NAME OF THE MEDICINE

CELSENTRI 150 mg and 300 mg film-coated tablets. CELSENTRI film-coated tablets contain maraviroc which is a member of a therapeutic class called CCR5 antagonists. Maraviroc is chemically described as 4,4- difluoro-N-{(1S)-3-[exo-3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-8- azabicyclo[3.2.1]oct-8-yl]-1-phenylpropyl}cyclohexanecarboxamide. The molecular formula is C29H41F2N5O and the structural formula is:

F F

O

NH

N

H3C

N N

N

CAS no. : 376348-65-1

DESCRIPTION

CH3 Maraviroc is a white to pale coloured powder with a molecular weight of 513.67. It is highly soluble across the physiological pH range (pH 1.0 to 7.5). CELSENTRI is supplied for oral administration in two strengths: 150 and 300 mg blue, biconvex, oval film-coated tablets debossed with "MVC" followed by the tablet strength on one tablet side. Each film-coated tablet contains either 150 or 300 mg of maraviroc and the following inactive ingredients: microcrystalline cellulose, calcium hydrogen phosphate (anhydrous), sodium starch glycollate, magnesium stearate. The film-coat [Opadry II Blue (85G20583)] contains indigo carmine CI73015, soya lecithin, macrogol 3350, polyvinyl alcohol, talc and titanium dioxide.

PHARMACOLOGY

Pharmacological actions

Pharmacotherapeutic group: Antivirals for systemic use, Other Antivirals ATC code: J05AX09

Mechanism of action:

Maraviroc is a member of a therapeutic class called CCR5 antagonists. Maraviroc selectively binds to the human chemokine receptor CCR5, preventing CCR5-tropic HIV-1 from entering cells.

Antiviral activity in cell culture:

Maraviroc inhibits the entry and replication of CCR5-tropic laboratory strains and clinical isolates of HIV-1 in models of acute T-cell infection. The in vitro IC50 (50% inhibitory concentration) for maraviroc against the replication of HIV-1 group M isolates (subtypes A to J and circulating recombinant form AE) and group O isolates ranged from 0.1 to 4.5 nM (0.05 to 2.3 nanogram/mL). HIV-1 clinical isolates resistant to nucleoside analogue reverse transcriptase inhibitors (NRTI), non- nucleoside analogue reverse transcriptase inhibitors (NNRTI), protease inhibitors (PI) and enfuvirtide were all susceptible to maraviroc in cell culture. When used with other antiretroviral agents in vitro, the combination of maraviroc produced additive/synergistic antiviral effects with protease inhibitors (amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir and saquinavir) and was generally additive with the NRTIs (abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine and zidovudine) and the NNRTIs (delavirdine, efavirenz and nevirapine). Maraviroc was additive/synergistic with the HIV fusion inhibitor enfuvirtide. Protein binding studies have shown that the antiviral activity of maraviroc decreases on average 2-fold in conditions where plasma proteins are present. Maraviroc has no antiviral activity in cell culture against viruses that can use CXCR4 as their entry co-receptor (dual-tropic or CXCR4-tropic viruses, collectively termed 'CXCR4-using' virus below). The antiviral activity of maraviroc against HIV-2 has not been evaluated.

Resistance:

Viral escape from maraviroc can occur via two routes: the selection of virus which can use CXCR4 as its entry co-receptor (CXCR4-using virus) or the selection of virus that continues to use exclusively CCR5 (CCR5-tropic virus).

Resistance in cell culture:

HIV-1 variants with reduced susceptibility to maraviroc have been selected in cell culture, following serial passage of two CCR5-tropic clinical viral isolates. The maraviroc-resistant viruses remained CCR5-tropic and there was no conversion from a CCR5-tropic virus to a CXCR4-using virus. Phenotypic resistance: concentration response curves for the maraviroc-resistant viruses were characterised by curves that did not reach 100% inhibition in assays using serial dilutions of maraviroc, consistent with the resistant viruses being able to use CCR5 as a co-receptor for cell entry even when maraviroc is bound. Traditional EC50 fold-change was not a useful parameter to measure phenotypic resistance, as those values were sometimes unchanged despite significantly reduced sensitivity.

Genotypic resistance

: mutations were found to accumulate in the gp120 envelope glycoprotein (the viral protein that binds to the CCR5 co-receptor). The position of these mutations was not consistent between different isolates. Hence, the relevance of these mutations to maraviroc susceptibility in other viruses is not known.

Tropism switching from CCR5- to CXCR4-tropic variants occurred spontaneously in vitro in maraviroc-treated and control cultures, and represents a theoretical mechanism for maraviroc resistance in vivo.

Cross-resistance: HIV-1 clinical isolates resistant to nucleoside analogue reverse transcriptase inhibitors (NRTI), non-nucleoside analogue reverse transcriptase inhibitors (NNRTI), protease inhibitors (PI) and enfuvirtide were all susceptible to maraviroc in cell culture. Maraviroc-resistant viruses that emerged in cell culture remained sensitive to the fusion inhibitor enfuvirtide and the protease inhibitor saquinavir.

Resistance in vivo:

The two mechanisms of resistance observed in vivo include the unmasking of CXCR4-using virus and the selection of virus that continues to use CCR5 but with reduced susceptibility to maraviroc, as indicated by a maximal plateau of inhibition of < 95%. Both routes to resistance have been observed in clinical studies of both treatment naive and treatment experienced patients. CXCR4-using virus presence at virological failure appears to originate from a pre- existing viral population. Resistance of R5-virus through the increase of EC50 does not appear to be an important mechanism of failure. Sequencing of the V3 loop of virus with reduced susceptibility to maraviroc has identified changes in the amino acid sequence for the majority; however, no signature mutation has been identified. Mutations within Gp160 but outside of the V3 loop, contributing to the maraviroc resistance phenotype have been reported but appear uncommon.

Treatment-experienced patients:

In the pivotal studies (MOTIVATE 1 and MOTIVATE 2), 7.6% of patients had a change in tropism result from CCR5-tropic to CXCR4-tropic or dual/mixed-tropic between screening and baseline (a period of four-six weeks).

Failure with CXCR4-using virus:

CXCR4-using virus was detected in approximately 55% of patients who failed treatment on maraviroc, as compared to 6% of patients who experienced treatment failure in the Optimised Background Therapy (OBT) alone arm. To investigate the likely origin of the on-treatment CXCR4-using virus, a detailed clonal analysis was conducted on virus from 20 representative patients (16 patients from the maraviroc arms and 4 patients from the OBT alone arm) in whom CXCR4-using virus was detected. This analysis indicated that CXCR4-using virus emerged from a pre-existing CXCR4-using reservoir not detected at baseline, rather than from mutation of CCR5-tropic virus present at baseline. An analysis of tropism following failure of maraviroc therapy with CXCR4-using virus in patients with

CCR5 virus at baseline, demonstrated that the virus population reverted back to CCR5 tropism in 33 of 36 patients with more than 35 days of follow up. At time of failure with CXCR4-using virus, the resistance pattern to other antiretrovirals appears similar to that of the CCR5-tropic population at baseline, based on available data. Hence, in the selection of a treatment regimen, it should be assumed that viruses forming part of the previously undetected CXCR4-using population (i.e. minor viral population) harbours the same resistance pattern as the CCR5- tropic population. Failure with CCR5-tropic virus: Phenotypic resistance: in patients with CCR5-tropic virus at time of treatment failure with maraviroc, 22 out of 58 patients had virus with reduced sensitivity to maraviroc. Additionally, CCR5-tropic virus from 2 of these treatment failure patients had 3-fold shifts in EC50 values for maraviroc at the time of failure, but the significance of this is unclear. In the remaining patients, there was no evidence of virus with reduced sensitivity as identified by exploratory virology analyses on a representative group. The latter group had markers of low exposure, in some cases associated with poor compliance. A clinically-validated cut-off value for reduced virological response has not yet been established. Therefore, continued use of maraviroc after treatment failure cannot be generally recommended regardless of the viral tropism seen.

Treatment naive patients

In the pivotal study of treatment naive patients (MERIT week 96), 13/343 (3.8%) had a change in tropism result from CCR5-tropic to CXCR4-tropic or dual/mixed-tropic in the four-six week interval between screening and baseline during which time no treatment was administered.

Failure with CXCR4-using virus:

CXCR4-using virus was detected at failure in approximately 24/86 (28%) of the patients with CCR5-tropic virus at baseline and who failed treatment on maraviroc, as compared to none of patients who experienced treatment failure in the efavirenz arm.

Based on a re-analysis using an enhanced sensitivity tropism assay, when patients with CXCR4-using virus at screening were censored from the analysis, of the patients with CCR5-tropic virus at baseline and who failed treatment on maraviroc, CXCR4- using virus was detected in 25/118 (21%) as compared to none in the efavirenz arm. A detailed clonal analysis was conducted for two previously antiretroviral treatment- naive patients enrolled in a Phase 2a monotherapy study in which CXCR4-using virus was observed after 10 days treatment with maraviroc. Consistent with the detailed clonal analysis conducted in treatment-experienced patients, the CXCR4-using variant was found to be pre-existing prior to starting therapy. All but one (11/12; 92%) of the maraviroc failures failing with CXCR4 or dual/mixed-tropic virus also had genotypic and phenotypic resistance to the background drug lamivudine at failure and 33% (4 /12) developed zidovudine- associated resistance substitutions.

Failure with CCR5-tropic virus:

Phenotypic resistance: In patients with CCR5-tropic virus at time of treatment failure with maraviroc, 6 out of 38 patients had virus with

reduced sensitivity to maraviroc. In the remaining 32 patients, there was no evidence of virus with reduced sensitivity as identified by exploratory virology analyses on a representative group. One additional subject had a >=3-fold shift in EC50 value for maraviroc at the time of failure.

Pharmacokinetics Absorption

The absorption of maraviroc is variable with multiple peaks. Median peak maraviroc plasma concentrations are attained at two hours (range 0.5-4 hours) following single oral doses of 300 mg commercial tablet administered to healthy volunteers. The pharmacokinetics of oral maraviroc are not dose proportional over the dose range of 1-1200 mg. The absolute bioavailability of a 100 mg dose is 23% and is predicted to be 33% at 300 mg. Maraviroc is a substrate for the efflux transporter P-glycoprotein.

Effect of food on oral absorption

Co-administration of a 300 mg tablet with a high fat breakfast reduced maraviroc Cmax and AUC by 33% in healthy volunteers. There were no food restrictions in the studies that demonstrated the efficacy and safety of maraviroc (see CLINICAL TRIALS). Therefore, maraviroc can be taken with or without food at the recommended doses (see DOSAGE AND ADMINISTRATION).

Distribution

Maraviroc is bound (approximately 76%) to human plasma proteins, and shows moderate affinity for albumin and alpha-1 acid glycoprotein. The volume of distribution of maraviroc is approximately 194L. Preclinical data indicate low cerebrospinal fluid exposure with concentrations of maraviroc in the CSF of rats approximately 10% of free plasma concentrations.

Metabolism

Studies in humans and in vitro studies using human liver microsomes and expressed enzymes have demonstrated that maraviroc is principally metabolised by the cytochrome P450 system, with CYP3A being the major metabolising enzyme. In vitro studies indicate that polymorphic enzymes CYP2C9, CYP2D6 and CYP2C19 do not contribute significantly to the metabolism of maraviroc. Maraviroc is the major circulating component (accounting for approximately 42% of drug related radioactivity) following a single oral dose of 300 mg[14C]-maraviroc. The most significant circulating metabolite in humans is a secondary amine (approximately 22% of plasma radioactivity) formed by N-dealkylation. This polar metabolite has no significant pharmacological activity. Other metabolites are products of mono-oxidation and are only minor components of plasma drug related radioactivity.

Excretion

A mass balance/excretion study was conducted using a single 300 mg dose of 14C- labeled maraviroc. Approximately 20% of the radiolabel was recovered in the urine and 76% was recovered in the faeces over 168 hours. Maraviroc was the major component present in urine (mean of 8% dose) and faeces (mean of 25% dose). The remainder was excreted as metabolites. After intravenous administration (30 mg), the half-life of maraviroc was 13.2 hours, 22% of the dose was excreted unchanged in the urine and the values of total clearance and renal clearance were 44.0 L/hour and 10.2 L/hour respectively.

Children

The pharmacokinetics of maraviroc in children below 16 years of age has not been established (see DOSAGE AND ADMINISTRATION and PRECAUTIONS).

Elderly

The pharmacokinetics of maraviroc in patients above 65 years of age has not been established (see DOSAGE AND ADMINISTRATION and PRECAUTIONS).

Renal impairment

A study compared the pharmacokinetics of a single 300 mg dose of CELSENTRI in patients with severe renal impairment (creatinine clearance < 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 patients with severe renal impairment, and 1.7-fold and 2.0-fold higher respectively for patients with ESRD as compared to patients with normal renal function in this study. Haemodialysis had a minimal effect on maraviroc clearance and exposure in patients with ESRD. Exposures observed in patients with severe renal impairment and ESRD were within the range observed in previous CELSENTRI 300 mg single-dose studies in healthy volunteers with normal renal function. However, maraviroc exposures in the patients 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 CELSENTRI without a potent CYP3A inhibitor or inducer. However, if patients with severe renal impairment or ESRD experience any symptoms of postural hypotension while taking CELSENTRI 300 mg twice daily, their dose should be reduced to 150 mg twice daily [see PRECAUTIONS, Renal Impairment and DOSAGE AND ADMINISTRATION]. In addition, the study compared the pharmacokinetics of multiple dose CELSENTRI in combination with saquinavir/ritonavir 1000/100 mg twice daily (a potent CYP3A inhibitor combination) for seven days in patients with mild renal impairment (creatinine clearance >50 and <=80 mL/min, n=6) and moderate renal impairment (creatinine clearance >=30 and <=50 mL/min, n=6) to healthy volunteers with normal renal function (n=6). Patients received 150 mg of CELSENTRI 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 patients 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 patients 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).

Hepatic impairment

CELSENTRI is primarily metabolized and eliminated by the liver. A study compared the pharmacokinetics of a single 300 mg dose of maraviroc in patients with mild (Child-Pugh Class A, n=8), and moderate (Child-Pugh Class B, n=8) hepatic impairment compared to healthy individuals (n=8). Geometric mean ratios for Cmax and AUClast were 11% and 25% higher respectively for patients with mild hepatic impairment, and 32% and 46% higher respectively for patients with moderate hepatic impairment compared to individuals with normal hepatic function. The effects of moderate hepatic impairment may be underestimated due to limited data in patients with decreased metabolic capacity and higher renal clearance in these patients. The results should therefore be interpreted with caution. The pharmacokinetics of maraviroc have not been studied in patients with severe hepatic impairment (see DOSAGE AND ADMINISTRATION and PRECAUTIONS).

Race

No dosage adjustment is necessary on the basis of race.

Gender

No dosage adjustment is necessary on the basis of gender.

CLINICAL TRIALS

The clinical efficacy and safety of CELSENTRI is derived from analyses of data from three ongoing studies in adult patients infected with CCR5-tropic HIV-1: MOTIVATE-1 A4001027 and MOTIVATE-2 A4001028, in antiretroviral treatment- experienced adult patients and MERIT A4001026 in treatment-naive patients. These studies are supported by a 48-week study in antiretroviral treatment-experienced adult patients infected with dual/mixed tropic HIV-1, A4001029.

Studies in CCR5-tropic Treatment-Experienced Patients:

The clinical efficacy of CELSENTRI (in combination with other antiretroviral medicinal products) on plasma HIV RNA levels and CD4+ cell counts have been investigated in two pivotal ongoing, randomised, double blind, multicentre studies (MOTIVATE-1 and MOTIVATE-2, n=1076) in patients infected with CCR5 tropic HIV-1. The primary objective of these studies was to assess whether CELSENTRI added to OBT provided an additional reduction in plasma HIV-1 RNA level compared with OBT alone, based on the mean changes from baseline in plasma HIV- 1 RNA level at Week 48. Efficacy analyses were performed on the full analysis set and per protocol populations. Patients were analysed as both As Treated and As

Randomised

to assess the effect on the results of subjects receiving treatments other than those to which they were randomised.

Patients who were eligible for these studies had prior exposure to at least three antiretroviral medicinal product 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. Patients were randomised in a 2:2:1 ratio to maraviroc 300 mg (dose equivalent) once daily, maraviroc 300 mg twice daily or placebo in combination with an OBT consisting of three to six antiretroviral medicinal products (excluding low- dose ritonavir). The OBT was selected on the basis of the patient's prior treatment history and baseline genotypic and phenotypic viral resistance measurements. Table 1 illustrates the demographic and baseline characteristics of patients from the pooled analysis from the MOTIVATE-1 and MOTIVATE-2 studies.

Table 1: Demographic and baseline characteristics of patients in studies MOTIVATE-1 and MOTIVATE -2 (week 48 pooled analysis)

a

OSS - Sum of active drugs in OBT based on combined information from genotypic and phenotypic testing.

b

Resistance mutations based on International Aids Society guidelines

Limited numbers of patients from races other than Caucasian were included in the pivotal clinical studies, therefore very limited data are available in these patient populations. After 24 weeks of therapy, the mean change in plasma HIV-1 RNA from baseline to week 24 was -1.96 log10 copies/mL for patients receiving CELSENTRI 300 mg twice daily + OBT compared to -0.99 log10 copies/mL for patients receiving OBT alone. The mean increase in CD4+ counts was higher on CELSENTRI 300 mg twice daily + OBT (106.34 cells/mm3) than on OBT alone (57.37 cells/mm3). The proportion of subjects with HIV-1 RNA <400/<50 copies/mL was 60.8%/45.3% for patients receiving CELSENTRI 300 mg twice daily + OBT, compared to 27.8%/23% for patients receiving OBT alone.

Table 2: Outcomes of randomised treatment at Week 48 (pooled studies MOTIVATE-1 and MOTIVATE-2)

p-values<0.0001

For all efficacy endpoints the confidence intervals were 95%, except for HIV-1 RNA Change from baseline which was 97.5%

Studies in Non-CCR5-tropic Treatment-Experienced Patients:

Study A4001029 was an exploratory, randomised, double blind, multicentre trial to determine the safety and efficacy of CELSENTRI in patients infected with dual/mixed or CXCR4 tropic HIV-1. The inclusion/exclusion criteria were similar to those for MOTIVATE-1 and MOTIVATE-2 above and the patients were randomised in a 1:1:1 ratio to CELSENTRI once daily, CELSENTRI twice daily or OBT alone. The mean changes in viral load and CD4+ counts are shown in Table 3.

Table 3: Outcomes of Randomised Treatment at Week 24 in Dual/Mixed-tropic Patients (Study A4001029)

Study in Treatment-Naive Patients:

Study A4001026 is a randomised, double-blind, multicenter study in patients infected with CCR5-tropic HIV-1 classified by the original TrofileTM tropism assay. The primary objective was to assess whether antiviral activity (plasma viral load <400/50 copies/ml at Week 48) of CELSENTRI in combination zidovudine/lamivudine was non-inferior to a reference regimen of efavirenz plus zidovudine/lamivudine. Patients 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. Patients were randomized in a 1:1:1 ratio to CELSENTRI 300 mg once daily, CELSENTRI 300 mg twice daily, or efavirenz 600 mg once daily, each in combination with zidovudine/lamivudine. The efficacy and safety of CELSENTRI are based on the comparison of CELSENTRI twice daily versus efavirenz. A one-sided 97.5% confidence interval (CI) was constructed based on the normal approximation to the binomial distribution for the treatment difference in percentages stratified by the randomisation strata (screening viral load and geographic region). A step down procedure was used to control for multiple comparisons (ie. <400 and <50). Non- inferiority was to be concluded if the lower bound of the one-sided 97.5% CI was > - 10%. In a pre-planned interim analysis at 16 weeks, the CELSENTRI 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 CELSENTRI and efavirenz treatment groups were comparable (Table 4). Patients 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.

Table 4: Demographic and Baseline Characteristics of Patients in the Treatment-Naive Study * (MERIT)

* Data from Full Analysis Set. Similar results were observed for the Per Protocol population.

The treatment outcomes through week 48 for the treatment-naive study (MERIT) are shown in Table 5. Treatment outcomes (responders) include 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.

Table 5: Outcomes * of Randomised Treatment at Week 48 in Treatment-Naive Patients (MERIT) * *

* Non-inferiority: Criterion: lower bound of 97.5% CI > -10%

* * Data obtained with Original Tropism Assay (unless otherwise indicated).

Adjusted for randomisation strata

Based on Time to Loss of Virologic Response (TLOVR) algorithm, Full Analysis Set.

Death during study or within 28 days of the last dose at week 48.

The primary efficacy endpoints were defined as the percentage of patients with HIV-1 RNA undetectable by the standard method (< 400 copies/mL and < 50 copies/mL). After 48 weeks of combination therapy with zidovudine/lamivudine, maraviroc 300 mg BID demonstrated non-inferiority to efavirenz 600 mg QD in the proportion of patients with undetectable viral load measured at < 400 copies/mL but not at < 50 copies/mL (lower bound of 97.5% CI > -10% for non-inferiority). However, reanalysis of the data following rescreening of the samples using the enhanced sensitivity tropism assay demonstrated non-inferiority for maraviroc 300 mg BID compared to efavirenz 600 mg QD in the proportion of patients with viral loads of < 400 copies/mL and < 50 copies/mL. The median increase from baseline in CD4+ cell counts at week 48 was 157 cells/mm3 for the CELSENTRI arm compared to 127 cells/mm3 for the efavirenz arm. The treatment outcomes at 96 weeks for the treatment-naive patients study (MERIT) are shown in Table 6. Treatment outcomes are based on reanalysis of the screening samples using the enhanced sensitivity tropism assay. Approximately 15% of the patients identified as CCR5-tropic virus in the original analysis had CXCR4-using virus. Screening with the enhanced sensitivity version of the Trofile tropism assay reduced the number of maraviroc virologic failures with CXCR4-using virus at failure to 12 compared to 24 when screening with the original Trofile HIV tropism assay. The main reason for discontinuation in the maraviroc BID treatment group was treatment failure while the main reason for discontinuation in the efavirenz group was treatment-related adverse events (see PRECAUTIONS) (Table 6). Note, the nucleoside backbone used in study A4001026 was zidovudine/lamivudine.

Table 6: Study Outcome at Week 96 Using Enhanced Sensitivity Assay+

+The total number of patients (Ns) in Table 6 represents the patients who had a CCR5-tropic virus in the

reanalysis of screening samples using the more sensitive tropism assay. This reanalysis reclassified approximately 15% of patients shown in Table 4 as having CXCR4-using virus. These numbers are different than those presented in Table 4 because the numbers in Table 4 reflect the patients with CCR5-tropic virus according to the original tropism assay.

Other reasons for discontinuation include lost to follow-up, withdrawn, protocol violation, and other.

The median increase from baseline in CD4+ cell counts at week 96 was 184 cells/mm3 for the CELSENTRI arm compared to 155 cells/mm3 for the efavirenz arm.

Tropism

Treatment-Experienced (MOTIVATE-1 and MOTIVATE-2)

In the majority of cases, treatment failure on maraviroc was associated with detection of CXCR4 using (i.e., CXCR4- or dual/mixed-tropic) virus which was not detected by the tropism assay prior to treatment. CXCR4-using virus was detected at failure in 54.8% of patients who failed treatment on maraviroc, as compared to 5.9% of patients who experienced treatment failure in the placebo arm. To investigate the likely origin of the on-treatment CXCR4-using virus, a detailed clonal analysis was conducted on virus from 20 representative patients (16 patients from the maraviroc arms and 4 patients from the placebo arm) in whom CXCR4-using virus was detected at treatment failure. From analysis of amino acid sequence differences and phylogenetic data, CXCR4-using virus in these patients emerged from a low level of pre-existing CXCR4-using virus not detected by the tropism assay (which is population-based) prior to treatment rather than from a coreceptor switch from CCR5-tropic virus to CXCR4-using virus resulting from mutation in the virus. At week 48 patients failing maraviroc BID with CXCR4-using virus had a lower median increase in CD4+ cell counts from baseline (+41 cells/mm3) than those patients failing with CCR5-tropic virus (+162 cells/mm3). The median increase in CD4+ cell count in patients failing in the placebo arm was +6.5 cells/mm3.

Treatment-Naive (MERIT)

In a 96-week study of antiretroviral treatment-naive patients, 14% (12/85) who had CCR5-tropic virus at screening with an enhanced sensitivity tropism assay (Trofile) and failed therapy on maraviroc had CXCR4-using virus at the time of treatment failure. A detailed clonal analysis was conducted in two previously antiretroviral treatment-naive patients enrolled in a Phase 2a monotherapy study who had CXCR4- using virus detected after 10 days treatment with maraviroc. Consistent with the detailed clonal analysis conducted in treatment-experienced patients, the CXCR4- using variants appear to emerge from outgrowth of a pre-existing undetected CXCR4- using virus. Screening with an enhanced sensitivity 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 tropism assay. Patients who had CCR5-tropic virus at baseline and failed maraviroc therapy with CXCR4-using virus had a median increase in CD4+ cell counts from baseline of +113 cells/mm3 while those patients failing with CCR5-tropic virus had an increase of +135 cells/mm3. The median increase in CD4+ cell count in patients failing in the efavirenz arm was + 95 cells/mm3 .This data is a summary for a cohort of patients identified as virologic failures using the TLOVR algorithm based on a response cut off of plasma HIV-1 RNA <50 copies/mL.

CONTRAINDICATIONS

Hypersensitivity to the active substance or to any of the excipients (see DESCRIPTION).

PRECAUTIONS

Initiating Therapy:

The following points should be considered when initiating therapy with CELSENTRI (see INDICATIONS, DOSAGE AND ADMINISTRATION, and

PHARMACOLOGY, Pharmacological actions): Tropism testing, resistance testing and treatment history should guide the use of CELSENTRI. The viral tropism cannot be predicted by treatment history or assessment of stored samples. Adult patients infected with only CCR5-tropic HIV-1 should use CELSENTRI. CCR5 tropism should be confirmed using a highly sensitive tropism assay prior to initiation of CELSENTRI therapy. Outgrowth of pre-existing low-level CXCR4- or dual/mixed tropic HIV-1 not detected by tropism testing at screening has been associated with virologic failure on CELSENTRI. CELSENTRI is not recommended in patients with dual/mixed or CXCR4-tropic HIV-1. In treatment-naive subjects, more subjects treated with CELSENTRI experienced virologic failure and developed lamivudine resistance compared to efavirenz. The main reason for discontinuations in the efavirenz group was treatment-related adverse events (see CLINICAL TRIALS, Table 6) The safety and efficacy of CELSENTRI have not been established in children younger than 18 years of age.

Hepatic safety:

An increase in hepatic adverse reactions with CELSENTRI was observed during studies of treatment-experienced patients with HIV infection, although there was no overall increase in ACTG Grade 3/4 liver function test abnormalities (see ADVERSE EFFECTS).

Hepatotoxicity accompanied by severe rash or systemic allergic reaction including potentially life-threatening events has been reported. Hepatic laboratory parameters including ALT, AST, and bilirubin should be obtained prior to starting CELSENTRI and at other time points during treatment as clinically indicated. If rash or symptoms or signs of hepatitis or allergic reaction develop, hepatic laboratory parameters should be monitored. Discontinuation of CELSENTRI should be strongly considered in any patient with signs or symptoms of acute hepatitis, in particular if drug-related hypersensitivity is suspected or with increased liver transaminases combined with rash or other systemic symptoms of potential hypersensitivity (e.g. pruritic rash, eosinophila or elevated IgE). Since there are very limited data in patients with hepatitis B/C co-infection, use caution when treating these patients with CELSENTRI. In case of concomitant antiviral therapy for hepatitis B and/or C, please refer also to the relevant prescribing information for these medicinal products. Patients with pre-existing liver dysfunction, including chronic active hepatitis, can have an increased frequency of liver function abnormalities during combination antiretroviral therapy and should be monitored according to standard practice. The safety and efficacy of CELSENTRI have not been specifically studied in patients with significant underlying liver disorders. Since there is limited experience in patients with reduced hepatic function, therefore CELSENTRI should be used with caution in this population (see DOSAGE AND ADMINISTRATION and PHARMACOLOGY, Pharmacokinetics).

Severe Skin and Hypersensitivity Reactions:

Hypersensitivity reactions including severe and potentially life threatening events have been reported in patients taking CELSENTRI, in most cases concomitantly with other drugs associated with these reactions. These reactions were characterised by features including rash, constitutional findings, and sometimes organ dysfunction and hepatic failure. Cases of Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug rash with eosinophilia and systemic symptoms (DRESS) have been reported (see ADVERSE EFFECTS). Discontinue maraviroc and other suspect agents immediately if signs or symptoms of severe skin or hypersensitivity reactions develop. Delay in stopping maraviroc treatment or other suspect drugs after the onset of rash may result in a life-threatening reaction. Clinical status including liver aminotransferases should be monitored and appropriate therapy initiated.

Cardiovascular Safety:

Use with caution in patients at increased risk for cardiovascular events. Eleven patients (1.3%) who received CELSENTRI had cardiovascular events that may be linked to coronary heart diseases including myocardial ischemia and/or infarction during the Phase 3 studies in CCR5 tropic patients in treatment-experienced studies [total exposure of 609 patient-years (309 patient-years for BD + 300 patient-years for OD)], while no patients who received placebo had such events (total exposure 111 patient-years). These patients generally had cardiac disease or cardiac risk factors prior to CELSENTRI use, and the relative contribution of CELSENTRI to these events is not known.

Postural Hypotension:

When CELSENTRI was administered in studies with healthy volunteers at doses higher than the recommended dose, cases of symptomatic postural hypotension were seen at a greater frequency than with placebo. Caution should be used when administering CELSENTRI in patients on concomitant medicinal products known to lower blood pressure. CELSENTRI should also be used with caution in patients with severe renal insufficiency, have risk factors for, or have a history of postural hypotension.

Patients with severe renal insufficiency who are treated with potent CYP3A inhibitors or boosted protease inhibitors (PIs) have an increased risk of experiencing postural hypotension due to an increase in maraviroc concentrations (see DOSAGE AND ADMINISTRATION, INTERACTIONS WITH OTHER MEDICINES and PHARMACOLOGY, Pharmacokinetics). Patients with cardiovascular co-morbidities could be at increased risk of cardiovascular adverse events triggered by postural hypotension.

Renal impairment:

the safety and efficacy of CELSENTRI have not been specifically studied in patients with renal impairment, therefore CELSENTRI should be used with caution in this population.

Study A4001075 evaluated the pharmacokinetics and safety of CELSENTRI in combination with saquinavir/ritonavir in participants with mild and moderate renal impairment compared to healthy adult volunteers (See PHARMACOLOGY, Pharmacokinetics, Renal Impairment). All 18 participants received saquinavir/ritonavir 1000/100 mg in addition to 150 mg maraviroc at different dose frequencies: healthy volunteers - every 12 hours (n=6); mild renal impairment - every 24 hours (n=6); moderate renal impairment - every 48 hours (n=6). Treatment duration was 7 days. The most frequently reported treatment related adverse event by preferred term was blood creatinine increased, reported in eight (8) of the twelve (12) participants with mild and moderate renal impairment. Nocturia, considered study drug related, was reported by 6 of the 12 participants with mild and moderate renal impairment. Patients in the study with normal renal function demonstrated a decrease in mean creatinine clearance over the course of the study, though no patient with normal function had decreased creatinine clearance reported as an adverse event. On the basis of these results it is recommended that renal function is monitored if patients on maraviroc are co-administered saquinavir/ritonavir. The effect of this drug interaction on renal function in patients with severe renal failure has not been studied. The effect of multiple dose treatment with maraviroc without concomitant CYP3A4 has not been studied. An increased risk of postural hypotension may occur in patients with severe renal insufficiency who are treated with boosted protease inhibitors (PIs) and CELSENTRI. This risk is due to potential increases in maraviroc maximum concentrations when maraviroc is co-administered with boosted PIs in these patients. The risk of postural hypotension is highest when maraviroc is co-administered with PIs having the most potent CYP3A4 inhibitory effect (saquinavir/ritonavir, darunavir/ritonavir, lopinavir/ritonavir). Caution should be used when administering CELSENTRI in patients with a history of postural hypotension or on concomitant medication known to reduce blood pressure. Patients with impaired renal function may frequently have cardiovascular co-morbidities, and could be at increased risk of cardiovascular adverse events triggered by postural hypotension. No studies have been performed in patients with severe renal impairment co-treated with potent CYP3A4 inhibitors. Table 13 provides dose and/or interval adjustment guidelines for patients with renal impairment with and without co-administered potent CYP3A4 inhibitors (see DOSAGE AND ADMINISTRATION, INTERACTIONS WITH OTHER MEDICINES and PHARMACOLOGY, Pharmacokinetics).

Immune Reconstitution Syndrome:

In HIV infected patients with severe immune deficiency at the time of starting of highly active antiretroviral therapy (HAART), an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first few weeks or months of initiation of HAART. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections, and pneumonia caused by Pneumocystis jiroveci (formerly known as Pneumocystis carinii). Any inflammatory symptoms should be evaluated and treatment initiated when necessary. Autoimmune disorders (such as Graves' disease, polymyositis and Guillain-Barre syndrome) have also been reported to occur in the setting of immune reconstitution, however, the time to onset is more variable,

and can occur many months after initiation of treatment and sometimes can be an atypical presentation.

Tropism:

CELSENTRI should be taken as part of an antiretroviral combination regimen. CELSENTRI should optimally be combined with other antiretrovirals to which the patient's virus is susceptible (see PHARMACOLOGY, Pharmacological actions).

Changes in viral tropism occur over time in HIV-1 infected patients. Therefore there is a need to start therapy shortly after a tropism test.

Dose Adjustment:

Physicians should ensure that appropriate dose adjustment of CELSENTRI is made when CELSENTRI is co-administered with CYP3A4 inhibitors and/or inducers since maraviroc concentrations and its therapeutic effects may be affected (see DOSAGE AND ADMINISTRATION and INTERACTIONS WITH

OTHER MEDICINES). Refer to the respective prescribing information of the other medicinal products used in combination with CELSENTRI.

Information for Patients:

Patients should be advised that antiretroviral therapies including CELSENTRI have not been shown to prevent the risk of transmission of HIV to others through sexual contact or contamination with blood. They should continue to use appropriate precautions. Patients should also be informed that CELSENTRI is not a cure for HIV-1 infection.

Potential Risk of Infections:

CELSENTRI antagonises 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 infections, as well as AIDS-defining category C infections, was comparable in the treatment groups during the Phase 3 studies of CELSENTRI. Patients should be monitored closely for evidence of infections while receiving CELSENTRI.

Potential Risk of Malignancy:

While no increase in malignancy has been observed in patients receiving CELSENTRI in Phase 3 studies, due to this drug's mechanism of action it could affect immune surveillance and lead to an increased risk of malignancy. Long-term follow-up is required to more fully assess whether CELSENTRI increases the risk of malignancy.

Effects on ability to drive and use machines

There have been no studies to investigate the effect of CELSENTRI on the ability to perform tasks that require judgement, motor or cognitive skills. However, patients should be informed about the possible occurrence of symptoms related to postural hypotension such as dizziness when taking CELSENTRI. If affected, patients should avoid potentially hazardous tasks such as driving or operating machinery.

Effects on fertility

Maraviroc did not impair mating or fertility of male or female rats, and did not affect sperm of male rats at oral doses up to 1000 mg/kg/day. Systemic exposure to free maraviroc at this dose level was 39-fold higher than the estimated free clinical AUC0- 24 h for a 300 mg twice daily dose.

Use in pregnancy

Pregnancy Category: B1 Embryofetal development studies were conducted in rats and rabbits at oral doses up to 1000 and 200 mg/kg/day, respectively. Systemic exposure to free maraviroc at these doses was 40- (rats) and 35-times (rabbits) the free clinical AUC0-24 h for a 300 mg twice daily dose. The animal studies revealed no evidence of harm to the embryo or fetus except for an increase in pre-implantation loss in rats dosed with maraviroc at a maternotoxic dose of 1000 mg/kg/day from 2 weeks prior to mating to gestation day 7. Pre- and postnatal development studies were performed in rats at oral doses up to 1000 mg/kg/day (relative exposure to free maraviroc, 28). The only effect in the offspring was a slight increase in motor activity in high-dose male rats at both weaning and as adults, while no effects were seen in females. Other developmental parameters of these offspring, including fertility and reproductive performance, were not affected by the maternal administration of maraviroc. No meaningful clinical data on exposure during pregnancy are available. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryofetal development, parturition or postnatal development. CELSENTRI should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Use in lactation

Studies in lactating rats indicate that maraviroc and its metabolites are extensively excreted into rat milk. It is unknown whether maraviroc is excreted in human milk. Mothers should be instructed not to breast-feed if they are receiving CELSENTRI because of the potential for HIV transmission and possible adverse effects in breast- fed infants.

Paediatric use

The safety and efficacy of CELSENTRI in paediatric patients have not been established, therefore use in children is not recommended (see DOSAGE AND ADMINISTRATION and PHARMACOLOGY, Pharmacokinetics)

Use in the elderly

There were insufficient numbers of patients aged 65 and over in the clinical studies to determine whether they respond differently from younger patients. In general, caution should be exercised when administering CELSENTRI in elderly patients, also reflecting the greater frequency of decreased hepatic and renal function, of concomitant disease and other drug therapy (see DOSAGE AND ADMINISTRATION and PHARMACOLOGY, Pharmacokinetics).

Carcinogenicity

Maraviroc was evaluated for carcinogenic potential in a six month transgenic mouse study and a 24 month study in rats. In mice, maraviroc did not cause a statistically significant increase in the incidence of any tumour type at oral doses up to 1500 mg/kg/day, producing systemic exposure to unbound maraviroc 39-(males) or 72- times (females) higher than that obtained in humans at the standard clinical dose of 300 mg twice daily. In rats, administration of maraviroc produced thyroid adenomas, associated with adaptive liver changes, at 900 mg/kg/day PO (relative exposure based on AUC0-24 h for free maraviroc, 18-25). The thyroid tumours in rats are unlikely to be of human relevance.

Genotoxicity

Maraviroc was not mutagenic or clastogenic in a battery of in vitro and in vivo assays including bacterial reverse mutation, chromosome aberrations in human lymphocytes and mouse bone marrow micronucleus.

INTERACTIONS WITH OTHER MEDICINES

Maraviroc is a substrate of cytochrome P450 CYP3A4. Co-administration of CELSENTRI with medicinal products that induce CYP3A4 may decrease maraviroc concentrations and reduce its therapeutic effects. Co-administration of CELSENTRI with medicinal products that inhibit CYP3A4 may increase maraviroc plasma concentrations. Dose adjustment of CELSENTRI is recommended when CELSENTRI is co-administered with CYP3A4 inhibitors and/or inducers. Further details for concomitantly administered medicinal products are provided below (see Table 7 and DOSAGE AND ADMINISTRATION, Table 12). Studies in human liver microsomes and recombinant enzyme systems have shown that maraviroc does not inhibit any of the major P450 enzymes at clinically relevant concentrations (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4). Maraviroc had no clinically relevant effect on the pharmacokinetics of midazolam, the oral contraceptives ethinylestradiol and levonorgestrel, or urinary 6b- hydroxycortisol/cortisol ratio, suggesting no inhibition or induction of CYP3A4 in vivo. at higher exposure of maraviroc a potential inhibition of CYP2D6 cannot be excluded. Based on the in vitro and clinical data, the potential for maraviroc to affect the pharmacokinetics of co-administered medicinal products is low. Renal clearance accounts for approximately 23% of total clearance of maraviroc when maraviroc is administered without CYP3A4 inhibitors. As both passive and active processes are involved, there is the potential for competition for elimination with other renally eliminated active substances. However, co-administration of CELSENTRI with tenofovir (substrate for renal elimination) and Cotrimoxazole (contains trimethoprim, a renal cation transport inhibitor), showed no effect on the pharmacokinetics of maraviroc. In addition, co-administration of CELSENTRI with lamivudine/zidovudine showed no effect of maraviroc on lamivudine (primarily renally cleared) or zidovudine (non-P450 metabolism and renal clearance) pharmacokinetics. Maraviroc inhibits P-glycoprotein (P-gp) in vitro (IC50 is 183 M). Systemic effects on P-gp are unlikely to be of relevance. Maraviroc could inhibit P-gp in the gut and may thus affect the bioavailability of certain drugs.

Table 7. Interactions and dose recommendations with other medicinal products

DOSAGE AND ADMINISTRATION

Therapy should be initiated by a physician experienced in the management of HIV infection. The following points should be considered when initiating therapy with CELSENTRI: Tropism testing, resistance testing and treatment history should guide the use of CELSENTRI. Adult patients infected with only CCR5-tropic HIV-1 should use CELSENTRI. CCR5 tropism should be confirmed using a highly sensitive tropism assay prior to initiation of CELSENTRI therapy. Outgrowth of pre-existing low-level CXCR4- or dual/mixed tropic HIV-1 not detected by tropism testing at screening has been associated with virologic failure on CELSENTRI.

• CELSENTRI is not recommended in patients with dual/mixed or CXCR4-tropic HIV-1.

• In treatment-naive subjects, more subjects treated with CELSENTRI experienced virologic failure and developed lamivudine resistance compared to efavirenz.

• The safety and efficacy of CELSENTRI have not been established in children younger than 18 years of age.

Adults

: the recommended dose of CELSENTRI is 150 mg, 300 mg or 600 mg twice daily depending on interactions with co-administered antiretroviral therapy and other medicinal products (see Table 12 and INTERACTIONS WITH OTHER MEDICINES).

CELSENTRI can be taken with or without food.

Table 12: Recommended Dosing Regimen

Children:

the safety and efficacy for the use of CELSENTRI in children younger than

18 years of age has not been established. Therefore, use in children is not recommended (see PHARMACOLOGY, Pharmacokinetics and PRECAUTIONS).

Elderly:

there is limited experience in patients above 65 years of age; therefore, caution should be exercised when administering CELSENTRI in elderly patients (see PHARMACOLOGY, Pharmacokinetics and PRECAUTIONS).

Renal impairment:

Table 13 provides dosing recommendations for patients based on renal function and concomitant medications.

Table 13: Recommended dosing regimens based on renal function

NR = not recommended

*See Table 7 for list of concomitant medications

# The CELSENTRI dose should be reduced to 150 mg twice daily if there are any symptoms of postural hypotension (see PRECAUTIONS, Renal Impairments)

Hepatic impairment:

limited data in mild and moderate hepatic impairment patients demonstrated small increase in the mean Cmax of maraviroc, suggesting no dose adjustment is required. However, CELSENTRI should be used with caution in patients with hepatic impairment (see PHARMACOLOGY, Pharmacokinetics and PRECAUTIONS).

OVERDOSAGE

The highest dose administered in clinical studies was 1200 mg. The dose limiting adverse reaction was postural hypotension. Prolongation of the QT interval was seen in dogs and monkeys at free plasma concentrations of maraviroc 6 times higher than that expected in humans at the standard clinical dose of 300 mg twice daily. However, no clinically significant QT prolongation compared to OBT alone was seen in the Phase 3 clinical studies using the recommended dose of maraviroc or in a specific pharmacokinetic study to evaluate the potential of CELSENTRI to prolong the QT interval. There is no specific antidote for overdose with CELSENTRI. 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 CELSENTRI should be achieved by emesis. Administration of activated charcoal may also be used to aid in removal of unabsorbed active substance. Since CELSENTRI is moderately protein bound, dialysis may be beneficial in removal of this medicine. Contact the Poisons Information Centre for advice on the management of an overdose.

PRESENTATION AND STORAGE CONDITIONS

High density polyethylene (HDPE) bottles with polypropylene child resistant closures and an aluminium foil/polyethylene heat induction seal containing 180 film-coated tablets for the 150 mg and 300 mg strengths. Polyvinyl chloride (PVC) blisters with aluminium foil backing in a carton containing 60, film-coated tablets for the 150 mg and 300 mg strengths. Store below 30degC.

NAME AND ADDRESS OF SPONSOR

ViiV Healthcare Pty Ltd Level 4, 436 Johnston Street Abbotsford VIC 3067

POISON SCHEDULE OF THE MEDICINE

Prescription only medicine (S4)

DATE OF FIRST INCLUSION ON THE AUSTRALIAN REGISTER OF THERAPEUTIC GOODS (THE ARTG):

22 January 2008

DATE OF MOST RECENT AMENDMENT:

21 October 2013

CELSENTRI(r) is a registered trade mark of the ViiV Healthcare group of companies.

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