Selzentry Information
Selzentry (Maraviroc)
Selzentry (Maraviroc) Indications And Usage
This indication is based on analyses of plasma HIV-1 RNA levels in two controlled studies of Selzentry (Maraviroc) in treatment-experienced subjects and one study in treatment-naïve subjects. Both studies in treatment-experienced subjects were conducted in clinically advanced, 3-class antiretroviral-experienced (NRTI, NNRTI, PI, or enfuvirtide) adults with evidence of HIV-1 replication despite ongoing antiretroviral therapy.
The following points should be considered when initiating therapy with SELZENTRY:
Selzentry (Maraviroc) Dosage And Administration
The recommended dose of Selzentry (Maraviroc) differs based on concomitant medications due to drug interactions (see ). Selzentry (Maraviroc) can be taken with or without food. Selzentry (Maraviroc) must be given in combination with other antiretroviral medications.
Table 1 gives the recommended dose adjustments [].
Table 2 provides dosing recommendations for patients based on renal function and concomitant medications.
Selzentry (Maraviroc) Contraindications
Selzentry (Maraviroc) should not be used in patients with severe renal impairment or end-stage renal disease (ESRD) (CrCl
Selzentry (Maraviroc) Warnings And Precautions
A case of possible SELZENTRY-induced hepatotoxicity with allergic features has been reported in a study of healthy volunteers. Discontinuation of Selzentry (Maraviroc) should be considered in any patient with signs or symptoms of hepatitis, or with increased liver transaminases combined with rash or other systemic symptoms.
The safety and efficacy of Selzentry (Maraviroc) have not been specifically studied in patients with significant underlying liver disorders. In studies of treatment-experienced HIV-infected subjects, approximately 6% of subjects were co-infected with hepatitis B and approximately 6% were co-infected with hepatitis C. Due to the small number of co-infected subjects studied, no conclusions can be drawn regarding whether they are at an increased risk for hepatic adverse events with Selzentry (Maraviroc) administration. However, caution should be used when administering Selzentry (Maraviroc) to patients with pre-existing liver dysfunction or who are co-infected with viral hepatitis B or C.
Use with caution in patients at increased risk for cardiovascular events. Eleven subjects (1.3%) who received Selzentry (Maraviroc) had cardiovascular events including myocardial ischemia and/or infarction during the Phase 3 studies in treatment-experienced studies [total exposure 609 patient-years (300 on once daily + 309 on twice daily SELZENTRY)], while no subjects who received placebo had such events (total exposure 111 patient-years). These subjects generally had cardiac disease or cardiac risk factors prior to Selzentry (Maraviroc) use, and the relative contribution of Selzentry (Maraviroc) to these events is not known.
In the Phase 2b/3 study in treatment-naïve subjects, 3 subjects (0.8%) who received Selzentry (Maraviroc) had events related to ischemic heart diseases and 5 subjects (1.4%) who received efavirenz had such events (total exposure 506 and 508 patient-years for Selzentry (Maraviroc) and efavirenz, respectively).
When Selzentry (Maraviroc) was administered to healthy volunteers at doses higher than the recommended dose, symptomatic postural hypotension was seen at a greater frequency than in placebo. However, when Selzentry (Maraviroc) was given at the recommended dose in HIV subjects in Phase 3 studies, postural hypotension was seen at a rate similar to placebo (approximately 0.5%). Caution should be used when administering Selzentry (Maraviroc) in patients with a history of postural hypotension or on concomitant medication known to lower blood pressure.
Selzentry (Maraviroc) antagonizes the CCR5 co-receptor located on some immune cells, and therefore could potentially increase the risk of developing infections. The overall incidence and severity of infection, as well as AIDS-defining category C infections, was comparable in the treatment groups during the Phase 3 treatment-experienced studies of SELZENTRY. While there was a higher rate of certain upper respiratory tract infections reported in the Selzentry (Maraviroc) arm compared to placebo (23% versus 13%), there was a lower rate of pneumonia (2% vs 5%) reported in subjects receiving SELZENTRY. A higher incidence of Herpes virus infections (11 per 100 patient-years) was also reported in the Selzentry (Maraviroc) arm when adjusted for exposure compared to placebo (8 per 100 patient-years).
In the Phase 2b/3 study in treatment-naïve subjects, the incidence of AIDS-defining Category C events when adjusted for exposure was 1.8 for Selzentry (Maraviroc) compared to 2.4 for efavirenz per 100 patient-years of exposure.
Patients should be monitored closely for evidence of infections while receiving SELZENTRY.
While no increase in malignancy has been observed with SELZENTRY, due to this drug's mechanism of action it could affect immune surveillance and lead to an increased risk of malignancy.
The exposure-adjusted rate for malignancies per 100 patient-years of exposure in treatment-experienced studies was 4.6 for Selzentry (Maraviroc) compared to 9.3 on placebo. In treatment-naïve subjects, the rates were 1.0 and 2.4 per 100 patient-years of exposure for Selzentry (Maraviroc) and efavirenz, respectively.
Long-term follow-up is needed to more fully assess this risk.
Selzentry (Maraviroc) Adverse Reactions
The following adverse reactions are discussed in other sections of the labeling:
The following events have been identified during post-approval use of SELZENTRY. Because these reactions are reported voluntarily from a population of unknown size, it is not possible to estimate their frequency or establish a causal relationship to Selzentry (Maraviroc) exposure.
Skin and Subcutaneous Tissue Disorders
Selzentry (Maraviroc) Use In Specific Populations
The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV infection.
Recommended doses of Selzentry (Maraviroc) 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 ]. 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 (Maraviroc) 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 (Maraviroc) 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 (Maraviroc) can be recommended, and Selzentry (Maraviroc) is contraindicated for these patients. [see ].
Selzentry (Maraviroc) Overdosage
The highest dose administered in clinical studies was 1200 mg. The dose-limiting adverse event was postural hypotension, which was observed at 600 mg. While the recommended dose for Selzentry (Maraviroc) in patients receiving a CYP3A inducer without a CYP3A inhibitor is 600 mg twice daily, this dose is appropriate due to enhanced metabolism.
Prolongation of the QT interval was seen in dogs and monkeys at plasma concentrations 6 and 12 times, respectively, those expected in humans at the intended exposure of 300 mg equivalents twice daily. However, no significant QT prolongation was seen in the studies in treatment-experienced subjects with HIV using the recommended doses of maraviroc or in a specific pharmacokinetic study to evaluate the potential of maraviroc to prolong the QT interval []
There is no specific antidote for overdose with maraviroc. Treatment of overdose should consist of general supportive measures including keeping the patient in a supine position, careful assessment of patient vital signs, blood pressure and ECG.
If indicated, elimination of unabsorbed active maraviroc should be achieved by emesis or gastric lavage. Administration of activated charcoal may also be used to aid in removal of unabsorbed drug. Since maraviroc is moderately protein-bound, dialysis may be beneficial in removal of this medicine.
Selzentry (Maraviroc) Description
Selzentry (Maraviroc) (maraviroc) is a selective, slowly reversible, small molecule antagonist of the interaction between human CCR5 and HIV-1 gp120. Blocking this interaction prevents CCR5-tropic HIV-1 entry into cells
Selzentry (Maraviroc) is available as film-coated tablets for oral administration containing either 150 or 300 mg of maraviroc and the following inactive ingredients: microcrystalline cellulose, dibasic calcium phosphate (anhydrous), sodium starch glycolate, and magnesium stearate. The film coat [Opadry® II Blue (85G20583)] contains FD&C blue #2 aluminum lake, soya lecithin, polyethylene glycol (macrogol 3350), polyvinyl alcohol, talc and titanium dioxide.
Maraviroc is chemically described as 4,4-difluoro--{(1)-3[-3-(3-isopropyl-5-methyl-4-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-phenylpropyl}cyclohexanecarboxamide.
The molecular formula is CHFNO and the structural formula is:
Maraviroc is a white to pale colored powder with a molecular weight of 513.67. It is highly soluble across the physiological pH range (pH 1.0 to 7.5).
Selzentry (Maraviroc) Clinical Studies
The clinical efficacy and safety of Selzentry (Maraviroc) is derived from analyses of data from three ongoing studies in adult subjects infected with CCR5-tropic HIV-1: A4001027 and A4001028, in antiretroviral treatment-experienced adult subjects and A4001026 in treatment-naïve subjects. These studies are supported by a 48-week study in antiretroviral treatment-experienced adult subjects infected with dual/mixed-tropic HIV-1, A4001029.
Studies A4001027 and A4001028 are ongoing, double-blind, randomized, placebo-controlled, multicenter studies in subjects infected with CCR5-tropic HIV-1. 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 to at least one member of each class. All subjects received an optimized background regimen 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 optimized background regimen, subjects were then randomized in a 2:2:1 ratio to maraviroc 300 mg once daily, maraviroc 300 mg twice daily, or placebo. Doses were adjusted based on background therapy as described in , Table 1.
In the pooled analysis for A4001027 and A4001028, the demographics and baseline characteristics of the treatment groups were comparable (Table 12). Of the 1043 subjects with a CCR5 tropism result at screening, 7.6% had a dual/mixed tropism result at the baseline visit 4 to 6 weeks later. This illustrates the background change from CCR5 to dual/mixed tropism result over time in this treatment-experienced population, prior to a change in antiretroviral regimen or administration of a CCR5 co-receptor antagonist.
The week 48 results for the pooled Studies A4001027 and A4001028 are shown in Table 13.
After 48 weeks of therapy, the proportion of subjects with HIV-1 RNA
Study A4001026 is an ongoing, randomized, double-blind, multicenter study in subjects infected with CCR5-tropic HIV-1 classified by the original Trofile tropism assay. Subjects were required to have plasma HIV-1 RNA ≥2000 copies/mL and could not have: 1) previously received any antiretroviral therapy for >14 days, 2) an active or recent opportunistic infection or a suspected primary HIV-1 infection, or 3) phenotypic or genotypic resistance to zidovudine, lamivudine, or efavirenz. Subjects were randomized in a 1:1:1 ratio to maraviroc 300 mg once daily, maraviroc 300 mg twice daily, or efavirenz 600 mg once daily, each in combination with zidovudine/lamivudine. The efficacy and safety of Selzentry (Maraviroc) are based on the comparison of Selzentry (Maraviroc) twice daily versus efavirenz. In a pre-planned interim analysis at 16 weeks, the maraviroc 300mg once per day treatment arm failed to meet the pre-specified criteria for demonstrating non-inferiority and was discontinued.
The demographic and baseline characteristics of the maraviroc and efavirenz treatment groups were comparable (Table 14). Subjects were stratified by screening HIV-1 RNA levels and by geographic region. The median CD4 cell counts and mean HIV-1 RNA at baseline were similar for both treatment groups.
The treatment outcomes at 96 weeks for study A4001026 are shown in Table 15. Treatment outcomes are based on reanalysis of the screening samples using a more sensitive tropism assay, Enhanced sensitivity Trofile HIV tropism assay, which became available after the week 48 analysis, approximately 15% of the subjects identified as CCR5-tropic in the original analysis had Dual/Mixed- or CXCR4-tropic virus. Screening with enhanced sensitivity version of the Trofile tropism assay reduced the number of maraviroc virologic failures with CXCR4- or Dual/Mixed-tropic virus at failure to 12 compared to 24 when screening with the original Trofile HIV tropism assay.
The median increase from baseline in CD4+ cell counts at week 96 was 184 cells/mmfor the Selzentry (Maraviroc) arm compared to 155 cells/mm3 for the efavirenz arm.
Selzentry (Maraviroc) How Supplied/storage And Handling
Selzentry (Maraviroc) film-coated tablets are available as follows:
150 and 300 mg tablets are blue, biconvex, oval, film-coated tablets debossed with "Pfizer" on one side and "MVC 150" or "MVC 300" on the other.
Bottle packs 150 mg tablets
Bottle packs 300 mg tablets
Selzentry (Maraviroc) Patient Counseling Information
Patients should be informed that if they develop signs or symptoms of hepatitis or allergic reaction following use of Selzentry (Maraviroc) (rash, skin or eyes look yellow, dark urine, vomiting, abdominal pain), they should stop Selzentry (Maraviroc) and seek medical evaluation immediately [].
Patients should be informed that Selzentry (Maraviroc) is not a cure for HIV infection and patients may still develop illnesses associated with HIV infection, including opportunistic infections. The use of Selzentry (Maraviroc) has not been shown to reduce the risk of transmission of HIV to others through sexual contact, sharing needles or blood contamination.
Patients should be advised that it is important to:
Patients should be advised that it is important to take all their anti-HIV medicines as prescribed and at the same time(s) each day.
Patients should be advised that when their Selzentry (Maraviroc) supply starts to run low, they should ask their doctor or pharmacist for a refill.
Patients should be advised that if they forget to take a dose, they should take the next dose of Selzentry (Maraviroc) as soon as possible and then take their next scheduled dose at its regular time. If it is less than 6 hours before their next scheduled dose, they should not take the missed dose and should instead wait and take the next dose at the regular time.
Caution should be used when administering Selzentry (Maraviroc) in patients with a history of postural hypotension or on concomitant medication known to lower blood pressure. Patients should be advised that if they experience dizziness while taking SELZENTRY, they should avoid driving or operating machinery.
Selzentry (Maraviroc)
Selzentry (Maraviroc)
Selzentry (Maraviroc)
Selzentry (Maraviroc)
