CELSENTRI® 150 mg film-coated tablets.
Each film-coated tablet contains 150 mg of maraviroc.
Excipient with known effect: each 150 mg film-coated tablet contains 0.84 mg of soya lecithin.
For the full list of excipients, see section 6.1.
Film-coated tablet.
Blue, biconvex, oval film-coated tablets debossed with “MVC 150”.
CELSENTRI, in combination with other antiretroviral medicinal products, is indicated for treatment-experienced adult patients infected with only CCR5-tropic HIV-1 detectable (see section 4.2).
This indication is based on safety and efficacy data from two double-blind, placebo-controlled trials in treatment-experienced patients (see section 5.1).
Therapy should be initiated by a physician experienced in the management of HIV infection.
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 eva luated. 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.
Hypersensitivity to the active substance or to peanut or soya or to any of the excipients listed in section 6.1.
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 eva luated 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 eva luated. 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.
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)
|
