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On May 27, 2010, FDA approved changes to the labeling for Selzentry (maraviroc) 150 mg and 300 mg tablets to expand the patient population to include dosing recommendations for patients with renal impairment, add a contraindication for patients with severe renal impairment or end-stage renal disease, add a warning regarding postural hypotension for renal impaired patients, and add new Pharmacokinetics information related to renal impairment, including the following highlights:
Section 2.2 Dose Recommendations for Patients with Renal Impairment was added to provide dosing recommendations for patients based on renal function and concomitant medications.
Section 4 Contraindications was updated to state SELZENTRY should not be used in patients with severe renal impairment or end-stage renal disease (ESRD) (CrCl < 30 mL/min) who are taking potent CYP3A inhibititors or inducers
Under 5.2 Cardiovascular Events
Postural Hypotension in Patients with Renal Impairment
Patients with impaired renal function may have cardiovascular co-morbidities and could be at increased risk of cardiovascular adverse events triggered by postural hypotension. An increased risk of postural hypotension may occur in patients with severe renal insufficiency or in those with end-stage renal disease (ESRD) due to increased maraviroc exposure in some patients. SELZENTRY should be used in patients with severe renal impairment or ESRD only if they are not receiving a
concomitant potent CYP3A inhibitor or inducer. However, the use of SELZENTRY in these patients should only be considered when no alternative treatment options are available. If patients with severe renal impairment or ESRD experience any symptoms of postural hypotension while taking 300 mg twice daily the dose should be reduced to 150 mg twice daily
Under 8.6 Renal Impairment
Recommended doses of SELZENTRY for patients with impaired renal function (CrCl ≤ 80 mL/min) are based on the results of a pharmacokinetic study conducted in healthy subjects with various degrees of renal impairment. The pharmacokinetics of maraviroc in subjects with mild and moderate renal impairment was similar to that in subjects with normal renal function [see Clinical Pharmacology (12.3)]. A limited number of subjects with mild and moderate renal impairment in the Phase 3 clinical trials (n= 131 and n= 12, respectively) received the same dose of SELZENTRY as that administered to subjects with normal renal function. In these subjects there was no apparent difference in the adverse event profile for maraviroc compared to subjects with normal renal function.
If patients with severe renal impairment or end-stage renal disease (ESRD) not receiving a concomitant potent CYP3A inhibitor or inducer experience any symptoms of postural hypotension while taking SELZENTRY 300 mg twice daily, the dose should be reduced to 150 mg twice daily. No studies have been performed in subjects with severe renal impairment or ESRD co-treated with potent CYP3A inhibitors or inducers. Hence, no dose of SELZENTRY can be recommended, and SELZENTRY is contraindicated for these patients. [see Dosage and Administration (2.2), Contraindications (4), Warnings and Precautions (5.2), and Clinical Pharmacology (12.3)].
Under 12.3 Pharmacokinetics
Renal Impairment
A study compared the pharmacokinetics of a single 300 mg dose of SELZENTRY in subjects with severe renal impairment (CLcr < 30 mL/min, n=6) and end-stage renal disease (ESRD) (n=6) to healthy volunteers (n=6). Geometric mean ratios for maraviroc Cmax and AUCinf were 2.4-fold and 3.2-fold higher respectively for subjects with severe renal impairment, and 1.7-fold and 2.0-fold higher respectively for subjects with ESRD as compared to subjects with normal renal function in this
study. Hemodialysis had a minimal effect on maraviroc clearance and exposure in subjects with ESRD. Exposures observed in subjects with severe renal impairment and ESRD were within the range observed in previous SELZENTRY 300 mg single-dose studies in healthy volunteers with normal renal function. However, maraviroc exposures in the subjects with normal renal function in this study were 50% lower than that observed in previous studies. Based on the results of this study, no dose
adjustment is recommended for patients with renal impairment receiving SELZENTRY without a potent CYP3A inhibitor or inducer. However, if patients with severe renal impairment or ESRD experience any symptoms of postural hypotension while taking SELZENTRY 300 mg twice daily, their dose should be reduced to 150 mg twice daily [see Dosage and Administration (2.2); Warnings and Precautions (5.2)].
In addition, the study compared the pharmacokinetics of multiple dose SELZENTRY in combination with saquinavir/ritonavir 1000/100 mg twice daily (a potent CYP3A inhibitor combination) for 7 days in subjects with mild renal impairment (CLcr >50 and £80 mL/min, n=6) and moderate renal impairment (CLcr ³30 and £50 mL/min, n=6) to healthy volunteers with normal renal function (n=6). Subjects received 150 mg of SELZENTRY at different dose frequencies (healthy volunteers – every 12 hours; mild renal impairment – every 24 hours; moderate renal impairment – every 48 hours). Compared to healthy volunteers (dosed every 12 hours), geometric mean ratios for maraviroc AUCtau, Cmax and Cmin were 50% higher, 20% higher and 43% lower, respectively for subjects with mild renal impairment (dosed every 24 hours). Geometric mean ratios for maraviroc AUCtau, Cmax and Cmin were 16% higher, 29% lower and 85% lower, respectively for subjects with moderate renal impairment (dosed every 48 hours) compared to healthy volunteers (dosed every 12 hours). Based on the data from this study, no adjustment in dose is recommended for patients with mild or moderate renal impairment [see Dosage and Administration (2.2)].
In addition, the Medication Guide for patients has been modified to include the following information:
Who should not take SELZENTRY?
People with severe kidney problems or who are on hemodialysis and are taking certain other medications should not take SELZENTRY. Talk to your healthcare provider before taking this medicine if you have kidney problems.
The complete revised labeling will be available soon on the FDA website at http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Label_ApprovalHistory
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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