ribavirin
Dosage Form: tablet, film coated
FULL PRESCRIBING INFORMATION
Copegus (ribavirin) monotherapy is not effective for the treatment of chronic hepatitis C virus infection and should not be used alone for this indication.
The primary clinical toxicity of ribavirin is hemolytic anemia. The anemia associated with ribavirin therapy may result in worsening of cardiac disease and lead to fatal and nonfatal myocardial infarctions. Patients with a history of significant or unstable cardiac disease should not be treated with Copegus [see Warnings and Precautions (5.2), Adverse Reactions (6.1), and Dosage and Administration (2.3)].
Significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin. In addition, ribavirin has a multiple dose half-life of 12 days, and it may persist in non-plasma compartments for as long as 6 months. Therefore, ribavirin, including Copegus, is contraindicated in women who are pregnant and in the male partners of women who are pregnant. Extreme care must be taken to avoid pregnancy during therapy and for 6 months after completion of therapy in both female patients and in female partners of male patients who are taking ribavirin therapy. At least two reliable forms of effective contraception must be utilized during treatment and during the 6-month post treatment follow-up period [see Contraindications (4), Warnings and Precautions (5.1), and Use in Specific Populations (8.1)].
Indications and Usage for Copegus
Copegus in combination with PEGASYS (peginterferon alfa-2a) is indicated for the treatment of patients 5 years of age and older with chronic hepatitis C (CHC) virus infection who have compensated liver disease and have not been previously treated with interferon alpha.
The following points should be considered when initiating Copegus combination therapy with PEGASYS:
- This indication is based on clinical trials of combination therapy in patients with CHC and compensated liver disease, some of whom had histological evidence of cirrhosis (Child-Pugh class A), and in adult patients with clinically stable HIV disease and CD4 count greater than 100 cells/mm3.
- This indication is based on achieving undetectable HCV-RNA after treatment for 24 or 48 weeks, based on HCV genotype, and maintaining a Sustained Virologic Response (SVR) 24 weeks after the last dose.
- Safety and efficacy data are not available for treatment longer than 48 weeks.
- The safety and efficacy of Copegus and PEGASYS therapy have not been established in liver or other organ transplant recipients, patients with decompensated liver disease, or previous non-responders to interferon therapy.
- The safety and efficacy of Copegus therapy for the treatment of adenovirus, RSV, parainfluenza or influenza infections have not been established. Copegus should not be used for these indications. Ribavirin for inhalation has a separate package insert, which should be consulted if ribavirin inhalation therapy is being considered.
Copegus Dosage and Administration
Copegus should be taken with food. Copegus should be given in combination with PEGASYS; it is important to note that Copegus should never be given as monotherapy. See PEGASYS Package Insert for all instructions regarding PEGASYS dosing and administration.
Chronic Hepatitis C Monoinfection
Adult Patients
The recommended dose of Copegus tablets is provided in Table 1. The recommended duration of treatment for patients previously untreated with ribavirin and interferon is 24 to 48 weeks.
The daily dose of Copegus is 800 mg to 1200 mg administered orally in two divided doses. The dose should be individualized to the patient depending on baseline disease characteristics (e.g., genotype), response to therapy, and tolerability of the regimen (see Table 1).
| Hepatitis C Virus (HCV) Genotype | PEGASYS Dose* (once weekly) | Copegus Dose (daily) | Duration |
|---|---|---|---|
| Genotypes 2 and 3 showed no increased response to treatment beyond 24 weeks (see Table 10). | |||
| Data on genotypes 5 and 6 are insufficient for dosing recommendations. | |||
| |||
| Genotypes 1, 4 | 180 mcg | <75 kg = 1000 mg ≥75 kg = 1200 mg | 48 weeks 48 weeks |
| Genotypes 2, 3 | 180 mcg | 800 mg | 24 weeks |
Pediatric Patients
PEGASYS is administered as 180 mcg/1.73m2 × BSA once weekly subcutaneously, to a maximum dose of 180 mcg, and should be given in combination with ribavirin. The recommended treatment duration for patients with genotype 2 or 3 is 24 weeks and for other genotypes is 48 weeks.
Copegus should be given in combination with PEGASYS. Copegus is available only as a 200 mg tablet and therefore the healthcare provider should determine if this sized tablet can be swallowed by the pediatric patient. The recommended doses for Copegus are provided in Table 2. Patients who initiate treatment prior to their 18th birthday should maintain pediatric dosing through the completion of therapy.
| Body Weight in kilograms (kg) | Copegus Daily Dose* | Copegus Number of Tablets |
|---|---|---|
| ||
| 23 – 33 | 400 mg/day | 1 × 200 mg tablet A.M. 1 × 200 mg tablet P.M. |
| 34 – 46 | 600 mg/day | 1 × 200 mg tablet A.M. 2 × 200 mg tablets P.M. |
| 47 – 59 | 800 mg/day | 2 × 200 mg tablets A.M. 2 × 200 mg tablets P.M. |
| 60 – 74 | 1000 mg/day | 2 × 200 mg tablets A.M. 3 × 200 mg tablets P.M. |
| ≥75 | 1200 mg/day | 3 × 200 mg tablets A.M. 3 × 200 mg tablets P.M. |
Chronic Hepatitis C with HIV Coinfection
Adult Patients
The recommended dose for treatment of chronic hepatitis C in patients coinfected with HIV is PEGASYS 180 mcg subcutaneous once weekly and Copegus 800 mg by mouth daily for a total duration of 48 weeks, regardless of HCV genotype.
Dose Modifications
Adult and Pediatric Patients
If severe adverse reactions or laboratory abnormalities develop during combination Copegus/PEGASYS therapy, the dose should be modified or discontinued, if appropriate, until the adverse reactions abate or decrease in severity. If intolerance persists after dose adjustment, Copegus/PEGASYS therapy should be discontinued. Table 3 provides guidelines for dose modifications and discontinuation based on the patient's hemoglobin concentration and cardiac status.
Copegus should be administered with caution to patients with pre-existing cardiac disease. Patients should be assessed before commencement of therapy and should be appropriately monitored during therapy. If there is any deterioration of cardiovascular status, therapy should be stopped [see Warnings and Precautions (5.2)].
| Body weight in kilograms (kg) | Laboratory Values | |
| Hemoglobin <10 g/dL in patients with no cardiac disease, or Decrease in hemoglobin of ≥2 g/dL during any 4 week period in patients with history of stable cardiac disease | Hemoglobin <8.5 g/dL in patients with no cardiac disease, or Hemoglobin <12 g/dL despite 4 weeks at reduced dose in patients with history of stable cardiac disease | |
| Adult Patients older than 18 years of age | ||
| Any weight | 1 × 200 mg tablet A.M. 2 × 200 mg tablets P.M. | Discontinue Copegus |
| Pediatric Patients 5 to 18 years of age | ||
| 23 – 33 kg | 1 × 200 mg tablet A.M. | Discontinue Copegus |
| 34 – 46 kg | 1 × 200 mg tablet A.M. 1 × 200 mg tablet P.M. | |
| 47 – 59 kg | 1 × 200 mg tablet A.M. 1 × 200 mg tablet P.M. | |
| 60 – 74 kg | 1 × 200 mg tablet A.M. 2 × 200 mg tablets P.M. | |
| ≥75 kg | 1 × 200 mg tablet A.M. 2 × 200 mg tablets P.M. | |
The guidelines for Copegus dose modifications outlined in this table also apply to laboratory abnormalities or adverse reactions other than decreases in hemoglobin values.
Adult Patients
Once Copegus has been withheld due to either a laboratory abnormality or clinical adverse reaction, an attempt may be made to restart Copegus at 600 mg daily and further increase the dose to 800 mg daily. However, it is not recommended that Copegus be increased to the original assigned dose (1000 mg to 1200 mg).
Pediatric Patients
Upon resolution of a laboratory abnormality or clinical adverse reaction, an increase in Copegus dose to the original dose may be attempted depending upon the physician's judgment. If Copegus has been withheld due to a laboratory abnormality or clinical adverse reaction, an attempt may be made to restart Copegus at one-half the full dose.
Renal Impairment
The total daily dose of Copegus should be reduced for patients with creatinine clearance less than or equal to 50 mL/min; and the weekly dose of PEGASYS should be reduced for creatinine clearance less than 30 mL/min as follows in Table 4 [see Use in Specific Populations (8.7), Pharmacokinetics (12.3), and PEGASYS Package Insert].
| Creatinine Clearance | PEGASYS Dose (once weekly) | Copegus Dose (daily) |
|---|---|---|
| 30 to 50 mL/min | 180 mcg | Alternating doses, 200 mg and 400 mg every other day |
| Less than 30 mL/min | 135 mcg | 200 mg daily |
| Hemodialysis | 135 mcg | 200 mg daily |
The dose of Copegus should not be further modified in patients with renal impairment. If severe adverse reactions or laboratory abnormalities develop, Copegus should be discontinued, if appropriate, until the adverse reactions abate or decrease in severity. If intolerance persists after restarting Copegus, Copegus/PEGASYS therapy should be discontinued.
No data are available for pediatric subjects with renal impairment.
Discontinuation of Dosing
Discontinuation of PEGASYS/Copegus therapy should be considered if the patient has failed to demonstrate at least a 2 log10 reduction from baseline in HCV RNA by 12 weeks of therapy, or undetectable HCV RNA levels after 24 weeks of therapy.
PEGASYS/Copegus therapy should be discontinued in patients who develop hepatic decompensation during treatment [see Warnings and Precautions (5.3)].
Dosage Forms and Strengths
Copegus (ribavirin) is available as a light pink to pink colored, flat, oval-shaped, film-coated tablet for oral administration. Each tablet contains 200 mg of ribavirin.
Contraindications
Copegus (ribavirin) is contraindicated in:
- Women who are pregnant. Copegus may cause fetal harm when administered to a pregnant woman. Copegus is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus [see Warnings and Precautions (5.1), Use in Specific Populations (8.1), and Patient Counseling Information (17)].
- Men whose female partners are pregnant.
- Patients with hemoglobinopathies (e.g., thalassemia major or sickle-cell anemia).
- In combination with didanosine. Reports of fatal hepatic failure, as well as peripheral neuropathy, pancreatitis, and symptomatic hyperlactatemia/lactic acidosis have been reported in clinical trials [see Drug Interactions (7.1)].
Copegus and PEGASYS combination therapy is contraindicated in patients with:
- Autoimmune hepatitis.
- Hepatic decompensation (Child-Pugh score greater than 6; class B and C) in cirrhotic CHC monoinfected patients before treatment [see Warnings and Precautions (5.3)].
- Hepatic decompensation (Child-Pugh score greater than or equal to 6) in cirrhotic CHC patients coinfected with HIV before treatment [see Warnings and Precautions (5.3)].
Warnings and Precautions
Significant adverse reactions associated with Copegus/PEGASYS 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 PEGASYS Package Insert should be reviewed in its entirety for additional safety information prior to initiation of combination treatment.
Pregnancy
Copegus 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.
Copegus 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 Copegus therapy and for 6 months after therapy has stopped [see Boxed Warning, Contraindications (4), Use in Specific Populations (8.1), and Patient Counseling Information (17)].
Anemia
The primary toxicity of ribavirin is hemolytic anemia, which was observed in approximately 13% of all Copegus/PEGASYS-treated subjects in clinical trials. Anemia associated with Copegus 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 (2.3)].
Fatal and nonfatal myocardial infarctions have been reported in patients with anemia caused by Copegus. 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 (2.3)]. Because cardiac disease may be worsened by drug-induced anemia, patients with a history of significant or unstable cardiac disease should not use Copegus [see Boxed Warning and Dosage and Administration (2.3)].
Hepatic Failure
Chronic hepatitis C (CHC) patients with cirrhosis may be at risk of hepatic decompensation and death when treated with alpha interferons, including PEGASYS. 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 (14.3)], 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 PEGASYS/Copegus should be discontinued immediately in patients with hepatic decompensation [see Contraindications (4)].
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 PEGASYS and Copegus 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 PEGASYS with and without ribavirin. Patients developing signs or symptoms of severe skin reactions must discontinue therapy [see Adverse Reactions (6.2)].
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 Copegus/PEGASYS 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. PEGASYS, Copegus, and azathioprine should be discontinued for pancytopenia, and pegylated interferon/ribavirin should not be re-introduced with concomitant azathioprine [see Drug Interactions (7.3)].
Pancreatitis
Copegus and PEGASYS 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
Pediatric subjects treated with PEGASYS plus Copegus combination therapy showed a delay in weight and height increases after 48 weeks of therapy compared with baseline. Both weight 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 growth curve percentiles for weight and height (mean weight for age percentile was 64% at baseline and 60% at 2 years post-treatment; mean height percentile was 54% at baseline and 56% at 2 years post-treatment). At the end of treatment, 43% of subjects experienced a weight percentile decrease of 15 percentiles or more, and 25% experienced a height percentile decrease of 15 percentiles or more on the normative growth curves. At 2 years post-treatment, 16% of subjects remained 15 percentiles or more below their baseline weight curve and 11% remained 15 percentiles or more below their baseline height curve.
Laboratory Tests
Before beginning PEGASYS/Copegus 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 PEGASYS/Copegus.
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 Copegus and PEGASYS 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 cells/mm3 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
Adverse Reactions
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% 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.
| CHC Combination Therapy Study NV15801 | ||
|---|---|---|
| Body System | PEGASYS 180 mcg + 1000 mg or 1200 mg Copegus 48 weeks | Intron A + 1000 mg or 1200 mg Rebetol® 48 weeks |
| N=451 | 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 |
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 (5.8)].
| Study NV17424 | ||
|---|---|---|
| System Organ Class | PEGASYS 180 mcg/1.73 m2 × BSA + Copegus 15 mg/kg (N=55) | PEGASYS 180 mcg/1.73 m2 × 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 |
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 (2.3)].
| Laboratory Parameter | PEGASYS + Ribavirin 1000/1200 mg 48 wks | Intron A + Ribavirin 1000/1200 mg 48 wks |
|---|---|---|
| (N=887) | (N=443) | |
| Neutrophils (cells/mm3) |
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