FDA Hepatitis Update - Labeling change for Pegasys and Copegus re: dosing patients with renal impairment

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FDA Hepatitis Update - Labeling change for Pegasys and Copegus re: dosing

patients with renal impairment

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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 DrugsFDA (DOT)

Klein

Office of Special Health Issues

Food and Drug Administration

Struble

Division of Antiviral Drug Products

Food and Drug Administration

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