4.1. Therapeutic indications

CELSENTRI, in combination with other antiretroviral medicinal products, is indicated for treatment-experienced adults, adolescents and children of 2 years of age, and older and weighing at least 10 kg infected with only CCR5-tropic HIV-1 detectable (see sections 4.2 and 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). 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 (with potent CYP3A inhibitor with or without a potent CYP3A inducer), 300 mg (without potent CYP3A inhibitors or inducers) or 600 mg twice daily (with potent CYP3A inducer without a potent CYP3A inhibitor) depending on interactions with 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 not exceed the recommended adult dose. CELSENTRI oral solution (20 mg per mL) formulation should be prescribed if a child is unable to reliably swallow CELSENTRI tablets.

The recommended dose of CELSENTRI differs depending on interactions with concomitant antiretroviral therapy and other medicinal products. Refer to section 4.5 for corresponding adult dosage.

Many medicines have profound effects on maraviroc exposure due to drug-drug interactions. Prior to deciding the dose of CELSENTRI by weight, please refer to Table 2 in section 4.5 to carefully determine the corresponding adult dose. The corresponding paediatric dose can then be obtained from 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 at least 10 kg

Adult dosage*

Concomitant Medications

Dose of CELSENTRI in children based on weight

10 to less than 20 kg

20 to less than 30 kg

30 to less than 40 kg

at least 40 kg

150 mg twice daily

CELSENTRI with products that are potent CYP3A inhibitors (with or without a CYP3A inducer)

50 mg twice daily

75 mg twice daily

100 mg twice daily

150 mg twice daily

300 mg twice daily

CELSENTRI with products that are not potent CYP3A inhibitors or potent CYP3A inducers

Data to support these doses are lacking.

300 mg twice daily

300 mg twice daily

600 mg twice daily

CELSENTRI with products that are CYP3A inducers (without a potent CYP3A inhibitor)

Data to support these doses are lacking and CELSENTRI is not recommended in children taking concomitant interacting medicinal products that in adults would require a 600 mg twice daily dose.

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

Special populations

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 adult 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 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 renal impairment. Therefore, CELSENTRI should be used with caution in this population.

Hepatic impairment

Limited data are available in adult patients with hepatic impairment and no data are available to recommend a specific dose for paediatric patients. Therefore, CELSENTRI should be used with caution 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 less than 10 kg has not been established (see section 5.2). No data are available.

Method of administration

Oral use.

CELSENTRI can be taken with or without food.

4.3. Contraindications

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

4.4. Special warnings and precautions for use

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 maraviroc, in most cases concomitantly with other medicinal products associated with these reactions. These reactions included rash, fever, and sometimes organ dysfunction and hepatic failure. Discontinue maraviroc 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 were 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 reactions 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 and autoimmune hepatitis) 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 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. 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 potent 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.

Excipients

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'.

4.5. Interaction with other medicinal products and other forms of interaction

Maraviroc is a metabolised by cytochrome P450 CYP3A4 and CYP3A5. 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 potent CYP3A4 inhibitors and/or inducers. Further details for concomitantly administered medicinal products are provided below (see Table 2).

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

Based on the in vitro and clinical data, the potential for maraviroc to affect the pharmacokinetics of co-administered medicinal products is low. In vitro studies have shown that maraviroc does not inhibit OATP1B1, MRP2 or 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.

Renal clearance accounts for approximately 23% of total clearance of maraviroc when maraviroc is administered without CYP3A4 inhibitors. In vitro studies have shown that maraviroc does not inhibit 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 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 2: Interactions and adulta dose recommendations with other medicinal products

Medicinal product by therapeutic areas

(dose of CELSENTRI used in study)

Effects on active substance levelsGeometric mean change if not stated otherwise

Recommendations concerning co-administration in adults

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 '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.

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.

ANTICONVULSANTS

Carbamezepine,

Phenobarbital,

Phenytoin

Not studied, but these are potent CYP3A4 inducers and would be expected to decrease maraviroc concentrations.

CELSENTRI dose should be increased to 600 mg twice daily when co-administered with carbamazepine, phenobarbital or phenytoin in the absence of a potent CYP3A4 inhibitor.

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

Anti-HBV

Pegylated interferon

Pegylated interferon has not been studied, no interaction is expected.

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

Anti-HCV

Ribavirin

Ribavirin has not been studied, no interaction is expected.

CELSENTRI 300 mg twice daily and 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.

a Refer to Table 1 for maraviroc paediatric dosing recommendations when co-administered with antiretroviral therapy and other medicinal products.

4.6. Fertility, pregnancy and lactation

Pregnancy

There are limited data from the use of maraviroc in pregnant women. The effect of maraviroc on human pregnancy is unknown. Studies in animals showed reproductive toxicity at high exposures. Primary pharmacological activity (CCR5 receptor affinity) was limited in the species studied (see section 5.3). Maraviroc should be used during pregnancy only if the expected benefit justifies the potential risk to the foetus.

Breast-feeding

It is unknown whether maraviroc is excreted in human milk. Available toxicological data in animals 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 the newborn/infants cannot be excluded.

It is recommended that women living with HIV do not breast-feed their infants 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

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

4.8. Undesirable effects

Summary of the safety profile

Adults

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).

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.

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 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

Vascular disorders

Postural hypotension (see section 4.4)

uncommon

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

Description of selected adverse reactions

Delayed type hypersensitivity reactions, typically occurring within 2-6 weeks after start of therapy and 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 combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic infections 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 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 4 shows the incidence ≥1% of Grade 3-4 Abnormalities (ACTG Criteria) based on the maximum shift in laboratory test values without regard to baseline values.

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

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.

Paediatric population

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 years received maraviroc twice-daily with optimised background therapy (OBT). Overall, the safety profile in paediatric patients was similar to that observed in adult clinical studies.

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 Yellow Card Scheme website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Symptoms

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.

Management

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.