Side Effects of Copegus (ribavirin)

Copegus (ribavirin) is an antiviral drug used in combination with interferon to treat chronic hepatitis C. Although the exact mechanism of its action is unknown, Copegus is thought to interfere with the production and/or action of viral DNA and RNA which are critical to the survival and multiplication of the virus. 

Common side effects of Copegus therapy interferon include

• flu-like syndrome (consisting of body aches and pains, fever, chills, headache, and malaise),
• fatigue,
• weakness,
• nausea,
• loss of appetite,
• heartburn,
• insomnia,
• irritability,
• difficulty breathing,
• rash,
• itching, and
• changes in taste.

Serious side effects of Copegus include

• anemia;
• aggravation of psychiatric conditions or triggering of a psychiatric condition such as depression, psychosis, aggressive behavior, hallucinations, or violent behavior; and
• abnormalities of the thyroid gland. 

Drug interactions of Copegus include other antiviral drugs with similar mechanisms of action such as those used to manage HIV infection, because it may cause a condition in which lactic acid accumulates in the blood (lactic acidosis) which can lead to serious medical problems.

Adding Copegus treatment among patients taking azathioprine increases the chance of severe pancytopenia (a reduction in the numbers of all types of blood cells) due to azathioprine.

This occurs because Copegus reduces the breakdown of a harmful chemical produced during the breakdown of azathioprine.

There are no studies of Copegus in pregnant women. Copegus should not be taken by pregnant women. In addition, women who are receiving Copegus therapy should wait at least 6 months after Copegus is stopped before becoming pregnant in order to prevent potential effects of Copegus on the fetus.

Since Copegus may cause abnormalities in sperm, men taking Copegus should avoid attempts to impregnate sexual partners and should wait six months after discontinuing the drug before attempting to impregnate.

Although it is unknown if Copegus passes into breast milk, the potential exists for serious adverse effects from combination therapy. Breastfeeding should be discontinued during treatment with Copegus.

The most common side effect seen with the combination of ribavirin and interferon is a flu-like syndrome consisting of:

• body aches and pains,
• fever,
• chills,
• headache, and
• malaise.

Other possible side effects that may occur during therapy with ribavirin and interferon are:

• fatigue,
• weakness,
• nausea,
• anorexia,
• heartburn,
• insomnia,
• irritability,
• difficulty breathing,
• rash,
• itching, and
• alterations in taste perception.

The most serious side effect seen with ribavirin is anemia. Careful consideration is advised if ribavirin is used in patients with heart or circulation problems since the anemia may aggravate these conditions.

Ribavirin should be avoided among patients who have severe kidney disease and have lost most of their kidneys' function.

Therapy with ribavirin and interferon may aggravate psychiatric conditions or may trigger a psychiatric condition such as

• depression,
• psychosis,
• aggressive behavior,
• hallucinations, or
• violent behavior.

Patients should be closely monitored for the development of these psychiatric conditions.

Therapy with ribavirin and interferon has caused abnormalities of the thyroid gland. If these abnormalities persist and cannot be controlled by medication, it may be necessary to discontinue therapy.

Pegasys in combination with Copegus causes a broad variety of serious adverse reactions. 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.

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.

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

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).

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

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

• 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 (64^th mean percentile at baseline, 60^th mean percentile at 2 years post-treatment) and height (54^th mean percentile at baseline, 56^th mean percentile at 2 years post-treatment).
• At the end of treatment, 43% (23 of 53) of subjects experienced a weight percentile decrease of more than 15 percentiles, and 25% (13 of 53) experienced a height percentile decrease of more than 15 percentiles on the normative growth curves.
• At 2 years post-treatment, 16% (6 of 38) of subjects were more than 15 percentiles below their baseline weight curve and 11% (4 of 38) were more than 15 percentiles below their baseline height curve.
• Thirty-eight of the 114 subjects enrolled in the long-term follow-up study, extending up to 6 years posttreatment. For most subjects, post-treatment recovery in growth at 2 years post-treatment was maintained to 6 years post-treatment.

Common Adverse Reactions in CHC with HIV Coinfection (Adults)

The adverse event profile of coinfected patients treated with 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.

Table 7 : Selected Laboratory Abnormalities During Treatment with Copegus in Combination With Either Pegasys or Intron A

Pediatric Patients

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

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

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

Pure red cell aplasia

Ear and Labyrinth Disorders

Hearing impairment, hearing loss

Eye Disorders

Serous retinal detachment

Immune Disorders

Liver and renal graft rejection

Metabolism and Nutrition Disorders

Dehydration

Skin and Subcutaneous Tissue Disorders

Stevens-Johnson Syndrome (SJS)

Toxic epidermal necrolysis (TEN)

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.
• 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).

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.

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.