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On 8/9/2011, FDA approved changes to the product labeling for Pegasys and Copegus. The following new recommendations for dosing of Pegasys and Copegus in patients with renal impairment have been added to product labeling based on a clinical study of 50 chronic hepatitis C subjects with moderate or severe renal impairment or end stage renal disease, and on pharmacokinetic modeling or simulation.
In the Copegus package insert:
2.4 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 3 [see Use in Specific Populations (8.7), Pharmacokinetics (12.3), and PEGASYS Package Insert]..
Table 3 Dosage Modification for Renal Impairment
| 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.
8.7 Renal Impairment
Renal function should be evaluated in all patients prior to initiation of COPEGUS by estimating the patient’s creatinine clearance.
A clinical trial evaluated treatment with COPEGUS and PEGASYS in 50 CHC subjects with moderate (creatinine clearance 30 – 50 mL/min) or severe (creatinine clearance less than 30 mL/min) renal impairment or end stage renal disease (ESRD) requiring chronic hemodialysis (HD). In 18 subjects with ESRD receiving chronic hemodialysis (HD), COPEGUS was administered at a dose of 200 mg daily with no apparent difference in the adverse event profile in comparison to subjects with normal renal function. Dose reductions and temporary interruptions of COPEGUS (due to COPEGUS-related adverse reactions, mainly anemia) were observed in up to one-third ESRD/HD subjects during treatment; and only one-third of these subjects received COPEGUS for 48 weeks. Ribavirin plasma exposures were approximately 20% lower in subjects with ESRD on HD compared to subjects with normal renal function receiving the standard 1000/1200 mg COPEGUS daily dose.
Subjects with moderate (n=17) or severe (n=14) renal impairment did not tolerate 600 mg or 400 mg daily doses of COPEGUS, respectively, due to COPEGUS-related adverse reactions, mainly anemia, and exhibited 20 to 30% higher ribavirin plasma exposures (despite frequent dose modifications) compared to subjects with normal renal function (creatinine clearance greater than 80 mL/min) receiving the standard dose of COPEGUS. Discontinuation rates were higher in subjects with severe renal impairment compared to that observed in subjects with moderate renal impairment or normal renal function. Pharmacokinetic modeling and simulation 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 exposure similar to patients with normal renal function receiving the approved regimen of COPEGUS. These doses have not been studied in patients [see Dosage and Administration (2.4), Use in Specific Populations (8.7), and Clinical Pharmacology (12.3)].
Based on the pharmacokinetic and safety results from this trial, patients with creatinine clearance less than or equal to 50 mL/min should receive a reduced dose of COPEGUS; and patients with creatinine clearance less than 30 mL/min should receive a reduced dose of PEGASYS. The clinical and hematologic status of patients with creatinine clearance less than or equal to 50 mL/min receiving COPEGUS should be carefully monitored. Patients with clinically significant laboratory abnormalities or adverse reactions which are persistently severe or worsening should have therapy withdrawn. [See Dosage and Administration (2.5), Clinical Pharmacology (12.3), and PEGASYS Package Insert].
From Section 12.3 Pharmacokinetics
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.
In the Pegasys package insert:
2.5 Renal Impairment
In patients with CrCL less than 30 mL/min, including patients with end-stage renal disease requiring hemodialysis, dose reduction to 135 mcg PEGASYS is recommended. Signs and symptoms of interferon toxicity should be closely monitored. If severe adverse reactions or laboratory abnormalities develop, the dose of PEGASYS may be reduced to 90 mcg until the adverse reactions abate. If intolerance persists after dose adjustment, PEGASYS/COPEGUS therapy should be discontinued.
Renal function should be evaluated in all patients on COPEGUS. The dose of COPEGUS should be reduced for patients with creatinine clearance less than or equal to 50 mL/min [see Clinical Pharmacology (12.3) and COPEGUS Package Insert].
Table 5 Dose Modification for Renal Impairment
| 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 |
| < 30 mL/min | 135 mcg | 200 mg daily |
| Hemodialysis | 135 mcg | 200 mg daily |
8.7 Renal impairment
Renal function should be evaluated in all patients prior to initiation of PEGASYS by estimating the patient’s creatinine clearance.
A clinical trial evaluated treatment with PEGASYS and COPEGUS in 50 CHC subjects with moderate (creatinine clearance 30 – 50 mL/min) or severe (creatinine clearance less than 30 mL/min) renal impairment or end stage renal disease (ESRD) requiring chronic hemodialysis (HD). In 18 subjects with ESRD receiving chronic HD, PEGASYS was administered at a dose of 135 mcg once weekly. Dose reductions and temporary interruptions of PEGASYS (due to PEGASYS-related adverse reactions, mainly anemia) were observed in up to 22% ESRD/HD subjects during treatment; and 17% of these subjects discontinued PEGASYS due to PEGASYS-related adverse reactions. Only one-third of ESRD/HD subjects received PEGASYS for 48 weeks. Subjects with severe (n=14) or moderate (n=17) renal impairment received PEGASYS 180 mcg once weekly. PEGASYS discontinuation rates were 36% and 0% in subjects with severe and moderate renal impairment, respectively, compared to 0% discontinuation rate in subjects with normal renal function.
Based on the pharmacokinetic and safety results from this trial, patients with creatinine clearance less than 30 mL/min should receive a reduced dose of PEGASYS, and patients with creatinine clearance less than or equal to 50 mL/min should receive a reduced dose of COPEGUS. In addition, patients with any degree of renal impairment should be carefully monitored for laboratory abnormalities (especially decreased hemoglobin) and adverse reactions, and should undergo careful monitoring of creatinine clearance. Patients with clinically significant laboratory abnormalities or adverse reactions which are persistently severe or worsening should have therapy withdrawn. [see Dosage and Administration (2.4, 2.5 ), Clinical Pharmacology (12.3) and COPEGUS Package Insert].
From Section 12.3 Pharmacokinetics
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). Subjects with moderate renal impairment receiving PEGASYS 180 mcg once weekly dose exhibited similar peginterferon alfa-2a plasma exposures compared to subjects with normal renal function (creatinine clearance greater than 80 mL/min) receiving the standard dose of PEGASYS. No PEGASYS dose adjustment is required for patients with mild or moderate renal impairment. [See Dosage and Administration (2.4); Use in Specific Populations (8.7)].
For subjects with severe renal impairment, peginterferon alfa-2a apparent clearance was 43% lower as compared to subjects with normal renal function. A reduced dose of 135 mcg once weekly PEGASYS is recommended in patients with severe renal impairment. This dose may result in 30% higher peginterferon alfa-2a exposure compared to that of the recommended dose for patients with normal renal function. Signs and symptoms of interferon toxicity should be closely monitored in patients with severe renal impairment and the dose reduced to 90 mcg once weekly as appropriate [see Dosage and Administration (2.4, 2.5), Use in Specific Populations (8.7)].
In 18 subjects with ESRD receiving chronic HD, PEGASYS was administered at a dose of 135 mcg once weekly. The apparent clearance of peginterferon alfa-2a was similar between subjects with ESRD and subjects with normal renal function. Despite a lower exposure to peginterferon alfa-2a with the 135 mcg dose, subjects with ESRD had a high rate of adverse events and discontinuations of PEGASYS in the trial. Therefore, a dose of 135 mcg once weekly should be used for patients with ESRD on HD. However, the potential for reduced efficacy and increased interferon toxicity in patients with ESRD receiving chronic HD should be closely monitored. The dose may be reduced to 90 mcg once weekly as appropriate [see Dosage and Administration (2.4 ); Use in Specific Populations (8.7)].
Pegasys and Copegus are products of Roche.
Complete revised labeling will be available soon at Drugs@FDA.
Richard Klein
Office of Special Health Issues
Food and Drug Administration
Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration
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