Traditional approval and label changes for Selzentry (maraviroc)
On November 25, 2008, FDA granted full, traditional approval for the use of maraviroc in treatment-experienced patients infected with CCR5-tropic HIV-1. The change from accelerated to traditional approval was based on 48 week data from two double-blind, randomized, placebo-controlled,multicenter studies in subjects infected with CCR5-tropic HIV-1(A4001027 and A4001028).
Subjects were required to have an HIV-1 RNA of greater than 5,000 copies/mL despite at least 6 months of prior therapy with at least one agent from three of the four antiretroviral drug classes [≥1 nucleoside reverse transcriptase inhibitors (NRTI), ≥1 non-nucleoside reverse transcriptase inhibitors (NNRTI), ≥2 protease inhibitors (PI), and/or enfuvirtide] or documented resistance or intolerance to at least one member of each class. All subjects received an optimized background therapy (OBT) consisting of 3 to 6 antiretroviral agents (excluding low-dose ritonavir) selected on the basis of the subject’s prior treatment history and baseline genotypic and phenotypic viral resistance measurements. In addition to the OBT, subjects were then randomized in a 2:2:1 ratio to maraviroc 300 mg once daily, maraviroc 300 mg twice daily, or placebo.
After 48 weeks of therapy, the proportion of subjects with HIV-1 RNA <400 copies/mL receiving maraviroc compared to placebo was 56% and 22%, respectively. The mean changes in plasma HIV-1 RNA from baseline to week 48 were –1.84 log10 copies/mL for subjects receiving maraviroc + OBT compared to –0.78 log10 copies/mL for subjects receiving OBT only. The mean increase in CD4+ counts was higher on maraviroc twice daily + OBT (124 cells/mm3) than on placebo + OBT (60 cells/mm3 ).
Some of the major labeling changes associated with the approval are shown below:
Under the “Indications and Usage” section of the label the first bullet now reads “Tropism testing is required for the appropriate use of SELZENTRY. “
Under the “Warnings and Precautions” section of the label the second sentence under subsection 5.2 Cardiovascular Events now reads “Eleven subjects (1.3%) who received SELZENTRY had cardiovascular events including myocardial ischemia and/or infarction during the Phase 3 studies [total exposure 609 patientyears, (300 on once daily + 309 on twice daily SELZENTRY)], while no subjects who received placebo had such events (total exposure 111 patient-years).
Under the “Use in Specific Population” section of the label, subsection 8.7 Hepatic Impairment, now reads “Maraviroc is principally metabolized by the liver; therefore, caution should be exercised when administering this drug to patients with hepatic impairment, because maraviroc concentrations may be increased. Maraviroc has not been studied in subjects with severe hepatic impairment. [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].
Under the “Clinical Pharmacology” section of the label, Hepatic Impairment section was added following the Excretion section and reads, “Maraviroc is
primarily metabolized and eliminated by the liver. A study compared the pharmacokinetics of a single 300 mg dose of SELZENTRY in patients with mild (Child-Pugh Class A, n=8), and moderate (Child-Pugh class B, n=8) hepatic impairment to pharmacokinetics in healthy subjects (n=8). The mean Cmax and AUC were 11% and 25% higher, respectively, for subjects with mild hepatic impairment, and 32% and 46% higher, respectively, for subjects with moderate hepatic impairment compared to subjects with normal hepatic function. These changes do not warrant a dose adjustment. Maraviroc concentrations are higher when SELZENTRY 150 mg is administered with a strong CYP3A inhibitor compared to following administration of 300 mg without a CYP3A inhibitor, so patients with moderate hepatic impairment who receive SELZENTRY 150 mg with a strong CYP3A inhibitor should be monitored closely for maraviroc associated adverse events. The pharmacokinetics of maraviroc have not been studied in subjects with severe hepatic impairment. [see Warnings and Precautions (5.1)].
Under the “Clinical Pharmacology” section of the label, subsection Effects of Maraviroc on the Pharmacokinetics of Concomitant Drugs, the following was added after the first paragraph: “Maraviroc does not induce CYP1A2 in vitro. In vitro results indicate that maraviroc could inhibit P-glycoprotein in the gut and may thus affect bioavailability of certain drugs.
The fourth sentence in the second paragraph of this section now reads, “Maraviroc had no effect on the debrisoquine metabolic ration (MR) at 300 mg twice daily or less in vivo and did not cause inhibition of CYP2D6 in vitro until concentrations > 100μM.”
Under the “Microbiology” section of the label, the Clinical Resistance subsection now reads, “Virologic failure on maraviroc can result from genotypic and phenotypic resistance to maraviroc or through outgrowth of undetected CXCR4-using virus present before maraviroc treatment (see Tropism below). Week 48 data from treatment-experienced subjects failing maraviroc-containing regimens with CCR5-tropic virus (n=58) have identified 22 viruses that had decreased susceptibility to maraviroc characterized in phenotypic drug assays by concentration response curves that did not reach 100% inhibition. Additionally, CCR5-tropic virus from 2 of these treatment failure subjects had ≥ 3-fold shifts in EC50 values for maraviroc at the time of failure. Fifteen of these viruses were sequenced in the gp 120 encoding region and multiple amino acid substitutions with unique patterns in the heterogeneous V3 loop region were detected. Changes at either amino acid position 308 or 323 (HXB2 numbering) were seen in the V3 lop in 7 of the subjects with decreased maraviroc susceptibility. Substitutions outside the V3 loop of gp 120 may also contribute to reduced susceptibility to maraviroc.”
Selzentry is distributed by Pfizer Labs.
Other minor changes made to the product label, which will be posted soon at Drugs@FDA
Office of Special Health Issues
Food and Drug Administration
Division of Antiviral Drug Products
Food and Drug Administration