Copegus

Copegus is a prescription medicine used with either interferon alfa-2b (Intron A) or peginterferon alfa-2b (PegIntron) to treat chronic (lasting a long time) hepatitis C infection in people 5 years and older with liver disease.

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

• Genentech, Inc.

Medications can interact with certain foods. In some cases, this may be harmful and your doctor may advise you to avoid certain foods. In the case of Copegus, there are no specific foods that you must exclude from your diet when receiving this medication.

WARNING: RISK OF SERIOUS DISORDERS AND COPEGUS-ASSOCIATED EFFECTS

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

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:

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

To make sure you can safely take ribavirin, tell your doctor if you have any of these other conditions:

• kidney or liver disease (other than hepatitis C);
• hepatitis B infection;
• a blood cell disorder such as hemolytic anemia (a lack of red blood cells);
• human immunodeficiency virus (HIV or AIDS);
• diabetes;
• a pancreas disorder;
• sarcoidosis;
• breathing problems;
• a thyroid disorder;
• new or worsening eye problems (such as retinopathy);
• a history of heart disease, high blood pressure, or a heart attack;
• a history of depression or suicide attempt;
• a history of a liver, kidney, or other organ transplant; or
• if you have ever received treatment for hepatitis C that did not work well.

This medication can cause birth defects or death in an unborn baby.

• If you are a woman, do not take ribavirin if you are pregnant. You will need frequent pregnancy tests to make sure you are not pregnant while taking ribavirin.
• If you are a man, do not take ribavirin if your female sexual partner is pregnant. An unborn baby could also be harmed if a man fathers the child while he is taking ribavirin. Your sexual partner will need frequent pregnancy tests to make sure she is not pregnant while you are taking ribavirin.
• Use at least two effective forms of birth control while either sexual partner is taking ribavirin, and 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.

Your name may need to be listed on a ribavirin pregnancy registry if you become pregnant while you or your male sexual partner are taking this medication or during the 6 months after treatment ends. 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 you are taking ribavirin.

Ribavirin may affect growth in children.

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.

This section provides information on the proper use of a number of products that contain ribavirin. It may not be specific to Copegus. Please read with care.

To help clear up your infection completely, ribavirin must be given for the full time of treatment, even if you or your child begins to feel better after a few days. Also, it is important to keep the amount of medicine in your body at a steady level. To help keep the amount constant, ribavirin must be given on a regular schedule.

You should take this medicine with food.

Swallow the capsule whole. Do not crush, break, or open it.

Measure the oral liquid with a marked measuring cup or spoon. Wash the cup or spoon after each use.

This medicine should come with a Medication Guide. Read and follow the information carefully. Ask your doctor if you have any questions. Ask your pharmacist for the Medication Guide if you do not have one.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For hepatitis C virus infection, in combination with interferon alfa-2b:
  • For oral dosage form (capsules):
    • Adults—Dose is based on body weight and must be determined by your doctor. The dose is usually 1000 to 1200 milligrams (mg) per day, given as two or three capsules in the morning and three capsules at night.
    • Children 3 years of age and older—Dose is based on body weight and must be determined by your doctor. The dose is usually 15 milligrams (mg) per kilogram (kg) of body weight per day, given in 2 divided doses and taken in the morning and evening.
    • Children younger than 3 years of age—Use and dose must be determined by your doctor.
  • For oral dosage form (solution):
    • Adults—Dose is based on body weight and must be determined by your doctor. The oral solution form of this medicine is not usually prescribed for adults and teenagers.
    • Children 3 years of age and older—Dose is based on body weight and must be determined by your doctor. The dose is usually 15 milligrams (mg) per kilogram (kg) of body weight per day, given in 2 divided doses and taken in the morning and evening.
    • Children younger than 3 years of age—Use and dose must be determined by your doctor.
• For hepatitis C virus infection, in combination with peginterferon alfa-2b:
  • For oral dosage form (capsules):
    • Adults—Dose is based on body weight and must be determined by your doctor. The dose is usually 800 to 1400 milligrams (mg) per day, given as two to three capsules in the morning and two to four capsules at night.
    • Children 3 years of age and older—Dose is based on body weight and must be determined by your doctor. The dose is usually 15 milligrams (mg) per kilogram (kg) of body weight per day, given in 2 divided doses and taken in the morning and evening.
    • Children younger than 3 years of age—Use and dose must be determined by your doctor.
  • For oral dosage form (solution):
    • Adults—Dose is based on body weight and must be determined by your doctor. The oral solution form of this medicine is not usually prescribed for adults and teenagers.
    • Children 3 years of age and older—Dose is based on body weight and must be determined by your doctor. The dose is usually 15 milligrams (mg) per kilogram (kg) of body weight per day, given in two divided doses and taken in the morning and evening.
    • Children younger than 3 years of age—Use and dose must be determined by your doctor.
• For hepatitis C virus infection, in combination with peginterferon alfa-2a:
  • For oral dosage form (tablets):
    • Adults—Dose is based on body weight and must be determined by your doctor. The dose is usually 800 to 1200 milligrams (mg) per day, given in 2 divided doses and taken in the morning and evening.
    • Children 5 years of age and older—Dose is based on body weight and must be determined by your doctor. The dose is usually 400 to 1200 mg per day, given in 2 divided doses and taken in the morning and evening.
    • Children younger than 5 years of age—Use and dose must be determined by your doctor.
• For hepatitis C with HIV virus coinfection, in combination with peginterferon alfa-2a:
  • For oral dosage form (tablets):
    • Adults—800 milligrams (mg) per day.
    • Children—Use and dose must be determined by your doctor.

Missed Dose

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Store the capsules and tablets in a closed container at room temperature, away from heat, moisture, and direct light.

Store the oral liquid in the refrigerator or at room temperature, away from heat and direct light. Do not freeze.

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

• Anxiety
• black, tarry stools
• body aches or pain
• chest pain
• congestion
• cough or hoarseness
• crying
• depersonalization
• diarrhea
• difficult or labored breathing
• discouragement
• dry mouth
• dryness of the throat
• dysphoria
• euphoria
• feeling sad or empty
• feeling unusually cold
• fever or chills
• general feeling of discomfort or illness
• headache
• hyperventilation
• irregular heartbeats
• irritability
• joint pain
• lack of appetite
• loss of interest or pleasure
• lower back or side pain
• mental depression
• muscle aches and pains
• nausea
• nervousness
• painful or difficult urination
• pale skin
• paranoia
• poor concentration
• quick to react or overreact emotionally
• rapidly changing moods
• restlessness
• right upper abdominal or stomach pain
• runny nose
• shaking
• shivering
• shortness of breath
• sleeplessness
• sore throat
• sores, ulcers, or white spots on the lips or in the mouth
• sweating
• tender, swollen glands in the neck
• tightness in the chest
• trouble with concentrating
• trouble with sleeping
• trouble with swallowing
• troubled breathing with exertion
• unable to sleep
• unusual bleeding or bruising
• unusual tiredness or weakness
• voice changes
• vomiting
• wheezing

• Bleeding gums
• blood in the urine or stools
• constipation
• depressed mood
• dry skin and hair
• feeling cold
• hair loss
• husky voice
• muscle cramps and stiffness
• pinpoint red spots on the skin
• right upper abdominal or stomach fullness
• slowed heartbeat
• weight gain

• Blistering, flaking, or peeling of the skin

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Acid or sour stomach
• being forgetful
• belching
• blurred vision
• bone pain
• change in taste or bad, unusual, or unpleasant (after) taste
• cracked, scaly skin
• crusting, irritation, itching, or reddening of the skin
• difficulty with moving
• dizziness or lightheadedness
• feeling of constant movement of self or surroundings
• hair loss or thinning of the hair
• heartburn
• indigestion
• lack or loss of strength
• menstrual changes
• pain or tenderness around the eyes and cheekbones
• rash
• sensation of spinning
• sneezing
• stomach discomfort, upset, or pain
• stuffy nose
• swelling
• swollen joints
• weight loss

• Back pain
• burning, dry, or itching eyes
• discharge, excessive tearing
• feeling of warmth
• redness of the face, neck, arms, and occasionally, upper chest
• redness, pain, swelling of the eye, eyelid, or inner lining of the eyelid
• skin rash, encrusted, scaly, and oozing

• Change in hearing
• loss of hearing

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

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

PEGASYS in combination with Copegus causes a broad variety of serious adverse reactions [see Boxed Warning and Warnings and Precautions (5)]. The most common serious or life-threatening adverse reactions induced or aggravated by Copegus/PEGASYS include depression, suicide, relapse of drug abuse/overdose, and bacterial infections each occurring at a frequency of less than 1%. Hepatic decompensation occurred in 2% (10/574) CHC/HIV patients [see Warnings and Precautions (5.3)].

Clinical Studies Experience

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

Adult Patients

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

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

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

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

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

PEGASYS dose was reduced in 12% of patients receiving 1000 mg to 1200 mg Copegus for 48 weeks and in 7% of patients receiving 800 mg Copegus for 24 weeks. Copegus dose was reduced in 21% of patients receiving 1000 mg to 1200 mg Copegus for 48 weeks and in 12% of patients receiving 800 mg Copegus for 24 weeks.

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

Pediatric Patients

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

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

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

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

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

Common Adverse Reactions in CHC with HIV Coinfection (Adults)

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

Laboratory Test Abnormalities

Adult Patients

Anemia due to hemolysis is the most significant toxicity of ribavirin therapy. Anemia (hemoglobin less than 10 g/dL) was observed in 13% of all Copegus and PEGASYS combination-treated patients in clinical trials. The maximum drop in hemoglobin occurred during the first 8 weeks of initiation of ribavirin therapy [see Dosage and Administration (2.3)].

Pediatric Patients

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

In patients randomized to combination therapy, the incidence of abnormalities during the entire treatment phase (up to 48 weeks plus 24 weeks follow-up) in comparison to the first 24 weeks increased slightly for neutrophils between 500 and 1,000 cells/mm3 and hemoglobin values between 8.5 and 10 g/dL. The majority of hematologic abnormalities occurred in the first 24 weeks of treatment.

Postmarketing Experience

The following adverse reactions have been identified and reported during post-approval use of PEGASYS/Copegus combination therapy. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and Lymphatic System disorders

Ear and Labyrinth disorders

Eye disorders

Immune disorders

Metabolism and Nutrition disorders

Skin and Subcutaneous Tissue disorders

Results from a pharmacokinetic sub-study demonstrated no pharmacokinetic interaction between PEGASYS (peginterferon alfa-2a) and ribavirin.

Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

In vitro data indicate ribavirin reduces phosphorylation of lamivudine, stavudine, and zidovudine. However, no pharmacokinetic (e.g., plasma concentrations or intracellular triphosphorylated active metabolite concentrations) or pharmacodynamic (e.g., loss of HIV/HCV virologic suppression) interaction was observed when ribavirin and lamivudine (n=18), stavudine (n=10), or zidovudine (n=6) were co-administered as part of a multi-drug regimen to HCV/HIV coinfected patients.

In Study NR15961 among the CHC/HIV coinfected cirrhotic patients receiving NRTIs, cases of hepatic decompensation (some fatal) were observed [see Warnings and Precautions (5.3)].

Patients receiving PEGASYS/Copegus and NRTIs should be closely monitored for treatment-associated toxicities. Physicians should refer to prescribing information for the respective NRTIs for guidance regarding toxicity management. In addition, dose reduction or discontinuation of PEGASYS, Copegus or both should also be considered if worsening toxicities are observed, including hepatic decompensation (e.g., Child-Pugh greater than or equal to 6) [see Warnings and Precautions (5.3) and Dosage and Administration (2.3)].

Didanosine

Co-administration of Copegus and didanosine is contraindicated. Didanosine or its active metabolite (dideoxyadenosine 5'-triphosphate) concentrations are increased when didanosine is co-administered with ribavirin, which could cause or worsen clinical toxicities. Reports of fatal hepatic failure as well as peripheral neuropathy, pancreatitis, and symptomatic hyperlactatemia/lactic acidosis have been reported in clinical trials [see Contraindications (4)].

Zidovudine

In Study NR15961, patients who were administered zidovudine in combination with PEGASYS/Copegus developed severe neutropenia (ANC less than 500) and severe anemia (hemoglobin less than 8 g/dL) more frequently than similar patients not receiving zidovudine (neutropenia 15% vs. 9%) (anemia 5% vs. 1%). Discontinuation of zidovudine should be considered as medically appropriate.

Drugs Metabolized by Cytochrome P450

In vitro studies indicate that ribavirin does not inhibit CYP 2C9, CYP 2C19, CYP 2D6 or CYP 3A4.

Azathioprine

The use of ribavirin to treat chronic hepatitis C in patients receiving azathioprine has been reported to induce severe pancytopenia and may increase the risk of azathioprine-related myelotoxicity. Inosine monophosphate dehydrogenase (IMDH) is required for one of the metabolic pathways of azathioprine. Ribavirin is known to inhibit IMDH, thereby leading to accumulation of an azathioprine metabolite, 6-methylthioinosine monophosphate (6-MTITP), which is associated with myelotoxicity (neutropenia, thrombocytopenia, and anemia). Patients receiving azathioprine with ribavirin should have complete blood counts, including platelet counts, monitored weekly for the first month, twice monthly for the second and third months of treatment, then monthly or more frequently if dosage or other therapy changes are necessary [see Warnings and Precautions (5.6)].

Mechanism of Action

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

Pharmacokinetics

Multiple dose ribavirin pharmacokinetic data are available for HCV patients who received ribavirin in combination with peginterferon alfa-2a. Following administration of 1200 mg/day with food for 12 weeks mean±SD (n=39; body weight greater than 75 kg) AUC0-12hr was 25,361±7110 ng∙hr/mL and Cmax was 2748±818 ng/mL. The average time to reach Cmax was 2 hours. Trough ribavirin plasma concentrations following 12 weeks of dosing with food were 1662±545 ng/mL in HCV infected patients who received 800 mg/day (n=89), and 2112±810 ng/mL in patients who received 1200 mg/day (n=75; body weight greater than 75 kg).

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

Effect of Food on Absorption of Ribavirin

Bioavailability of a single oral dose of ribavirin was increased by co-administration with a high-fat meal. The absorption was slowed (Tmax was doubled) and the AUC0-192h and Cmax increased by 42% and 66%, respectively, when Copegus was taken with a high-fat meal compared with fasting conditions [see Dosage and Administration (2) and Patient Counseling Information (17)].

Elimination and Metabolism

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

Renal Impairment

A clinical trial evaluated 50 CHC subjects with either moderate (creatinine clearance 30 to 50 mL/min) or severe (creatinine clearance less than 30 mL/min) renal impairment or end stage renal disease (ESRD) requiring chronic hemodialysis (HD). The apparent clearance of ribavirin was reduced in subjects with creatinine clearance less than or equal to 50 mL/min, including subjects with ESRD on HD, exhibiting approximately 30% of the value found in subjects with normal renal function. Pharmacokinetic modeling and simulation indicates 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 exposures similar to that observed in patients with normal renal function receiving the standard 1000/1200 mg Copegus daily dose. These doses have not been studied in patients.

In 18 subjects with ESRD receiving chronic HD, Copegus was administered at a dose of 200 mg daily. Ribavirin plasma exposures in these subjects were approximately 20% lower compared to subjects with normal renal function receiving the standard 1000/1200 mg Copegus daily dose [see Dosage and Administration (2.4), Use in Specific Populations (8.7)].

Plasma ribavirin is removed by hemodialysis with an extraction ratio of approximately 50%; however, due to the large volume of distribution of ribavirin, plasma exposure is not expected to change with hemodialysis.

Microbiology

Mechanism of Action

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

Antiviral Activity in Cell Culture

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

Resistance

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

Cross-resistance

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

Applies to ribavirin: oral capsule, oral solution, oral tablet

Other dosage forms:

• inhalation powder for solution

Along with its needed effects, ribavirin (the active ingredient contained in Copegus) may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking ribavirin:

• Anxiety
• black, tarry stools
• body aches or pain
• chest pain
• congestion
• cough or hoarseness
• crying
• depersonalization
• diarrhea
• difficult or labored breathing
• discouragement
• dry mouth
• dryness of the throat
• dysphoria
• euphoria
• feeling sad or empty
• feeling unusually cold
• fever or chills
• general feeling of discomfort or illness
• headache
• hyperventilation
• irregular heartbeats
• irritability
• joint pain
• lack of appetite
• loss of interest or pleasure
• lower back or side pain
• mental depression
• muscle aches and pains
• nausea
• nervousness
• painful or difficult urination
• pale skin
• paranoia
• poor concentration
• quick to react or overreact emotionally
• rapidly changing moods
• restlessness
• right upper abdominal or stomach pain
• runny nose
• shaking
• shivering
• shortness of breath
• sleeplessness
• sore throat
• sores, ulcers, or white spots on the lips or in the mouth
• sweating
• tender, swollen glands in the neck
• tightness in the chest
• trouble with concentrating
• trouble with sleeping
• trouble with swallowing
• troubled breathing with exertion
• unable to sleep
• unusual bleeding or bruising
• unusual tiredness or weakness
• voice changes
• vomiting
• wheezing

• Bleeding gums
• blood in the urine or stools
• constipation
• depressed mood
• dry skin and hair
• feeling cold
• hair loss
• husky voice
• muscle cramps and stiffness
• pinpoint red spots on the skin
• right upper abdominal or stomach fullness
• slowed heartbeat
• weight gain

• Blistering, flaking, or peeling of the skin

Some side effects of ribavirin may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Acid or sour stomach
• being forgetful
• belching
• blurred vision
• bone pain
• change in taste or bad, unusual, or unpleasant (after) taste
• cracked, scaly skin
• crusting, irritation, itching, or reddening of the skin
• difficulty with moving
• dizziness or lightheadedness
• feeling of constant movement of self or surroundings
• hair loss or thinning of the hair
• heartburn
• indigestion
• lack or loss of strength
• menstrual changes
• pain or tenderness around the eyes and cheekbones
• rash
• sensation of spinning
• sneezing
• stomach discomfort, upset, or pain
• stuffy nose
• swelling
• swollen joints
• weight loss

• Back pain
• burning, dry, or itching eyes
• discharge, excessive tearing
• feeling of warmth
• redness of the face, neck, arms, and occasionally, upper chest
• redness, pain, swelling of the eye, eyelid, or inner lining of the eyelid
• skin rash, encrusted, scaly, and oozing

• Change in hearing
• loss of hearing