CELSENTRI 150 mg film-coated tablets.

2.1 General Description

Each film-coated tablet contains 150 mg of maraviroc.

2.2 Qualitative and quantitative composition

Excipients

Each 150 mg film-coated tablet contains 0.84 mg of soya lecithin.

For a full list of excipients, see section 6.1.

Film-coated tablet.

Blue, biconvex, oval film-coated tablets debossed with “MVC 150”.

CELSENTRI, in combination with other antiretroviral medicinal products, is indicated for treatment-experienced adult patients infected with only CCR5-tropic HIV-1 detectable (see section 4.2).

This indication is based on safety and efficacy data from two double-blind, placebo-controlled trials in treatment-experienced patients (see section 5.1).

Therapy should be initiated by a physician experienced in the management of HIV infection.

Before taking CELSENTRI it has to be confirmed that only CCR5-tropic HIV-1 is detectable (i.e. CXCR4 or dual/mixed tropic virus not detected) using an adequately validated and sensitive detection method on a newly drawn blood sample. The Monogram Trofile assay was used in the clinical studies of CELSENTRI (see sections 4.4 and 5.1). Other phenotypic and genotypic assays are currently being evaluated. The viral tropism cannot be safely predicted by treatment history and assessment of stored samples.

There are currently no data regarding the reuse of CELSENTRI in patients that currently have only CCR5-tropic HIV-1 detectable, but have a history of failure on CELSENTRI (or other CCR5 antagonists) with a CXCR4 or dual/mixed tropic virus. There are no data regarding the switch from a medicinal product of a different antiretroviral class to CELSENTRI in virologically suppressed patients. Alternative treatment options should be considered.

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 2 in Section 4.5). CELSENTRI can be taken with or without food.

Children: CELSENTRI is not recommended for use in children due to lack of data on safety, efficacy and pharmacokinetics (see section 5.2).

Elderly: there is limited experience in patients >65 years of age (see section 5.2), therefore CELSENTRI should be used with caution in this population.

Renal impairment: dosage adjustment is only recommended in patients with renal impairment who are receiving potent CYP3A4 inhibitors such as:

• protease inhibitors (except tipranavir/ritonavir)

• ketoconazole, itraconazole, clarithromycin, telithromycin.

CELSENTRI should be used with caution in patients with severe renal impairment (CLcr < 30mL/min) who are receiving potent CYP3A4 inhibitors (see sections 4.4 and 5.2).

The dose and dosing interval for CELSENTRI should be modified in renally impaired patients (CLcr <80 mL/min), including patients with end stage renal disease (ESRD) requiring dialysis (Table 1 below). These dosing recommendations are based on data from a renal impairment study (see section 5.2) in addition to modelling of pharmacokinetic data in subjects with varying degrees of renal impairment.

Table 1. Dose and interval adjustments for patients with renal impairment

Hepatic impairment: limited data are available in patients with hepatic impairment, therefore CELSENTRI should be used with caution in this population (see sections 4.4 and 5.2).

Hypersensitivity to the active substance or to peanut or soya or to any of the excipients.

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 sensitive (see section 5.1).

CELSENTRI should only be used when only CCR5-tropic HIV-1 is detectable (i.e. CXCR4 or dual/mixed tropic virus not detected) as determined by an adequately validated and sensitive detection method (see sections 4.1, 4.2 and 5.1). The Monogram Trofile assay was used in the clinical studies of CELSENTRI. Other phenotypic and genotypic assays are currently being evaluated. The viral tropism cannot be predicted by treatment history or assessment of stored samples.

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.

Background resistance to other classes of antiretrovirals have been shown to be similar in previously undetected CXCR4-tropic virus of the minor viral population, as that found in CCR5-tropic virus.

CELSENTRI is not recommended to be used in treatment-naïve patients based on the results of a clinical study in this population (see section 5.1).

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 sections 4.2 and 4.5). Please also refer to the respective Summary of Product Characteristics of the other antiretroviral medicinal products used in the combination.

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.

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. However, when CELSENTRI was given at the recommended dose in HIV infected patients in Phase 3 studies, postural hypotension was seen at a similar rate compared to placebo (approximately 0.5%). Caution should be used when administering CELSENTRI in patients with a history of postural hypotension or on concomitant medicinal products known to lower blood pressure.

Potential effect on immunity: CCR5 antagonists could potentially impair the immune response to certain infections. This should be taken into consideration when treating infections such as active tuberculosis and invasive fungal infections. The incidence of AIDS-defining infections was similar between CELSENTRI and placebo arms in the pivotal studies.

Cardiovascular safety: limited data exist with the use of CELSENTRI in patients with severe cardiovascular disease, therefore special caution should be exercised when treating these patients with CELSENTRI. In the pivotal studies of treatment-experienced patients (MOTIVATE) coronary heart disease events was more common in patients treated with CELSENTRI than with placebo (11 during 609 PY vs 0 during 111 PY of follow-up). In treatment-naïve patients (MERIT) such events occurred at a similarly low rate with CELSENTRI and control (efavirenz).

When CELSENTRI was administered to healthy volunteers at doses higher than the recommended dose, cases of symptomatic postural hypotension were seen at a greater frequency than with placebo. However, when CELSENTRI was given at the recommended dose in HIV infected patients in Phase 3 studies, postural hypotension was seen at a similar rate compared to placebo/comparator. Caution should be used when administering CELSENTRI in patients with a history of postural hypotension or on concomitant medicinal products known to lower blood pressure.

Immune reconstitution syndrome: in HIV infected patients with severe immune deficiency at the time of institution of combination antiretroviral therapy (CART), 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 CART. 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.

Osteonecrosis: although the etiology is considered to be multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported particularly in patients with advanced HIV-disease and/or long-term exposure to combination antiretroviral therapy (CART). Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.

Hepatic safety: the safety and efficacy of CELSENTRI have not been specifically studied in patients with significant underlying liver disorders.

Cases of hepatotoxicity and hepatic failure with allergic features have been reported in association with CELSENTRI. In addition, an increase in hepatic adverse reactions with CELSENTRI was observed during studies of treatment-experienced subjects with HIV infection, although there was no overall increase in ACTG Grade 3/4 liver function test abnormalities (see section 4.8). Hepatobiliary disorders reported in treatment-naïve patients were uncommon and balanced between treatment groups (see section 4.8). 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.

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, special caution should be exercised when treating these patients with CELSENTRI. In case of concomitant antiviral therapy for hepatitis B and/or C, please refer also to the relevant product information for these medicinal products.

There is limited experience in patients with reduced hepatic function, therefore CELSENTRI should be used with caution in this population (see sections 4.2 and 5.2).

Renal impairment: 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 CELSENTRI is co-administered with boosted PIs in these patients. The risk of postural hypotension is highest when CELSENTRI is co-administered with PIs having the most potent CYP3A4 inhibitory effect (saquinavir/ ritonavir, darunavir/ ritonavir, lopinavir/ ritonavir). 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 subjects with severe renal impairment co-treated with potent CYP3A4 inhibitors. Dose adjustments are based on modelling and simulations (see sections 4.2, 4.5 and 5.2)

Soya lecithin: CELSENTRI contains soya lecithin. If a patient is hypersensitive to peanut or soya, CELSENTRI should not be used.

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 2).

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 6β-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. In vitro results indicate that maraviroc could inhibit P-glycoprotein in the gut and may thus affect bioavailability of certain drugs.

Table 2. Interactions and dose recommendations with other medical products

No meaningful clinical data on exposure during pregnancy are available. Studies in rats and rabbits showed reproductive toxicity at high exposures. Primary pharmacological activity (CCR5 receptor affinity) was limited in these species (see section 5.3). CELSENTRI should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.

Studies in lactating rats indicate that maraviroc is extensively secreted into rat milk. Primary pharmacological activity (CCR5 receptor affinity) was limited in these species. It is not known whether maraviroc is secreted into human milk. Mothers should be instructed not to breast-feed if they are receiving CELSENTRI because of the potential for HIV transmission as well as any possible undesirable effects in breast-fed infants.

No studies on the effects on the ability to drive and use machines have been performed. CELSENTRI may cause dizziness. Patients should be instructed that if they experience dizziness they should avoid potentially hazardous tasks such as driving or operating machinery.

The safety profile of CELSENTRI is based on 1,374 HIV-1 infected patients who received at least one dose of CELSENTRI during Phase 2b/3 clinical studies. This includes 426 treatment-experienced patients and 360 treatment-naïve patients who received the recommended dose 300 mg twice daily and a further 588 treatment-experienced and treatment-naïve patients who received 300 mg once daily. Assessment of treatment related adverse reactions is based on pooled data from two Phase 2b/3 studies in treatment-experienced adult patients (MOTIVATE 1 and MOTIVATE 2) and one study in treatment-naïve adult patients (MERIT) infected with CCR5-tropic HIV-1 (see section 4.4 and 5.1)..

The most frequently reported adverse reactions occurring in the Phase 2b/3 studies were nausea, diarrhoea, fatigue and headache. These adverse reactions were common ( 1/100 to < 1/10). The reported frequencies for these events as well as the rates of discontinuation due to any adverse reactions were similar in patients receiving CELSENTRI in Phase 2b/3 studies compared to those receiving comparator.

The adverse reactions are listed by system organ class (SOC) and frequency. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Frequencies are defined as very common ( 1/10), common ( 1/100 to < 1/10), uncommon (1/1000 to <1/100), and rare (1/10,000 to <1/1,000). The adverse reactions and laboratory abnormalities presented below are not exposure adjusted.

The following table presents clinically important adverse reactions of moderate intensity or more occurring among patients receiving CELSENTRI in Phase 2b/3 studies at rates greater than rates in the comparator.

Table 3. Clinically important adverse reactions of moderate intensity or more occurring among patients receiving CELSENTRI at rates greater than rates in the comparator

N.B. Adverse reactions from clinical trials in table 3 were assessed as possibly related to study drug by investigators

^* From spontaneous reporting during post marketing surveillance

In HIV infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise (see section 4.4).

Laboratory abnormalities

Table 4 shows the incidence 1% of Grade 3-4 Abnormalities (ACTG Criteria) based on the maximum shift in laboratory test values without regard to baseline values.

Table 4: Incidence 1% of grade 3-4 abnormalities (ACTG criteria) based on maximum shift in laboratory test values without regard to baseline studies MOTIVATE 1 and MOTIVATE 2 (pooled analysis, up to 48 weeks)

ULN: Upper Limit of Normal

OBT: Optimised Background Therapy

* Percentages based on total patients evaluated for each laboratory parameter

In treatment-naïve patients, the incidence of grade 3 and 4 laboratory abnormalities using ACTG criteria was similar among the CELSENTRI and efavirenz treatment groups.

Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk factors, advanced HIV disease or long-term exposure to combination antiretroviral therapy (CART). The frequency of this is unknown (see section 4.4).

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 plasma concentrations 6 and 12 times, respectively, those expected in humans at the maximum recommended 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 maraviroc should be achieved by emesis or gastric lavage. Administration of activated charcoal may also be used to aid in removal of unabsorbed active substance. Since maraviroc is moderately protein bound, dialysis may be beneficial in removal of this medicine.

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 vitro:

Maraviroc has no antiviral activity in vitro against viruses which can use CXCR4 as their entry co-receptor (dual-tropic or CXCR4-tropic viruses, collectively termed 'CXCR4-using' virus below). The serum adjusted EC90 value in 43 primary HIV-1 clinical isolates was 0.57 (0.06 – 10.7) ng/mL without significant changes between different subtypes tested. The antiviral activity of maraviroc against HIV-2 has not been evaluated. For details please refer to http://www.ema.europa.eu/htms/human/epar/eparintro.

When used with other antiretroviral medicinal products in cell culture, the combination of maraviroc was not antagonistic with a range of NRTIs ,NNRTIs, PIs or the HIV fusion inhibitor enfuvirtide.

Resistance:

Viral escape from maraviroc can occur via 2 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).

In vitro:

HIV-1 variants with reduced susceptibility to maraviroc have been selected in vitro, following serial passage of two CCR5-tropic viruses (0 laboratory strains, 2 clinical 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 characterized phenotypically by curves that did not reach 100% inhibition in assays using serial dilutions of maraviroc. Traditional IC₅₀/IC₉₀ 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.

Cross-resistance in vitro:

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 vitro remained sensitive to the fusion inhibitor enfuvirtide and the protease inhibitor saquinavir.

In vivo:

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 4-6 weeks).

Failure with CXCR4-using virus:

CXCR4-using virus was detected at failure in approximately 60% of subjects who failed treatment on CELSENTRI, as compared to 6% of subjects who experienced treatment failure in the 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 subjects (16 subjects from the CELSENTRI arms and 4 subjects from the OBT alone arm) in whom CXCR4-using virus was detected at treatment failure. This analysis indicated that CXCR4-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 CELSENTRI 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 CELSENTRI, 22 out of 58 patients had virus with reduced sensitivity to maraviroc. In the remaining 36 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 correlating to low compliance (low and variable drug levels and often a calculated high residual sensitivity score of the OBT). In patients failing therapy with R5-virus only, maraviroc might be considered still active if the maximal percentage inhibition (MPI) value is 95% (Phenosense Entry assay). Residual activity in vivo for viruses with MPI-values <95% has not been determined.

Genotypic resistance: Key mutations (V3-loop) can presently not be suggested due to the high variability of the V3-sequence, and the low number of samples analysed.

Clinical Results

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, randomized, double blind, multicentre studies (MOTIVATE 1 and MOTIVATE 2, n=1076 ) in patients infected with CCR5 tropic HIV-1 as determined by the Monogram Trofile Assay.

Patients who were eligible for these studies had prior exposure to at least 3 antiretroviral medicinal product classes [1 nucleoside reverse transcriptase inhibitors (NRTI), 1 non-nucleoside reverse transcriptase inhibitors (NNRTI), 2 protease inhibitors (PI), and/or enfurvirtide] or documented resistance to at least one member of each class. Patients were randomised in a 2:2:1 ratio to CELSENTRI 300 mg (dose equivalence) once daily, twice daily or placebo in combination with an optimized background consisting of 3 to 6 antiretroviral medicinal products (excluding low-dose ritonavir). The OBT was selected on the basis of the subject's prior treatment history and baseline genotypic and phenotypic viral resistance measurements.

Table 5: Demographic and baseline characteristics of patients in studies MOTIVATE 1 and MOTIVATE 2 (Pooled Analysis)

GeneSeq resistance assay

Limited numbers of patients from ethnicities other than Caucasian were included in the pivotal clinical studies, therefore very limited data are available in these patient populations.

The mean increase in CD4+ cell count from baseline in patients who failed with a change in tropism result to dual/mixed tropic or CXCR4, in the CELSENTRI 300 mg twice daily + OBT (+56 cells/mm³) group was greater than that seen in patients failing OBT alone (+13.8 cells/mm³) regardless of tropism.

Table 6. Outcomes of randomised treatment at week 48 (pooled studies MOTIVATE 1 and MOTIVATE 2)

¹ p-values < 0.0001

² For all efficacy endpoints the confidence intervals were 95%, except for HIV-1 RNA Change from baseline which was 97.5%

CELSENTRI 300 mg twice daily + OBT was superior to OBT alone across all subgroups of patients analysed (see Table 7). Patients with very low CD4+ count at baseline (i.e. <50 cells/uL) had a less favourable outcome. This subgroup had a high degree of bad prognostic markers, i.e. extensive resistance and high baseline viral loads. However, a significant treatment benefit for CELSENTRI compared to OBT alone was still demonstrated (see Table 7).

Table 7. Proportion of patients achieving <50 copies/mL at Week 48 by subgroup (pooled Studies MOTIVATE 1 and MOTIVATE 2, ITT)

¹Discontinuations or virological failures considered as failures.

²Based on GSS.

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

Study A4001029 was an exploratory study in patients infected with dual/mixed or CXCR4 tropic HIV-1 with a similar design as the studies MOTIVATE 1 and MOTIVATE 2. In this study, neither superiority nor non-inferiority to OBT alone were demonstrated although there was no adverse outcome on viral load or CD4+ cell count

Studies in Treatment-Naïve Patients

An ongoing randomised, double-blinded study (MERIT), is exploring CELSENTRI versus efavirenz, both in combination with zidovudine/lamivudine (n=721, 1:1). After 48 weeks of treatment, CELSENTRI did not reach non-inferiority to efavirenz for the endpoint of HIV-1 RNA < 50 copies/mL (65.3 vs. 69.3 % respectively, lower confidence bound -11.9%). More patients treated with CELSENTRI discontinued due to lack of efficacy (43 vs.15) and among patients with lack of efficacy, the proportion acquiring NRTI resistance (mainly lamivudine) was higher in the CELSENTRI arm. Fewer patients discontinued CELSENTRI due to adverse events (15 vs.49).

Absorption: the absorption of maraviroc is variable with multiple peaks. Median peak maraviroc plasma concentrations is attained at 2 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. 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.

Coadministration of a 300 mg tablet with a high fat breakfast reduced maraviroc C_max and AUC by 33% in healthy volunteers. There were no food restrictions in the studies that demonstrated the efficacy and safety of CELSENTRI (see section 5.1). Therefore, CELSENTRI can be taken with or without food at the recommended doses (see section 4.2).

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 194 L.

Metabolism: studies in humans and in vitro studies using human liver microsomes and expressed enzymes have demonstrated that maraviroc is principally metabolized by the cytochrome P450 system to metabolites that are essentially inactive against HIV-1. In vitro studies indicate that CYP3A4 is the major enzyme responsible for maraviroc metabolism. In vitro studies also indicate that polymorphic enzymes CYP2C9, CYP2D6 and CYP2C19 do not contribute significantly to the metabolism of maraviroc.

Maraviroc is the major circulating component (approximately 42% radioactivity) following a single oral dose of 300 mg. The most significant circulating metabolite in humans is a secondary amine (approximately 22% 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 radioactivity.

Elimination: 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 h, 22% of the dose was excreted unchanged in the urine and the values of total clearance and renal clearance were 44.0 L/h and 10.17 L/h respectively.

Children: the pharmacokinetics of maraviroc in paediatric patients have not been established (see section 4.2).

Elderly: population analysis of the Phase 1/2a and Phase 3 studies (16-65 years of age) has been conducted and no effect of age has been observed (see section 4.2).

Renal impairment: a study compared the pharmacokinetics of a single 300 mg dose of CELSENTRI in subjects with severe renal impairment (CLcr < 30 mL/min, n=6) and end stage renal disease (ESRD) to healthy volunteers (n=6). The geometric mean AUC_inf (CV%) for CELSENTRI was as follows: healthy volunteers (normal renal function) 1348.4 ng·h/mL (61%); severe renal function 4367.7 ng·h/mL (52%); ESRD (dosing after dialysis) 2677.4 ng·h/mL (40%); and ESRD (dosing before dialysis) 2805.5 ng·h/mL (45%). The C _max (CV%) was 335.6 ng/mL (87%) in healthy volunteers (normal renal function); 801.2 ng/mL (56%) in severe renal function; 576.7 ng/mL (51%) in ESRD (dosing after dialysis) and 478.5 ng/mL (38%) in ESRD (dosing before dialysis). Dialysis had a minimal effect on exposure in subjects with ESRD. Exposures observed in subjects with severe renal impairment and ESRD were within the range observed in single CELSENTRI 300 mg dose studies in healthy volunteers with normal renal function. Therefore, no dose adjustment is necessary in patients with renal impairment receiving CELSENTRI without a potent CYP3A4 inhibitor (see sections 4.2, 4.4 and 4.5).

In addition, the study compared the pharmacokinetics of multiple dose CELSENTRI in combination with saquinavir/ritonavir 1000/100 mg BID (a potent CYP3A4 inhibitor) for 7 days in subjects with mild renal impairment (CLcr >50 and 80 mL/min, n=6) and moderate renal impairment (CLcr 30 and 50 mL/min, n=6) to healthy volunteers (n=6). Subjects 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). The average concentration (Cavg) of CELSENTRI over 24 hours was 445.1 ng/mL, 338.3 ng/mL, and 223.7 ng/mL for subjects with normal renal function, mild renal impairment, and moderate renal impairment, respectively. The Cavg of CELSENTRI from 24-48 hours for subjects with moderate renal impairment was low (Cavg: 32.8 ng/mL). Therefore, dosing frequencies of longer than 24 hours in subjects with renal impairment may result in inadequate exposures between 24-48 hours.

Dose adjustment is necessary in patients with renal impairment receiving CELSENTRI with potent CYP3A4 inhibitors (see sections 4.2 and 4.4 and 4.5).

Hepatic impairment: maraviroc is primarily metabolized and eliminated by the liver. A study compared the pharmacokinetics of a single 300 mg dose of CELSENTRI in patients with mild (Child-Pugh Class A, n=8), and moderate (Child-Pugh Class B, n=8) hepatic impairment compared to healthy subjects (n=8). Geometric mean ratios for C_max and AUC_last 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. 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 subjects. The results should therefore be interpreted with caution. The pharmacokinetics of maraviroc have not been studied in subjects with severe hepatic impairment (see sections 4.2 and 4.4).

Race: no relevant difference between Caucasian, Asian and Black subjects has been observed. The pharmacokinetics in other races has not been evaluated.

Gender: no relevant differences in pharmacokinetics have been observed.

Primary pharmacological activity (CCR5 receptor affinity) was present in the monkey (100% receptor occupancy) and limited in the mouse, rat, rabbit and dog. In mice and human beings that lack CCR5 receptors through genetic deletion, no significant adverse consequences have been reported.

In vitro and in vivo studies showed that maraviroc has a potential to increase QTc interval at supratherapeutic doses with no evidence of arrhythmia.

Repeated dose toxicity studies in rats identified the liver as the primary target organ for toxicity (increases in transaminases, bile duct hyperplasia, necrosis).

Maraviroc was evaluated for carcinogenic potential by a 6 month transgenic mouse study and a 24 month study in rats. In mice, no statistically significant increase in the incidence of tumors was reported at systemic exposures from 7 to 39-times the human exposure (unbound AUC 0-24h measurement) at a dose of 300 mg twice daily. In rats, administration of maraviroc at a systemic exposure 21-times the expected human exposure produced thyroid adenomas associated with adaptive liver changes. These findings are considered of low human relevance. In addition, cholangiocarcinomas (2/60 males at 900 mg/kg) and cholangioma (1/60 females at 500 mg/kg) were reported in the rat study at a systemic exposure at least 15-times the expected free human exposure.

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

Maraviroc did not impair mating or fertility of male or female rats, and did not affect sperm of treated male rats up to 1000 mg/kg. The exposure at this dose level corresponded to 39-fold the estimated free clinical AUC for a 300 mg twice daily dose.

Embryofoetal development studies were conducted in rats and rabbits at doses up to 39- and 34-fold the estimated free clinical AUC for a 300 mg twice daily dose. In rabbit, 7 foetuses had external anomalies at maternally toxic doses and 1 foetus at the mid dose of 75 mg/kg.

Pre- and post-natal developmental studies were performed in rats at doses up to 27-fold the estimated free clinical AUC for a 300 mg twice daily dose. A slight increase in motor activity in high-dose male rats at both weaning and as adults was noted, 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.

Tablet core:

Cellulose, microcrystalline

Calcium hydrogen phosphate, anhydrous

Sodium starch glycolate

Magnesium stearate

Film-coat:

Poly (vinyl alcohol)

Titanium dioxide

Macrogol 3350

Talc

Soya Lecithin

Indigo carmine aluminium lake (E132)

Not applicable.

4 years.

This medicinal product does not require any special storage condition.

High density polyethylene bottles (HDPE) with polypropylene child resistant (CR) closures and an aluminium foil/polyethylene heat induction seal containing 180 film-coated tablets.

Polyvinyl chloride (PVC) blisters with aluminium foil backing in a carton containing 30, 60, 90 film-coated tablets and multipacks containing 180 (2 packs of 90) film-coated tablets.

Not all pack sizes may be marketed.

Any unused product or waste material should be disposed of in accordance with local requirements.

ViiV Healthcare UK Ltd

980 Great West Road

Brentford

Middlesex

TW8 9GS

United Kingdom

EU/1/07/418/001

EU/1/07/418/002

EU/1/07/418/003

EU/1/07/418/004

EU/1/07/418/005

18^th September 2007

22 November 2011

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu