CELSENTRI 20mg / ml oral solution medication leaflet

CELSENTRI 20 mg/mL oral solution

Each mL of oral solution contains 20 mg maraviroc.

Excipient with known effect: Each mL of oral solution contains 1 mg sodium benzoate (E211).

For the full list of excipients, see section 6.1.

Oral solution.

Clear, colourless, oral solution.

CELSENTRI, in combination with other antiretroviral medicinal products, is indicated fortreatment-experienced adults, adolescents and children of 2 years of age, and older and weighing atleast 10 kg infected with only CCR5-tropic HIV-1 detectable (see sections 4.2 and 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 sensitivedetection method on a newly drawn blood sample. The Monogram Trofile assay was used in theclinical studies of CELSENTRI (see sections 4.4 and 5.1). The viral tropism cannot be safelypredicted 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 CCR5antagonists) with a CXCR4 or dual/mixed tropic virus. There are no data regarding the switch froma medicinal product of a different antiretroviral class to CELSENTRI in virologically suppressedpatients. Alternative treatment options should be considered.

The recommended dose of CELSENTRI is 150 mg (with potent CYP3A inhibitor with or without apotent CYP3A inducer), 300 mg (without potent CYP3A inhibitors or inducers) or 600 mg twicedaily (with potent CYP3A inducer without a potent CYP3A inhibitor) depending on interactionswith concomitant antiretroviral therapy and other medicinal products (see section 4.5).

Children from 2 years of age and weighing at least 10kg

The recommended dose of CELSENTRI should be based on body weight (kg) and should notexceed the recommended adult dose. CELSENTRI oral solution (20 mg per mL) formulationshould be prescribed if a child is unable to reliably swallow CELSENTRI tablets.

The recommended dose of CELSENTRI differs depending on interactions with concomitantantiretroviral therapy and other medicinal products. Refer to section 4.5 for corresponding adultdosage.

Many medicines have profound effects on maraviroc exposure due to drug-drug interactions. Priorto deciding the dose of CELSENTRI by weight, please refer to Table 2 in section 4.5 to carefullydetermine the corresponding adult dose. The corresponding paediatric dose can then be obtainedfrom Table 1 below. If uncertainty still exists, contact a pharmacist for advice.

Table 1. Recommended dosing regimen in children aged 2 years and above and weighing atleast 10 kg

Dose of CELSENTRI in children based on weight

Adult Concomitant20 to 30 todosage* Medications 10 to at leastless than less thanless than 20 kg 40 kg30 kg 40 kg

CELSENTRIwith productsthat are potent150 mg twice 50 mg 75 mg 100 mg 150 mg

CYP3Adaily twice daily twice daily twice daily twice dailyinhibitors (withor without a

CYP3A inducer)

CELSENTRIwith productsthat are not300 mg twice Data to support these doses are 300 mg 300 mgpotent CYP3Adaily lacking. twice daily twice dailyinhibitors orpotent CYP3Ainducers

CELSENTRI

Data to support these doses are lacking and CELSENTRI is notwith productsrecommended in children taking concomitant interacting600 mg twice that are CYP3Amedicinal products that in adults would require a 600 mg twicedaily inducers (withoutdaily dose.

a potent CYP3Ainhibitor)

* Based on drug-drug interactions (refer to section 4.5)

There is limited experience in patients >65 years of age (see section 5.2), therefore CELSENTRIshould be used with caution in this population.

In adult patients with a creatinine clearance of <80 mL/min, who are also receiving potent CYP3A4inhibitors, the dose interval of maraviroc should be adjusted to 150 mg once daily (see sections 4.4and 4.5).

Examples of agents/regimens with such potent CYP3A4-inhibiting activity are:

* ritonavir-boosted protease inhibitors (with the exception of tipranavir/ritonavir),

* cobicistat,

* itraconazole, voriconazole, clarithromycin and telithromycin,

* telaprevir and boceprevir.

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

There are no data available to recommend a specific dose in paediatric patients with renalimpairment. Therefore, CELSENTRI should be used with caution in this population.

Limited data are available in adult patients with hepatic impairment and no data are available torecommend a specific dose for paediatric patients. Therefore, CELSENTRI should be used withcaution in patients with hepatic impairment (see sections 4.4 and 5.2).

Paediatric patients (children younger than 2 years of age or weighing less than 10 kg)

The safety and efficacy of CELSENTRI in children younger than 2 years of age or weighing lessthan 10 kg has not been established (see section 5.2). No data are available.

Oral use.

CELSENTRI can be taken with or without food.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Hepatic disease

The safety and efficacy of maraviroc have not been specifically studied in patients with significantunderlying liver disorders.

Cases of hepatotoxicity and hepatic failure with allergic features have been reported in associationwith maraviroc. In addition, an increase in hepatic adverse reactions with maraviroc was observedduring studies of treatment-experienced subjects with HIV infection, although there was no overallincrease in ACTG Grade 3/4 liver function test abnormalities (see section 4.8). Hepatobiliarydisorders reported in treatment-naïve patients were uncommon and balanced between treatmentgroups (see section 4.8). Patients with pre-existing liver dysfunction, including chronic activehepatitis, can have an increased frequency of liver function abnormalities during combinationantiretroviral therapy and should be monitored according to standard practice.

Discontinuation of maraviroc should be strongly considered in any patient with signs or symptomsof acute hepatitis, in particular if drug-related hypersensitivity is suspected or with increased livertransaminases combined with rash or other systemic symptoms of potential hypersensitivity (e.g.

pruritic rash, eosinophilia or elevated IgE).

There are limited data in patients with hepatitis B and/or C virus co-infection (see section 5.1).

Caution should be exercised when treating these patients. In case of concomitant antiviral therapyfor hepatitis B and/or C, please refer to the relevant product information for these medicinalproducts.

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

Severe skin and hypersensitivity reactions

Hypersensitivity reactions including severe and potentially life threatening events have beenreported in patients taking maraviroc, in most cases concomitantly with other medicinal productsassociated with these reactions. These reactions included rash, fever, and sometimes organdysfunction and hepatic failure. Discontinue maraviroc and other suspect agents immediately ifsigns or symptoms of severe skin or hypersensitivity reactions develop. Clinical status and relevantblood chemistry should be monitored and appropriate symptomatic therapy initiated.

Limited data exist with the use of maraviroc in patients with severe cardiovascular disease,therefore special caution should be exercised when treating these patients with maraviroc. In thepivotal studies of treatment-experienced patients coronary heart disease events were more commonin patients treated with maraviroc than with placebo (11 during 609 PY vs 0 during 111 PY offollow-up). In treatment-naïve patients such events occurred at a similarly low rate with maravirocand control (efavirenz).

Postural hypotension

When maraviroc was administered in studies with healthy volunteers at doses higher than therecommended dose, cases of symptomatic postural hypotension were seen at a greater frequencythan with placebo. Caution should be used when administering maraviroc in patients onconcomitant medicinal products known to lower blood pressure. Maraviroc should also be usedwith caution in patients with severe renal insufficiency and in patients who have risk factors for, orhave a history of postural hypotension. Patients with cardiovascular co-morbidities could be atincreased risk of cardiovascular adverse reactions triggered by postural hypotension.

An increased risk of postural hypotension may occur in patients with severe renal insufficiencywho are treated with potent CYP3A inhibitors or boosted protease inhibitors (PIs) and maraviroc.

This risk is due to potential increases in maraviroc maximum concentrations when maraviroc isco-administered with potent CYP3A inhibitors or boosted PIs in these patients.

Immune reconstitution syndrome

In HIV infected patients with severe immune deficiency at the time of institution of combinationantiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunisticpathogens 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). Anyinflammatory symptoms should be evaluated and treatment initiated when necessary. Autoimmunedisorders (such as Graves’ disease and autoimmune hepatitis) have also been reported to occur inthe setting of immune reactivation; however, the reported time to onset is more variable and theseevents can occur many months after initiation of treatment.

Tropism

Maraviroc should only be used when only CCR5-tropic HIV-1 is detectable (i.e. CXCR4 ordual/mixed tropic virus not detected) as determined by an adequately validated and sensitivedetection method (see sections 4.1, 4.2 and 5.1). The Monogram Trofile assay was used in theclinical studies of maraviroc. The viral tropism cannot be predicted by treatment history orassessment of stored samples.

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

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

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

Physicians should ensure that appropriate dose adjustment of maraviroc is made when maraviroc isco-administered with potent CYP3A4 inhibitors and/or inducers since maraviroc concentrationsand its therapeutic effects may be affected (see sections 4.2 and 4.5). Please also refer to therespective Summary of Product Characteristics of the other antiretroviral medicinal products usedin the combination.

Although the aetiology is considered to be multifactorial (including corticosteroid use, alcoholconsumption, severe immunosuppression, higher body mass index), cases of osteonecrosis havebeen reported particularly in patients with advanced HIV-disease and/or long-term exposure tocombination antiretroviral therapy (CART). Patients should be advised to seek medical advice ifthey experience joint aches and pain, joint stiffness or difficulty in movement.

Potential effect on immunity

CCR5 antagonists could potentially impair the immune response to certain infections. This shouldbe taken into consideration when treating infections such as active tuberculosis and invasive fungalinfections. The incidence of AIDS-defining infections was similar between maraviroc and placeboarms in the pivotal studies.

CELSENTRI contains 1 mg sodium benzoate (E211) in each mL.

CELSENTRI contains less than 1 mmol sodium (23 mg) in each mL, that is to say essentially‘sodium free’.

Maraviroc is a metabolised by cytochrome P450 CYP3A4 and CYP3A5. Co-administration ofmaraviroc with medicinal products that induce CYP3A4 may decrease maraviroc concentrationsand reduce its therapeutic effects. Co-administration of maraviroc with medicinal products thatinhibit CYP3A4 may increase maraviroc plasma concentrations. Dose adjustment of maraviroc isrecommended when maraviroc is co-administered with potent CYP3A4 inhibitors and/or inducers.

Further details for concomitantly administered medicinal products are provided below (see Table2).

Maraviroc is a substrate for the transporters P-glycoprotein and OATP1B1, but the effect of thesetransporters on the exposure to maraviroc is not known.

Based on the in vitro and clinical data, the potential for maraviroc to affect the pharmacokinetics ofco-administered medicinal products is low. In vitro studies have shown that maraviroc does notinhibit OATP1B1, MRP2 or any of the major P450 enzymes at clinically relevant concentrations(CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4). Maraviroc had noclinically relevant effect on the pharmacokinetics of midazolam, the oral contraceptivesethinylestradiol and levonorgestrel, or urinary 6β-hydroxycortisol/cortisol ratio, suggesting noinhibition or induction of CYP3A4 in vivo. At higher exposure of maraviroc a potential inhibitionof CYP2D6 cannot be excluded.

Renal clearance accounts for approximately 23% of total clearance of maraviroc when maraviroc isadministered without CYP3A4 inhibitors. In vitro studies have shown that maraviroc does notinhibit any of the major renal uptake transporters at clinically relevant concentrations (OAT1,

OAT3, OCT2, OCTN1, and OCTN2). Additionally, co-administration of maraviroc with tenofovir(substrate for renal elimination) and cotrimoxazole (contains trimethoprim, a renal cation transportinhibitor), showed no effect on the pharmacokinetics of maraviroc. In addition, co-administrationof maraviroc with lamivudine/zidovudine showed no effect of maraviroc on lamivudine (primarilyrenally cleared) or zidovudine (non-P450 metabolism and renal clearance) pharmacokinetics.

Maraviroc inhibits P-glycoprotein in vitro (IC50 is 183 μM). However, maraviroc does notsignificantly affect the pharmacokinetics of digoxin in vivo. It may not be excluded that maraviroccan increase the exposure to the P-glycoprotein substrate dabigatran etexilate.

Table 2: Interactions and adulta dose recommendations with other medicinal products

Medicinal product by Effects on active substance levels Recommendationstherapeutic areas Geometric mean change if not concerning co-(dose of CELSENTRI stated otherwise administration in adultsused in study)

ANTI-INFECTIVES

Antiretrovirals

Pharmacokinetic Enhancers

Cobicistat Interaction not studied. CELSENTRI dose should bedecreased to 150 mg twice

Cobicistat is a potent CYP3A daily when co-administeredinhibitor. with cobicistat containingregimen.

Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs)

Lamivudine 150 mg BID Lamivudine AUC12: ↔ 1.13 No significant interaction(maraviroc 300 mg BID) Lamivudine Cmax: ↔ 1.16 seen/expected. CELSENTRI

Maraviroc concentrations not 300 mg twice daily andmeasured, no effect is expected. NRTIs can be

Tenofovir 300 mg QD Maraviroc AUC12: ↔ 1.03 co-administered without dose(maraviroc 300 mg BID) Maraviroc Cmax: ↔ 1.03 adjustment.

Tenofovir concentrations notmeasured, no effect is expected.

Zidovudine 300 mg BID Zidovudine AUC12: ↔ 0.98(maraviroc 300 mg BID) Zidovudine Cmax: ↔ 0.92

Maraviroc concentrations notmeasured, no effect is expected.

Integrase Inhibitors

Elvitegravir/ritonavir Maraviroc AUC12: ↑ 2.86 (2.33-3.51) Elvitegravir as a single agent150/100mg QD Maraviroc Cmax: ↑ 2.15 (1.71-2.69) is indicated only in(maraviroc 150 mg BID) Maraviroc C12: ↑ 4.23 (3.47-5.16) combination with certainritonavir boosted PIs.

Elvitegravir AUC24: ↔ 1.07(0.96-1.18) Elvitegravir per se is not

Elvitegravir Cmax: ↔ 1.01 (0.89-1.15) expected to affect maraviroc

Elvitegravir C24: ↔ 1.09 (0.95-1.26) exposure to a clinicallyrelevant degree and theobserved effect is attributed toritonavir.

Thus, CELSENTRI doseshould be modified in linewith the recommendation forco-administration withrespective PI/ritonavircombination (see ‘Protease

Inhibitors’).

Raltegravir 400 mg BID Maraviroc AUC12: ↓ 0.86 No clinically significant(maraviroc 300 mg BID) Maraviroc Cmax: ↓ 0.79 interaction seen.

CELSENTRI 300 mg twice

Raltegravir AUC12: ↓ 0.63 daily and raltegravir can be

Raltegravir Cmax: ↓ 0.67 co-administered without dose

Raltegravir C12: ↓ 0.72 adjustment.

Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

Efavirenz 600 mg QD Maraviroc AUC12: ↓ 0.55 CELSENTRI dose should be(maraviroc 100 mg BID) Maraviroc Cmax: ↓ 0.49 increased to 600 mg twice

Efavirenz concentrations not daily when co-administeredmeasured, no effect is expected. with efavirenz in the absenceof a potent CYP3A4 inhibitor.

For combination withefavirenz + PI, see separaterecommendations below.

Etravirine 200 mg BID Maraviroc AUC12: ↓ 0.47 Etravirine is only approved(maraviroc 300 mg BID) Maraviroc Cmax: ↓ 0.40 for use with boosted proteaseinhibitors. For combination

Etravirine AUC12: ↔ 1.06 with etravirine + PI, see

Etravirine Cmax: ↔ 1.05 below.

Etravirine C12: ↔ 1.08

Nevirapine 200 mg BID Maraviroc AUC12: ↔ compared to Comparison to exposure in(maraviroc 300 mg Single historical controls historical controls suggests

Dose) Maraviroc Cmax: ↑ compared to that CELSENTRI 300 mghistorical controls twice daily and nevirapine

Nevirapine concentrations not can be co-administeredmeasured, no effect is expected. without dose adjustment.

Protease Inhibitors (PIs)

Atazanavir 400 mg QD Maraviroc AUC12 ↑ 3.57 CELSENTRI dose should be(maraviroc 300 mg BID) Maraviroc Cmax: ↑ 2.09 decreased to 150 mg twice

Atazanavir concentrations not daily when co-administeredmeasured, no effect is expected. with a PI; except in

Atazanavir/ritonavir Maraviroc AUC12 ↑ 4.88 combination with300 mg/100 mg QD Maraviroc Cmax: ↑ 2.67 tipranavir/ritonavir where the(maraviroc 300 mg BID) Atazanavir/ritonavir concentrations CELSENTRI dose should benot measured, no effect is expected. 300 mg BID.

Lopinavir/ritonavir Maraviroc AUC12 ↑ 3.95400 mg/100 mg BID Maraviroc Cmax: ↑ 1.97(maraviroc 300 mg BID) Lopinavir/ritonavir concentrations notmeasured, no effect is expected.

Saquinavir/ritonavir Maraviroc AUC12 ↑ 9.771000 mg/100 mg BID Maraviroc Cmax: ↑ 4.78(maraviroc 100 mg BID) Saquinavir/ritonavir concentrationsnot measured, no effect is expected.

Darunavir/ritonavir Maraviroc AUC12 ↑ 4.05600 mg/100 mg BID Maraviroc Cmax: ↑ 2.29(maraviroc 150 mg BID) Darunavir/ritonavir concentrationswere consistent with historical data.

Nelfinavir Limited data are available for co-administration with nelfinavir.

Nelfinavir is a potent CYP3A4inhibitor and would be expected toincrease maraviroc concentrations.

Indinavir Limited data are available for co-administration with indinavir.

Indinavir is a potent CYP3A4inhibitor. Population PK analysis inphase 3 studies suggests dosereduction of maraviroc whenco-administered with indinavir givesappropriate maraviroc exposure.

Tipranavir/ritonavir Maraviroc AUC12 ↔ 1.02500 mg/200 mg BID Maraviroc Cmax: ↔ 0.86(maraviroc 150 mg BID) Tipranavir/ritonavir concentrationswere consistent with historical data.

Fosamprenavir/ritonavir Maraviroc AUC12: ↑ 2.49 Concomitant use is not700 mg/100 mg BID Maraviroc Cmax: ↑ 1.52 recommended. Significant(maraviroc 300 mg BID) Maraviroc C12: ↑ 4.74 reductions in amprenavir Cminobserved may result in

Amprenavir AUC12: ↓ 0.65 virological failure in patients

Amprenavir Cmax: ↓ 0.66

Amprenavir C12: ↓ 0.64

Ritonavir AUC12: ↓ 0.66

Ritonavir Cmax: ↓ 0.61

Ritonavir C12: ↔ 0.86

NNRTI + PI

Efavirenz 600 mg QD + Maraviroc AUC12: ↑ 2.53 CELSENTRI dose should belopinavir/ritonavir Maraviroc Cmax: ↑ 1.25 decreased to 150 mg twice400mg/100 mg BID Efavirenz, lopinavir/ritonavir daily when co-administered(maraviroc 300 mg BID) concentrations not measured, no with efavirenz and a PIeffect expected. (except tipranavir/ritonavir

Efavirenz 600 mg QD + Maraviroc AUC12: ↑ 5.00 where the dose should be 600saquinavir/ritonavir Maraviroc Cmax: ↑ 2.26 mg twice daily).

1000 mg/100 mg BID Efavirenz, saquinavir/ritonavir Concomitant use of(maraviroc 100 mg BID) concentrations not measured, no CELSENTRI andeffect expected. fosamprenavir/ritonavir is not

Efavirenz and Not studied. Based on the extent of recommended.

atazanavir/ritonavir or inhibition by atazanavir/ritonavir ordarunavir/ritonavir darunavir/ritonavir in the absence ofefavirenz, an increased exposure isexpected.

Etravirine and Maraviroc AUC12: ↑ 3.10 CELSENTRI dose should bedarunavir/ritonavir Maraviroc Cmax: ↑ 1.77 decreased to 150 mg twice(maraviroc 150 mg BID) daily when co-administered

Etravirine AUC12: ↔ 1.00 with etravirine and a PI.

Etravirine Cmax: ↔ 1.08 Concomitant use of

Etravirine C12: ↓ 0.81 CELSENTRI andfosamprenavir/ritonavir is not

Darunavir AUC12: ↓ 0.86 recommended.

Darunavir Cmax: ↔ 0.96

Darunavir C12: ↓ 0.77

Ritonavir AUC12: ↔ 0.93

Ritonavir Cmax: ↔ 1.02

Ritonavir C12: ↓ 0.74

Etravirine and Not studied. Based on the extent oflopinavir/ritonavir, inhibition by lopinavir/ritonavir,saquinavir/ritonavir or saquinavir/ritonavir oratazanavir/ritonavir atazanavir/ritonavir in the absence ofetravirine, an increased exposure isexpected.

ANTIBIOTICS

Sulphamethoxazole/ Maraviroc AUC12: ↔ 1.11 CELSENTRI 300 mg twice

Trimethoprim Maraviroc Cmax: ↔ 1.19 daily and sulphamethoxazole/800 mg/160 mg BID Sulphamethoxazole/trimethoprim trimethoprim can be(maraviroc 300 mg BID) concentrations not measured, no co-administered without doseeffect expected. adjustment.

Rifampicin 600 mg QD Maraviroc AUC: ↓ 0.37 CELSENTRI dose should be(maraviroc 100 mg BID) Maraviroc Cmax: ↓ 0.34 increased to 600 mg twice

Rifampicin concentrations not daily when co-administeredmeasured, no effect expected. with rifampicin in the absenceof a potent CYP3A4 inhibitor.

This dose adjustment has notbeen studied in HIV patients.

See also section 4.4.

Rifampicin + efavirenz Combination with two inducers has Concomitant use ofnot been studied. There may be a risk CELSENTRI and rifampicinof suboptimal levels with risk of loss + efavirenz is notof virologic response and resistance recommended.

development.

Rifabutin + PI Not studied. Rifabutin is considered CELSENTRI dose should beto be a weaker inducer than decreased to 150 mg twicerifampicin. When combining rifabutin daily when co-administeredwith protease inhibitors that are with rifabutin and a PIpotent inhibitors of CYP3A4 a net (except tipranavir/ritonavirinhibitory effect on maraviroc is where the dose should be 300expected. mg twice daily). See alsosection 4.4.

Concomitant use of

CELSENTRI andfosamprenavir/ritonavir is notrecommended.

Clarithromycin, Not studied, but both are potent CELSENTRI dose should be

Telithromycin CYP3A4 inhibitors and would be decreased to 150 mg twiceexpected to increase maraviroc daily when co-administeredconcentrations. with clarithromycin andtelithromycin.

ANTICONVULSANTS

Carbamezepine, Not studied, but these are potent CELSENTRI dose should be

Phenobarbital, CYP3A4 inducers and would be increased to 600 mg twice

Phenytoin expected to decrease maraviroc daily when co-administeredconcentrations. with carbamazepine,phenobarbital or phenytoin inthe absence of a potent

CYP3A4 inhibitor.

ANTIFUNGALS

Ketoconazole 400 mg QD Maraviroc AUCtau: ↑ 5.00 CELSENTRI dose should be(maraviroc 100 mg BID) Maraviroc Cmax: ↑ 3.38 decreased to 150 mg twice

Ketoconazole concentrations not daily when co-administeredmeasured, no effect is expected. with ketoconazole.

Itraconazole Not studied. Itraconazole, is a potent CELSENTRI dose should be

CYP3A4 inhibitor and would be decreased to 150 mg twiceexpected to increase the exposure of daily when co-administeredmaraviroc. with itraconazole.

Fluconazole Fluconazole is considered to be a CELSENTRI 300 mg twicemoderate CYP3A4 inhibitor. daily should be administered

Population PK studies suggest that a with caution whendose adjustment of maraviroc is not co-administered withrequired. fluconazole.

ANTIVIRALS

Anti-HBV

Pegylated interferon Pegylated interferon has not been CELSENTRI 300 mg twicestudied, no interaction is expected. daily and pegylated interferoncan be co-administeredwithout dose adjustment.

Anti-HCV

Ribavirin Ribavirin has not been studied, no CELSENTRI 300 mg twiceinteraction is expected. daily and ribavirin can beco-administered without doseadjustment.

DRUG ABUSE

Methadone Not studied, no interaction expected. CELSENTRI 300 mg twicedaily and methadone can beco-administered without doseadjustment.

Buprenorphine Not studied, no interaction expected. CELSENTRI 300 mg twicedaily and buprenorphine canbe co-administered withoutdose adjustment.

LIPID LOWERING

MEDICINAL PRODUCTS

Statins Not studied, no interaction expected. CELSENTRI 300 mg twicedaily and statins can beco-administered without doseadjustment.

ANTIARRHYTHMICS

Digoxin 0.25 mg Digoxin. AUCt: ↔ 1.00 CELSENTRI 300 mg twice

Single Dose Digoxin. Cmax: ↔ 1.04 daily and digoxin can be(maraviroc 300 mg BID) Maraviroc concentrations not co-administered without dosemeasured, no interaction expected. adjustment.

The effect of maraviroc ondigoxin at the dose of 600 mg

BID has not been studied.

ORAL CONTRACEPTIVES

Ethinylestradiol 30 mcg QD Ethinylestradiol. AUCt: ↔ 1.00 CELSENTRI 300 mg twice(maraviroc 100 mg BID) Ethinylestradiol. Cmax: ↔ 0.99 daily. and ethinylestradiol can

Maraviroc concentrations not be co-administered withoutmeasured, no interaction expected. dose adjustment.

Levonorgestrel 150 mcg Levonorgestrel. AUC12: ↔ 0.98 CELSENTRI 300 mg twice

QD Levonorgestrel. Cmax: ↔ 1.01 daily and levonorgestrel can(maraviroc 100 mg BID) Maraviroc concentrations not be co-administered withoutmeasured, no interaction expected. dose adjustment.

SEDATIVES

Benzodiazepines

Midazolam 7.5 mg Single Midazolam. AUC: ↔ 1.18 CELSENTRI 300 mg twice

Dose Midazolam. Cmax: ↔ 1.21 daily and midazolam can be(maraviroc 300 mg BID) Maraviroc concentrations not co-administered without dosemeasured, no interaction expected. adjustment.

HERBAL PRODUCTS

St. John’s Wort Co-administration of maraviroc with Concomitant use of maraviroc(Hypericum Perforatum) St. John's Wort is expected to and St. John's Wort orsubstantially decrease maraviroc products containing St. John'sconcentrations and may result in Wort is not recommended.

suboptimal levels and lead to loss ofvirologic response and possibleresistance to maraviroc.a Refer to Table 1 for maraviroc paediatric dosing recommendations when co-administered with antiretroviral therapy and othermedicinal products.

There are limited data from the use of maraviroc in pregnant women. The effect of maraviroc onhuman pregnancy is unknown. Studies in animals showed reproductive toxicity at high exposures.

Primary pharmacological activity (CCR5 receptor affinity) was limited in the species studied (seesection 5.3). Maraviroc should be used during pregnancy only if the expected benefit justifies thepotential risk to the foetus.

It is unknown whether maraviroc is excreted in human milk. Available toxicological data inanimals has shown extensive excretion of maraviroc in milk. Primary pharmacological activity(CCR5 receptor affinity) was limited in the species studied (see section 5.3). A risk to thenewborn/infants cannot be excluded.

It is recommended that women living with HIV do not breast-feed their infants in order to avoidtransmission of HIV.

There is no data on the effects of maraviroc on human fertility. In rats, there were no adverseeffects on male or female fertility (see section 5.3).

Maraviroc may have a minor influence on the ability to drive and use machines. Patients should beinformed that dizziness has been reported during treatment with maraviroc. The clinical status ofthe patient and the adverse reaction profile of maraviroc should be borne in mind when consideringthe patient's ability to drive, cycle or operate machinery.

Assessment of treatment related adverse reactions is based on pooled data from two Phase 2b/3studies in treatment-experienced adult patients (MOTIVATE 1 and MOTIVATE 2) and one studyin treatment-naïve adult patients (MERIT) infected with CCR5-tropic HIV-1 (see sections 4.4 and5.1).

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 adverse reactions are listed by system organ class (SOC) and frequency. Within eachfrequency 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), rare (≥1/10,000 to <1/1000) , or not known (cannot be estimated from theavailable data). The adverse reactions and laboratory abnormalities presented below are notexposure adjusted.

Table 3: Adverse reactions observed in clinical trials or post-marketing

System Organ Class Adverse reaction Frequency

Infections and infestations Pneumonia, oesophageal candidiasis uncommon

Neoplasm benign, malignant and Bile duct cancer, diffuse large B-cell rareunspecified (including cysts and lymphoma, Hodgkin’s disease,polyps) metastases to bone, metastases toliver, metastases to peritoneum,nasopharyngeal cancer, oesophagealcarcinoma

Blood and lymphatic system Anaemia commondisorders Pancytopenia, granulocytopenia rare

Metabolism and nutrition disorders Anorexia common

Psychiatric disorders Depression, insomnia common

Nervous system disorders Seizures and seizure disorders uncommon

Cardiac disorders Angina pectoris rare

Vascular disorders Postural hypotension (see section 4.4) uncommon

Gastrointestinal disorders Abdominal pain, flatulence, nausea common

Hepatobiliary disorders Alanine aminotransferase increased, commonaspartate aminotransferase increased

Hyperbilirubinaemia, gamma- uncommonglutamyltransferase increased

Hepatitis toxic, hepatic failure, rarehepatic cirrhosis, blood alkalinephosphatase increased

Hepatic failure with allergic features very rare

Skin and subcutaneous tissue Rash commondisorders Stevens-Johnson syndrome/Toxic rare/not knownepidermal necrolysis

Musculoskeletal and connective Myositis, blood creatine uncommontissue disorders phosphokinase increased

Muscle atrophy rare

Renal and urinary disorders Renal failure, proteinuria uncommon

General disorders and Asthenia commonadministration site conditions

Delayed type hypersensitivity reactions, typically occurring within 2-6 weeks after start of therapyand including rash, fever, eosinophilia and liver reactions have been reported (see also section 4.4).

Skin and liver reactions can occur as single events, or in combination.

In HIV infected patients with severe immune deficiency at the time of initiation of combinationantiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunisticinfections may arise. Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis)have also been reported; however, the reported time to onset is more variable and these events canoccur many months after initiation of treatment (see section 4.4).

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

Cases of syncope caused by postural hypotension have been reported.

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

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

Maraviroc 300 mg Placebo + OBT

Laboratory parameter Limit twice daily+ OBT N =207*

N =421* (%)(%)

Aspartate aminotransferase >5.0x ULN 4.8 2.9

Alanine aminotransferase >5.0x ULN 2.6 3.4

Total bilirubin >5.0x ULN 5.5 5.3

Amylase >2.0x ULN 5.7 5.8

Lipase >2.0x ULN 4.9 6.3

Absolute neutrophil count <750/mm3 4.3 1.9

ULN: Upper Limit of Normal

OBT: Optimised Background Therapy

* Percentages based on total patients evaluated for each laboratory parameter

The MOTIVATE studies were extended beyond 96 weeks, with an observational phase extended to5 years in order to assess the long term safety of maraviroc. The Long Term Safety/Selected

Endpoints (LTS/SE) included death, AIDS-defining events, hepatic failure, Myocardialinfarction/cardiac ischaemia, malignancies, rhabdomyolysis and other serious infectious eventswith maraviroc treatment. The incidence of these selected endpoints for subjects on maraviroc inthis observational phase was consistent with the incidence seen at earlier timepoints in the studies.

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

The adverse reaction profile in paediatric patients is based on 48 Week safety data from study

A4001031 in which 103 HIV-1 infected, treatment-experienced patients aged 2 to <18 yearsreceived maraviroc twice-daily with optimised background therapy (OBT). Overall, the safetyprofile in paediatric patients was similar to that observed in adult clinical studies.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

The highest dose administered in clinical studies was 1,200 mg. The dose limiting adverse reactionwas postural hypotension.

Prolongation of the QT interval was seen in dogs and monkeys at plasma concentrations 6 and 12times, respectively, those expected in humans at the maximum recommended dose of 300 mg twicedaily. However, no clinically significant QT prolongation compared to placebo + OBT was seen inthe Phase 3 clinical studies using the recommended dose of maraviroc or in a specificpharmacokinetic 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 ofgeneral supportive measures including keeping the patient in a supine position, careful assessmentof patient vital signs, blood pressure and ECG.

If indicated, elimination of unabsorbed active maraviroc should be achieved by emesis or gastriclavage. Administration of activated charcoal may also be used to aid in removal of unabsorbedactive substance. Since maraviroc is moderately protein bound, dialysis may be beneficial inremoval of this medicine. Further management should be as recommended by the national poisonscentre, where available.

Pharmacotherapeutic group: Antivirals for systemic use, other antivirals, ATC code: J05AX09

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

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/mLwithout significant changes between different subtypes tested. The antiviral activity of maravirocagainst HIV-2 has not been evaluated. For details please refer to the pharmacology section of the

CELSENTRI European Public Assessment Report (EPAR) on the European Medicines Agency(EMA) website.

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

Virologic Escape

Virologic escape from maraviroc can occur via 2 routes: the emergence of pre-existing virus whichcan use CXCR4 as its entry co-receptor (CXCR4-using virus) or the selection of virus thatcontinues to use exclusively drug-bound CCR5 (CCR5-tropic virus).

In vitro

HIV-1 variants with reduced susceptibility to maraviroc have been selected in vitro, followingserial 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 characterizedphenotypically by curves that did not reach 100% inhibition in assays using serial dilutions ofmaraviroc (<100% maximal percentage inhibition (MPI)). Traditional IC50/IC90 fold-change wasnot a useful parameter to measure phenotypic resistance, as those values were sometimesunchanged despite significantly reduced sensitivity.

Genotypic resistance

Mutations were found to accumulate in the gp120 envelope glycoprotein (the viral protein thatbinds to the CCR5 co-receptor). The position of these mutations was not consistent betweendifferent isolates. Hence, the relevance of these mutations to maraviroc susceptibility in otherviruses is not known.

Cross-resistance in vitro

HIV-1 clinical isolates resistant to NRTIs, NNRTIs, PIs and enfuvirtide were all susceptible tomaraviroc in cell culture. Maraviroc-resistant viruses that emerged in vitro remained sensitive tothe fusion inhibitor enfuvirtide and the PI, saquinavir.

In vivo

Treatment-Experienced Adult Patients

In the pivotal studies (MOTIVATE 1 and MOTIVATE 2), 7.6% of patients had a change intropism result from CCR5-tropic to CXCR4-tropic or dual/mixed-tropic between screening andbaseline (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 treatmenton maraviroc, as compared to 6% of subjects who experienced treatment failure in the placebo +

OBT arm. To investigate the likely origin of the on-treatment CXCR4-using virus, a detailed clonalanalysis was conducted on virus from 20 representative subjects (16 subjects from the maravirocarms and 4 subjects from the placebo + OBT arm) in whom CXCR4-using virus was detected attreatment failure. 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 viruspresent 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 revertedback to CCR5 tropism in 33 of 36 patients with more than 35 days of follow-up.

At the time of failure with CXCR4-using virus, the resistance pattern to other antiretroviralsappears 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 thepreviously undetected CXCR4 -using population (i.e. minor viral population) harbours the sameresistance 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 58patients had virus with reduced sensitivity to maraviroc. In the remaining 36 patients, there was noevidence of virus with reduced sensitivity as identified by exploratory virology analyses on arepresentative group. The latter group had markers correlating to low compliance (low and variabledrug levels and often a calculated high residual sensitivity score of the OBT). In patients failingtherapy with CCR5-tropic virus only, maraviroc might be considered still active if the MPI value is≥95% (PhenoSense Entry assay). Residual activity in vivo for viruses with MPI-values <95% hasnot been determined.

Genotypic resistance

A relatively small number of individuals receiving maraviroc-containing therapy have failed withphenotypic resistance (i.e. the ability to use drug-bound CCR5 with MPI <95%). To date, nosignature mutation(s) have been identified. The gp120 amino acid substitutions identified so farare context dependent and inherently unpredictable with regards to maraviroc susceptibility.

Treatment-Experienced Paediatric Patients

In the Week 48 analysis (N=103), non-CCR5 tropic-virus was detected in 5/23 (22%) subjects atvirologic failure. One additional subject had CCR5 tropic-virus with reduced susceptibility tomaraviroc at virologic failure, although this was not retained at the end of treatment. Subjects withvirologic failure generally appeared to have low compliance to both maraviroc and the backgroundantiretroviral elements of their regimens. Overall, the mechanisms of resistance to maravirocobserved in this treatment-experienced paediatric population were similar to those observed inadult populations.

Studies in Treatment-Experienced Adult Patients Infected with CCR5-tropic Virus

The clinical efficacy of maraviroc (in combination with other antiretroviral medicinal products) onplasma HIV RNA levels and CD4+ cell counts have been investigated in two pivotal randomized,double blind, multicentre studies (MOTIVATE 1 and MOTIVATE 2, n=1076) in patients infectedwith 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 medicinalproduct classes [≥1 NRTIs, ≥1 NNRTIs, ≥2 PIs, and/or enfurvirtide] or documented resistance to atleast one member of each class. Patients were randomised in a 2:2:1 ratio to maraviroc 300 mg(dose equivalence) once daily, twice daily or placebo in combination with an optimizedbackground 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 genotypicand phenotypic viral resistance measurements.

Table 5: Demographic and baseline characteristics of patients (pooled studies MOTIVATE 1and MOTIVATE 2)

Maraviroc 300 mg Placebo + OBT

Demographic and Baseline Characteristics twice daily+ OBT

N = 209

N = 426

Age (years) 46.3 45.7(Range, years) 21-73 29-72

Male Sex 89.7% 88.5%

Race (White/Black/Other) 85.2%/12%/2.8% 85.2%/12.4%/2.4%

Mean Baseline HIV-1 RNA (log10 copies/mL) 4.85 4.86

Median Baseline CD4+ Cell Count (cells/mm3) 166.8 171.3(range, cells/mm3) (2.0-820.0) (1.0-675.0)

Screening Viral Load >100,000 copies/mL 179 (42.0%) 84 (40.2%)

Baseline CD4+ Cell Count ≤200 cells/mm3 250 (58.7%) 118 (56.5%)

Number (Percentage) of patients with GSS score1:

0 102 (23.9%) 51 (24.4%)1 138 (32.4%) 53 (25.4%)2 80 (18.8%) 41 (19.6%)≥3 104 (24.4%) 59 (28.2%)1Based on GeneSeq resistance assay

Limited numbers of patients from ethnicities other than Caucasian were included in the pivotalclinical 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 intropism result to dual/mixed tropic or CXCR4, in the maraviroc 300 mg twice daily + OBT(+56 cells/mm3) group was greater than that seen in patients failing placebo + OBT(+13.8 cells/mm3) regardless of tropism.

Table 6: Efficacy Outcomes at week 48 (pooled studies MOTIVATE 1 and MOTIVATE 2)

Outcomes Maraviroc 300 mg Placebo + Difference1twice daily OBT (Confidence+ OBT Interval2)

N=426 N=209

HIV-1 RNA

Mean change from baseline -1.837 -0.785 -1.055(log copies/mL) (-1.327, -0.783)

Percentage of patients with 56.1% 22.5% Odds ratio: 4.76

HIV-1 RNA <400 copies/mL (3.24, 7.00)

Percentage of patients with 45.5% 16.7% Odds ratio: 4.49

HIV-1 RNA <50 copies/mL (2.96, 6.83)

CD4+ cell count 59.17

Mean change from baseline 122.78 63.13(cells/µL) (44.28, 81.99)21 p-values < 0.00012 For all efficacy endpoints the confidence intervals were 95%, except for HIV-1 RNA Changefrom baseline, which was 97.5%

In a retrospective analysis of the MOTIVATE studies with a more sensitive assay for screening oftropism (Trofile ES), the response rates (<50 copies/mL at week 48) in patients with only CCR5-tropic virus detected at baseline was 48.2% in those treated with maraviroc + OBT (n=328), and16.3% in those treated with placebo + OBT (n=178).

Maraviroc 300 mg twice daily + OBT was superior to placebo + OBT across all subgroups ofpatients analysed (see Table 7). Patients with very low CD4+ count at baseline (i.e. <50 cells/µL)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 formaraviroc compared to placebo + OBT 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)

HIV-1 RNA <50 copies/mL

Maraviroc300 mg Placebo + OBT

Subgroups twice daily + OBT

N=426 N=209

Screening HIV-1 RNA (copies/mL):

<100,000 58.4% 26.0%≥100,000 34.7% 9.5%

Baseline CD4+ (cells/µL):

<50 16.5% 2.6%50-100 36.4% 12.0%101-200 56.7% 21.8%201-350 57.8% 21.0%≥ 350 72.9% 38.5%

Number of active ARVs in OBT1:

0 32.7% 2.0%1 44.5% 7.4%2 58.2% 31.7%≥3 62% 38.6%1Based on GSS.

Studies in Treatment-Experienced Adult Patients Infected with Non-CCR5-tropic Virus

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. Use of maravirocwas not associated with a significant decrease in HIV 1 RNA compared with placebo in thesesubjects and no adverse effect on CD4+ cell count was noted.

Studies in Treatment-Naïve Adult Patients Infected with CCR5-tropic Virus

A randomised, double-blinded study (MERIT), explored maraviroc versus efavirenz, both incombination with zidovudine/lamivudine (n=721, 1:1). After 48 weeks of treatment, maraviroc didnot 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 maravirocdiscontinued due to lack of efficacy (43 vs.15) and among patients with lack of efficacy, theproportion acquiring NRTI resistance (mainly lamivudine) was higher in the maraviroc arm. Fewerpatients discontinued maraviroc due to adverse events (15 vs. 49).

Studies in Adult Patients Co-infected with Hepatitis B and/or Hepatitis C virus

The hepatic safety of maraviroc in combination with other antiretroviral agents in CCR5-tropic

HIV-1-infected subjects with HIV RNA <50 copies/mL, co-infected with Hepatitis C and/or

Hepatitis B Virus was evaluated in a multicentre, randomized, double blinded, placebo-controlledstudy. 70 subjects (Child-Pugh Class A, n=64; Child-Pugh Class B, n=6) were randomized to themaraviroc group and 67 subjects (Child-Pugh Class A, n=59; Child-Pugh Class B, n=8) wererandomized to the placebo group.

The primary objective assessed the incidence of Grade 3 and 4 ALT abnormalities (>5x upper limitof normal (ULN) if baseline ALT ≤ ULN; or >3.5x baseline if baseline ALT > ULN) at Week 48.

One subject in each treatment arm met the primary endpoint by Week 48 (at Week 8 for placeboand Week 36 for the maraviroc arm).

Studies in Treatment-Experienced Paediatric Patients Infected with CCR5-tropic Virus

Study A4001031 is an open-label, multicenter trial in paediatric patients (aged 2 years to less than18 years) infected with CCR5-tropic HIV-1, determined by the enhanced-sensitivity Trofile assay.

Subjects were required to have HIV-1 RNA greater than 1,000 copies per mL at Screening.

All subjects (n = 103) received maraviroc twice daily and OBT. Maraviroc dosing was based onbody surface area and doses were adjusted based on whether the subject was receiving potent

CYP3A inhibitors and/or inducers.

In paediatric patients with a successful tropism test, dual mixed/CXCR4-tropic virus was detectedin around 40% of screening samples (8/27, 30% in 2-6 year-olds, 31/81, 38% in 6-12 year-olds and41/90, 46% in 12-18 year-olds), underscoring the importance of tropism testing also in thepaediatric population.

The population was 52% female and 69% black, with mean age of 10 years (range: 2 years to17 years). At baseline, mean plasma HIV-1 RNA was 4.3 log10 copies/mL (range 2.4 to 6.2 log10copies per mL), mean CD4+ cell count was 551 cells/mm3 (range 1 to 1654 cells/mm3) and mean

CD4+ % was 21% (range 0% to 42%).

At 48 weeks, using a missing, switch or discontinuation equals failure analysis, 48% of subjectstreated with maraviroc and OBT achieved plasma HIV-1 RNA less than 48 copies/mL and 65% ofsubjects achieved plasma HIV-1 RNA less than 400 copies per mL. The mean CD4+ cell count(percent) increase from baseline to Week 48 was 247 cells/mm3 (5%).

The absorption of maraviroc is variable with multiple peaks. Median peak maraviroc plasmaconcentrations are attained at 2 hours (range 0.5-4 hours) following single oral doses of 300 mgcommercial tablet administered to healthy volunteers. The pharmacokinetics of oral maraviroc arenot 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.

Co-administration of a 300 mg tablet with a high fat breakfast reduced maraviroc Cmax and AUC by33% and co-administration of 75 mg of oral solution with a high fat breakfast reduced maraviroc

AUC by 73% in adult healthy volunteers. Studies with the tablets demonstrated a reduced food-effect at higher doses.

There were no food restrictions in the adult studies (using tablet formulations) or in the paediatricstudy (using both tablet and oral solution formulations). The results did not indicate any relevantefficacy or safety concern related to either fed or fasted dosing conditions. Therefore, maraviroctablets and oral solution can be taken with or without food at the recommended doses in adults,adolescents and children aged 2 years and older and weighing at least 10 kg (see section 4.2).

Maraviroc is bound (approximately 76%) to human plasma proteins, and shows moderate affinityfor albumin and alpha-1 acid glycoprotein. The volume of distribution of maraviroc isapproximately 194 L.

Studies in humans and in vitro studies using human liver microsomes and expressed enzymes havedemonstrated that maraviroc is principally metabolized by the cytochrome P450 system tometabolites that are essentially inactive against HIV-1. In vitro studies indicate that CYP3A4 is themajor enzyme responsible for maraviroc metabolism. In vitro studies also indicate thatpolymorphic enzymes CYP2C9, CYP2D6 and CYP2C19 do not contribute significantly to themetabolism of maraviroc.

Maraviroc is the major circulating component (approximately 42% radioactivity) following a singleoral 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 nosignificant pharmacological activity. Other metabolites are products of mono-oxidation and areonly minor components of plasma radioactivity.

A mass balance/excretion study was conducted using a single 300 mg dose of 14C-labeledmaraviroc. Approximately 20% of the radiolabel was recovered in the urine and 76% wasrecovered in the faeces over 168 hours. Maraviroc was the major component present in urine (meanof 8% dose) and faeces (mean of 25% dose). The remainder was excreted as metabolites. Afterintravenous administration (30 mg), the half-life of maraviroc was 13.2 h, 22% of the dose wasexcreted unchanged in the urine and the values of total clearance and renal clearance were 44.0 L/hand 10.17 L/h respectively.

Intensive pharmacokinetics of maraviroc were evaluated in 50 treatment-experienced, CCR5-tropic, HIV-1 infected paediatric patients aged 2 to 18 years (weight 10.0 to 57.6 kg) in the dose-finding stage of clinical trial A4001031. Doses were given with food on intensive pharmacokineticevaluation days and optimised to achieve an average concentration over the dosing interval (Cavg)of greater than 100 ng/mL; otherwise, maraviroc was given with or without food. The initial doseof maraviroc was scaled from adult doses using a body surface area (BSA) of 1.73 m2 to childrenand adolescent BSA (m2)-based bands. In addition, dosing was based on whether subjects werereceiving potent CYP3A inhibitors (38/50), potent CYP3A inducers (2/50) or other concomitantmedicinal products that are not potent CYP3A inhibitors or potent CYP3A inducers (10/50) as partof OBT. Sparse pharmacokinetics were evaluated in all subjects including the additional 47subjects receiving potent CYP3A inhibitors that did not take part in the dose-finding stage. Theimpact of potent CYP3A inhibitors and/or inducers on maraviroc pharmacokinetic parameters inpaediatric patients was similar to that observed in adults.

BSA (m2)-based bands have been modified to weight (kg)-based bands to simplify dosing andreduce dosing errors (see section 4.2). Use of weight (kg)-based doses in treatment-experienced

HIV-1-infected paediatrics results in maraviroc exposures similar to those observed in treatment-experienced adults receiving recommended doses with concomitant medications. Thepharmacokinetics of maraviroc in paediatric patients below 2 years of age have not beenestablished (see section 4.2).

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

A study compared the pharmacokinetics of a single 300 mg dose of maraviroc in subjects withsevere renal impairment (CLcr < 30 mL/min, n=6) and end stage renal disease (ESRD) to healthyvolunteers (n=6). The geometric mean AUCinf (CV%) for maraviroc was as follows: healthyvolunteers (normal renal function) 1348.4 ng·h/mL (61%); severe renal impairment 4367.7ng·h/mL (52%); ESRD (dosing after dialysis) 2677.4 ng·h/mL (40%); and ESRD (dosing beforedialysis) 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 impairment; 576.7 ng/mL (51%) in

ESRD (dosing after dialysis) and 478.5 ng/mL (38%) in ESRD (dosing before dialysis). Dialysishad a minimal effect on exposure in subjects with ESRD. Exposures observed in subjects withsevere renal impairment and ESRD were within the range observed in single maraviroc 300 mgdose studies in healthy volunteers with normal renal function. Therefore, no dose adjustment isnecessary in patients with renal impairment receiving maraviroc without a potent CYP3A4inhibitor (see sections 4.2, pct. 4.4 and 4.5).

In addition, the study compared the pharmacokinetics of multiple dose maraviroc in combinationwith saquinavir/ritonavir 1000/100 mg BID (a potent CYP3A4 inhibitor) for 7 days in subjects withmild 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 maraviroc atdifferent dose frequencies (healthy volunteers - every 12 hours; mild renal impairment - every 24hours; moderate renal impairment - every 48 hours). The average concentration (Cavg) ofmaraviroc over 24 hours was 445.1 ng/mL, 338.3 ng/mL, and 223.7 ng/mL for subjects withnormal renal function, mild renal impairment, and moderate renal impairment, respectively. The

Cavg of maraviroc 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 renalimpairment may result in inadequate exposures between 24-48 hours.

Dose adjustment is necessary in patients with renal impairment receiving maraviroc with potent

CYP3A4 inhibitors (see sections 4.2 and 4.4 and 4.5).

Maraviroc is primarily metabolized and eliminated by the liver. A study compared thepharmacokinetics 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 subjects(n=8). Geometric mean ratios for Cmax and AUClast were 11% and 25% higher respectively forsubjects with mild hepatic impairment, and 32% and 46% higher respectively for subjects withmoderate hepatic impairment compared to subjects with normal hepatic function. The effects ofmoderate hepatic impairment may be underestimated due to limited data in patients with decreasedmetabolic capacity and higher renal clearance in these subjects. The results should therefore beinterpreted with caution. The pharmacokinetics of maraviroc has not been studied in subjects withsevere hepatic impairment (see sections 4.2 and 4.4).

No relevant difference between Caucasian, Asian and Black subjects has been observed. Thepharmacokinetics in other races has not been evaluated.

No relevant differences in pharmacokinetics have been observed.

Pharmacogenomics

The pharmacokinetics of maraviroc is dependent on CYP3A5 activity and expression level, whichcan be modulated by genetic variation. Subjects with a functional CYP3A5 (CYP3A5*1 allele)have been shown to have a reduced exposure to maraviroc compared to subjects with defect

CYP3A5 activity (e.g., CYP3A5*3, CYP3A5*6, and CYP3A5*7). The CYP3A5 allelic frequencydepends on ethnicity: the majority of Caucasians (~90%) are poor metabolisers of CYP3A5substrates (i.e., subjects with no copy of functional CYP3A5 alleles) while approximately 40% of

African-Americans and 70% of Sub-Saharan Africans are extensive metabolisers (i.e., subjectswith two copies of functional CYP3A5 alleles).

In a Phase 1 study conducted in healthy subjects, Blacks with a CYP3A5 genotype conferringextensive maraviroc metabolism (2 CYP3A5*1 alleles; n=12) had a 37% and 26% lower AUCwhen dosed with maraviroc 300 mg twice daily compared with Black (n=11) and Caucasian (n=12)subjects with CYP3A5 genotype conferring poor maraviroc metabolism (no CYP3A5*1 allele),respectively. The difference in maraviroc exposure between CYP3A5 extensive and poormetabolisers was reduced when maraviroc was administered together with a strong CYP3Ainhibitor: extensive CYP3A5 metabolisers (n=12) had a 17% lower maraviroc AUC compared withpoor CYP3A5 metabolisers (n=11) when dosed with maraviroc 150 mg once daily in the presenceof darunavir/cobicistat (800/150 mg).

All subjects in the Phase 1 study achieved the Cavg concentrations that have been shown to beassociated with near maximal virologic efficacy with maraviroc (75 ng/mL) in the Phase 3 study intreatment-naïve adult patients (MERIT). Therefore, despite differences in CYP3A5 genotypeprevalence by race, the effect of CYP3A5 genotype on maraviroc exposure is not consideredclinically significant and no maraviroc dose adjustment according to CYP3A5 genotype, race orethnicity is needed.

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 thatlack CCR5 receptors through genetic deletion, no significant adverse consequences have beenreported.

In vitro and in vivo studies showed that maraviroc has a potential to increase QTc interval atsupratherapeutic 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, and necrosis).

Maraviroc was evaluated for carcinogenic potential by a 6 month transgenic mouse study and a 24month study in rats. In mice, no statistically significant increase in the incidence of tumours wasreported at systemic exposures from 7 to 39-times the human exposure (unbound AUC 0-24hmeasurement) at a dose of 300 mg twice daily. In rats, administration of maraviroc at a systemicexposure 21-times the expected human exposure produced thyroid adenomas associated withadaptive 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 humanexposure.

Maraviroc was not mutagenic or genotoxic in a battery of in vitro and in vivo assays includingbacterial reverse mutation, chromosome aberrations in human lymphocytes and mouse bonemarrow micronucleus.

Maraviroc did not impair mating or fertility of male or female rats, and did not affect sperm oftreated male rats up to 1000 mg/kg. The exposure at this dose level corresponded to 39-fold theestimated 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 hadexternal 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 theestimated free clinical AUC for a 300 mg twice daily dose. A slight increase in motor activity inhigh-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 reproductiveperformance, were not affected by the maternal administration of maraviroc.

6 PHARMACEUTICAL PARTICULARS

Citric acid (anhydrous)

Sodium citrate dihydrate

Sucralose

Sodium benzoate (E211)

Strawberry flavouring

Purified water

Not applicable.

4 years.

After first opening: 60 days

Store below 30 ºC. Discard 60 days after first opening. The discard date of the oral solution shouldbe written on the carton in the space provided. The date should be written as soon as the bottle hasbeen opened for first use.

High density polyethylene (HDPE) bottle, with a child resistant closure, containing 230 mLmaraviroc 20 mg/mL solution. The pack also includes a thermoplastic elastomeric press in bottleadapter, and a 10 ml oral applicator comprised of a polypropylene barrel (with mL graduations) anda polyethylene plunger.

The oral applicator is provided for accurate measurement of the prescribed dose of oral solution.

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

ViiV Healthcare BV

Van Asch van Wijckstraat 55H3811 LP Amersfoort

Netherlands

EU/1/07/418/013

Date of first authorisation: 18th September 2007

Date of latest renewal: 20 July 2012

Detailed information on this medicinal product is available on the website of the European

Medicines Agency http://www.ema.europa.eu