ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
CELSENTRI 150 mg film-coated tablets.
2.
2.1 General description
Each film-coated tablet contains 150 mg of maraviroc.
2.2 Qualitative and quantitative composition
Excipients
Each 150 mg film-coated tablet contains 0.84 mg of soya lecithin.
For a full list of excipients, see section 6.1.
3.
Film-coated tablet.
Blue, biconvex, oval film-coated tablets debossed with “MVC 150”.
4.
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.
Before taking CELSENTRI it has to be confirmed that only CCR5-tropic HIV-1 is detectable (i.e.
CXCR4 or dual/mixed tropic virus not detected) using an adequately validated and sensitive detection
method on a newly drawn blood sample. The Monogram Trofile assay was used in the clinical studies
of CELSENTRI (see sections 4.4 and 5.1). Other phenotypic and genotypic assays are currently being
evaluated. The viral tropism cannot be safely predicted by treatment history and assessment of stored
samples.
There are currently no data regarding the reuse of CELSENTRI in patients that currently have only
CCR5-tropic HIV-1 detectable, but have a history of failure on CELSENTRI (or other CCR5
antagonists) with a CXCR4 or dual/mixed tropic virus. There are no data regarding the switch from a
medicinal product of a different antiretroviral class to CELSENTRI in virologically suppressed
patients. Alternative treatment options should be considered.
Adults
: the recommended dose of CELSENTRI is 150 mg, 300 mg or 600 mg twice daily depending
on interactions with co-administered antiretroviral therapy and other medicinal products (see Table 2
in Section 4.5). CELSENTRI can be taken with or without food.
2
Children:
CELSENTRI is not recommended for use in children due to lack of data on safety, efficacy
and pharmacokinetics (see section 5.2).
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:
dosage adjustment is only recommended in patients with renal impairment who are
receiving potent CYP3A4 inhibitors such as:
•
protease inhibitors (except tipranavir/ritonavir)
•
ketoconazole, itraconazole, clarithromycin, telithromycin.
CELSENTRI should be used with caution in patients with severe renal impairment (CLcr <
30mL/min) who are receiving potent CYP3A4 inhibitors (see sections 4.4 and 5.2).
The dose and dosing interval for CELSENTRI should be modified in renally impaired patients (CLcr
<80 mL/min), including patients with end stage renal disease (ESRD) requiring dialysis (Table 1
below). These dosing recommendations are based on data from a renal impairment study (see section
5.2) in addition to modelling of pharmacokinetic data in subjects with varying degrees of renal
impairment.
Table 1. Dose and interval adjustments for patients with renal impairment
Recommended CELSENTRI dose
interval
Creatinine clearance
<80 mL/min
If administered without potent
CYP3A4 inhibitors or if
co-administered with
tipranavir/ritonavir
No dose interval adjustment required
If co-administered with
fosamprenavir/ritonavir
CELSENTRI 150 mg every 12 hours
If co-administered with potent
CYP3A4 inhibitors, e.g.
saquinavir/ritonavir,
lopinavir/ritonavir,
darunavir/ritonavir,
atazanavir/ritonavir, ketoconazole
CELSENTRI 150 mg every 24 hours
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).
Hypersensitivity to the active substance or to peanut or soya or to any of the excipients.
CELSENTRI should be taken as part of an antiretroviral combination regimen. CELSENTRI should
optimally be combined with other antiretrovirals to which the patient's virus is sensitive (see section
5.1).
CELSENTRI 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
CELSENTRI. Other phenotypic and genotypic assays are currently being evaluated. The viral tropism
cannot be predicted by treatment history or assessment of stored samples.
3
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.
CELSENTRI 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 CELSENTRI is made
when CELSENTRI 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.
Information for patients:
patients should be advised that antiretroviral therapies including
CELSENTRI
have not been shown to prevent the risk of transmission of HIV to others through sexual
contact or contamination with blood. They should continue to use appropriate precautions. Patients
should also be informed that CELSENTRI
is not a cure for HIV-1 infection.
Postural hypotension
: when CELSENTRI 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. However, when CELSENTRI was given at the recommended dose in
HIV infected patients in Phase 3 studies, postural hypotension was seen at a similar rate compared to
placebo (approximately 0.5%). Caution should be used when administering CELSENTRI in patients
with a history of postural hypotension or on concomitant medicinal products known to lower blood
pressure.
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 CELSENTRI and placebo arms in the pivotal studies.
Cardiovascular safety:
limited data exist with the use of CELSENTRI in patients with severe
cardiovascular disease, therefore special caution should be exercised when treating these patients with
CELSENTRI. In the pivotal studies of treatment-experienced patients (MOTIVATE) coronary heart
disease events was more common in patients treated with CELSENTRI than with placebo (11 during
609 PY vs 0 during 111 PY of follow-up). In treatment-naïve patients (MERIT) such events occurred
at a similarly low rate with CELSENTRI and control (efavirenz).
When CELSENTRI was administered to healthy volunteers at doses higher than the recommended
dose, cases of symptomatic postural hypotension were seen at a greater frequency than with placebo.
However, when CELSENTRI was given at the recommended dose in HIV infected patients in Phase 3
studies, postural hypotension was seen at a similar rate compared to placebo/comparator. Caution
should be used when administering CELSENTRI in patients with a history of postural hypotension or
on concomitant medicinal products known to lower blood pressure.
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.
Osteonecrosis
:
although the etiology is considered to be multifactorial (including corticosteroid use,
alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis
4
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.
Hepatic safety:
the safety and efficacy of CELSENTRI
have not been specifically studied in patients
with significant underlying liver disorders.
A case of possible CELSENTRI-induced hepatotoxicity with allergic features has been reported in a
study in healthy volunteers. In addition, an increase in hepatic adverse reactions with CELSENTRI
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 CELSENTRI should be 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, eosinophila or elevated IgE).
Since there are very limited data in patients with hepatitis B/C co-infection, special caution should be
exercised when treating these patients with CELSENTRI. In case of concomitant antiviral therapy for
hepatitis B and/or C, please refer also to the relevant product information for these medicinal products.
There is limited experience in patients with reduced hepatic function, therefore CELSENTRI
should
be used with caution in this population (see sections 4.2 and 5.2).
Renal impairment:
An increased risk of postural hypotension may occur in patients with severe renal
insufficiency who are treated with boosted protease inhibitors (PIs) and CELSENTRI. This risk is due
to potential increases in maraviroc maximum concentrations when CELSENTRI is co-administered
with boosted PIs in these patients. The risk of postural hypotension is highest when CELSENTRI is
co-administered with PIs having the most potent CYP3A4 inhibitory effect (saquinavir/ ritonavir,
darunavir/ ritonavir, lopinavir/ ritonavir). Patients with impaired renal function may frequently have
cardiovascular co-morbidities, and could be at increased risk of cardiovascular adverse events
triggered by postural hypotension. No studies have been performed in subjects with severe renal
impairment co-treated with potent CYP3A4 inhibitors. Dose adjustments are based on modelling and
simulations (see sections 4.2, 4.5 and 5.2).
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 CELSENTRI
with
medicinal products that induce CYP3A4 may decrease maraviroc concentrations and reduce its
therapeutic effects. Co-administration of CELSENTRI
with medicinal products that inhibit CYP3A4
may increase maraviroc plasma concentrations. Dose adjustment of CELSENTRI
is recommended
when CELSENTRI is co-administered with CYP3A4 inhibitors and/or inducers. Further details for
concomitantly administered medicinal products are provided below (see Table 2).
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.
5
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,
coadministration of CELSENTRI
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 CELSENTRI
with lamivudine/zidovudine showed no
effect of maraviroc on lamivudine (primarily renally cleared) or zidovudine (non-P450 metabolism
and renal clearance) pharmacokinetics.
In vitro
results indicate that maraviroc could inhibit P-
glycoprotein in the gut and may thus affect bioavailability of certain drugs.
Table 2. Interactions and dose recommendations with other medical products
Medicinal product by
therapeutic areas
(dose of CELSENTRI
used in study)
Effects on drug levels
Geometric mean change if not stated
otherwise
Recommendations concerning
coadministration
ANTI-INFECTIVES
Antiretrovirals
NRTIs
Lamivudine 150 mg
BID
(maraviroc 300 mg
BID)
Lamivudine AUC
12
: ↔ 1.13
Lamivudine C
max
: ↔ 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 AUC
12
: ↔ 1.03
Maraviroc C
max
: ↔ 1.03
Tenofovir concentrations not measured, no
effect is expected.
Zidovudine 300 mg
BID
(maraviroc 300 mg
BID)
Zidovudine AUC
12
: ↔ 0.98
Zidovudine C
max
: ↔ 0.92
Maraviroc concentrations not measured,
no effect is expected.
Integrase Inhibitors
Raltegravir 400 mg
BID
(maraviroc 300 mg
BID)
Maraviroc AUC
12
: ↓ 0.86
Maraviroc C
max
: ↓ 0.79
No clinically significant interaction
seen.
CELSENTRI 300 mg twice
daily and raltegravir can be
co-administered without dose
adjustment.
Raltegravir AUC
12
: ↓ 0.63
Raltegravir C
max
: ↓ 0.67
Raltegravir C
12
: ↓ 0.72
NNRTIs
Efavirenz 600 mg QD
(maraviroc 100 mg
BID)
Maraviroc AUC
12
: ↓ 0.55
Maraviroc C
max
: ↓ 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 AUC
12
: ↓ 0.47
Maraviroc C
max
: ↓ 0.40
Etravirine is only approved for
use with boosted protease
inhibitors.
For combination with
etravirine + PI, see below.
Etravirine AUC
12
: ↔ 1.06
Etravirine C
max
: ↔ 1.05
Etravirine C
12
: ↔ 1.08
6
Nevirapine 200 mg BID
(maraviroc 300 mg
Single Dose)
Maraviroc AUC
12
: ↔ compared to
historical controls
Maraviroc C
max
: ↑ 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.
PIs
Atazanavir 400 mg QD
(maraviroc 300 mg
BID)
Maraviroc AUC
12
↑ 3.57
Maraviroc C
max
: ↑ 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
or
fosamprenavir/ritonavir
where
the CELSENTRI dose should be
300 mg BID.
Maraviroc does not significantly
affect PI drug levels.
Atazanavir/ritonavir
300 mg/100 mg QD
(maraviroc 300 mg
BID)
Maraviroc AUC
12
↑ 4.88
Maraviroc C
max
: ↑ 2.67
Atazanavir/ritonavir concentrations not
measured, no effect is expected.
Lopinavir/ritonavir
400 mg/100 mg BID
(maraviroc 300 mg
BID)
Maraviroc AUC
12
↑ 3.95
Maraviroc C
max
: ↑ 1.97
Lopinavir/ritonavir concentrations not
measured, no effect is expected.
Saquinavir/ritonavir
1000 mg/100 mg BID
(maraviroc 100 mg
BID)
Maraviroc AUC
12
↑ 9.77
Maraviroc C
max
: ↑ 4.78
Saquinavir/ritonavir concentrations not
measured, no effect is expected.
Darunavir/ritonavir
600 mg/100 mg BID
(maraviroc 150 mg
BID)
Maraviroc AUC
12
↑ 4.05
Maraviroc C
max
: ↑ 2.29
Darunavir/ritonavir concentrations were
consistent with historical data.
Nelfinavir
Limited data are available for
coadministration with nelfinavir.
Nelfinavir is a potent CYP3A4 inhibitor
and would be expected to increase
maraviroc concentrations.
Limited data are available for
coadministration 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.
Fosamprenavir/ritonavir Fosamprenavir 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
and tipranavir/ritonavir or
fosamprenavir/ritonavir can be
co-administered without dose
adjustment.
Tipranavir/ritonavir
500 mg/200 mg BID
(maraviroc 150 mg
BID)
Maraviroc AUC
12
↔ 1.02
Maraviroc C
max
: ↔ 0.86
Tipranavir/ritonavir concentrations were
consistent with historical data.
NNRTI + PI
Efavirenz 600 mg QD +
lopinavir/ritonavir
400mg/100 mg BID
(maraviroc 300 mg
BID)
Maraviroc AUC
12:
↑ 2.53
Maraviroc C
max
: ↑ 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
fosamprenavir/ritonavir where
7
Indinavir
Efavirenz 600 mg QD +
saquinavir/ritonavir
1000 mg/100 mg BID
(maraviroc 100 mg
BID)
Maraviroc AUC
12:
↑ 5.00
Maraviroc C
max
: ↑ 2.26
Efavirenz, saquinavir/ritonavir
concentrations not measured, no effect
expected.
the dose should be 300 mg twice
daily or tipranavir/ritonavir
where the dose should be 600 mg
twice daily).
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 AUC
12:
↑ 3.10
Maraviroc C
max
: ↑ 1.77
CELSENTRI dose should be
decreased to 150 mg twice daily
when co-administered with
etravirine and a PI (except
fosamprenavir/ritonavir where
the dose should be 300 mg twice
daily).
Etravirine AUC
12
: ↔ 1.00
Etravirine C
max
: ↔ 1.08
Etravirine C
12
: ↓ 0.81
Darunavir AUC
12
: ↓ 0.86
Darunavir C
max
: ↔ 0.96
Darunavir C
12
: ↓ 0.77
Ritonavir AUC
12
: ↔ 0.93
Ritonavir C
max
: ↔ 1.02
Ritonavir C
12
: ↓ 0.74
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 AUC
12
: ↔ 1.11
Maraviroc C
max
: ↔ 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 C
max
: ↓ 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 or
fosamprenavir/ritonavir where
the dose should be 300 mg twice
daily) .
See also section 4.4.
8
Clarithromycin,
Telithromycin
Not studied, but both are potent CYP3A4
inhibitors and would be expected to
increase maraviroc concentrations.
CELSENTRI dose should be
decreased to 150 mg twice daily
when co-administered with
clarithromycin and
telithromycin.
Antifungals
Ketoconazole 400 mg
QD (maraviroc 100 mg
BID)
Maraviroc AUC
tau
: ↑ 5.00
Maraviroc C
max
: ↑ 3.38
Ketoconazole concentrations not
measured, no effect is expected.
CELSENTRI dose should be
decreased to 150 mg twice daily
when co-administered with
ketoconazole.
Itraconazole
Not studied. Itraconazole, is a potent
CYP3A4 inhibitor and would be expected
to increase the exposure of maraviroc.
CELSENTRI dose should be
decreased to 150 mg twice daily
when co-administered with
itraconazole.
Fluconazole
Fluconazole is considered to be a moderate
CYP3A4 inhibitor. Population PK studies
suggest that a dose adjustment of
maraviroc is not required.
CELSENTRI 300 mg twice daily
should be administered with
caution when co-administered
with fluconazole.
Antivirals
HCV agents
Pegylated interferon and ribavirin have not
been studied, no interaction is expected.
CELSENTRI 300 mg twice daily
and pegylated interferon or
ribavirin can be co-administered
without dose adjustment.
DRUG ABUSE
Methadone
Not studied, no interaction expected.
CELSENTRI 300 mg twice daily
and methadone can be
co-administered without dose
adjustment.
Buprenorphine
Not studied, no interaction expected.
CELSENTRI 300 mg twice daily
and buprenorphine can be
co-administered without dose
adjustment.
LIPID LOWERING
MEDICINAL PRODUCTS
Statins
Not studied, no interaction expected.
CELSENTRI 300 mg twice daily
and statins can be
co-administered without dose
adjustment.
O
RAL
CONTRACEPTIVES
Ethinylestradiol 30 mcg
QD
(maraviroc 100 mg
BID)
Ethinylestradiol. AUC
t:
↔ 1.00
Ethinylestradiol. C
max
: ↔ 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. AUC
12:
↔ 0.98
Levonorgestrel. C
max
: ↔ 1.01
Maraviroc concentrations not measured,
no interaction expected.
CELSENTRI 300 mg twice daily
and levonorgestrel can be
co-administered without dose
adjustment.
S
EDATIVES
Benzodiazepines
Midazolam 7.5 mg
Single Dose
(maraviroc 300 mg
BID)
Midazolam. AUC: ↔ 1.18
Midazolam. C
max
: ↔ 1.21
Maraviroc concentrations not measured,
no interaction expected.
CELSENTRI 300 mg twice daily
and midazolam can be
co-administered without dose
adjustment.
9
HERBAL
PRODUCTS
St John’s Wort
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 (Hypericum
Perforatum) or products
containing St. John's wort is not
recommended.
No meaningful clinical data on exposure during pregnancy are available. Studies in rats and rabbits
showed reproductive toxicity at high exposures. Primary pharmacological activity (CCR5 receptor
affinity) was limited in these species (see section 5.3). CELSENTRI should be used during pregnancy
only if the potential benefit justifies the potential risk to the foetus.
Studies in lactating rats indicate that maraviroc is extensively secreted into rat milk. Primary
pharmacological activity (CCR5 receptor affinity) was limited in these species. It is not known
whether maraviroc is secreted into human milk. Mothers should be instructed not to breast-feed if they
are receiving CELSENTRI because of the potential for HIV transmission as well as any possible
undesirable effects in breast-fed infants.
No studies on the effects on the ability to drive and use machines have been performed. CELSENTRI
may cause dizziness. Patients should be instructed that if they experience dizziness they should avoid
potentially hazardous tasks such as driving or operating machinery.
The safety profile of CELSENTRI is based on 1,374 HIV-1 infected patients who received at least one
dose of CELSENTRI 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.
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 section 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 CELSENTRI in Phase 2b/3 studies compared to those
receiving comparator.
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), and rare
(≥1/10,000 to <1/1,000). 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 CELSENTRI in Phase 2b/3 studies at rates greater than rates in the
comparator.
10
Table 3. Clinically important adverse reactions of moderate intensity or more
occurring among
patients receiving CELSENTRI at 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 (incl. cysts and polyps)
Bile duct cancer, diffuse large B-cell
lymphoma, Hodgkin’s disease,
metastases to bone, metastases to
liver, metastases to peritoneum,
nasopharyngeal cancer, oesophageal
carcinoma
rare
Blood and lymphatic system
disorders
Anaemia
common
Pancytopenia, granulocytopenia
rare
Metabolism and nutrition disorders Anorexia
common
Psychiatric disorders
Depression, insomnia
common
Nervous system disorders
Seizures and seizure disorders
uncommon
Cardiac disorders
Angina pectoris
rare
Gastrointestinal disorders
Abdominal pain, flatulence, nausea
common
Hepatobiliary disorders
Alanine aminotransferase increased,
aspartate aminotransferase increased
common
Hyperbilirubinaemia, gamma-
glutamyltransferase increased
uncommon
Hepatitis toxic, hepatic failure,
hepatic cirrhosis, blood alkaline
phosphatase increased
rare
Skin and subcutaneous tissue
disorders
Rash
common
Stevens-Johnson syndrome
rare
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
N.B. Adverse reactions captured in table 3 were assessed as possibly related to study drug by
investigators
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 (see section 4.4).
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
Celsentri 300 mg
twice daily
+ OBT
N =421
*
(%)
OBT
alone
N =207
*
(%)
Hepatobiliary disorders
Aspartate aminotransferase
>5.0x ULN
4.8
2.9
11
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/mm
3
4.3
1.9
ULN: Upper Limit of Normal
OBT: Optimised Background Therapy
* Percentages based on total patients evaluated for each laboratory parameter
In treatment-naïve patients, the incidence of grade 3 and 4 laboratory abnormalities using ACTG
criteria was similar among the CELSENTRI and efavirenz treatment groups.
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).
The highest dose administered in clinical studies was 1200 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 OBT alone 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 CELSENTRI to prolong the QT interval.
There is no specific antidote for overdose with CELSENTRI. 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.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antivirals for systemic use, Other Antivirals ATC code: J05AX09
Mechanism of action:
Maraviroc is a member of a therapeutic class called CCR5 antagonists. Maraviroc selectively binds to
the human chemokine receptor CCR5, preventing CCR5-tropic HIV-1 from entering cells.
Antiviral activity
in vitro
:
Maraviroc has no antiviral activity
in vitro
against viruses which can use CXCR4 as their entry co-
receptor (dual-tropic or CXCR4-tropic viruses, collectively termed ‘CXCR4-using’ virus below). The
serum adjusted EC90 value in 43 primary HIV-1 clinical isolates was 0.57 (0.06 – 10.7) ng/mL
without significant changes between different subtypes tested. The antiviral activity of maraviroc
against HIV-2 has not been evaluated. For details please refer to
http://www.ema.europa.eu/htms/human/epar/eparintro.
12
When used with other antiretroviral medicinal products in cell culture, the combination of maraviroc
was not antagonistic with a range of NRTIs, NNRTIs, PIs or the HIV fusion inhibitor enfuvirtide.
Resistance:
Viral escape from maraviroc can occur via 2 routes: the selection of virus which can use CXCR4 as its
entry co-receptor (CXCR4-using virus) or the selection of virus that continues to use exclusively
CCR5 (CCR5-tropic virus).
In vitro:
HIV-1 variants with reduced susceptibility to maraviroc have been selected
in vitro
, following serial
passage of two CCR5-tropic viruses (0 laboratory strains, 2 clinical isolates). The maraviroc-resistant
viruses remained CCR5-tropic and there was no conversion from a CCR5-tropic virus to a CXCR4-
using virus.
Phenotypic resistance: concentration response curves for the maraviroc-resistant viruses were
characterized phenotypically by curves that did not reach 100% inhibition in assays using serial
dilutions of maraviroc. Traditional IC
50
/IC
90
fold-change was not a useful parameter to measure
phenotypic resistance, as those values were sometimes unchanged despite significantly reduced
sensitivity.
Genotypic resistance: mutations were found to accumulate in the gp120 envelope glycoprotein
(the viral protein that binds to the CCR5 co-receptor). The position of these mutations was not
consistent between different isolates. Hence, the relevance of these mutations to maraviroc
susceptibility in other viruses is not known.
Cross-resistance
in vitro
:
HIV-1 clinical isolates resistant to nucleoside analogue reverse transcriptase inhibitors (NRTI), non-
nucleoside analogue reverse transcriptase inhibitors (NNRTI), protease inhibitors (PI) and enfuvirtide
were all susceptible to maraviroc in cell culture. Maraviroc-resistant viruses that emerged
in vitro
remained sensitive to the fusion inhibitor enfuvirtide and the protease inhibitor saquinavir.
In vivo:
Treatment-experienced patients
In the pivotal studies (MOTIVATE 1 and MOTIVATE 2), 7.6% of patients had a change in tropism
result from CCR5-tropic to CXCR4-tropic or dual/mixed-tropic between screening and baseline (a
period of 4-6 weeks).
Failure with CXCR4-using virus:
CXCR4-using virus was detected at failure in approximately 60% of subjects who failed treatment on
CELSENTRI, as compared to 6% of subjects who experienced treatment failure in the OBT alone
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 CELSENTRI arms and 4
subjects from the OBT alone 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 CELSENTRI 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.
13
Failure with CCR5-tropic virus:
Phenotypic resistance: in patients with CCR5-tropic virus at time of treatment failure with
CELSENTRI, 22 out of 58 patients had virus with reduced sensitivity to maraviroc. In the remaining
36 patients, there was no evidence of virus with reduced sensitivity as identified by exploratory
virology analyses on a representative group. The latter group had markers correlating to low
compliance (low and variable drug levels and often a calculated high residual sensitivity score of the
OBT). In patients failing therapy with R5-virus only, maraviroc might be considered still active if the
maximal percentage inhibition (MPI) value is ≥95% (Phenosense Entry assay). Residual activity
in
vivo
for viruses with MPI-values <95% has not been determined.
Genotypic resistance: Key mutations (V3-loop) can presently not be suggested due to the high
variability of the V3-sequence, and the low number of samples analysed.
Clinical Results
Studies in CCR5-tropic Treatment-Experienced Patients:
The clinical efficacy of CELSENTRI (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
CELSENTRI 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 5: Demographic and baseline characteristics of patients in studies MOTIVATE 1 and
MOTIVATE 2 (Pooled Analysis)
Demographic and Baseline Characteristics
CELSENTRI
300 mg twice daily
+ OBT
N = 426
OBT
alone
N = 209
Age (years)
(Range, years)
46.3
21-73
45.7
29-72
Male Sex
89.7%
88.5%
Race (White/Black/Other)
85.2% / 12% / 2.8% 85.2% / 12.4% / 2.4%
Mean Baseline HIV-1 RNA (log
10
copies/mL)
4.85
4.86
Median Baseline CD4+ Cell Count (cells/mm
3
)
(range, cells/mm
3
)
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/mm
3
250 (58.7%)
118 (56.5%)
Number (Percentage) of patients with GSS score:
0
1
2
≥3
102 (23.9%)
138 (32.4%)
80 (18.8%)
104 (24.4%)
51 (24.4%)
53 (25.4%)
41 (19.6%)
59 (28.2%)
GeneSeq
resistance assay
Limited numbers of patients from ethnicities other than Caucasian were included in the pivotal clinical
studies, therefore very limited data are available in these patient populations.
14
The mean increase in CD4+ cell count from baseline in patients who failed with a change in tropism
result to dual/mixed tropic or CXCR4, in the CELSENTRI 300 mg twice daily + OBT
(+56 cells/mm
3
) group was greater than that seen in patients failing OBT alone (+13.8 cells/mm
3
)
regardless of tropism.
Table 6. Outcomes of randomised treatment at week 48 (pooled studies MOTIVATE 1 and
MOTIVATE 2)
Outcomes
CELSENTRI 300 mg
twice daily
+ OBT
N=426
OBT
alone
N=209
Treatment Difference
1
(Confidence
Interval
2
)
HIV-1 RNA
Change from baseline
(log
10
copies/mL)
-1.84
-0.78
-1.05
(-1.33, -0.78)
Proportion of patients with
HIV RNA <400 copies/mL
56.1%
22.5%
Odds ratio: 4.76
(3.24, 7.00)
Proportion of patients with
HIV RNA <50 copies/mL
45.5%
16.7%
Odds ratio: 4.49
(2.96, 6.83)
CD4+ cell count
Change from baseline
(cells/mm
3
)
124.07
60.93
63.13
(44.28, 81.99)
1
p-values < 0.0001
2
For all efficacy endpoints the confidence intervals were 95%, except for HIV-1 RNA Change from
baseline which was 97.5%
CELSENTRI 300 mg twice daily + OBT was superior to OBT alone across all subgroups of patients
analysed (see Table 7).
Patients with very low CD4+ count at baseline (i.e. <50 cells/uL) had a less
favourable outcome. This subgroup had a high degree of bad prognostic markers, i.e. extensive
resistance and high baseline viral loads. However, a significant treatment benefit for CELSENTRI
compared to OBT alone was still demonstrated (see Table 7).
Table 7. Proportion of patients achieving <50 copies/mL at Week 48 by subgroup (pooled
Studies MOTIVATE 1 and MOTIVATE 2, ITT)
Subgroups
HIV-1 RNA <50 copies/mL
CELSENTRI 300 mg
twice daily
+ OBT
N=426
OBT
alone
N=209
Baseline HIV-1 RNA:
<5.0 log
10
copies/mL
≥5.0 log
10
copies/mL
58.4%
34.7%
26.0%
9.5%
Baseline CD4+ (cells/uL):
<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 OBT
1,2
:
0
1
2
≥3
32.7%
44.5%
58.2%
62%
2.0%
7.4%
31.7%
38.6%
1
Discontinuations or virological failures considered as failures.
2
Based on GSS.
15
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 OBT alone were demonstrated although there was no adverse
outcome on viral load or CD4+ cell count
Studies in Treatment-Naïve Patients
An ongoing randomised, double-blinded study (MERIT), is exploring CELSENTRI versus efavirenz,
both in combination with zidovudine/lamivudine (n=721, 1:1). After 48 weeks of treatment,
CELSENTRI 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
CELSENTRI 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 CELSENTRI arm.
Fewer patients discontinued CELSENTRI due to adverse events (15 vs. 49).
5.2 Pharmacokinetic properties
Absorption:
the absorption of maraviroc is variable with multiple peaks. Median peak maraviroc
plasma concentrations is attained at 2 hours (range 0.5-4 hours) following single oral doses of 300 mg
commercial tablet administered to healthy volunteers. The pharmacokinetics of oral maraviroc are not
dose proportional over the dose range. The absolute bioavailability of a 100 mg dose is 23% and is
predicted to be 33% at 300 mg. Maraviroc is a substrate for the efflux transporter P-glycoprotein.
Coadministration of a 300 mg tablet with a high fat breakfast reduced maraviroc C
max
and AUC by
33% in healthy volunteers. There were no food restrictions in the studies that demonstrated the
efficacy and safety of CELSENTRI (see section 5.1). Therefore, CELSENTRI can be taken with or
without food at the recommended doses (see section 4.2).
Distribution
:
maraviroc is bound (approximately 76%) to human plasma proteins, and shows moderate
affinity for albumin and alpha-1 acid glycoprotein. The volume of distribution of maraviroc is
approximately 194 L.
Metabolism
:
studies in humans and
in vitro
studies using human liver microsomes and expressed
enzymes have demonstrated that maraviroc is principally metabolized by the cytochrome P450 system
to metabolites that are essentially inactive against HIV-1.
In vitro
studies indicate that CYP3A4 is the
major enzyme responsible for maraviroc metabolism.
In vitro
studies also indicate that polymorphic
enzymes CYP2C9, CYP2D6 and CYP2C19 do not contribute significantly to the metabolism of
maraviroc.
Maraviroc is the major circulating component (approximately 42% radioactivity) following a single
oral dose of 300 mg. The most significant circulating metabolite in humans is a secondary amine
(approximately 22% radioactivity) formed by N-dealkylation. This polar metabolite has no significant
pharmacological activity. Other metabolites are products of mono-oxidation and are only minor
components of plasma radioactivity.
Elimination
:
a mass balance/excretion study was conducted using a single 300 mg dose of
14
C-labeled
maraviroc. Approximately 20% of the radiolabel was recovered in the urine and 76% was recovered in
the faeces over 168 hours. Maraviroc was the major component present in urine (mean of 8% dose)
and faeces (mean of 25% dose). The remainder was excreted as metabolites. After intravenous
administration (30 mg), the half-life of maraviroc was 13.2 h, 22% of the dose was excreted
unchanged in the urine and the values of total clearance and renal clearance were 44.0 L/h and 10.17
L/h respectively.
Children:
the pharmacokinetics of maraviroc in paediatric patients have not been established (see
section 4.2).
16
Elderly
: population analysis of the Phase 1/2a and Phase 3 studies (16-65 years of age) has been
conducted and no effect of age has been observed (see section 4.2).
Renal impairment:
a study compared the pharmacokinetics of a single 300 mg dose of CELSENTRI in
subjects with severe renal impairment (CLcr < 30 mL/min, n=6) and end stage renal disease (ESRD)
to healthy volunteers (n=6). The geometric mean AUC
inf
(CV%) for CELSENTRI was as follows:
healthy volunteers (normal renal function) 1348.4 ng·h/mL (61%); severe renal function 4367.7
ng·h/mL (52%); ESRD (dosing after dialysis) 2677.4 ng·h/mL (40%); and ESRD (dosing before
dialysis) 2805.5 ng·h/mL (45%). The C
max
(CV%) was 335.6 ng/mL (87%) in healthy volunteers
(normal renal function); 801.2 ng/mL (56%) in severe renal function; 576.7 ng/mL (51%) in ESRD
(dosing after dialysis) and 478.5 ng/mL (38%) in ESRD (dosing before dialysis). Dialysis had a
minimal effect on exposure in subjects with ESRD. Exposures observed in subjects with severe renal
impairment and ESRD were within the range observed in single CELSENTRI 300 mg dose studies in
healthy volunteers with normal renal function. Therefore, no dose adjustment is necessary in patients
with renal impairment receiving CELSENTRI without a potent CYP3A4 inhibitor (see sections 4.2,
4.4 and 4.5).
In addition, the study compared the pharmacokinetics of multiple dose CELSENTRI in combination
with saquinavir/ritonavir 1000/100 mg BID (a potent CYP3A4 inhibitor) for 7 days in subjects with
mild renal impairment (CLcr >50 and ≤80 mL/min, n=6) and moderate renal impairment (CLcr ≥30
and ≤50 mL/min, n=6) to healthy volunteers (n=6). Subjects received 150 mg of CELSENTRI at
different dose frequencies (healthy volunteers – every 12 hours; mild renal impairment – every 24
hours; moderate renal impairment – every 48 hours). The average concentration (Cavg) of
CELSENTRI over 24 hours was 445.1 ng/mL, 338.3 ng/mL, and 223.7 ng/mL for subjects with
normal renal function, mild renal impairment, and moderate renal impairment, respectively. The Cavg
of CELSENTRI from 24-48 hours for subjects with moderate renal impairment was low (Cavg: 32.8
ng/mL). Therefore, dosing frequencies of longer than 24 hours in subjects with renal impairment may
result in inadequate exposures between 24-48 hours.
Dose adjustment is necessary in patients with renal impairment receiving CELSENTRI with potent
CYP3A4 inhibitors (see sections 4.2 and 4.4 and 4.5).
Hepatic impairment:
maraviroc is primarily metabolized and eliminated by the liver. A study
compared the pharmacokinetics of a single 300 mg dose of CELSENTRI in patients with mild (Child-
Pugh Class A, n=8), and moderate (Child-Pugh Class B, n=8) hepatic impairment compared to healthy
subjects (n=8). Geometric mean ratios for C
max
and AUC
last
were 11% and 25% higher respectively for
subjects with mild hepatic impairment, and 32% and 46% higher respectively for subjects with
moderate hepatic impairment compared to subjects with normal hepatic function. The effects of
moderate hepatic impairment may be underestimated due to limited data in patients with decreased
metabolic capacity and higher renal clearance in these subjects. The results should therefore be
interpreted with caution. The pharmacokinetics of maraviroc have not been studied in subjects with
severe hepatic impairment (see sections 4.2 and 4.4).
Race:
no relevant difference between Caucasian, Asian and Black subjects has been observed. The
pharmacokinetics in other races has not been evaluated.
Gender:
no relevant differences in pharmacokinetics have been observed.
5.3 Preclinical safety data
Primary pharmacological activity (CCR5 receptor affinity) was present in the monkey (100% receptor
occupancy) and limited in the mouse, rat, rabbit and dog. In mice and human beings that lack CCR5
receptors through genetic deletion, no significant adverse consequences have been reported.
In vitro
and
in vivo
studies showed that maraviroc has a potential to increase QTc interval at
supratherapeutic doses with no evidence of arrhythmia.
17
Repeated dose toxicity studies in rats identified the liver as the primary target organ for toxicity
(increases in transaminases, bile duct hyperplasia, necrosis).
Maraviroc was evaluated for carcinogenic potential by a 6 month transgenic mouse study and a 24
month study in rats. In mice, no statistically significant increase in the incidence of tumors was
reported at systemic exposures from 7 to 39-times the human exposure (unbound AUC 0-24h
measurement) at a dose of 300 mg twice daily. In rats, administration of maraviroc at a systemic
exposure 21-times the expected human exposure produced thyroid adenomas associated with adaptive
liver changes. These findings are considered of low human relevance. In addition,
cholangiocarcinomas (2/60 males at 900 mg/kg) and cholangioma (1/60 females at 500 mg/kg) were
reported in the rat study at a systemic exposure at least 15-times the expected free human exposure.
Maraviroc was not mutagenic or genotoxic in a battery of
in vitro
and
in vivo
assays including
bacterial reverse mutation, chromosome aberrations in human lymphocytes and rat bone marrow
micronucleus.
Maraviroc did not impair mating or fertility of male or female rats, and did not affect sperm of treated
male rats up to 1000 mg/kg. The exposure at this dose level corresponded to 39-fold the estimated free
clinical AUC for a 300 mg twice daily dose.
Embryofoetal development studies were conducted in rats and rabbits at doses up to 39- and 34-fold
the estimated free clinical AUC for a 300 mg twice daily dose. In rabbit, 7 foetuses had external
anomalies at maternally toxic doses and 1 foetus at the mid dose of 75 mg/kg.
Pre- and post-natal developmental studies were performed in rats at doses up to 27-fold the estimated
free clinical AUC for a 300 mg twice daily dose. A slight increase in motor activity in high-dose male
rats at both weaning and as adults was noted, while no effects were seen in females. Other
developmental parameters of these offspring, including fertility and reproductive performance, were
not affected by the maternal administration of maraviroc.
6
6.1 List of excipients
Tablet core:
Cellulose, microcrystalline
Calcium hydrogen phosphate, anhydrous
Sodium starch glycolate
Magnesium stearate
Film-coat:
Poly (vinyl alcohol)
Titanium dioxide
Macrogol 3350
Talc
Soya Lecithin
Indigo carmine aluminium lake (E132)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
4 years.
18
6.4
Special precautions for storage
This medicinal product does not require any special storage condition.
6.5 Nature and contents of container
High density polyethylene bottles (HDPE) with polypropylene child resistant (CR) closures and an
aluminium foil/polyethylene heat induction seal containing 180 film-coated tablets.
Polyvinyl chloride (PVC) blisters with aluminium foil backing in a carton containing 30, 60, 90 film-
coated tablets and multipacks containing 180 (2 packs of 90) film-coated tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
Any unused product or waste material should be disposed of in accordance with local requirements.
7
ViiV Healthcare UK Ltd
980 Great West Road
Brentford
Middlesex
TW8 9GS
United Kingdom
8.
EU/1/07/418/001
EU/1/07/418/002
EU/1/07/418/003
EU/1/07/418/004
EU/1/07/418/005
9.
18
th
September 2007
Detailed information on this medicinal product is available on the website of the European Medicines
Agency http://www.ema.europa.eu
19
1.
CELSENTRI 300 mg film-coated tablets.
2.
2.1 General description
Each film-coated tablet contains 300 mg of maraviroc.
2.2 Qualitative and quantitative composition
Excipients
Each 300 mg film-coated tablet contains 1.68 mg of soya lecithin.
For a full list of excipients, see section 6.1.
3.
Film-coated tablet.
Blue, biconvex, oval film-coated tablets debossed with “MVC 300”.
4.
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.
Before taking CELSENTRI it has to be confirmed that only CCR5-tropic HIV-1 is detectable (i.e.
CXCR4 or dual/mixed tropic virus not detected) using an adequately validated and sensitive detection
method on a newly drawn blood sample. The Monogram Trofile assay was used in the clinical studies
of CELSENTRI (see sections 4.4 and 5.1). Other phenotypic and genotypic assays are currently being
evaluated. The viral tropism cannot be safely predicted by treatment history and assessment of stored
samples.
There are currently no data regarding the reuse of CELSENTRI in patients that currently have only
CCR5-tropic HIV-1 detectable, but have a history of failure on CELSENTRI (or other CCR5
antagonists) with a CXCR4 or dual/mixed tropic virus. There are no data regarding the switch from a
medicinal product of a different antiretroviral class to CELSENTRI in virologically suppressed
patients. Alternative treatment options should be considered.
Adults
: the recommended dose of CELSENTRI is 150 mg, 300 mg or 600 mg twice daily depending
on interactions with co-administered antiretroviral therapy and other medicinal products (see Table 2
in Section 4.5). CELSENTRI can be taken with or without food.
20
Children:
CELSENTRI is not recommended for use in children due to lack of data on safety, efficacy
and pharmacokinetics (see section 5.2).
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:
dosage adjustment is only recommended in patients with renal impairment who are
receiving potent CYP3A4 inhibitors such as:
•
protease inhibitors (except tipranavir/ritonavir)
•
ketoconazole, itraconazole, clarithromycin, telithromycin.
CELSENTRI should be used with caution in patients with severe renal impairment (CLcr <
30mL/min) who are receiving potent CYP3A4 inhibitors (see sections 4.4 and 5.2).
The dose and dosing interval for CELSENTRI should be modified in renally impaired patients (CLcr
<80 mL/min), including patients with end stage renal disease (ESRD) requiring dialysis (Table 1
below). These dosing recommendations are based on data from a renal impairment study (see section
5.2) in addition to modelling of pharmacokinetic data in subjects with varying degrees of renal
impairment.
Table 1. Dose and interval adjustments for patients with renal impairment
Recommended CELSENTRI dose
interval
Creatinine clearance
<80 mL/min
If administered without potent
CYP3A4 inhibitors or if
co-administered with
tipranavir/ritonavir
No dose interval adjustment required
If co-administered with
fosamprenavir/ritonavir
CELSENTRI 150 mg every 12 hours
If co-administered with potent
CYP3A4 inhibitors, e.g.
saquinavir/ritonavir,
lopinavir/ritonavir,
darunavir/ritonavir,
atazanavir/ritonavir, ketoconazole
CELSENTRI 150 mg every 24 hours
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).
Hypersensitivity to the active substance or to peanut or soya or to any of the excipients.
CELSENTRI should be taken as part of an antiretroviral combination regimen. CELSENTRI should
optimally be combined with other antiretrovirals to which the patient's virus is sensitive (see section
5.1).
CELSENTRI 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
CELSENTRI. Other phenotypic and genotypic assays are currently being evaluated. The viral tropism
cannot be predicted by treatment history or assessment of stored samples.
21
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.
CELSENTRI 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 CELSENTRI is made
when CELSENTRI 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.
Information for patients:
patients should be advised that antiretroviral therapies including
CELSENTRI
have not been shown to prevent the risk of transmission of HIV to others through sexual
contact or contamination with blood. They should continue to use appropriate precautions. Patients
should also be informed that CELSENTRI
is not a cure for HIV-1 infection.
Postural hypotension
: when CELSENTRI 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. However, when CELSENTRI was given at the recommended dose in
HIV infected patients in Phase 3 studies, postural hypotension was seen at a similar rate compared to
placebo (approximately 0.5%). Caution should be used when administering CELSENTRI in patients
with a history of postural hypotension or on concomitant medicinal products known to lower blood
pressure.
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 CELSENTRI and placebo arms in the pivotal studies.
Cardiovascular safety:
limited data exist with the use of CELSENTRI in patients with severe
cardiovascular disease, therefore special caution should be exercised when treating these patients with
CELSENTRI. In the pivotal studies of treatment-experienced patients (MOTIVATE) coronary heart
disease events was more common in patients treated with CELSENTRI than with placebo (11 during
609 PY vs 0 during 111 PY of follow-up). In treatment-naïve patients (MERIT) such events occurred
at a similarly low rate with CELSENTRI and control (efavirenz).
When CELSENTRI was administered to healthy volunteers at doses higher than the recommended
dose, cases of symptomatic postural hypotension were seen at a greater frequency than with placebo.
However, when CELSENTRI was given at the recommended dose in HIV infected patients in Phase 3
studies, postural hypotension was seen at a similar rate compared to placebo/comparator. Caution
should be used when administering CELSENTRI in patients with a history of postural hypotension or
on concomitant medicinal products known to lower blood pressure.
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.
22
Osteonecrosis
:
although the etiology 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.
Hepatic safety:
the safety and efficacy of CELSENTRI
have not been specifically studied in patients
with significant underlying liver disorders.
A case of possible CELSENTRI-induced hepatotoxicity with allergic features has been reported in a
study in healthy volunteers. In addition, an increase in hepatic adverse reactions with CELSENTRI
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 CELSENTRI should be 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, eosinophila or elevated IgE).
Since there are very limited data in patients with hepatitis B/C co-infection, special caution should be
exercised when treating these patients with CELSENTRI. In case of concomitant antiviral therapy for
hepatitis B and/or C, please refer also to the relevant product information for these medicinal products.
There is limited experience in patients with reduced hepatic function, therefore CELSENTRI
should
be used with caution in this population (see sections 4.2 and 5.2).
Renal impairment:
An increased risk of postural hypotension may occur in patients with severe renal
insufficiency who are treated with boosted protease inhibitors (PIs) and CELSENTRI. This risk is due
to potential increases in maraviroc maximum concentrations when CELSENTRI is co-administered
with boosted PIs in these patients. The risk of postural hypotension is highest when CELSENTRI is
co-administered with PIs having the most potent CYP3A4 inhibitory effect (saquinavir/ ritonavir,
darunavir/ ritonavir, lopinavir/ ritonavir). Patients with impaired renal function may frequently have
cardiovascular co-morbidities, and could be at increased risk of cardiovascular adverse events
triggered by postural hypotension. No studies have been performed in subjects with severe renal
impairment co-treated with potent CYP3A4 inhibitors. Dose adjustments are based on modelling and
simulations (see sections 4.2, 4.5 and 5.2).
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. Coadministration of CELSENTRI
with
medicinal products that induce CYP3A4 may decrease maraviroc concentrations and reduce its
therapeutic effects. Coadministration of CELSENTRI
with medicinal products that inhibit CYP3A4
may increase maraviroc plasma concentrations. Dose adjustment of CELSENTRI
is recommended
when CELSENTRI is co-administered with CYP3A4 inhibitors and/or inducers. Further details for
concomitantly administered medicinal products are provided below (see Table 2).
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
23
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,
coadministration of CELSENTRI
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, coadministration of CELSENTRI
with lamivudine/zidovudine showed no
effect of maraviroc on lamivudine (primarily renally cleared) or zidovudine (non-P450 metabolism
and renal clearance) pharmacokinetics.
In vitro
results indicate that maraviroc could inhibit P-
glycoprotein in the gut and may thus affect bioavailability of certain drugs.
Table 2. Interactions and dose recommendations with other medical products
Medicinal product by
therapeutic areas
(dose of CELSENTRI
used in study)
Effects on drug levels
Geometric mean change if not stated
otherwise
Recommendations concerning
coadministration
ANTI-INFECTIVES
Antiretrovirals
NRTIs
Lamivudine 150 mg
BID
(maraviroc 300 mg
BID)
Lamivudine AUC
12
: ↔ 1.13
Lamivudine C
max
: ↔ 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 AUC
12
: ↔ 1.03
Maraviroc C
max
: ↔ 1.03
Tenofovir concentrations not measured, no
effect is expected.
Zidovudine 300 mg
BID
(maraviroc 300 mg
BID)
Zidovudine AUC
12
: ↔ 0.98
Zidovudine C
max
: ↔ 0.92
Maraviroc concentrations not measured,
no effect is expected.
Integrase Inhibitors
Raltegravir 400 mg BID
(maraviroc 300 mg
BID)
Maraviroc AUC
12
: ↓ 0.86
Maraviroc C
max
: ↓ 0.79
No clinically significant
interaction seen.
CELSENTRI
300 mg twice daily and
raltegravir can be
co-administered without dose
adjustment.
Raltegravir AUC
12
: ↓ 0.63
Raltegravir C
max
: ↓ 0.67
Raltegravir C
12
: ↓ 0.72
NNRTIs
Efavirenz 600 mg QD
(maraviroc 100 mg
BID)
Maraviroc AUC
12
: ↓ 0.55
Maraviroc C
max
: ↓ 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 AUC
12
: ↓ 0.47
Maraviroc C
max
: ↓ 0.40
Etravirine is only approved for
use with boosted protease
inhibitors.
For combination with
etravirine + PI, see below.
Etravirine AUC
12
: ↔ 1.06
Etravirine C
max
: ↔ 1.05
Etravirine C
12
: ↔ 1.08
24
Nevirapine 200 mg BID
(maraviroc 300 mg
Single Dose)
Maraviroc AUC
12
: ↔ compared to
historical controls
Maraviroc C
max
: ↑ 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.
PIs
Atazanavir 400 mg QD
(maraviroc 300 mg
BID)
Maraviroc AUC
12
↑ 3.57
Maraviroc C
max
: ↑ 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
or
fosamprenavir/ritonavir where
the CELSENTRI dose should be
300 mg BID.
Maraviroc does not significantly
affect PI drug levels.
Atazanavir/ritonavir
300 mg/100 mg QD
(maraviroc 300 mg
BID)
Maraviroc AUC
12
↑ 4.88
Maraviroc C
max
: ↑ 2.67
Atazanavir/ritonavir concentrations not
measured, no effect is expected.
Lopinavir/ritonavir
400 mg/100 mg BID
(maraviroc 300 mg
BID)
Maraviroc AUC
12
↑ 3.95
Maraviroc C
max
: ↑ 1.97
Lopinavir/ritonavir concentrations not
measured, no effect is expected.
Saquinavir/ritonavir
1000 mg/100 mg BID
(maraviroc 100 mg
BID)
Maraviroc AUC
12
↑ 9.77
Maraviroc C
max
: ↑ 4.78
Saquinavir/ritonavir concentrations not
measured, no effect is expected.
Darunavir/ritonavir
600 mg/100 mg BID
(maraviroc 150 mg
BID)
Maraviroc AUC
12
↑ 4.05
Maraviroc C
max
: ↑ 2.29
Darunavir/ritonavir concentrations were
consistent with historical data.
Nelfinavir
Limited data are available for
coadministration with nelfinavir.
Nelfinavir is a potent CYP3A4 inhibitor
and would be expected to increase
maraviroc concentrations.
Limited data are available for
coadministration 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.
Fosamprenavir/ritonavir Fosamprenavir 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
and tipranavir/ritonavir or
fosamprenavir/ritonavir can be
co-administered without dose
adjustment.
Tipranavir/ritonavir
500 mg/200 mg BID
(maraviroc 150 mg
BID)
Maraviroc AUC
12
↔ 1.02
Maraviroc C
max
: ↔ 0.86
Tipranavir/ritonavir concentrations were
consistent with historical data.
NNRTI + PI
Efavirenz 600 mg QD +
lopinavir/ritonavir
400mg/100 mg BID
(maraviroc 300 mg
BID)
Maraviroc AUC
12:
↑ 2.53
Maraviroc C
max
: ↑ 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
fosamprenavir/ritonavir where
25
Indinavir
Efavirenz 600 mg QD +
saquinavir/ritonavir
1000 mg/100 mg BID
(maraviroc 100 mg
BID)
Maraviroc AUC
12:
↑ 5.00
Maraviroc C
max
: ↑ 2.26
Efavirenz, saquinavir/ritonavir
concentrations not measured, no effect
expected.
the dose should be 300 mg twice
daily or tipranavir/ritonavir
where the dose should be 600 mg
twice daily).
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 AUC
12:
↑ 3.10
Maraviroc C
max
: ↑ 1.77
CELSENTRI dose should be
decreased to 150 mg twice daily
when co-administered with
etravirine and a PI (except
fosamprenavir/ritonavir where
the dose should be 300 mg twice
daily).
Etravirine AUC
12
: ↔ 1.00
Etravirine C
max
: ↔ 1.08
Etravirine C
12
: ↓ 0.81
Darunavir AUC
12
: ↓ 0.86
Darunavir C
max
: ↔ 0.96
Darunavir C
12
: ↓ 0.77
Ritonavir AUC
12
: ↔ 0.93
Ritonavir C
max
: ↔ 1.02
Ritonavir C
12
: ↓ 0.74
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 AUC
12
: ↔ 1.11
Maraviroc C
max
: ↔ 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 C
max
: ↓ 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 or
fosamprenavir/ritonavir where
the dose should be 300 mg twice
daily) .
See also section 4.4.
26
Clarithromycin,
Telithromycin
Not studied, but both are potent CYP3A4
inhibitors and would be expected to
increase maraviroc concentrations.
CELSENTRI dose should be
decreased to 150 mg twice daily
when co-administered with
clarithromycin and
telithromycin.
Antifungals
Ketoconazole 400 mg
QD (maraviroc 100 mg
BID)
Maraviroc AUC
tau
: ↑ 5.00
Maraviroc C
max
: ↑ 3.38
Ketoconazole concentrations not
measured, no effect is expected.
CELSENTRI dose should be
decreased to 150 mg twice daily
when co-administered with
ketoconazole.
Itraconazole
Not studied. Itraconazole, is a potent
CYP3A4 inhibitor and would be expected
to increase the exposure of maraviroc.
CELSENTRI dose should be
decreased to 150 mg twice daily
when co-administered with
itraconazole.
Fluconazole
Fluconazole is considered to be a moderate
CYP3A4 inhibitor. Population PK studies
suggest that a dose adjustment of
maraviroc is not required.
CELSENTRI 300 mg twice daily
should be administered with
caution when co-administered
with fluconazole.
Antivirals
HCV agents
Pegylated interferon and ribavirin have not
been studied, no interaction is expected.
CELSENTRI 300 mg twice daily
and pegylated interferon or
ribavirin can be co-administered
without dose adjustment.
DRUG ABUSE
Methadone
Not studied, no interaction expected.
CELSENTRI 300 mg twice daily
and methadone can be
co-administered without dose
adjustment.
Buprenorphine
Not studied, no interaction expected.
CELSENTRI 300 mg twice daily
and buprenorphine can be
co-administered without dose
adjustment.
LIPID LOWERING
MEDICINAL PRODUCTS
Statins
Not studied, no interaction expected.
CELSENTRI 300 mg twice daily
and statins can be
co-administered without dose
adjustment.
O
RAL
CONTRACEPTIVES
Ethinylestradiol 30 mcg
QD
(maraviroc 100 mg
BID)
Ethinylestradiol. AUC
t:
↔ 1.00
Ethinylestradiol. C
max
: ↔ 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. AUC
12:
↔ 0.98
Levonorgestrel. C
max
: ↔ 1.01
Maraviroc concentrations not measured,
no interaction expected.
CELSENTRI 300 mg twice daily
and levonorgestrel can be
co-administered without dose
adjustment.
S
EDATIVES
Benzodiazepines
Midazolam 7.5 mg
Single Dose
(maraviroc 300 mg
BID)
Midazolam. AUC: ↔ 1.18
Midazolam. C
max
: ↔ 1.21
Maraviroc concentrations not measured,
no interaction expected.
CELSENTRI 300 mg twice daily
and midazolam can be
co-administered without dose
adjustment.
27
HERBAL
PRODUCTS
St John’s Wort
Coadministration 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 (Hypericum
Perforatum) or products
containing St. John's wort is not
recommended.
No meaningful clinical data on exposure during pregnancy are available. Studies in rats and rabbits
showed reproductive toxicity at high exposures. Primary pharmacological activity (CCR5 receptor
affinity) was limited in these species (see section 5.3). CELSENTRI should be used during pregnancy
only if the potential benefit justifies the potential risk to the foetus.
Studies in lactating rats indicate that maraviroc is extensively secreted into rat milk. Primary
pharmacological activity (CCR5 receptor affinity) was limited in these species. It is not known
whether maraviroc is secreted into human milk. Mothers should be instructed not to breast-feed if they
are receiving CELSENTRI because of the potential for HIV transmission as well as any possible
undesirable effects in breast-fed infants.
No studies on the effects on the ability to drive and use machines have been performed. CELSENTRI
may cause dizziness. Patients should be instructed that if they experience dizziness they should avoid
potentially hazardous tasks such as driving or operating machinery.
The safety profile of CELSENTRI is based on 1,374 HIV-1 infected patients who received at least one
dose of CELSENTRI 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 section
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 CELSENTRI in Phase 2b/3 studies compared to those
receiving comparator.
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), and rare
(≥1/10,000 to <1/1000). 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 CELSENTRI in Phase 2b/3 studies at rates greater than rates in the
comparator.
28
Table 3. Clinically important adverse reactions of moderate intensity or more
occurring among
patients receiving CELSENTRI at rates greater than rates in the compar
ator.
System Organ Class
Adverse Reaction
Frequency
Infections and infestations
Pneumonia, oesophageal candidiasis uncommon
Neoplasm benign, malignant and
unspecified (incl. cysts and polyps)
Bile duct cancer, diffuse large B-cell
lymphoma, Hodgkin’s disease,
metastases to bone, metastases to
liver, metastases to peritoneum,
nasopharyngeal cancer, oesophageal
carcinoma
rare
Blood and lymphatic system
disorders
Anaemia
common
Pancytopenia, granulocytopenia
rare
Metabolism and nutrition disorders Anorexia
common
Psychiatric disorders
Depression, insomnia
common
Nervous system disorders
Seizures and seizure disorders
uncommon
Cardiac disorders
Angina pectoris
rare
Gastrointestinal disorders
Abdominal pain, flatulence, nausea
common
Hepatobiliary disorders
Alanine aminotransferase increased,
aspartate aminotransferase increased
common
Hyperbilirubinaemia, gamma-
glutamyltransferase increased
uncommon
Hepatitis toxic, hepatic failure,
hepatic cirrhosis, blood alkaline
phosphatase increased
rare
Skin and subcutaneous tissue
disorders
Rash
common
Stevens-Johnson syndrome
rare
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
N.B. Adverse reactions captured in table 3 were assessed as possibly related to study drug by
investigators
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 (see section 4.4).
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
Celsentri 300 mg
twice daily
+ OBT
N =421
*
(%)
OBT
alone
N =207
*
(%)
Hepatobiliary disorders
Aspartate aminotransferase
>5.0x ULN
4.8
2.9
Alanine aminotransferase
>5.0x ULN
2.6
3.4
29
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/mm
3
4.3
1.9
ULN: Upper Limit of Normal
OBT: Optimised Background Therapy
* Percentages based on total patients evaluated for each laboratory parameter
In treatment-naïve patients, the incidence of grade 3 and 4 laboratory abnormalities using ACTG
criteria was similar among the CELSENTRI and efavirenz treatment groups.
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).
The highest dose administered in clinical studies was 1200 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 OBT alone 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 CELSENTRI to prolong the QT interval.
There is no specific antidote for overdose with CELSENTRI. 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.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antivirals for systemic use, Other Antivirals ATC code: J05AX09
Mechanism of action:
Maraviroc is a member of a therapeutic class called CCR5 antagonists. Maraviroc selectively binds to
the human chemokine receptor CCR5, preventing CCR5-tropic HIV-1 from entering cells.
Antiviral activity
in vitro
:
Maraviroc has no antiviral activity
in vitro
against viruses which can use CXCR4 as their entry co-
receptor (dual-tropic or CXCR4-tropic viruses, collectively termed ‘CXCR4-using’ virus below). The
serum adjusted EC90 value in 43 primary HIV-1 clinical isolates was 0.57 (0.06 – 10.7) ng/mL
without significant changes between different subtypes tested. The antiviral activity of maraviroc
against HIV-2 has not been evaluated. For details please refer to
http://www.ema.europa.eu/htms/human/epar/eparintro.
30
When used with other antiretroviral medicinal products in cell culture, the combination of maraviroc
was not antagonistic with a range of NRTIs, NNRTIs, PIs or the HIV fusion inhibitor enfuvirtide.
Resistance:
Viral escape from maraviroc can occur via 2 routes: the selection of virus which can use CXCR4 as its
entry co-receptor (CXCR4-using virus) or the selection of virus that continues to use exclusively
CCR5 (CCR5-tropic virus).
In vitro:
HIV-1 variants with reduced susceptibility to maraviroc have been selected
in vitro
, following serial
passage of two CCR5-tropic viruses (0 laboratory strains, 2 clinical isolates). The maraviroc-resistant
viruses remained CCR5-tropic and there was no conversion from a CCR5-tropic virus to a CXCR4-
using virus.
Phenotypic resistance: concentration response curves for the maraviroc-resistant viruses were
characterized phenotypically by curves that did not reach 100% inhibition in assays using serial
dilutions of maraviroc. Traditional IC
50
/IC
90
fold-change was not a useful parameter to measure
phenotypic resistance, as those values were sometimes unchanged despite significantly reduced
sensitivity.
Genotypic resistance: mutations were found to accumulate in the gp120 envelope glycoprotein
(the viral protein that binds to the CCR5 co-receptor). The position of these mutations was not
consistent between different isolates. Hence, the relevance of these mutations to maraviroc
susceptibility in other viruses is not known.
Cross-resistance
in vitro
:
HIV-1 clinical isolates resistant to nucleoside analogue reverse transcriptase inhibitors (NRTI), non-
nucleoside analogue reverse transcriptase inhibitors (NNRTI), protease inhibitors (PI) and enfuvirtide
were all susceptible to maraviroc in cell culture. Maraviroc-resistant viruses that emerged
in vitro
remained sensitive to the fusion inhibitor enfuvirtide and the protease inhibitor saquinavir.
In vivo:
Treatment-experienced patients
In the pivotal studies (MOTIVATE 1 and MOTIVATE 2), 7.6% of patients had a change in tropism
result from CCR5-tropic to CXCR4-tropic or dual/mixed-tropic between screening and baseline (a
period of 4-6 weeks).
Failure with CXCR4-using virus:
CXCR4-using virus was detected at failure in approximately 60% of subjects who failed treatment on
CELSENTRI, as compared to 6% of subjects who experienced treatment failure in the OBT alone
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 CELSENTRI arms and 4
subjects from the OBT alone 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 CELSENTRI 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.
31
Failure with CCR5-tropic virus:
Phenotypic resistance: in patients with CCR5-tropic virus at time of treatment failure with
CELSENTRI, 22 out of 58 patients had virus with reduced sensitivity to maraviroc. In the remaining
36 patients, there was no evidence of virus with reduced sensitivity as identified by exploratory
virology analyses on a representative group. The latter group had markers correlating to low
compliance (low and variable drug levels and often a calculated high residual sensitivity score of the
OBT). In patients failing therapy with R5-virus only, maraviroc might be considered still active if the
maximal percentage inhibition (MPI) value is ≥95% (Phenosense Entry assay). Residual activity
in
vivo
for viruses with MPI-values <95% has not been determined.
Genotypic resistance:
Key mutations (V3-loop) can presently not be suggested due to the high
variability of the V3-sequence, and the low number of samples analysed.
Clinical Results
Studies in CCR5-tropic Treatment-Experienced Patients:
The clinical efficacy of CELSENTRI (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
CELSENTRI 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 5: Demographic and baseline characteristics of patients in studies MOTIVATE 1 and
MOTIVATE 2 (Pooled Analysis)
Demographic and Baseline Characteristics
CELSENTRI
300 mg twice daily
+ OBT
N = 426
OBT
alone
N = 209
Age (years)
(Range, years)
46.3
21-73
45.7
29-72
Male Sex
89.7%
88.5%
Race (White/Black/Other)
85.2% / 12% / 2.8% 85.2% / 12.4% / 2.4%
Mean Baseline HIV-1 RNA (log
10
copies/mL)
4.85
4.86
Median Baseline CD4+ Cell Count (cells/mm
3
)
(range, cells/mm
3
)
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/mm
3
250 (58.7%)
118 (56.5%)
Number (Percentage) of patients with GSS score:
0
1
2
≥3
102 (23.9%)
138 (32.4%)
80 (18.8%)
104 (24.4%)
51 (24.4%)
53 (25.4%)
41 (19.6%)
59 (28.2%)
GeneSeq
resistance assay
Limited numbers of patients from ethnicities other than Caucasian were included in the pivotal clinical
studies, therefore very limited data are available in these patient populations.
32
The mean increase in CD4+ cell count from baseline in patients who failed with a change in tropism
result to dual/mixed tropic or CXCR4, in the CELSENTRI 300 mg twice daily + OBT
(+56 cells/mm
3
) group was greater than that seen in patients failing OBT alone (+13.8 cells/mm
3
)
regardless of tropism.
Table 6. Outcomes of randomised treatment at week 48 (pooled studies MOTIVATE 1 and
MOTIVATE 2)
Outcomes
CELSENTRI 300 mg
twice daily
+ OBT
N=426
OBT
alone
N=209
Treatment Difference
1
(Confidence
Interval
2
)
HIV-1 RNA
Change from baseline
(log
10
copies/mL)
-1.84
-0.78
-1.05
(-1.33, -0.78)
Proportion of patients with
HIV RNA <400 copies/mL
56.1%
22.5%
Odds ratio: 4.76
(3.24, 7.00)
Proportion of patients with
HIV RNA <50 copies/mL
45.5%
16.7%
Odds ratio: 4.49
(2.96, 6.83)
CD4+ cell count
Change from baseline
(cells/mm
3
)
124.07
60.93
63.13
(44.28, 81.99)
1
p-values < 0.0001
2
For all efficacy endpoints the confidence intervals were 95%, except for HIV-1 RNA Change from
baseline which was 97.5%
CELSENTRI 300 mg twice daily + OBT was superior to OBT alone across all subgroups of patients
analysed (see Table 7).
Patients with very low CD4+ count at baseline (i.e. <50 cells/uL) had a less
favourable outcome. This subgroup had a high degree of bad prognostic markers, i.e. extensive
resistance and high baseline viral loads. However, a significant treatment benefit for CELSENTRI
compared to OBT alone was still demonstrated (see Table 7).
Table 7. Proportion of patients achieving <50 copies/mL at Week 48 by subgroup (pooled
Studies MOTIVATE 1 and MOTIVATE 2, ITT)
Subgroups
HIV-1 RNA <50 copies/mL
CELSENTRI 300 mg
twice daily
+ OBT
N=426
OBT
alone
N=209
Baseline HIV-1 RNA:
<5.0 log
10
copies/mL
≥5.0 log
10
copies/mL
58.4%
34.7%
26.0%
9.5%
Baseline CD4+ (cells/uL):
<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 OBT
1,2
:
0
1
2
≥3
32.7%
44.5%
58.2%
62%
2.0%
7.4%
31.7%
38.6%
1
Discontinuations or virological failures considered as failures.
2
Based on GSS.
33
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 OBT alone were demonstrated although there was no adverse
outcome on viral load or CD4+ cell count
Studies in Treatment-Naïve Patients
An ongoing randomised, double-blinded study (MERIT), is exploring CELSENTRI versus efavirenz,
both in combination with zidovudine/lamivudine (n=721, 1:1). After 48 weeks of treatment,
CELSENTRI 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
CELSENTRI 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 CELSENTRI arm.
Fewer patients discontinued CELSENTRI due to adverse events (15 vs. 49).
5.2 Pharmacokinetic properties
Absorption:
the absorption of maraviroc is variable with multiple peaks. Median peak maraviroc
plasma concentrations is attained at 2 hours (range 0.5-4 hours) following single oral doses of 300 mg
commercial tablet administered to healthy volunteers. The pharmacokinetics of oral maraviroc are not
dose proportional over the dose range. The absolute bioavailability of a 100 mg dose is 23% and is
predicted to be 33% at 300 mg. Maraviroc is a substrate for the efflux transporter P-glycoprotein.
Coadministration of a 300 mg tablet with a high fat breakfast reduced maraviroc C
max
and AUC by
33% in healthy volunteers. There were no food restrictions in the studies that demonstrated the
efficacy and safety of CELSENTRI (see section 5.1). Therefore, CELSENTRI can be taken with or
without food at the recommended doses (see section 4.2).
Distribution
:
maraviroc is bound (approximately 76%) to human plasma proteins, and shows moderate
affinity for albumin and alpha-1 acid glycoprotein. The volume of distribution of maraviroc is
approximately 194 L.
Metabolism
:
studies in humans and
in vitro
studies using human liver microsomes and expressed
enzymes have demonstrated that maraviroc is principally metabolized by the cytochrome P450 system
to metabolites that are essentially inactive against HIV-1.
In vitro
studies indicate that CYP3A4 is the
major enzyme responsible for maraviroc metabolism.
In vitro
studies also indicate that polymorphic
enzymes CYP2C9, CYP2D6 and CYP2C19 do not contribute significantly to the metabolism of
maraviroc.
Maraviroc is the major circulating component (approximately 42% radioactivity) following a single
oral dose of 300 mg. The most significant circulating metabolite in humans is a secondary amine
(approximately 22% radioactivity) formed by N-dealkylation. This polar metabolite has no significant
pharmacological activity. Other metabolites are products of mono-oxidation and are only minor
components of plasma radioactivity.
Elimination
:
a mass balance/excretion study was conducted using a single 300 mg dose of
14
C-labeled
maraviroc. Approximately 20% of the radiolabel was recovered in the urine and 76% was recovered in
the faeces over 168 hours. Maraviroc was the major component present in urine (mean of 8% dose)
and faeces (mean of 25% dose). The remainder was excreted as metabolites. After intravenous
administration (30 mg), the half-life of maraviroc was 13.2 h, 22% of the dose was excreted
unchanged in the urine and the values of total clearance and renal clearance were 44.0 L/h and 10.17
L/h respectively.
Children:
the pharmacokinetics of maraviroc in paediatric patients have not been established (see
section 4.2).
34
Elderly
: population analysis of the Phase 1/2a and Phase 3 studies (16-65 years of age) has been
conducted and no effect of age has been observed (see section 4.2).
Renal impairment:
a study compared the pharmacokinetics of a single 300 mg dose of CELSENTRI in
subjects with severe renal impairment (CLcr < 30 mL/min, n=6) and end stage renal disease (ESRD)
to healthy volunteers (n=6). The geometric mean AUC
inf
(CV%) for CELSENTRI was as follows:
healthy volunteers (normal renal function) 1348.4 ng·h/mL (61%); severe renal function 4367.7
ng·h/mL (52%); ESRD (dosing after dialysis) 2677.4 ng·h/mL (40%); and ESRD (dosing before
dialysis) 2805.5 ng·h/mL (45%). The C
max
(CV%) was 335.6 ng/mL (87%) in healthy volunteers
(normal renal function); 801.2 ng/mL (56%) in severe renal function; 576.7 ng/mL (51%) in ESRD
(dosing after dialysis) and 478.5 ng/mL (38%) in ESRD (dosing before dialysis). Dialysis had a
minimal effect on exposure in subjects with ESRD. Exposures observed in subjects with severe renal
impairment and ESRD were within the range observed in single CELSENTRI 300 mg dose studies in
healthy volunteers with normal renal function. Therefore, no dose adjustment is necessary in patients
with renal impairment receiving CELSENTRI without a potent CYP3A4 inhibitor (see sections 4.2,
4.4 and 4.5).
In addition, the study compared the pharmacokinetics of multiple dose CELSENTRI in combination
with saquinavir/ritonavir 1000/100 mg BID (a potent CYP3A4 inhibitor) for 7 days in subjects with
mild renal impairment (CLcr >50 and ≤80 mL/min, n=6) and moderate renal impairment (CLcr ≥30
and ≤50 mL/min, n=6) to healthy volunteers (n=6). Subjects received 150 mg of CELSENTRI at
different dose frequencies (healthy volunteers – every 12 hours; mild renal impairment – every 24
hours; moderate renal impairment – every 48 hours). The average concentration (Cavg) of
CELSENTRI over 24 hours was 445.1 ng/mL, 338.3 ng/mL, and 223.7 ng/mL for subjects with
normal renal function, mild renal impairment, and moderate renal impairment, respectively. The Cavg
of CELSENTRI from 24-48 hours for subjects with moderate renal impairment was low (Cavg: 32.8
ng/mL). Therefore, dosing frequencies of longer than 24 hours in subjects with renal impairment may
result in inadequate exposures between 24-48 hours.
Dose adjustment is necessary in patients with renal impairment receiving CELSENTRI with potent
CYP3A4 inhibitors (see sections 4.2 and 4.4 and 4.5).
Hepatic impairment:
maraviroc is primarily metabolized and eliminated by the liver. A study
compared the pharmacokinetics of a single 300 mg dose of CELSENTRI in patients with mild (Child-
Pugh Class A, n=8), and moderate (Child-Pugh Class B, n=8) hepatic impairment compared to healthy
subjects (n=8). Geometric mean ratios for C
max
and AUC
last
were 11% and 25% higher respectively for
subjects with mild hepatic impairment, and 32% and 46% higher respectively for subjects with
moderate hepatic impairment compared to subjects with normal hepatic function. The effects of
moderate hepatic impairment may be underestimated due to limited data in patients with decreased
metabolic capacity and higher renal clearance in these subjects. The results should therefore be
interpreted with caution. The pharmacokinetics of maraviroc have not been studied in subjects with
severe hepatic impairment (see sections 4.2 and 4.4).
Race:
no relevant difference between Caucasian, Asian and Black subjects has been observed. The
pharmacokinetics in other races has not been evaluated.
Gender:
no relevant differences in pharmacokinetics have been observed.
5.3 Preclinical safety data
Primary pharmacological activity (CCR5 receptor affinity) was present in the monkey (100% receptor
occupancy) and limited in the mouse, rat, rabbit and dog. In mice and human beings that lack CCR5
receptors through genetic deletion, no significant adverse consequences have been reported.
In vitro
and
in vivo
studies showed that maraviroc has a potential to increase QTc interval at
supratherapeutic doses with no evidence of arrhythmia.
35
Repeated dose toxicity studies in rats identified the liver as the primary target organ for toxicity
(increases in transaminases, bile duct hyperplasia, necrosis).
Maraviroc was evaluated for carcinogenic potential by a 6 month transgenic mouse study and a 24
month study in rats. In mice, no statistically significant increase in the incidence of tumors was
reported at systemic exposures from 7 to 39-times the human exposure (unbound AUC 0-24h
measurement) at a dose of 300 mg twice daily. In rats, administration of maraviroc at a systemic
exposure 21-times the expected human exposure produced thyroid adenomas associated with adaptive
liver changes. These findings are considered of low human relevance. In addition,
cholangiocarcinomas (2/60 males at 900 mg/kg) and cholangioma (1/60 females at 500 mg/kg) were
reported in the rat study at a systemic exposure at least 15-times the expected free human exposure.
Maraviroc was not mutagenic or genotoxic in a battery of
in vitro
and
in vivo
assays including
bacterial reverse mutation, chromosome aberrations in human lymphocytes and rat bone marrow
micronucleus.
Maraviroc did not impair mating or fertility of male or female rats, and did not affect sperm of treated
male rats up to 1000 mg/kg. The exposure at this dose level corresponded to 39-fold the estimated free
clinical AUC for a 300 mg twice daily dose.
Embryofoetal development studies were conducted in rats and rabbits at doses up to 39- and 34-fold
the estimated free clinical AUC for a 300 mg twice daily dose. In rabbit, 7 foetuses had external
anomalies at maternally toxic doses and 1 foetus at the mid dose of 75 mg/kg.
Pre- and post-natal developmental studies were performed in rats at doses up to 27-fold the estimated
free clinical AUC for a 300 mg twice daily dose. A slight increase in motor activity in high-dose male
rats at both weaning and as adults was noted, while no effects were seen in females. Other
developmental parameters of these offspring, including fertility and reproductive performance, were
not affected by the maternal administration of maraviroc.
6
6.1 List of excipients
Tablet core:
Cellulose, microcrystalline
Calcium hydrogen phosphate, anhydrous
Sodium starch glycolate
Magnesium stearate
Film-coat:
Poly (vinyl alcohol)
Titanium dioxide
Macrogol 3350
Talc
Soya Lecithin
Indigo carmine aluminium lake (E132)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
4 years.
36
6.4 Special precautions for storage
This medicinal product does not require any special storage condition.
6.5 Nature and contents of container
High density polyethylene bottles (HDPE) with polypropylene child resistant (CR) closures and an
aluminium foil/polyethylene heat induction seal containing 180 film-coated tablets.
Polyvinyl chloride (PVC) blisters with aluminium foil backing in a carton containing 30, 60, 90 film-
coated tablets and multipacks containing 180 (2 packs of 90) film-coated tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
Any unused product or waste material should be disposed of in accordance with local requirements.
7
ViiV Healthcare UK Ltd
980 Great West Road
Brentford
Middlesex
TW8 9GS
United Kingdom
8.
EU/1/07/418/006
EU/1/07/418/007
EU/1/07/418/008
EU/1/07/418/009
EU/1/07/418/010
9.
18
th
September 2007
Detailed information on this medicinal product is available on the website of the European Medicines
Agency http://www.ema.europa.eu
37
ANNEX II
A.
MANUFACTURING AUTHORISATION HOLDER
RESPONSIBLE FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
38
A. MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturers responsible for batch release
Pfizer Manufacturing Deutschland GmbH
Betriebsstātte Freiburg
Mooswaldallee 1
79090 Freiburg
Germany
B. CONDITIONS OF THE MARKETING AUTHORISATION
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product
Characteristics, section 4.2).
•
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable.
•
OTHER CONDITIONS
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance, presented in Module 1.8.1. of the
Marketing Authorisation, is in place and functioning before and whilst the product is on the market.
Risk Management plan
The MAH commits to performing the studies and additional pharmacovigilance activities detailed in
the Pharmacovigilance Plan, as agreed in version 1.4 of the Risk Management Plan (RMP) presented
in Module 1.8.2. of the Marketing Authorisation Application and any subsequent updates of the RMP
agreed by the CHMP.
As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, the
updated RMP should be submitted at the same time as the next Periodic Safety Update Report
(PSUR).
In addition, an updated RMP should be submitted
•
When new information is received that may impact on the current Safety Specification,
Pharmacovigilance Plan or risk minimisation activities
•
Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being
reached
•
At the request of the European Medicines Agency..
39
ANNEX III
LABELLING AND PACKAGE LEAFLET
40
A. LABELLING
41
PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING
Bottle label - 150 mg film-coated tablets
1.
CELSENTRI 150 mg film-coated tablets
maraviroc
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each film-coated tablet contains 150 mg of maraviroc.
3.
LIST OF EXCIPIENTS
Contains soya lecithin: see the package leaflet for further information.
4.
180 film-coated tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP {MM-YYYY }
9.
SPECIAL STORAGE CONDITIONS
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
42
OF REACH AND SITE OF CHILDREN
ViiV Healthcare UK Ltd
980 Great West Road
Brentford
Middlesex
TW8 9GS
United Kingdom
EU/1/07/418/001
13. BATCH NUMBER
Lot:
{number}
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Celsentri 150 mg
43
PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING
Bottle label - 300 mg film-coated tablets
1.
CELSENTRI 300 mg film-coated tablets
maraviroc
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each film-coated tablet contains 300 mg of maraviroc.
3.
LIST OF EXCIPIENTS
Contains soya lecithin: see the package leaflet for further information.
4.
180 film-coated tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP {MM-YYYY }
9.
SPECIAL STORAGE CONDITIONS
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
44
OF REACH AND SITE OF CHILDREN
ViiV Healthcare UK Ltd
980 Great West Road
Brentford
Middlesex
TW8 9GS
United Kingdom
EU/1/07/418/006
13. BATCH NUMBER
Lot:
{number}
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Celsentri 300 mg
45
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
Carton for blister pack containing 150 mg maraviroc film-coated tablets
1.
CELSENTRI 150 mg film-coated tablets
maraviroc
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each film-coated tablet contains 150 mg of maraviroc.
3.
LIST OF EXCIPIENTS
Contains soya lecithin: see the package leaflet for further information.
4.
30 film-coated tablets
60 film-coated tablets
90 film-coated tablets
Multipack containing 180 (2 packs of 90) film-coated tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
Sealed pack
Do not use if box has been opened
8.
EXPIRY DATE
EXP {MM-YYYY }
9.
SPECIAL STORAGE CONDITIONS
46
OF REACH AND SITE OF CHILDREN
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
ViiV Healthcare UK Ltd
980 Great West Road
Brentford
Middlesex
TW8 9GS
United Kingdom
EU/1/07/418/002
EU/1/07/418/003
EU/1/07/418/004
EU/1/07/418/005
13. BATCH NUMBER
Lot:
{number}
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Celsentri 150 mg
47
APPROPRIATE
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
Carton for blister pack containing 300 mg maraviroc film-coated tablets
1.
CELSENTRI 300 mg film-coated tablets
maraviroc
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each film-coated tablet contains 300 mg of maraviroc.
3.
LIST OF EXCIPIENTS
Contains soya lecithin: see the package leaflet for further information.
4.
30 film-coated tablets
60 film-coated tablets
90 film-coated tablets
Multipack containing 180 (2 packs of 90) film-coated tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
Sealed pack
Do not use if box has been opened
8.
EXPIRY DATE
EXP {MM-YYYY }
9.
SPECIAL STORAGE CONDITIONS
48
OF REACH AND SITE OF CHILDREN
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
ViiV Healthcare UK Ltd
980 Great West Road
Brentford
Middlesex
TW8 9GS
United Kingdom
EU/1/07/418/007
EU/1/07/418/008
EU/1/07/418/009
EU/1/07/418/010
13. BATCH NUMBER
Lot:
{number}
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Celsentri 300 mg
49
APPROPRIATE
PARTICULARS TO APPEAR ON THE INTERMEDIATE CARTON
Multipacks of 180 (2 packs of 90 film-coated tablets) - without blue box - 150 mg film-coated tablets
1.
Celsentri 150 mg film-coated tablets
maraviroc
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each film-coated tablet contains 150 mg of maraviroc.
3.
LIST OF EXCIPIENTS
Contains soya lecithin: see the package leaflet for further information.
4.
Component of a multipack comprising 2 packs, each containing 90 film-coated
tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF REACH AND SITE OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
Sealed pack
Do not use if box has been opened
8.
EXPIRY DATE
EXP {MM-YYYY }
9.
SPECIAL STORAGE CONDITIONS
50
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
ViiV Healthcare UK Ltd
980 Great West Road
Brentford
Middlesex
TW8 9GS
United Kingdom
EU/1/07/418/005
13. BATCH NUMBER
Lot:
{number}
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Celsentri 150 mg
51
PARTICULARS TO APPEAR ON THE INTERMEDIATE CARTON
Multipacks of 180 (2 packs of 90 film-coated tablets) - without blue box - 300 mg film-coated tablets
1.
Celsentri 300 mg film-coated tablets
maraviroc
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each film-coated tablet contains 300 mg of maraviroc.
3.
LIST OF EXCIPIENTS
Contains soya lecithin: see the package leaflet for further information.
4.
Component of a multipack comprising 2 packs, each containing 90 film-coated
tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF REACH AND SITE OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
Sealed pack
Do not use if box has been opened
8.
EXPIRY DATE
EXP {MM-YYYY }
9.
SPECIAL STORAGE CONDITIONS
52
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
ViiV Healthcare UK Ltd
980 Great West Road
Brentford
Middlesex
TW8 9GS
United Kingdom
EU/1/07/418/010
13. BATCH NUMBER
Lot:
{number}
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Celsentri 300 mg
53
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
Outer wrapper label on multi packs of 180 (2 packs of 90 film-coated tablets) wrapped in transparent
foil - including the blue box - 150 mg film-coated tablets
1.
Celsentri 150 mg film-coated tablets
maraviroc
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each film-coated tablet contains 150 mg of maraviroc.
3.
LIST OF EXCIPIENTS
Contains soya lecithin: see the package leaflet for further information.
4.
Multipack comprising 2 packs, each containing 90 film-coated
tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF REACH AND SITE OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
Sealed pack
Do not use if box has been opened
8.
EXPIRY DATE
EXP {MM-YYYY }
9.
SPECIAL STORAGE CONDITIONS
54
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
ViiV Healthcare UK Ltd
980 Great West Road
Brentford
Middlesex
TW8 9GS
United Kingdom
EU/1/07/418/005
13. BATCH NUMBER
Lot:
{number}
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
55
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
Outer wrapper label on multi packs of 180 (2 packs of 90 film-coated tablets) wrapped in transparent
foil - including the blue box - 300 mg film-coated tablets
1.
Celsentri 300 mg film-coated tablets
maraviroc
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each film-coated tablet contains 300 mg of maraviroc.
3.
LIST OF EXCIPIENTS
Contains soya lecithin: see the package leaflet for further information.
4.
Multipack comprising 2 packs, each containing 90 film-coated
tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF REACH AND SITE OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
Sealed pack
Do not use if box has been opened
8.
EXPIRY DATE
EXP {MM-YYYY }
9.
SPECIAL STORAGE CONDITIONS
56
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
ViiV Healthcare UK Ltd
980 Great West Road
Brentford
Middlesex
TW8 9GS
United Kingdom
EU/1/07/418/010
13. BATCH NUMBER
Lot:
{number}
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
57
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
Blister Pack of 10 x 150 mg maraviroc film-coated tablets
1.
CELSENTRI 150 mg film-coated tablets
maraviroc
2.
ViiV Healthcare (logo)
3.
EXPIRY DATE
EXP {MM-YYYY }
4.
BATCH NUMBER
Lot:
{number}
5.
OTHER
58
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
Blister Pack of 10 x 300 mg maraviroc film-coated tablets
1.
CELSENTRI 300 mg film-coated tablets
maraviroc
2.
ViiV Healthcare (logo)
3.
EXPIRY DATE
EXP {MM-YYYY }
4.
BATCH NUMBER
Lot:
{number}
5.
OTHER
59
B. PACKAGE LEAFLET
60
PACKAGE LEAFLET: INFORMATION FOR THE USER
CELSENTRI 150 mg film-coated tablets
CELSENTRI 300 mg film-coated tablets
maraviroc
Read all of this leaflet carefully before you start taking this medicine.
-
If you have any further questions, ask your doctor or your pharmacist.
-
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or your pharmacist.
In this leaflet:
1. What CELSENTRI is and what it is used for
2. Before you take CELSENTRI
3. How to take CELSENTRI
4. Possible side effects
5.
How to store CELSENTRI
6.
Further information
1.
WHAT CELSENTRI IS AND WHAT IT IS USED FOR
CELSENTRI is an antiretroviral medicine used in the treatment of Human Immunodeficiency Virus
type-1 (HIV-1) infection. Its active ingredient, maraviroc, belongs to a group of medicines called
CCR5 antagonists.
CELSENTRI prevents the entry of HIV-1 into the cells in your blood that are attacked by HIV (called
CD4 or T-cells). CELSENTRI works by blocking a receptor called CCR5 that HIV use to gain entry
into these cells. CELSENTRI reduces the amount of HIV in your body and enhances your immune
system.
CELSENTRI must be taken in combination with other medicines used to treat HIV.
2
BEFORE YOU TAKE CELSENTRI
Do not take CELSENTRI
if you are allergic (hypersensitive) to maraviroc or to peanut or soya or to
any of the other ingredients of CELSENTRI (see section 2, Important information about some of the
ingredients of CELSENTRI).
Take special care with CELSENTRI:
Your doctor must take blood samples to test whether CELSENTRI is an appropriate treatment for you.
Before taking this medicine, make sure that your doctor knows if you:
•
have problems with your liver including chronic hepatitis B or C as there is only limited
experience in patients with liver problems. Your liver function may need to be closely monitored.
If you notice symptoms of hepatitis (loss of appetite, fever, feeling sick/being sick and/or
yellowing of skin or eyes), rash and/or itching, you should stop taking CELSENTRI and inform
your doctor immediately.
61
-
Keep this leaflet. You may need to read it again.
•
have or previously had low blood pressure and/or if you are taking any medicines to lower blood
pressure
•
have tuberculosis or serious fungal infections as due to the way CELSENTRI works on certain
immune cells, CELSENTRI could potentially increase the risk of developing infections. However,
there has been no evidence of an increase in the occurrence of AIDS-related infections associated
with the use of CELSENTRI in clinical studies
•
have or previously had any kidney problems particularly if you are taking certain antibiotics
(clarithromycin, telithromycin, antifungal medicines (ketoconazole, itraconazole) and/or protease
inhibitors (except for tipranavir/ritonavir)
•
have problems with your heart or circulatory system as there is only limited experience in patients
with serious problems of this type.
It is not known if CELSENTRI works in children. Therefore CELSENTRI is not recommended for use
in children.
CELSENTRI has only been used in limited numbers of patients 65 years or older. If you belong to this
age group please discuss with your doctor if you can use CELSENTRI.
CELSENTRI is not a cure for HIV infection or AIDS (advanced HIV infection). CELSENTRI does
not reduce the risk of passing HIV to others through sexual contact, sharing needles or exposure to
your blood. It is important to continue to take appropriate precautions to prevent passing HIV to
others.
In some patients with AIDS and a history of opportunistic infection (an infection that can occur when
your immune system is impaired), signs and symptoms of inflammation from previous infections may
occur soon after anti-HIV treatment is started. It is believed that these symptoms are due to an
improvement in the body’s immune response, enabling the body to fight infections that may have been
present with no obvious symptoms. If you notice any symptoms of infection, please inform your
doctor immediately.
Some patients taking combination antiretroviral therapy may develop a bone disease called
osteonecrosis (death of bone tissue caused by loss of blood supply to the bone). The length of
combination antiretroviral therapy, corticosteroid use, alcohol consumption, severe
immunosuppression, higher body mass index, among others, may be some of the many risk factors for
developing this disease. Signs of osteonecrosis are joint stiffness, aches and pains (especially of the
hip, knee and shoulder) and difficulty in movement. If you notice any of these symptoms please
inform your doctor.
Taking other medicines
Please tell your doctor and your pharmacist if you are taking or have recently taken any other
medicines, including medicines obtained without a prescription. Some medicines may affect the levels
of CELSENTRI in the body when they are taken at the same time as CELSENTRI. Therefore the dose
of CELSENTRI may need to be adjusted. Tell your doctor if you are taking any medicines including
other medicines to treat HIV infection (e.g. efavirenz, etravirine, lopinavir, saquinavir, darunavir,
atazanavir, nelfinavir, indinavir), antibiotics (clarithromycin, telithromycin, rifampicin) and antifungal
medicines (ketoconazole, itraconazole). This will allow your doctor to prescribe the most appropriate
dose of CELSENTRI for you.
Medicines containing St. John’s wort (
Hypericum perforatum
) are likely to prevent CELSENTRI from
working properly and should not be taken together with CELSENTRI.
62
Taking CELSENTRI with food and drink
CELSENTRI can be taken with or without food.
Pregnancy
Tell your doctor if you are pregnant, planning to become pregnant or become pregnant whilst taking
this medicine. If you are pregnant, CELSENTRI should only be taken after careful discussion with
your doctor. The safe use of CELSENTRI in pregnancy has not been established.
Ask your doctor or pharmacist for advice before taking any medicine.
Breast-feeding
It is not known whether the active ingredient in CELSENTRI can pass into your breast milk.
Therefore, mothers should not breast-feed during treatment with CELSENTRI. In general, women
infected with HIV should not breast-feed because the virus may be transmitted through the breast
milk.
Driving and using machines
CELSENTRI may cause dizziness. If you experience dizziness while taking CELSENTRI do not drive
and do not operate any tools or machines.
Important information about some of the ingredients of CELSENTRI
CELSENTRI contains soya lecithin. If you are allergic to peanut or soya do not use this medicinal
product.
3.
HOW TO TAKE CELSENTRI
Always take CELSENTRI exactly as your doctor has instructed. You should check with your doctor or
pharmacist if you are not sure how to take CELSENTRI.
The usual dose of CELSENTRI
is 150 mg, 300 mg or 600 mg twice per day
depending on other
medicines that you are taking at the same time as CELSENTRI
.
Always take the dose recommended
by your doctor.
CELSENTRI can be taken with or without food.
CELSENTRI should always be taken by mouth.
You should continue to take CELSENTRI for as long as instructed by your doctor.
CELSENTRI must be taken in combination with other medicines used to treat HIV. Please refer to the
Package Leaflets of these other medicines for guidance on how to take them.
If you take more CELSENTRI than you should
If you accidentally take more than the prescribed dose of CELSENTRI, contact your doctor or the
nearest hospital right away. You may feel dizzy or light-headed when you stand or sit up quickly. This
is due to a sudden fall in your blood pressure. If this happens, lie down until you feel better. When you
get up, do so as slowly as possible.
If you forget to take CELSENTRI
If you miss a dose of CELSENTRI, take the missed dose as soon as possible and then take your next
scheduled dose at its regular time. If it is almost time for your next dose, do not take the missed dose.
63
Wait and take the next dose at its regular time.
Do not take a double dose to make up for a
forgotten dose.
If you stop taking CELSENTRI
It has been shown that taking all doses at the appropriate times may greatly increase the effectiveness
of your antiretroviral medicines. Therefore, unless your doctor instructs you to stop treatment, it is
important to keep taking CELSENTRI correctly, as described above.
If you have any further questions on the use of this product, ask your doctor or your pharmacist.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, CELSENTRI can cause side effects, although not everybody gets them. When
treating HIV infection, it is not always easy to identify what side effects are caused by CELSENTRI,
by the other medicines you are taking, or by the HIV infection itself. Tell your doctor if you notice
anything unusual about your health.
Common side effects
(likely to occur in fewer than 1 in 10 patients) include:
•
diarrhoea, feeling sick, stomach ache, flatulence
•
headache, sleepiness, problems sleeping, depression
•
rash, feeling weak, anaemia, loss of appetite
•
increased levels of substances that measure the function of the liver. These can be seen in the
results of blood tests and can be a sign of reduced function or damage of the liver. If you
experience symptoms, such as loss of appetite, feeling sick/being sick and/or yellowing of skin or
eyes, you should inform your doctor.
Uncommon side effects
(likely to occur in fewer than 1 in 100 patients) include:
•
pneumonia, fungal infection of the oesophagus
•
fits
•
muscle aches and pains
•
an increase in a substance which may be found in blood tests when muscles are inflamed or
damaged
•
kidney failure, passing protein in urine
Rare Side Effects
(likely to occur in fewer than 1 in 1,000 patients) include:
•
reduction in number of blood cells, chest pain caused by reduced blood flow to the heart, liver
diseases, decrease in the size of muscle, severe skin reaction, some types of cancer like cancer of
the oesophagus and bile duct
If any of the side effects get serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor or pharmacist.
5.
HOW TO STORE CELSENTRI
•
Keep out of the reach and sight of children.
•
Do not use CELSENTRI after the expiry date which is stated on the carton, blister or bottle label.
The expiry date refers to the last day of that month.
•
This medicine does not require any special storage conditions.
64
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
6.
FURTHER INFORMATION
What CELSENTRI contains
•
The active ingredient in CELSENTRI is maraviroc. Each film-coated tablet contains either 150 mg
or 300 mg of maraviroc.
•
The other ingredients are:
Tablet core:
cellulose microcrystalline, calcium hydrogen phosphate anhydrous, sodium starch
glycolate, magnesium stearate
Film-coat:
poly (vinyl alcohol), titanium dioxide, macrogol 3350, talc, soya lecithin, indigo
carmine aluminium lake (E132).
What CELSENTRI looks like and contents of the pack
CELSENTRI film-coated tablets are blue coloured with “MVC 150” or “MVC 300”.
CELSENTRI 150 mg and 300 mg film-coated tablets are supplied in bottles of 180 tablets or in blister
packs of 30, 60, 90 film-coated tablets and multipacks containing 180 (2 packs of 90) film-coated
tablets.
Not all pack sizes may be marketed in all countries.
Marketing Authorisation Holder and Manufacturer
The Marketing Authorisation Holder is:
ViiV Healthcare UK Ltd, 980 Great West Road, Brentford, Middlesex, TW8 9GS United Kingdom.
The Manufacturer is:
Pfizer Manufacturing Deutschland GmbH, Betriebsstātte Freiburg, Mooswaldallee 1, 79090 Freiburg,
Germany.
For any information about this medicinal product, please contact the local representative of the
Marketing Authorisation Holder:
België/Belgique/Belgien
ViiV Healthcare sprl/bvba .
Tél/Tel: + 32 (0)2 656 25 11
Luxembourg/Luxemburg
ViiV Healthcare sprl/bvba
Belgique/Belgien
Tél/Tel: + 32 (0)2 656 25 11
България
ГлаксоСмитКлайн ЕООД
Teл.: + 359 2 953 10 34
Magyarország
GlaxoSmithKline Kft.
Tel.: + 36 1 225 5300
65
Česká republika
GlaxoSmithKline s.r.o.
Tel: + 420 222 001 111
gsk.czmail@gsk.com
Malta
GlaxoSmithKline Malta
Tel: + 356 21 238131
Danmark
GlaxoSmithKline Pharma A/S
Tlf: + 45 36 35 91 00
dk-info@gsk.com
Nederland
ViiV Healthcare BV
Tel: + 31 (0)30 6986060
contact-nl@viivhealthcare.com
Deutschland
ViiV Healthcare GmbH
Tel.: + 49 (0)89 203 0038-10
viiv.med.info@viivhealthcare.com
Norge
GlaxoSmithKline AS
Tlf: + 47 22 70 20 00
firmapost@gsk.no
Eesti
GlaxoSmithKline Eesti OÜ
Tel: + 372 6676 900
estonia@gsk.com
Österreich
GlaxoSmithKline Pharma GmbH
Tel: + 43 (0)1 97075 0
at.info@gsk.com
Ελλάδα
GlaxoSmithKline A.E.B.E.
Τηλ: + 30 210 68 82 100
Polska
GSK Commercial Sp. z o.o.
Tel.: + 48 (0)22 576 9000
España
Laboratorios ViiV Healthcare, S.L.
Tel: + 34 902 051 260
es-ci@viivhealthcare.com
Portugal
VIIVHIV HEALTHCARE, UNIPESSOAL, LDA.
Tel: + 351 21 094 08 01
viiv.fi.pt@viivhealthcare.com
France
ViiV Healthcare SAS
Tél.: + 33 (0)1 39 17 6969
Infomed@viivhealthcare.com
România
GlaxoSmithKline (GSK) S.R.L.
Tel: + 4021 3028 208
Ireland
GlaxoSmithKline (Ireland) Limited
Tel: + 353 (0)1 4955000
Slovenija
GlaxoSmithKline d.o.o.
Tel: + 386 (0)1 280 25 00
medical.x.si@gsk.com
Ísland
GlaxoSmithKline ehf.
Sími:+ 354 530 3700
Slovenská republika
GlaxoSmithKline Slovakia s. r. o.
Tel: + 421 (0)2 48 26 11 11
recepcia.sk@gsk.com
Italia
ViiV Healthcare S.r.l. .
Tel: + 39 (0)45 9212611
Suomi/Finland
GlaxoSmithKline Oy
Puh/Tel: + 358 (0)10 30 30 30
Finland.tuoteinfo@gsk.com
Κύπρος
GlaxoSmithKline (Cyprus) Ltd
Τηλ: + 357 22 39 70 00
Sverige
GlaxoSmithKline AB
Tel: + 46 (0)8 638 93 00
info.produkt@gsk.com
66
Latvija
GlaxoSmithKline Latvia SIA
Tel: + 371 67312687
lv-epasts@gsk.com
United Kingdom
ViiV Healthcare UK Ltd
Tel: + 44 (0)800 221441
customercontactuk@gsk.com
Lietuva
GlaxoSmithKline Lietuva UAB
Tel: + 370 5 264 90 00
info.lt@gsk.com
This leaflet was last approved in
Detailed information on this medicine is available on the European Medicines Agency website:
http://www.ema.europa.eu
/
.
67
Source: European Medicines Agency
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