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Copegus

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Copegus

Side Effects
Interactions

SIDE EFFECTS

PEGASYS in combination with COPEGUS causes a broad variety of serious adverse reactions [see BOXED WARNING and WARNINGS AND PRECAUTIONS]. 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].

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% 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)

Body System CHC Combination Therapy
Study NV15801
PEGASYS 180 mcg + 1000 mg or 1200 mg COPEGUS
48 weeks
N=451
%
Intron A + 1000 mg or 1200 mg Rebetol®
48 weeks
N=443
%
Application Site Disorders
  Injection site reaction 23 16
Endocrine Disorders
  Hypothyroidism 4 5
Flu-like Symptoms and Signs
  Fatigue/Asthenia 65 68
  Pyrexia 41 55
  Rigors 25 37
  Pain 10 9
Gastrointestinal
  Nausea/Vomiting 25 29
  Diarrhea 11 10
  Abdominal pain 8 9
  Dry mouth 4 7
  Dyspepsia 6 5
Hematologic*
  Lymphopenia 14 12
  Anemia 11 11
  Neutropenia 27 8
  Thrombocytopenia 5 < 1
Metabolic and Nutritional
  Anorexia 24 26
  Weight decrease 10 10
Musculoskeletal, Connective Tissue and Bone
  Myalgia 40 49
  Arthralgia 22 23
  Back pain 5 5
Neurological
  Headache 43 49
  Dizziness (excluding vertigo) 14 14
  Memory impairment 6 5
Psychiatric
  Irritability/Anxiety/Nervousness 33 38
  Insomnia 30 37
  Depression 20 28
  Concentration impairment 10 13
  Mood alteration 5 6
Resistance Mechanism Disorders
  Overall 12 10
Respiratory, Thoracic and Mediastinal
  Dyspnea 13 14
  Cough 10 7
  Dyspnea exertional 4 7
Skin and Subcutaneous Tissue
  Alopecia 28 33
  Pruritus 19 18
  Dermatitis 16 13
  Dry skin 10 13
  Rash 8 5
  Sweating increased 6 5
  Eczema 5 4
Visual Disorders
  Vision blurred 5 2
* Severe hematologic abnormalities (lymphocyte less than 500 cells/mm³; hemoglobin less than 10 g/dL; neutrophil less than 750 cells/mm³; platelet less than 50,000 cells/mm³).

Pediatric Subjects

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).

Growth inhibition was observed in pediatric subjects. During combination therapy for up to 48 weeks with PEGASYS and COPEGUS, negative changes in weight for age z-score and height for age z-score after 48 weeks of therapy compared with baseline were observed [see WARNINGS AND PRECAUTIONS].

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)

System Organ Class Study NV17424
PEGASYS 180 mcg/1.73 m x BSA + COPEGUS 15 mg/kg
(N=55)
%
PEGASYS 180 mcg/1.73 m x BSA + Placebo**
(N=59)
%
General disorders and administration site conditions
  Influenza like illness 91 81
  Injection site reaction 44 42
  Fatigue 25 20
  Irritability 24 14
Gastrointestinal disorders
  Gastrointestinal disorder 49 44
Nervous system disorders
  Headache 51 39
Skin and subcutaneous tissue disorders
  Rash 15 10
  Pruritus 11 12
Musculoskeletal, connective tissue and bone disorders
  Musculoskeletal pain 35 29
Psychiatric disorders
  Insomnia 9 12
Metabolism and nutrition disorders
  Decreased appetite 11 14
* Displayed adverse drug reactions include all grades of reported adverse clinical events considered possibly, probably, or definitely related to study drug.
**Subjects in the PEGASYS plus placebo arm who did not achieve undetectable viral load at week 24 switched to combination treatment thereafter. Therefore, only the first 24 weeks are presented for the comparison of combination therapy with monotherapy.

In pediatric subjects randomized to combination therapy, the incidence of most adverse reactions were 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.

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].

Table 7 : Selected Laboratory Abnormalities During Treatment With COPEGUS in Combination With Either PEGASYS or Intron A

Laboratory Parameter PEGASYS + Ribavirin 1000/1200 mg 48 wks
(N=887)
Intron A + Ribavirin 1000/1200 mg 48 wks
(N=443)
Neutrophils (cells/mm³)
1,000 < 1,500 34% 38%
500 < 1,000 49% 21%
< 500 5% 1%
Platelets (cells/mm³)
50,000 - < 75,000 11% 4%
20,000 - < 50,000 5% < 1%
< 20,000 0 0
Hemoglobin (g/dL)
8.5 -9.9 11% 11%
< 8.5 2% < 1%

Pediatric Patients

Decreases in hemoglobin, neutrophils and platelets may require dose reduction or permanent discontinuation from treatment [see DOSAGE AND ADMINISTRATION]. 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

Laboratory Parameter PEGASYS 180 mcg/1.73 m x BSA + COPEGUS 15 mg/kg
(N=55)
PEGASYS 180 mcg/1.73 m x BSA + Placebo*
(N=59)
Neutrophils (cells/mm³)
1,000 - < 1,500 31% 39%
750 - < 1,000 27% 17%
500 - < 750 25% 15%
< 500 7% 5%
Platelets (cells/mm³)
75,000 - < 100,000 4% 2%
50,000 - < 75,000 0% 2%
< 50,000 0% 0%
Hemoglobin (g/dL)
8.5 - < 10 7% 3%
< 8.5 0% 0%
* Subjects in the PEGASYS plus placebo arm who did not achieve undetectable viral load at week 24 switched to combination treatment thereafter. Therefore, only the first 24 weeks are presented for the comparison of combination therapy with monotherapy.

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/mm 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)

Read the Copegus (ribavirin) Side Effects Center for a complete guide to possible side effects

DRUG INTERACTIONS

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].

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 and DOSAGE AND ADMINISTRATION].

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].

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].

Read the Copegus Drug Interactions Center for a complete guide to possible interactions

Last reviewed on RxList: 3/4/2013
This monograph has been modified to include the generic and brand name in many instances.

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