gastrointestinal

Most signs and symptoms reported in exposed health care workers resolved within minutes to hours of stopping close exposure to aerosolized ribavirin (the active ingredient contained in Moderiba) [Ref]

Gastrointestinal side effects associated with oral ribavirin in combination with peginterferon alfa-2a, peginterferon alfa-2b, or interferon alfa-2b have included nausea (up to 47%), nausea and vomiting (up to 29%), diarrhea (up to 22%), vomiting (up to 14%), abdominal pain (up to 13%), dry mouth (up to 12%), dyspepsia (up to 16%), and constipation (5%). Peptic ulcer, gastrointestinal bleeding, pancreatitis, and colitis have been reported in less than 1% of patients treated with peginterferon alfa-2a alone or in combination with ribavirin tablets. Nausea has been reported in health care workers exposed to aerosolized ribavirin.[Ref]

Musculoskeletal

Musculoskeletal side effects associated with oral ribavirin (the active ingredient contained in Moderiba) in combination with peginterferon alfa-2a, peginterferon alfa-2b, or interferon alfa-2b have included myalgia (up to 64%), arthralgia (up to 34%), musculoskeletal pain (up to 28%), and back pain (5%). Myositis has been reported in less than 1% of patients treated with peginterferon alfa-2a alone or in combination with ribavirin tablets. At least 6 cases of mild to moderate gout have been reported with ribavirin capsules/oral solution in combination with peginterferon alfa-2b or interferon alfa-2b.[Ref]

Nervous system

Nervous system side effects associated with oral ribavirin (the active ingredient contained in Moderiba) in combination with peginterferon alfa-2a, peginterferon alfa-2b, or interferon alfa-2b have included headache (up to 66%), dizziness (excluding vertigo; 26%), and memory impairment (up to 6%). Peripheral neuropathy, coma, and cerebral hemorrhage have been reported in less than 1% of patients treated with peginterferon alfa-2a alone or in combination with ribavirin tablets. Taste perversion (up to 9%) has been reported with ribavirin capsules/oral solution in combination with peginterferon alfa-2b or interferon alfa-2b. Hearing impairment and hearing loss have been reported during postmarketing experience with ribavirin tablets in combination with peginterferon alfa-2a. Vertigo and hearing disorder have been reported during postmarketing experience with ribavirin capsules/oral solution in combination with interferon alfa-2b or peginterferon alfa-2b. Headache and dizziness have been reported in health care workers exposed to aerosolized ribavirin. Seizures have been reported with experimental intravenous ribavirin.[Ref]

Most signs and symptoms reported in exposed health care workers resolved within minutes to hours of stopping close exposure to aerosolized ribavirin.[Ref]

Metabolic

Metabolic side effects associated with oral ribavirin (the active ingredient contained in Moderiba) in combination with peginterferon alfa-2a, peginterferon alfa-2b, or interferon alfa-2b have included anorexia (up to 32%) and weight decrease (up to 29%). Diabetes mellitus has been reported in less than 1% of patients treated with peginterferon alfa-2a alone or in combination with ribavirin tablets. Falsely low hemoglobin A1c levels have been reported. Dehydration has been reported during postmarketing experience with ribavirin tablets in combination with peginterferon alfa-2a. Diabetes has been reported during postmarketing experience with ribavirin capsules/oral solution in combination with interferon alfa-2b or peginterferon alfa-2b.[Ref]

Falsely low hemoglobin A1c levels may be due to ribavirin-induced hemolysis decreasing the number of circulating glycosylated hemoglobin molecules.[Ref]

Psychiatric

Psychiatric side effects associated with oral ribavirin (the active ingredient contained in Moderiba) in combination with peginterferon alfa-2a, peginterferon alfa-2b, or interferon alfa-2b have included irritability/anxiety/nervousness/emotional lability (up to 47%), insomnia (up to 41%), depression (up to 36%), concentration impairment (up to 21%), mood alteration (up to 9%), and agitation (up to 8%). Suicide, suicidal ideation, psychosis, aggression, anxiety, drug abuse/overdose, psychotic disorder, and hallucination have been reported in less than 1% of patients treated with peginterferon alfa-2a alone or in combination with ribavirin tablets. Impairment of desire and the potential to affect sexual satisfaction have been reported with ribavirin tablets in combination with peginterferon alfa-2a in male patients.[Ref]

Endocrine

Endocrine side effects associated with oral ribavirin (the active ingredient contained in Moderiba) in combination with peginterferon alfa-2a, peginterferon alfa-2b, or interferon alfa-2b have included hypothyroidism (up to 5%).[Ref]

Other

Other side effects frequently associated with ribavirin (the active ingredient contained in Moderiba) tablets in combination with peginterferon alfa-2a have included influenza-like symptoms (such as fatigue, pyrexia, myalgia, headache, and rigors). Fatigue/asthenia (up to 70%), pyrexia (up to 55%), rigors (up to 48%), chills (up to 39%), influenza-like illness (up to 18%), unspecified pain (up to 13%), right upper quadrant pain (up to 12%), pain (up to 10%), chest pain (up to 9%), and malaise (up to 6%) have been associated with oral ribavirin in combination with peginterferon alfa-2a, peginterferon alfa-2b, or interferon alfa-2b. Hyperuricemia (in association with hemolysis; up to 38%) and flushing (up to 4%) have been reported with ribavirin capsules/oral solution in combination with peginterferon alfa-2b or interferon alfa-2b. Asthenia has been reported with experimental intravenous ribavirin.[Ref]

Hepatic

Hepatic side effects have included hepatic dysfunction, fatty liver, and cholangitis in less than 1% of patients treated with peginterferon alfa-2a alone or in combination with ribavirin (the active ingredient contained in Moderiba) tablets. Hepatic decompensation has been reported in 2% of CHC-HIV coinfected patients receiving peginterferon alfa-2a in combination with ribavirin tablets. Hyperbilirubinemia (in association with hemolysis; up to 14%), hepatomegaly (4%), and increased ALT have been reported with ribavirin capsules/oral solution in combination with peginterferon alfa-2b or interferon alfa-2b.[Ref]

Changes in laboratory values during treatment with ribavirin capsules/oral solution in combination with peginterferon alfa-2b or interferon alfa-2b have included increased total bilirubin (1.5 to 3 mg/dL: up to 32%; 3.1 to 6 mg/dL: up to 3%; 6.1 to 12 mg/dL: up to 0.4%) and ALT (2 x baseline: up to 0.6%; 2.1 to 5 x baseline: up to 3%).[Ref]

Immunologic

Immunologic side effects associated with peginterferon alfa-2a alone or in combination with ribavirin (the active ingredient contained in Moderiba) tablets have included bacterial infection (e.g., sepsis, osteomyelitis, endocarditis, pyelonephritis, pneumonia) in 3% of CHC and 5% of CHC-HIV patients and autoimmune phenomena (such as hyperthyroidism, hypothyroidism, sarcoidosis, systemic lupus erythematosus, rheumatoid arthritis) in less than 1% of patients. Resistance mechanism disorders (overall: up to 12%), including viral infection (12%) and fungal infection (up to 6%), have been associated with oral ribavirin in combination with peginterferon alfa-2a, peginterferon alfa-2b, or interferon alfa-2b. Liver and renal graft rejections have been reported during postmarketing experience with ribavirin tablets in combination with peginterferon alfa-2a.[Ref]

Genitourinary

Genitourinary side effects associated with ribavirin (the active ingredient contained in Moderiba) tablets in combination with peginterferon alfa-2a have included sexual dysfunction in male patients. Menstrual disorder has been reported with ribavirin capsules/oral solution in combination with peginterferon alfa-2b or interferon alfa-2b.[Ref]

Local

Local side effects have included injection site reactions (up to 58%) in patients treated with oral ribavirin (the active ingredient contained in Moderiba) in combination with interferon alfa-2b, peginterferon alfa-2b, or peginterferon alfa-2a. Injection site inflammation (up to 25%) has been reported with ribavirin capsules/oral solution in combination with peginterferon alfa-2b or interferon alfa-2b. Skin disorders associated with ribavirin tablets in combination with peginterferon alfa-2a have included cutaneous necrosis at peginterferon alfa-2a injection sites. Hyperpigmentation around/over peginterferon alfa-2a injection sites has been reported.[Ref]

Some side effects of Moderiba may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Significant adverse reactions associated with Moderiba (ribavirin, USP)/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

Moderiba 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.

Moderiba 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 Moderiba therapy and for 6 months after therapy has stopped [see BOXED WARNING, CONTRAINDICATIONS, Use In Specific Populations, and PATIENT INFORMATION].

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].

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]. Because cardiac disease may be worsened by drug-induced anemia, patients with a history of significant or unstable cardiac disease should not use Moderiba [see BOXED WARNING and DOSAGE AND ADMINISTRATION].

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], 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/Moderiba should be discontinued immediately in patients with hepatic decompensation [see CONTRAINDICATIONS].

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 Moderiba 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].

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 Moderiba/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, Moderiba, and azathioprine should be discontinued for pancytopenia, and pegylated interferon/ribavirin should not be re-introduced with concomitant azathioprine [see DRUG INTERACTIONS].

Pancreatitis

Moderiba 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].

Laboratory Tests

Before beginning peginterferon alfa-2a/Moderiba 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 peginterferon alfa-2a/Moderiba.

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/mm³ or 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

Patient Counseling Information

See FDA-approved patient labeling (Medication Guide)

Patients must be informed that ribavirin may cause birth defects and/or death of the exposed fetus. Moderiba 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 Moderiba therapy and for 6 months post therapy. Patients should use two reliable methods of birth control while taking Moderiba therapy and for 6 months post therapy. Moderiba 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 Moderiba 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 and WARNINGS AND PRECAUTIONS].

The most common adverse event associated with ribavirin is anemia, which may be severe [see BOXED WARNING, WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS]. Patients should be advised that laboratory evaluations are required prior to starting Moderiba therapy and periodically thereafter [see WARNINGS AND PRECAUTIONS]. 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 Moderiba with food.

Patients should be questioned about prior history of drug abuse before initiating Moderiba/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. Patients should be informed about what to do in the event they miss a dose of Moderiba. 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/Moderiba treatment of hepatitis C infection on transmission is not known, and that appropriate precautions to prevent transmission of hepatitis C virus during treatment or in the event of treatment failure should be taken.

Patients should be informed regarding the potential benefits and risks attendant to the use of Moderiba. 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.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

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.

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.

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 ribavirininduced 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 Moderiba unless the patient and his/her partner are using effective contraception (two reliable forms). Based on a multiple dose half-life (t ½) 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.

Use In Specific Populations

Pregnancy

Pregnancy: Category X

[see CONTRAINDICATIONS].

Ribavirin produced significant embryocidal and/or teratogenic effects in all animal species in which adequate studies have been conducted. Malformations of the skull, palate, eye, jaw, limbs, skeleton, and gastrointestinal tract were noted. The incidence and severity of teratogenic effects increased with escalation of the drug dose. Survival of fetuses and offspring was reduced [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS].

In conventional embryotoxicity/teratogenicity studies in rats and rabbits, observed no-effect dose levels were well below those for proposed clinical use (0.3 mg/kg/day for both the rat and rabbit; approximately 0.06 times the recommended daily human dose of ribavirin). No maternal toxicity or effects on offspring were observed in a peri/postnatal toxicity study in rats dosed orally at up to 1 mg/kg/day (approximately 0.01 times the maximum recommended daily human dose of ribavirin).

Ribavirin is known to accumulate in intracellular components from where it is cleared very slowly. It is not known whether ribavirin is contained in sperm, and if so, will exert a potential teratogenic effect upon fertilization of the ova. However, because of the potential human teratogenic effects of ribavirin, male patients should be advised to take every precaution to avoid risk of pregnancy for their female partners.

Moderiba should not be used by pregnant women or by men whose female partners are pregnant. Female patients of childbearing potential and male patients with female partners of childbearing potential should not receive Moderiba unless the patient and his/her partner are using effective contraception (two reliable forms) during therapy and for 6 months post therapy [see CONTRAINDICATIONS].

A Ribavirin Pregnancy Registry has been established to monitor maternal-fetal outcomes of pregnancies of female patients and female partners of male patients exposed to ribavirin during treatment and for 6 months following cessation of treatment. Healthcare providers and patients are encouraged to report such cases by calling 1-800-593-2214.

Nursing Mothers

It is not known whether ribavirin is excreted in human milk. Because many drugs are excreted in human milk and to avoid any potential for serious adverse reactions in nursing infants from ribavirin, a decision should be made either to discontinue nursing or therapy with Moderiba, based on the importance of the therapy to the mother.

Pediatric Use

Pharmacokinetic evaluations in pediatric patients have not been performed.

Safety and effectiveness of Moderiba tablets have not been established in patients below the age of 5 years.

Geriatric Use

Clinical studies of ribavirin and peginterferon alfa-2a did not include sufficient numbers of subjects aged 65 or over to determine whether they respond differently from younger subjects. Specific pharmacokinetic evaluations for ribavirin in the elderly have not been performed. The risk of toxic reactions to this drug may be greater in patients with impaired renal function. The dose of Moderiba should be reduced in patients with creatinine clearance less than or equal to 50 mL/min; and the dose of peginterferon alfa-2a should be reduced in patients with creatinine clearance less than 30 mL/min [see DOSAGE AND ADMINISTRATION; Use In Specific Populations].

Race

A pharmacokinetic study in 42 subjects demonstrated there is no clinically significant difference in ribavirin pharmacokinetics among Black (n=14), Hispanic (n=13) and Caucasian (n=15) subjects.

Renal Impairment

Renal function should be evaluated in all patients prior to initiation of Moderiba by estimating the patient's creatinine clearance.

A clinical trial evaluated treatment with ribavirin and peginterferon alfa-2a in 50 CHC subjects with moderate (creatinine clearance 30 – 50 mL/min) or severe (creatinine clearance less than 30 mL/min) renal impairment or end stage renal disease (ESRD) requiring chronic hemodialysis (HD). In 18 subjects with ESRD receiving chronic HD, ribavirin was administered at a dose of 200 mg daily with no apparent difference in the adverse event profile in comparison to subjects with normal renal function. Dose reductions and temporary interruptions of ribavirin (due to ribavirin-related adverse reactions, mainly anemia) were observed in up to one-third ESRD/HD subjects during treatment; and only one-third of these subjects received ribavirin for 48 weeks. Ribavirin plasma exposures were approximately 20% lower in subjects with ESRD on HD compared to subjects with normal renal function receiving the standard 1000/1200 mg ribavirin daily dose.

Subjects with moderate (n=17) or severe (n=14) renal impairment did not tolerate 600 mg or 400 mg daily doses of ribavirin, respectively, due to ribavirin-related adverse reactions, mainly anemia, and exhibited 20% to 30% higher ribavirin plasma exposures (despite frequent dose modifications) compared to subjects with normal renal function (creatinine clearance greater than 80 mL/min) receiving the standard dose of ribavirin. Discontinuation rates were higher in subjects with severe renal impairment compared to that observed in subjects with moderate renal impairment or normal renal function. Pharmacokinetic modeling and simulation indicate that a dose of 200 mg daily in patients with severe renal impairment and a dose of 200 mg daily alternating with 400 mg the following day in patients with moderate renal impairment will provide plasma ribavirin exposure similar to patients with normal renal function receiving the approved regimen of ribavirin. These doses have not been studied in patients [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY].

Based on the pharmacokinetic and safety results from this trial, patients with creatinine clearance less than or equal to 50 mL/min should receive a reduced dose of ribavirin; and patients with creatinine clearance less than 30 mL/min should receive a reduced dose of peginterferon alfa-2a. The clinical and hematologic status of patients with creatinine clearance less than or equal to 50 mL/min receiving ribavirin should be carefully monitored. Patients with clinically significant laboratory abnormalities or adverse reactions which are persistently severe or worsening should have therapy withdrawn [see DOSAGE AND ADMINISTRATION, CLINICAL PHARMACOLOGY, and Peginterferon alfa-2a Package Insert].

Hepatic Impairment

The effect of hepatic impairment on the pharmacokinetics of ribavirin following administration of ribavirin has not been evaluated. The clinical trials of ribavirin were restricted to patients with Child- Pugh class A disease.

Gender

No clinically significant differences in the pharmacokinetics of ribavirin were observed between male and female subjects.

Ribavirin pharmacokinetics, when corrected for weight, are similar in male and female patients.

Organ Trans Plant Recipients

The safety and efficacy of peginterferon alfa-2a and ribavirin treatment have not been established in patients with liver and other transplantations. As with other alpha interferons, liver and renal graft rejections have been reported on peginterferon alfa-2a, alone or in combination with ribavirin [see ADVERSE REACTIONS].