- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
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.
PosologyBefore 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.
AdultsThe 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).
ElderlyThere is limited experience in patients >65 years of age (see section 5.2), therefore CELSENTRI should be used with caution in this population.
Renal impairmentIn 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 impairmentLimited 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 populationThe 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 administrationOral use.CELSENTRI can be taken with or without food.
Hepatic diseaseThe 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 reactionsHypersensitivity 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 safetyLimited 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 hypotensionWhen 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 impairmentAn 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 syndromeIn 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.
TropismMaraviroc 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 adjustmentPhysicians 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.
OsteonecrosisAlthough 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 immunityCCR5 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 lecithinCELSENTRI contains soya lecithin. If a patient is hypersensitive to peanut or soya, CELSENTRI should not be used.
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 levelsGeometric mean change if not stated otherwise||Recommendations concerning co-administration|
|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.|
|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.|
|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.|
|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.|
|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.|
|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.|
|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.|
|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.|
|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.|
|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.|
PregnancyNo 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-feedingStudies 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.
FertilityThere 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).
Summary of the safety profileThe 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 reactionsThe 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|
|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|
|Renal and urinary disorders||Renal failure, proteinuria||uncommon|
|General disorders and administration site conditions||Asthenia||common|
Description of selected adverse reactionsIn 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 abnormalitiesTable 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 + OBTN =421* (%)||Placebo + OBT N =207* (%)|
|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|
|Blood and lymphatic system disorders|
|Absolute neutrophil count||<750/mm3||4.3||1.9|
Reporting of suspected adverse reactionsReporting 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 Kingdomthe Yellow Card Scheme at: www.mhra.gov.uk/yellowcardIrelandHPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; E-mail: firstname.lastname@example.org
Mechanism of actionMaraviroc 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 vitroMaraviroc 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.
ResistanceViral 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 patientsIn 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.
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 + OBTN = 426||Placebo + OBT N = 209|
|Age (years) (Range, years)||46.3 21-73||45.7 29-72|
|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%)|
Table 5: Efficacy Outcomes at week 48 (pooled studies MOTIVATE 1 and MOTIVATE 2)
|Outcomes||Maraviroc 300 mg twice daily + OBTN=426||Placebo + OBT |
|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|
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 + OBTN=426||Placebo + OBTN=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%|
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 PatientsAn 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 virusThe 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).
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