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Celsentri 300mg film-coated tablets

Last Updated on eMC 21-Sep-2016 View changes  | ViiV Healthcare UK Ltd Contact details

1. Name of the medicinal product

CELSENTRI® 300 mg film-coated tablets.

2. Qualitative and quantitative composition

Each film-coated tablet contains 300 mg of maraviroc.

Excipient with known effect:

each 300 mg film-coated tablet contains 1.68 mg of soya lecithin.

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Film-coated tablet.

Blue, biconvex, oval film-coated tablets debossed with “MVC 300”.

4. Clinical particulars
4.1 Therapeutic indications

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).

4.2 Posology and method of administration

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

Posology

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 1 in section 4.5).

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

In patients with a creatinine clearance of <80 mL/min, who are also receiving potent CYP3A4 inhibitors, the dose interval of maraviroc should be adjusted to 150 mg once daily (see sections 4.4 and 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 patients with severe renal impairment (CLcr <30 mL/min) who are receiving potent CYP3A4 inhibitors (see sections 4.4 and 5.2).

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).

Paediatric population

The safety and efficacy of CELSENTRI in children younger than 18 years of age has not been established. No data available (see section 5.2).

Method of administration

Oral use.

CELSENTRI can be taken with or without food.

4.3 Contraindications

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

4.4 Special warnings and precautions for use

While effective viral suppression with antiretroviral therapy has been proven to substantially reduce the risk of sexual transmission, a residual risk cannot be excluded. Precautions to prevent transmission should be taken in accordance with national guidelines.

Hepatic disease

The safety and efficacy of maraviroc 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 maraviroc. In addition, an increase in hepatic adverse reactions with maraviroc 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 maraviroc 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, 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 therapy for hepatitis B and/or C, please refer to the relevant product information for these medicinal products.

There is limited experience in patients with reduced hepatic function, therefore maraviroc should be 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 been reported in patients taking CELSENTRI, in most cases concomitantly with other drugs associated with these reactions. These reactions included rash, fever, and sometimes organ dysfunction and hepatic failure. Discontinue CELSENTRI and other suspect agents immediately if signs or symptoms of severe skin or hypersensitivity reactions develop. Clinical status and relevant blood chemistry should be monitored and appropriate symptomatic therapy initiated.

Cardiovascular safety

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 the pivotal studies of treatment-experienced patients coronary heart disease events was more common in patients treated with maraviroc than with placebo (11 during 609 PY vs 0 during 111 PY of follow-up). In treatment-naïve patients such events occurred at a similarly low rate with maraviroc and control (efavirenz).

Postural hypotension

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

Renal impairment

An increased risk of postural hypotension may occur in patients with severe renal insufficiency who 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 is co-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 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. Autoimmune disorders (such as Graves' disease) have also been reported to occur in the setting of immune reactivation; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment.

Tropism

Maraviroc should be taken as part of an antiretroviral combination regimen. Maraviroc should optimally be combined with other antiretrovirals to which the patient's virus is sensitive (see section 5.1).

Maraviroc 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 maraviroc. 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.

Maraviroc 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 maraviroc is made when maraviroc 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.

Osteonecrosis

Although the aetiology 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.

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 maraviroc and placebo arms in the pivotal studies.

Soya lecithin

CELSENTRI contains soya lecithin.

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

4.5 Interaction with other medicinal products and other forms of interaction

Maraviroc is a substrate of cytochrome P450 CYP3A4. Co-administration of maraviroc with medicinal products that induce CYP3A4 may decrease maraviroc concentrations and reduce its therapeutic effects. Co-administration of maraviroc with medicinal products that inhibit CYP3A4 may increase maraviroc plasma concentrations. Dose adjustment of maraviroc is recommended when maraviroc is co-administered with CYP3A4 inhibitors and/or inducers. Further details for concomitantly administered medicinal products are provided below (see Table 1).

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 maraviroc 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 maraviroc with lamivudine/zidovudine showed no effect of maraviroc on lamivudine (primarily renally cleared) or zidovudine (non-P450 metabolism and renal clearance) pharmacokinetics. Maraviroc inhibits P-glycoprotein in vitro (IC50 is 183 μM). However, maraviroc does not significantly affect the pharmacokinetics of digoxin in vivo. It may not be excluded that maraviroc can increase the exposure to the P-glycoprotein substrate dabigatran etexilate.

Table 1: Interactions and dose recommendations with other medicinal products

Medicinal product by therapeutic areas

(dose of CELSENTRI used in study)

Effects on active substance levels

Geometric mean change if not stated otherwise

Recommendations concerning co-administration

ANTI-INFECTIVES

Antiretrovirals

Pharmacokinetic Enhancers

Cobicistat

Interaction not studied.

Cobicistat is a potent CYP3A inhibitor.

CELSENTRI dose should be decreased to 150 mg twice daily when co-administered with cobicistat containing regimen.

Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs)

Lamivudine 150 mg BID

(maraviroc 300 mg BID)

Lamivudine AUC12: ↔ 1.13

Lamivudine Cmax: ↔ 1.16

Maraviroc concentrations not measured, no effect is expected.

No significant interaction seen/expected. CELSENTRI 300 mg twice daily and NRTIs can be co-administered without dose adjustment.

Tenofovir 300 mg QD

(maraviroc 300 mg BID)

Maraviroc AUC12: ↔ 1.03

Maraviroc Cmax: ↔ 1.03

Tenofovir concentrations not measured, no effect is expected.

Zidovudine 300 mg BID

(maraviroc 300 mg BID)

Zidovudine AUC12: ↔ 0.98

Zidovudine Cmax: ↔ 0.92

Maraviroc concentrations not measured, no effect is expected.

Integrase Inhibitors

Elvitegravir/ritonavir 150/100mg QD

(maraviroc 150 mg BID)

Maraviroc AUC12: ↑ 2.86 (2.33-3.51)

Maraviroc Cmax: ↑ 2.15 (1.71-2.69)

Maraviroc C12: ↑ 4.23 (3.47-5.16)

Elvitegravir AUC24: ↔ 1.07 (0.96-1.18)

Elvitegravir Cmax: ↔ 1.01 (0.89-1.15)

Elvitegravir C24: ↔ 1.09 (0.95-1.26)

Elvitegravir as a single agent is indicated only in combination with certain ritonavir boosted PIs.

Elvitegravir per se is not expected to affect maraviroc exposure to a clinically relevant degree and the observed effect is attributed to ritonavir.

Thus, CELSENTRI dose should be modified in line with the recommendation for co-administration with respective PI/ritonavir combination (see 'HIV Protease Inhibitors').

Raltegravir 400 mg BID

(maraviroc 300 mg BID)

Maraviroc AUC12: ↓ 0.86

Maraviroc Cmax: ↓ 0.79

Raltegravir AUC12: ↓ 0.63

Raltegravir Cmax: ↓ 0.67

Raltegravir C12: ↓ 0.72

No clinically significant interaction seen. CELSENTRI 300 mg twice daily and raltegravir can be co-administered without dose adjustment.

Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

Efavirenz 600 mg QD

(maraviroc 100 mg BID)

Maraviroc AUC12: ↓ 0.55

Maraviroc Cmax: ↓ 0.49

Efavirenz concentrations not measured, no effect is expected.

CELSENTRI dose should be increased to 600 mg twice daily when co-administered with efavirenz in the absence of a potent CYP3A4 inhibitor. For combination with efavirenz + PI, see separate recommendations below.

Etravirine 200 mg BID

(maraviroc 300 mg BID)

Maraviroc AUC12: ↓ 0.47

Maraviroc Cmax: ↓ 0.40

Etravirine AUC12: ↔ 1.06

Etravirine Cmax: ↔ 1.05

Etravirine C12: ↔ 1.08

Etravirine is only approved for use with boosted protease inhibitors. For combination with etravirine + PI, see below.

Nevirapine 200 mg BID

(maraviroc 300 mg Single Dose)

Maraviroc AUC12: ↔ compared to historical controls

Maraviroc Cmax: ↑ compared to historical controls

Nevirapine concentrations not measured, no effect is expected.

Comparison to exposure in historical controls suggests that CELSENTRI 300 mg twice daily and nevirapine can be co-administered without dose adjustment.

HCV Protease Inhibitors

Boceprevir

800 mg TID

(maraviroc 150 mg BID)

Maraviroc AUC12 ↑ 3.02 (2.53, 3.59)

Maraviroc Cmax: ↑ 3.33 (2.54, 4.36)

Maraviroc C12: ↑ 2.78 (2.40-3.23)

Boceprevir concentrations are not likely to be affected by maraviroc co-administration (based on historical data and the elimination pathway of boceprevir).

Maraviroc 150 mg twice daily when co-administered with boceprevir

Telaprevir

750 mg TID

(maraviroc 150 mg BID)

Maraviroc AUC12 ↑ 9.49 (7.94, 11.34)

Maraviroc Cmax: ↑ 7.81 (5.92, 10.32)

Maraviroc C12: ↑ 10.17 (8.73-11.85)

Telaprevir concentrations are not likely to be affected by maraviroc co-administration (based on historical data and the elimination pathway of telaprevir).

Maraviroc 150 mg twice daily when co-administered with telaprevir

HIV Protease Inhibitors (PIs)

Atazanavir 400 mg QD

(maraviroc 300 mg BID)

Maraviroc AUC12 ↑ 3.57

Maraviroc Cmax: ↑ 2.09

Atazanavir concentrations not measured, no effect is expected.

CELSENTRI dose should be decreased to 150 mg twice daily when co-administered with a PI; except in combination with tipranavir/ritonavir where the CELSENTRI dose should be 300 mg BID.

Atazanavir/ritonavir 300 mg/100 mg QD

(maraviroc 300 mg BID)

Maraviroc AUC12 ↑ 4.88

Maraviroc Cmax: ↑ 2.67

Atazanavir/ritonavir concentrations not measured, no effect is expected.

Lopinavir/ritonavir 400 mg/100 mg BID

(maraviroc 300 mg BID)

Maraviroc AUC12 ↑ 3.95

Maraviroc Cmax: ↑ 1.97

Lopinavir/ritonavir concentrations not measured, no effect is expected.

Saquinavir/ritonavir 1000 mg/100 mg BID

(maraviroc 100 mg BID)

Maraviroc AUC12 ↑ 9.77

Maraviroc Cmax: ↑ 4.78

Saquinavir/ritonavir concentrations not measured, no effect is expected.

Darunavir/ritonavir 600 mg/100 mg BID

(maraviroc 150 mg BID)

Maraviroc AUC12 ↑ 4.05

Maraviroc Cmax: ↑ 2.29

Darunavir/ritonavir concentrations were consistent with historical data.

Nelfinavir

Limited data are available for co-administration with nelfinavir. Nelfinavir is a potent CYP3A4 inhibitor and would be expected to increase maraviroc concentrations.

Indinavir

Limited data are available for co-administration with indinavir. Indinavir is a potent CYP3A4 inhibitor. Population PK analysis in phase 3 studies suggests dose reduction of maraviroc when co-administered with indinavir gives appropriate maraviroc exposure.

Tipranavir/ritonavir 500 mg/200 mg BID

(maraviroc 150 mg BID)

Maraviroc AUC12 ↔ 1.02

Maraviroc Cmax: ↔ 0.86

Tipranavir/ritonavir concentrations were consistent with historical data.

Fosamprenavir/ritonavir 700 mg/100 mg BID

(maraviroc 300 mg BID)

Maraviroc AUC12: ↑ 2.49

Maraviroc Cmax: ↑ 1.52

Maraviroc C12: ↑ 4.74

Amprenavir AUC12: ↓ 0.65

Amprenavir Cmax: ↓ 0.66

Amprenavir C12: ↓ 0.64

Ritonavir AUC12: ↓ 0.66

Ritonavir Cmax: ↓ 0.61

Ritonavir C12: ↔ 0.86

Concomitant use is not recommended. Significant reductions in amprenavir Cmin observed may result in virological failure in patients

NNRTI + PI

Efavirenz 600 mg QD + lopinavir/ritonavir 400mg/100 mg BID

(maraviroc 300 mg BID)

Maraviroc AUC12: ↑ 2.53

Maraviroc Cmax: ↑ 1.25

Efavirenz, lopinavir/ritonavir concentrations not measured, no effect expected.

CELSENTRI dose should be decreased to 150 mg twice daily when co-administered with efavirenz and a PI (except tipranavir/ritonavir where the dose should be 600 mg twice daily).

Concomitant use of CELSENTRI and fosamprenavir/ritonavir is not recommended.

Efavirenz 600 mg QD + saquinavir/ritonavir 1000 mg/100 mg BID

(maraviroc 100 mg BID)

Maraviroc AUC12: ↑ 5.00

Maraviroc Cmax: ↑ 2.26

Efavirenz, saquinavir/ritonavir concentrations not measured, no effect expected.

Efavirenz and atazanavir/ritonavir or darunavir/ritonavir

Not studied. Based on the extent of inhibition by atazanavir/ritonavir or darunavir/ritonavir in the absence of efavirenz, an increased exposure is expected.

Etravirine and darunavir/ritonavir

(maraviroc 150 mg BID)

Maraviroc AUC12: ↑ 3.10

Maraviroc Cmax: ↑ 1.77

Etravirine AUC12: ↔ 1.00

Etravirine Cmax: ↔ 1.08

Etravirine C12: ↓ 0.81

Darunavir AUC12: ↓ 0.86

Darunavir Cmax: ↔ 0.96

Darunavir C12: ↓ 0.77

Ritonavir AUC12: ↔ 0.93

Ritonavir Cmax: ↔ 1.02

Ritonavir C12: ↓ 0.74

CELSENTRI dose should be decreased to 150 mg twice daily when co-administered with etravirine and a PI.

Concomitant use of CELSENTRI and fosamprenavir/ritonavir is not recommended.

Etravirine and lopinavir/ritonavir, saquinavir/ritonavir or atazanavir/ritonavir

Not studied. Based on the extent of inhibition by lopinavir/ritonavir, saquinavir/ritonavir or atazanavir/ritonavir in the absence of etravirine, an increased exposure is expected.

ANTIBIOTICS

Sulphamethoxazole/ Trimethoprim 800 mg/160 mg BID

(maraviroc 300 mg BID)

Maraviroc AUC12: ↔ 1.11

Maraviroc Cmax: ↔ 1.19

Sulphamethoxazole/trimethoprim concentrations not measured, no effect expected.

CELSENTRI 300 mg twice daily and sulphamethoxazole/ trimethoprim can be co-administered without dose adjustment.

Rifampicin 600 mg QD

(maraviroc 100 mg BID)

Maraviroc AUC: ↓ 0.37

Maraviroc Cmax: ↓ 0.34

Rifampicin concentrations not measured, no effect expected.

CELSENTRI dose should be increased to 600 mg twice daily when co-administered with rifampicin in the absence of a potent CYP3A4 inhibitor. This dose adjustment has not been studied in HIV patients. See also section 4.4.

Rifampicin + efavirenz

Combination with two inducers has not been studied. There may be a risk of suboptimal levels with risk of loss of virologic response and resistance development.

Concomitant use of CELSENTRI and rifampicin + efavirenz is not recommended.

Rifabutin + PI

Not studied. Rifabutin is considered to be a weaker inducer than rifampicin. When combining rifabutin with protease inhibitors that are potent inhibitors of CYP3A4 a net inhibitory effect on maraviroc is expected.

CELSENTRI dose should be decreased to 150 mg twice daily when co-administered with rifabutin and a PI (except tipranavir/ritonavir where the dose should be 300 mg twice daily). See also section 4.4.

Concomitant use of CELSENTRI and fosamprenavir/ritonavir is not recommended.

Clarithromycin, Telithromycin

Not studied, but both are potent CYP3A4 inhibitors and would be expected to increase maraviroc concentrations.

CELSENTRI dose should be decreased to 150 mg twice daily when co-administered with clarithromycin and telithromycin.

ANTIFUNGALS

Ketoconazole 400 mg QD

(maraviroc 100 mg BID)

Maraviroc AUCtau: ↑ 5.00

Maraviroc Cmax: ↑ 3.38

Ketoconazole concentrations not measured, no effect is expected.

CELSENTRI dose should be decreased to 150 mg twice daily when co-administered with ketoconazole.

Itraconazole

Not studied. Itraconazole, is a potent CYP3A4 inhibitor and would be expected to increase the exposure of maraviroc.

CELSENTRI dose should be decreased to 150 mg twice daily when co-administered with itraconazole.

Fluconazole

Fluconazole is considered to be a moderate CYP3A4 inhibitor. Population PK studies suggest that a dose adjustment of maraviroc is not required.

CELSENTRI 300 mg twice daily should be administered with caution when co-administered with fluconazole.

ANTIVIRALS

HCV agents

Pegylated interferon and ribavirin have not been studied, no interaction is expected.

CELSENTRI 300 mg twice daily and pegylated interferon or ribavirin can be co-administered without dose adjustment.

DRUG ABUSE

Methadone

Not studied, no interaction expected.

CELSENTRI 300 mg twice daily and methadone can be co-administered without dose adjustment.

Buprenorphine

Not studied, no interaction expected.

CELSENTRI 300 mg twice daily and buprenorphine can be co-administered without dose adjustment.

LIPID LOWERING

MEDICINAL PRODUCTS

Statins

Not studied, no interaction expected.

CELSENTRI 300 mg twice daily and statins can be co-administered without dose adjustment.

ANTIARRHYTHMICS

Digoxin 0.25 mg

Single Dose

(maraviroc 300 mg BID)

Digoxin. AUCt: ↔ 1.00

Digoxin. Cmax: ↔ 1.04

Maraviroc concentrations not measured, no interaction expected.

CELSENTRI 300 mg twice daily and digoxin can be co-administered without dose adjustment.

The effect of maraviroc on digoxin at the dose of 600 mg BID has not been studied.

ORAL CONTRACEPTIVES

Ethinylestradiol 30 mcg QD

(maraviroc 100 mg BID)

Ethinylestradiol. AUCt: ↔ 1.00

Ethinylestradiol. Cmax: ↔ 0.99

Maraviroc concentrations not measured, no interaction expected.

CELSENTRI 300 mg twice daily. and ethinylestradiol can be co-administered without dose adjustment.

Levonorgestrel 150 mcg QD

(maraviroc 100 mg BID)

Levonorgestrel. AUC12: ↔ 0.98

Levonorgestrel. Cmax: ↔ 1.01

Maraviroc concentrations not measured, no interaction expected.

CELSENTRI 300 mg twice daily and levonorgestrel can be co-administered without dose adjustment.

SEDATIVES

Benzodiazepines

Midazolam 7.5 mg Single Dose

(maraviroc 300 mg BID)

Midazolam. AUC: ↔ 1.18

Midazolam. Cmax: ↔ 1.21

Maraviroc concentrations not measured, no interaction expected.

CELSENTRI 300 mg twice daily and midazolam can be co-administered without dose adjustment.

HERBAL PRODUCTS

St. John's Wort

(Hypericum Perforatum)

Co-administration of maraviroc with St. John's Wort is expected to substantially decrease maraviroc concentrations and may result in suboptimal levels and lead to loss of virologic response and possible resistance to maraviroc.

Concomitant use of maraviroc and St. John's Wort or products containing St. John's Wort is not recommended.

4.6 Fertility, pregnancy and lactation

Pregnancy

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). Maraviroc should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.

Breast-feeding

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.

It is recommended that mothers infected by HIV do not breast-feed their infants under any circumstances in order to avoid transmission of HIV.

Fertility

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

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

Summary of the safety profile

The safety profile of maraviroc is based on 1,374 HIV-1 infected patients who received at least one dose of maraviroc 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 for at least 24 weeks. 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 sections 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 maraviroc in Phase 2b/3 studies compared to those receiving comparator.

Tabulated list of adverse reactions

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), rare (≥1/10,000 to <1/1000) , or not known (cannot be estimated from the available data). 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 maraviroc in Phase 2b/3 studies at rates greater than rates in the comparator. Adverse reactions from clinical trials in table 2 were assessed as possibly related to study drug by investigators.

Table 2: Clinically important adverse reactions of, moderate intensity or more occurring among patients receiving maravirocat rates greater than rates in the comparator.

System Organ Class

Adverse reaction

Frequency

Infections and infestations

Pneumonia, oesophageal candidiasis

uncommon

Neoplasm benign, malignant and unspecified (including cysts and polyps)

Bile duct cancer, diffuse large B-cell lymphoma, Hodgkin's disease, metastases to bone, metastases to liver, metastases to peritoneum, nasopharyngeal cancer, oesophageal carcinoma

rare

Blood and lymphatic system disorders

Anaemia

common

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

Gastrointestinal disorders

Abdominal pain, flatulence, nausea

common

Hepatobiliary disorders*

Alanine aminotransferase increased, aspartate aminotransferase increased

common

Hyperbilirubinaemia, gamma-glutamyltransferase increased

uncommon

Hepatitis toxic, hepatic failure, hepatic cirrhosis, blood alkaline phosphatase increased

rare

Hepatic failure with allergic features

very rare

Skin and subcutaneous tissue disorders*

Rash

common

Stevens-Johnson syndrome / Toxic epidermal necrolysis

Rare/ not known

Musculoskeletal and connective tissue disorders

Myositis, blood creatine phosphokinase increased

uncommon

Muscle atrophy

rare

Renal and urinary disorders

Renal failure, proteinuria

uncommon

General disorders and administration site conditions

Asthenia

common

* Skin and liver reactions can occur as single events, or in combination. Delayed type hypersensitivity reactions, typically within 2-6 weeks after start of therapy, including rash, fever, eosinophilia and liver reactions have been reported, see also section 4.4.

Description of selected adverse reactions

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. Autoimmune disorders (such as Graves' disease) have also been reported; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment (see section 4.4).

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).

Cases of syncope caused by postural hypotension have been reported.

Laboratory abnormalities

Table 3 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 3: 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)

Laboratory parameter

Limit

Maraviroc 300 mg twice daily + OBT

N =421*

(%)

Placebo + OBT

N =207*

(%)

Hepatobiliary disorders

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

Gastrointestinal disorders

Amylase

>2.0x ULN

5.7

5.8

Lipase

>2.0x ULN

4.9

6.3

Blood and lymphatic system disorders

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 to 5 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, Myocardial infarction/cardiac ischaemia, malignancies, rhabdomyolysis and other serious infectious events with maraviroc treatment. The incidence of these selected endpoints for subjects on maraviroc in this 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 ACTG criteria was similar among the maraviroc and efavirenz treatment groups.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via:

United Kingdom

the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard

Ireland

HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; E-mail: medsafety@hpra.ie

4.9 Overdose

The highest dose administered in clinical studies was 1,200 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 placebo + OBT 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 maraviroc to prolong the QT interval.

There is no specific antidote for overdose with maraviroc. Treatment of overdose should consist of general supportive measures including keeping the patient in a supine position, careful assessment of patient vital signs, blood pressure and ECG.

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

5. Pharmacological properties
5.1 Pharmacodynamic properties

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 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 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 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 clonal analysis was conducted on virus from 20 representative subjects (16 subjects from the maraviroc arms and 4 subjects from the placebo + OBT 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 maraviroc therapy with CXCR4-using virus in patients with CCR5 virus at baseline, demonstrated that the virus population reverted back to CCR5 tropism in 33 of 36 patients with more than 35 days of follow-up.

At time of failure with CXCR4-using virus, the resistance pattern to other antiretrovirals appears similar to that of the CCR5-tropic population at baseline, based on available data. Hence, in the selection of a treatment regimen, it should be assumed that viruses forming part of the previously undetected CXCR4 -using population (i.e. minor viral population) harbours the same resistance pattern as the CCR5-tropic population.

Failure with CCR5-tropic virus:

Phenotypic resistance: in patients with CCR5-tropic virus at time of treatment failure with maraviroc, 22 out of 58 patients had virus with reduced sensitivity to maraviroc. 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 maraviroc (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 maraviroc 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 4: Demographic and baseline characteristics of patients (pooled studies MOTIVATE 1 and MOTIVATE 2)

Demographic and Baseline Characteristics

Maraviroc 300 mg twice daily + OBT

N = 426

Placebo + OBT

N = 209

Age (years)

(Range, years)

46.3

21-73

45.7

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)

(range, cells/mm3)

166.8

(2.0-820.0)

171.3

(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 score:

0

1

2

≥3

 

102 (23.9%)

138 (32.4%)

80 (18.8%)

104 (24.4%)

 

51 (24.4%)

53 (25.4%)

41 (19.6%)

59 (28.2%)

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

Outcomes

Maraviroc 300 mg twice daily + OBT

N=426

Placebo + OBT
 

N=209

Difference1

(Confidence Interval2)

HIV-1 RNA

Mean change from baseline

(log copies/mL)

 

-1.837

 

-0.785

 

-1.055

(-1.327, -0.783)

Percentage of patients with HIV-1 RNA <400 copies/mL

56.1%

22.5%

Odds ratio: 4.76

(3.24, 7.00)

Percentage of patients with HIV-1 RNA <50 copies/mL

45.5%

16.7%

Odds ratio: 4.49

(2.96, 6.83)

CD4+ cell count

Mean change from baseline (cells/µL)

 

122.78

59.17

 

63.13

(44.28, 81.99)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%

In a retrospective analysis of the MOTIVATE studies with a more sensitive assay for screening of tropism (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), and 16.3% in those treated with placebo + OBT (n=178).

Maraviroc300 mg twice daily + OBT was superior to placebo + OBT across all subgroups of patients analysed (see Table 6). 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 for maraviroc compared to placebo + OBT was still demonstrated (see Table 6).

Table 6: Proportion of patients achieving <50 copies/mL at Week 48 by subgroup (pooled Studies MOTIVATE 1 and MOTIVATE 2)

Subgroups

HIV-1 RNA <50 copies/mL

Maraviroc300 mg twice daily + OBT

N=426

Placebo + OBT

N=209

Screening HIV-1 RNA (copies/mL):

<100,000

≥100,000

 

58.4%

34.7%

 

26.0%

9.5%

Baseline CD4+ (cells/µL):

<50

50-100

101-200

201-350

≥ 350

 

16.5%

36.4%

56.7%

57.8%

72.9%

 

2.6%

12.0%

21.8%

21.0%

38.5%

Number of active ARVs in OBT1:

0

1

2

≥3

 

32.7%

44.5%

58.2%

62%

 

2.0%

7.4%

31.7%

38.6%

1Based 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 placebo + OBT 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 maraviroc versus efavirenz, both in combination with zidovudine/lamivudine (n=721, 1:1). After 48 weeks of treatment, maraviroc 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 maraviroc 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 maraviroc arm. Fewer patients discontinued maraviroc due to adverse events (15 vs. 49).

Studies on Patients co-infected with hepatitis B and/or hepatitis C virus

The hepatic safety of maraviroc in combination with other antiretroviral agents in 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-controlled study. 70 subjects (Child-Pugh Class A, n=64; Child-Pugh Class B, n=6) were randomized to the maraviroc group and 67 subjects (Child-Pugh Class A, n=59; Child-Pugh Class B, n=8) were randomized to the placebo group.

The primary objective assessed the incidence of Grade 3 and 4 ALT abnormalities (>5x upper limit of 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 placebo and Week 36 for the maraviroc arm).

5.2 Pharmacokinetic properties

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.

Co-administration of a 300 mg tablet with a high fat breakfast reduced maraviroc Cmax and AUC by 33% in healthy volunteers. There were no food restrictions in the studies that demonstrated the efficacy and safety of maraviroc (see section 5.1). Therefore, maraviroc 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.

Biotransformation: 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.

Paediatric population: 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 maraviroc 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 AUCinf (CV%) for maraviroc 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 maraviroc 300 mg dose studies in healthy volunteers with normal renal function. Therefore, no dose adjustment is necessary in patients with renal impairment receiving maraviroc without a potent CYP3A4 inhibitor (see sections 4.2, 4.4 and 4.5).

In addition, the study compared the pharmacokinetics of multiple dose maraviroc 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 maraviroc 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 maraviroc 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 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 renal impairment 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).

Hepatic impairment: maraviroc is primarily metabolized and eliminated by the liver. A study compared the pharmacokinetics of a single 300 mg dose of maraviroc in patients with mild (Child-Pugh Class A, n=8), and moderate (Child-Pugh Class B, n=8) hepatic impairment compared to healthy subjects (n=8). Geometric mean ratios for Cmax and AUClast 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 has 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.

5.3 Preclinical safety data

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, and 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.

6. Pharmaceutical particulars
6.1 List of excipients

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)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

5 years.

6.4 Special precautions for storage

This medicinal product does not require any special storage condition.

6.5 Nature and contents of container

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.

6.6 Special precautions for disposal and other handling

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

7. Marketing authorisation holder

ViiV Healthcare UK Ltd

980 Great West Road

Brentford

Middlesex

TW8 9GS

United Kingdom

8. Marketing authorisation number(s)

EU/1/07/418/006

EU/1/07/418/007

EU/1/07/418/008

EU/1/07/418/009

EU/1/07/418/010

9. Date of first authorisation/renewal of the authorisation

Date of first authorisation: 18th September 2007

Date of latest renewal: 20 July 2012

10. Date of revision of the text

09 September 2016

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

Company contact details

ViiV Healthcare UK Ltd

Company image
Address

Stockley Park West, Uxbridge, Middlesex,, UB11 1BT, UK

Fax

+44 (0)208 990 4328

Telephone

+44 (0)800 221 441

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Active ingredients

maraviroc

Legal categories

POM - Prescription Only Medicine

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