ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Volibris 5 mg film-coated tablets
2.
Each tablet contains 5 mg of ambrisentan.
Excipients
Each tablet contains lactose monohydrate (approximately 95 mg), Lecithin (Soya) (E322)
(approximately 0.25 mg) and Allura red AC Aluminium Lake (E129) (approximately 0.11 mg).
For a full list of excipients, see section 6.1.
3.
Film-coated tablet.
Pale-pink, square, convex, film-coated tablet with “GS” debossed on one side and “K2C” on the other
side.
4.
Volibris is indicated for the treatment of patients with pulmonary arterial hypertension (PAH)
classified as WHO functional class II and III, to improve exercise capacity (see section 5.1). Efficacy
has been shown in idiopathic PAH (IPAH) and in PAH associated with connective tissue disease.
Treatment must be initiated by a physician experienced in the treatment of PAH.
Posology
Volibris is to be taken orally at a dose of 5 mg once daily.
Some additional efficacy has been observed with 10 mg Volibris in patients with class III symptoms,
however an increase in peripheral oedema has also been observed. Patients with PAH associated with
connective tissue disease may require 10 mg Volibris for optimal efficacy. Confirm that the 5 mg dose
is well tolerated before considering an increase in dose to 10 mg Volibris in these patients (see
sections 4.4 and 4.8).
Limited data suggest that the abrupt discontinuation of Volibris is not associated with rebound
worsening of PAH.
When co-administered with cyclosporine A, the dose of ambrisentan should be limited to 5 mg once
daily and the patient should be carefully monitored (see sections 4.5 and 5.2).
Children and adolescents
2
Volibris is not recommended for use in patients below 18 years of age due to a lack of data on safety
and efficacy.
Elderly
No dose adjustment is required in patients over the age of 65 (see section 5.2).
Patients with renal impairment
No dose adjustment is required in patients with renal impairment (see section 5.2). There is limited
experience with Volibris in individuals with severe renal impairment (creatinine clearance
<30 ml/min); initiate therapy cautiously in this subgroup and take particular care if the dose is
increased to 10 mg Volibris.
Patients with hepatic impairment
Volibris has not been studied in individuals with severe hepatic impairment (with or without
cirrhosis). Since the main routes of metabolism of ambrisentan are glucuronidation and oxidation with
subsequent elimination in the bile, hepatic impairment would be expected to increase exposure (C
max
and AUC) to ambrisentan. Therefore Volibris should not be initiated in patients with severe hepatic
impairment, or clinically significant elevated hepatic aminotransferases (greater than 3 times the
Upper Limit of Normal (>3xULN); see sections 4.3 and 4.4).
Method of administration
It is recommended that the tablet is swallowed whole and it can be taken with or without food.
• Hypersensitivity to the active substance, to soya, or to any of the excipients (see sections 4.4 and
6.1).
• Pregnancy (see section 4.6).
• Women of child-bearing potential who are not using reliable contraception (see sections 4.4 and 4.6).
• Lactation (see section 4.6).
• Severe hepatic impairment (with or without cirrhosis) (see section 4.2).
• Baseline values of hepatic aminotransferases (aspartate aminotransferases (AST) and/or alanine
aminotransferases (ALT))>3xULN (see sections 4.2 and 4.4).
Volibris has not been studied in a sufficient number of patients to establish the benefit/risk balance in
WHO functional class I PAH.
The efficacy of Volibris as monotherapy has not been established in patients with WHO functional
class IV PAH. Therapy that is recommended at the severe stage of the disease (e.g. epoprostenol)
should be considered if the clinical condition deteriorates.
Liver function
Liver function abnormalities have been associated with PAH. Hepatic enzyme elevations potentially
related to therapy have been observed with endothelin receptor antagonists (ERAs) (see section 5.1).
3
Therefore hepatic aminotransferases (ALT and AST) should be evaluated prior to initiation of
Volibris. Volibris treatment should not be initiated in patients with baseline values of ALT and/or
AST>3xULN (see section 4.3).
Monthly monitoring of ALT and AST is recommended. If patients develop sustained, unexplained,
clinically significant ALT and/or AST elevation, or if ALT and/or AST elevation is accompanied by
signs or symptoms of hepatic injury (e.g. jaundice), Volibris therapy should be discontinued.
In patients without clinical symptoms of hepatic injury or of jaundice, re-initiation of Volibris may be
considered following resolution of hepatic enzyme abnormalities. The advice of a hepatologist is
recommended.
Haemoglobin concentration
Reductions in haemoglobin concentrations and haematocrit have been associated with ERAs including
Volibris (see section 4.8). Most of these decreases were detected during the first 4 weeks of treatment
and haemoglobin generally stabilised thereafter.
Initiation of Volibris is not recommended for patients with clinically significant anaemia. It is
recommended that haemoglobin and/or haematocrit levels are measured during treatment with
Volibris, for example at 1 month, 3 months and periodically thereafter in line with clinical practice. If
a clinically significant decrease in haemoglobin or haematocrit is observed, and other causes have
been excluded, dose reduction or discontinuation of treatment should be considered.
Fluid retention
Peripheral oedema has been observed with ERAs including ambrisentan. Most cases of peripheral
oedema in clinical studies with ambrisentan were mild to moderate in severity, although it appeared to
occur with greater frequency and severity in patients ≥65 years. Peripheral oedema was reported more
frequently with 10 mg ambrisentan (see section 4.8).
Post-marketing reports of fluid retention occurring within weeks after starting ambrisentan have been
received and, in some cases, have required intervention with a diuretic or hospitalisation for fluid
management or decompensated heart failure. If patients have pre-existing fluid overload, this should
be managed as clinically appropriate prior to starting ambrisentan.
If clinically significant fluid retention develops during therapy with ambrisentan, with or without
associated weight gain, further evaluation should be undertaken to determine the cause, such as
ambrisentan or underlying heart failure, and the possible need for specific treatment or discontinuation
of ambrisentan therapy.
Women of child-bearing potential
Volibris treatment must not be initiated in women of child-bearing potential unless the result of a pre-
treatment pregnancy test is negative and reliable contraception is practiced. If there is any doubt on
what contraceptive advice should be given to the individual patient, consultation with a gynaecologist
should be considered. Monthly pregnancy tests during treatment with Volibris are recommended (see
sections 4.3 and 4.6).
Pulmonary veno-occlusive disease
Cases of pulmonary oedema have been reported with vasodilating agents, such as endothelin receptor
antagonists, when used in patients with pulmonary veno-occlusive disease. Consequently, if PAH
patients develop acute pulmonary oedema when treated with ambrisentan, the possibility of pulmonary
veno-occlusive disease should be considered.
4
Concomitant use with other medicinal products
Rifampicin
: Patients on ambrisentan therapy should be closely monitored when starting treatment with
rifampicin (see sections 4.5 and 5.2).
Excipients
Volibris tablets contain lactose monohydrate. Patients with rare hereditary problems of galactose
intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this
medicine.
Volibris tablets contain the azo colouring agent Allura red AC Aluminium Lake (E129), which can
cause allergic reactions.
Ambrisentan does not inhibit or induce phase I or II drug metabolizing enzymes at clinically relevant
concentrations in
in vitro
and
in vivo
non-clinical studies, suggesting a low potential for ambrisentan
to alter the profile of medicinal products metabolized by these pathways.
The potential for ambrisentan to induce CYP3A4 activity was explored in healthy volunteers with
results suggesting a lack of inductive effect of ambrisentan on the CYP3A4 isoenzyme.
Co-administration of ambrisentan with a phosphodiesterase inhibitor, either sildenafil or tadalafil (both
substrates of CYP3A4) in healthy volunteers did not significantly affect the pharmacokinetics of the
phosphodiesterase inhibitor or ambrisentan (see section 5.2).
Steady-state administration of ketoconazole (a strong inhibitor of CYP3A4) did not result in a
clinically significant increase in exposure to ambrisentan (see section 5.2).
Ambrisentan had no effects on the steady-state pharmacokinetics and anti-coagulant activity of
warfarin in a healthy volunteer study (see section 5.2). Warfarin also had no clinically significant
effects on the pharmacokinetics of ambrisentan. In addition, in patients, ambrisentan had no overall
effect on the weekly warfarin-type anticoagulant dose, prothrombin time (PT) and international
normalized ratio (INR).
Steady-state co-administration of ambrisentan and cyclosporine A resulted in a 2-fold increase in
ambrisentan exposure in healthy volunteers. This may be due to the inhibition by cyclosporine A of
transporters and metabolic enzymes involved in the pharmacokinetics of ambrisentan. Therefore the
dose of ambrisentan should be limited to 5 mg once daily when co-administered with cyclosporine A
(see section 4.2). Multiple doses of ambrisentan had no effect on cyclosporine A exposure, and no
dose adjustment of cyclosporine A is warranted.
Co-administration of rifampicin (an inhibitor of OATP, a strong inducer of CYP3A and 2C19, and
inducer of P-gp and uridine-diphospho-glucuronosyltransferases [UGTs]) was associated with a
transient (approximately 2-fold) increase in ambrisentan exposure following initial doses in healthy
volunteers. However, by day 8, steady state administration of rifampicin had no clinically relevant
effect on ambrisentan exposure. Patients on ambrisentan therapy should be closely monitored when
starting treatment with rifampicin (see sections 4.4 and 5.2).
In a clinical study in healthy volunteers, steady-state dosing with ambrisentan 10 mg once daily did
not significantly affect the single-dose pharmacokinetics of the ethinyl estradiol and norethindrone
components of a combined oral contraceptive (see section 5.2). Based on this pharmacokinetic study,
ambrisentan would not be expected to significantly affect exposure to oestrogen- or progestogen-
based contraceptives.
5
The efficacy and safety of Volibris when co-administered with other treatments for PAH (e.g.
prostanoids and phosphodiesterase type V inhibitors) has not been specifically studied in controlled
clinical trials in PAH patients (see section 5.1). Therefore, caution is recommended in the case of co-
administration.
Effect of ambrisentan on xenobiotic transporters
In vitro
, ambrisentan has no inhibitory effect on the P-glycoprotein (Pgp)-mediated efflux of digoxin
and is a weak substrate for Pgp-mediated efflux. Additional
in vitro
studies in rat and human
hepatocytes showed that ambrisentan did not inhibit sodium-taurocholate co-transporter (NTCP),
organic anion export pump (OATP), bile salt export pump (BSEP) and multi-drug resistance protein
isoform-2 (MRP2).
In vitro
studies in rat hepatocytes also showed that ambrisentan has no inductive
effects on Pgp, BSEP or MRP2.
Steady-state administration of ambrisentan in healthy volunteers had no clinically relevant effects on
the single-dose pharmacokinetics of digoxin, a substrate for Pgp (see section 5.2).
Pregnancy
Volibris is contraindicated in pregnancy (see section 4.3). Animal studies have shown that
ambrisentan is teratogenic. There is no experience in humans.
Volibris treatment must not be initiated in women of child-bearing potential unless the result of a pre-
treatment pregnancy test is negative and reliable contraception is practiced. Monthly pregnancy tests
during treatment with Volibris are recommended.
Women receiving Volibris must be advised of the risk of foetal harm and alternative therapy initiated
if pregnancy occurs (see sections 4.3, 4.4 and 5.3).
Lactation
It is not known whether ambrisentan is excreted in human breast milk. The excretion of ambrisentan in
milk has not been studied in animals. Therefore lactation is contraindicated in patients taking Volibris
(see section 4.3).
Male fertility
The development of testicular tubular atrophy in male animals has been linked to the chronic
administration of ERAs, including ambrisentan (see section 5.3). The effect on male human fertility is
not known. Chronic administration of ambrisentan was not associated with a change in plasma
testosterone in clinical studies.
No studies on the effects on the ability to drive and use machines have been performed.
Safety of Volibris has been evaluated in clinical trials of more than 483 patients with PAH (see section
5.1). Adverse drug reactions (ADR) identified from 12 week placebo controlled clinical trial data are
listed below by system organ class and frequency. With longer observation in uncontrolled studies
6
(mean observation of 79 weeks), the safety profile was similar to that observed in the short term
studies. Frequencies are defined as: very common (≥ 1/10); common (≥ 1/100 to <1/10); uncommon
(≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000). For dose-related adverse
reactions the frequency category reflects the higher dose of Volibris. Frequency categories do not
account for other factors including varying study duration, pre-existing conditions and baseline patient
characteristics. Adverse reaction frequency categories assigned based on clinical trial experience may
not reflect the frequency of adverse events occurring during normal clinical practice. Within each
frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Cardiac disorders
Palpitation
Common
Blood and lymphatic system disorders
Anaemia (decreased haemoglobin, decreased haematocrit)
Common
Nervous system disorders
Headache (including sinus headache, migraine)
1
Very
common
Respiratory, thoracic and mediastinal disorders
Upper respiratory (e.g. nasal
2
, sinus) congestion, sinusitis,
nasopharyngitis, rhinitis
Common
Gastrointestinal disorders
Abdominal pain
Common
Constipation
Common
Vascular disorders
Flushing
Common
General disorders and administration site conditions
Peripheral oedema, fluid retention
3
Very
common
Chest pain/discomfort
Common
Immune system disorders
Hypersensitivity reactions (e.g. angioedema, rash, pruritus) Uncommon
1
The frequency of headache appeared higher with 10 mg Volibris.
2
The incidence of nasal congestion was dose related during Volibris therapy.
3
Peripheral oedema was reported more frequently with 10 mg Volibris. In clinical studies peripheral
oedema was reported more commonly and tended to be more severe in patients ≥65 years (see section
4.4).
Laboratory abnormalities
Decreased haemoglobin (see section 4.4).
The frequency of decreased haemoglobin (anaemia) was higher with 10 mg Volibris. Across the
12 week placebo controlled Phase III clinical studies, mean haemoglobin concentrations decreased for
patients in the Volibris groups and were detected as early as week 4 (decrease by 0.83 g/dl); mean
7
changes from baseline appeared to stabilise over the subsequent 8 weeks. A total of 17 patients (6.5%)
in the Volibris treatment groups had decreases in haemoglobin of ≥15% from baseline and which fell
below the lower limit of normal.
Post-marketing data
In addition to adverse reactions identified from clinical studies, the following adverse reactions were
identified during post-approval use of Volibris. Frequencies are defined as: ‘not known’ (cannot be
estimated from the available data).
Nervous system disorders
Dizziness
Not known
Cardiac disorders
Cardiac failure
4
Not known
Vascular disorders
Syncope, hypotension
Not known
Respiratory, thoracic and mediastinal disorders
Dyspnoea
5
Not known
Gastrointestinal disorders
Nausea, vomiting, diarrhoea
Not known
Hepatobiliary disorders
Hepatic transaminases increased
Common
4
Most of the reported cases of cardiac failure were associated with fluid retention.
5
Cases of worsening dyspnoea of unclear aetiology have been reported shortly after starting Volibris
therapy.
There is no experience in PAH patients of Volibris at daily doses greater than 10 mg. In healthy
volunteers, single doses of 50 and 100 mg (5 to 10 times the maximum recommended dose) were
associated with headache, flushing, dizziness, nausea and nasal congestion.
Due to the mechanism of action, an overdose of Volibris could potentially result in hypotension (see
section 5.3). In the case of pronounced hypotension, active cardiovascular support may be required.
No specific antidote is available.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: other anti-hypertensives, ATC code: C02KX02
Mechanism of action
Ambrisentan is an orally active, propanoic acid-class, ERA selective for the endothelin A (ET
A
)
receptor. Endothelin plays a significant role in the pathophysiology of PAH.
8
•
Ambrisentan is a potent (Ki 0.016 nM) and highly selective ET
A
antagonist (approximately
4000-fold more selective for ET
A
as compared to ET
B
).
•
Ambrisentan blocks the ET
A
receptor subtype, localized predominantly on vascular smooth
muscle cells and cardiac myocytes. This prevents endothelin-mediated activation of second
messenger systems that result in vasoconstriction and smooth muscle cell proliferation.
•
The selectivity of ambrisentan for the ET
A
over the ET
B
receptor is expected to retain ET
B
receptor mediated production of the vasodilators nitric oxide and prostacyclin.
Efficacy
Two randomised, double-blind, multi-centre, placebo controlled, Phase 3 pivotal studies were
conducted (ARIES-1 and 2). ARIES-1 included 201 patients and compared Volibris 5 mg and 10 mg
with placebo. ARIES-2 included 192 patients and compared Volibris 2.5 mg and 5 mg with placebo.
In both studies, Volibris was added to patients’ supportive/background medication, which could have
included a combination of digoxin, anticoagulants, diuretics, oxygen and vasodilators (calcium
channel blockers, ACE inhibitors). Patients enrolled had IPAH or PAH associated with connective
tissue disease. The majority of patients had WHO functional Class II (38.4%) or Class III (55.0%)
symptoms. Patients with pre-existent hepatic disease (cirrhosis or clinically significantly elevated
aminotransferases) and patients using other targeted therapy for PAH (e.g. prostanoids) were
excluded. Haemodynamic parameters were not assessed in these studies.
The primary endpoint defined for the Phase 3 studies was improvement in exercise capacity assessed
by change from baseline in 6 minute walk distance (6MWD) at 12 weeks. In both studies, treatment
with Volibris resulted in a significant improvement in 6MWD for each dose of Volibris.
The placebo-adjusted improvement in mean 6MWD at week 12 compared to baseline was 30.6 m
(95% CI: 2.9 to 58.3; p=0.008) and 59.4 m (95% CI: 29.6 to 89.3; p<0.001) for the 5 mg group, in
ARIES 1 and 2 respectively. The placebo-adjusted improvement in mean 6MWD at week 12 in
patients in the 10 mg group in ARIES-1 was 51.4 m (95% CI: 26.6 to 76.2; p <0.001).
A pre-specified combined analysis of the Phase 3 studies (ARIES-C) was conducted. The placebo-
adjusted mean improvement in 6MWD was 44.6 m (95% CI: 24.3 to 64.9; p<0.001) for the 5 mg dose,
and 52.5 m (95% CI: 28.8 to 76.2; p<0.001) for the 10 mg dose.
In ARIES-2, Volibris (combined dose group) significantly delayed the time to clinical worsening of
PAH compared to placebo (p<0.001), the hazard ratio demonstrated a 80% reduction (95% CI: 47% to
92%). The measure included: death, lung transplantation, hospitalisation for PAH, atrial septostomy,
addition of other PAH therapeutic agents and early escape criteria. A statistically significant increase
(3.41 ± 6.96) was observed for the combined dose group in the physical functioning scale of the SF-36
Health Survey compared with placebo (-0.20 ± 8.14, p=0.005). Treatment with Volibris led to a
statistically significant improvement in Borg Dyspnea Index (BDI) at week 12 (placebo-adjusted BDI
of -1.1 (95% CI: -1.8 to -0.4; p=0.019; combined dose group)).
Long term data
Patients enrolled into ARIES 1 and 2 were eligible to enter a long term open label extension study
ARIES E (n=383).
The effect of Volibris on the outcome of the disease is unknown. The observed probability of survival
at 1 year for subjects receiving Volibris (combined Volibris dose group) was 95% and at 2 years was
84%.
In an open label study (AMB222), Volibris was studied in 36 patients to evaluate the incidence of
increased serum aminotransferase concentrations in patients who had previously discontinued other
ERA therapy due to aminotransferase abnormalities. During a mean of 53 weeks of treatment with
9
Volibris, none of the patients enrolled had a confirmed serum ALT>3xULN that required permanent
discontinuation of treatment. Fifty percent of patients had increased from 5 mg to 10 mg Volibris
during this time.
The cumulative incidence of serum aminotransferase abnormalities>3xULN in all Phase 2 and 3
studies (including respective open label extensions) was 17 of 483 subjects over a mean exposure
duration of 79.5 weeks. This is an event rate of 2.3 events per 100 patient years of exposure for
Volibris.
Other clinical information
An improvement in haemodynamic parameters was observed in patients with PAH after 12 weeks
(n=29) in a Phase 2 study (AMB220). Treatment with Volibris resulted in an increase in mean cardiac
index, a decrease in mean pulmonary artery pressure, and a decrease in mean pulmonary vascular
resistance.
No clinically meaningful effects on the pharmacokinetics of ambrisentan or sildenafil were seen
during a drug-drug interaction study in healthy volunteers, and the combination was well tolerated.
The number of patients who received concomitant Volibris and sildenafil in ARIES-E and AMB222
was 22 patients (5.7%) and 17 patients (47%), respectively. No additional safety concerns were
identified in these patients.
5.2 Pharmacokinetic properties
Absorption
Ambrisentan is absorbed rapidly in humans. After oral administration, maximum plasma
concentrations (C
max
) of ambrisentan typically occur around 1.5 hours post-dose under both fasted and
fed conditions. C
max
and area under the plasma concentration-time curve (AUC) increase dose
proportionally over the therapeutic dose range. Steady-state is generally achieved following 4 days of
repeat dosing.
A food-effect study involving administration of ambrisentan to healthy volunteers under fasting
conditions and with a high-fat meal indicated that the C
max
was decreased 12% while the AUC
remained unchanged. This decrease in peak concentration is not clinically significant, and therefore
ambrisentan can be taken with or without food.
Distribution
Ambrisentan is highly plasma protein bound. The
in vitro
plasma protein binding of ambrisentan was,
on average, 98.8% and independent of concentration over the range of 0.2 – 20 microgram/ml.
Ambrisentan is primarily bound to albumin (96.5%) and to a lesser extent to alpha
1
-acid glycoprotein.
The distribution of ambrisentan into red blood cells is low, with a mean blood:plasma ratio of 0.57 and
0.61 in males and females, respectively.
Metabolism
Ambrisentan is a non-sulphonamide (propanoic acid) ERA.
Ambrisentan is glucuronidated via several UGT isoenzymes (UGT1A9S, UGT2B7S and UGT1A3S)
to form ambrisentan glucuronide (13%). Ambrisentan also undergoes oxidative metabolism mainly by
CYP3A4 and to a lesser extent by CYP3A5 and CYP2C19 to form 4-hydroxymethyl ambrisentan
(21%) which is further glucuronidated to 4-hydroxymethyl ambrisentan glucuronide (5%). The
binding affinity of 4-hydroxymethyl ambrisentan for the human endothelin receptor is 65-fold less
than ambrisentan. Therefore at concentrations observed in the plasma (approximately 4% relative to
10
parent ambrisentan), 4-hydroxymethyl ambrisentan is not expected to contribute to pharmacological
activity of ambrisentan.
In vitro
data have shown that at therapeutic concentrations, ambrisentan does not inhibit UGT1A1,
UGT1A6, UGT1A9, UGT2B7 or cytochrome P450 enzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6,
2E1 and 3A4. Additional
in vitro
studies showed that ambrisentan does not inhibit NTCP, OATP or
BSEP. Furthermore, ambrisentan does not induce MRP2, Pgp or BSEP.
The effects of steady-state ambrisentan (10 mg once daily) on the pharmacokinetics and
pharmacodynamics of a single dose of warfarin (25 mg), as measured by PT and INR, were
investigated in 20 healthy volunteers. Ambrisentan did not have any clinically relevant effects on the
pharmacokinetics or pharmacodynamics of warfarin. Similarly, co-administration with warfarin did
not affect the pharmacokinetics of ambrisentan (see section 4.5).
The effect of 7-day dosing of sildenafil (20 mg three times daily) on the pharmacokinetics of a single
dose of ambrisentan, and the effects of 7-day dosing of ambrisentan (10 mg once daily) on the
pharmacokinetics of a single dose of sildenafil were investigated in 19 healthy volunteers. With the
exception of a 13% increase in sildenafil C
max
following co-administration with ambrisentan, there
were no other changes in the pharmacokinetic parameters of sildenafil, N-desmethyl-sildenafil and
ambrisentan. This slight increase in sildenafil C
max
is not considered clinically relevant (see section
4.5).
The effects of steady-state ambrisentan (10 mg once daily) on the pharmacokinetics of a single dose of
tadalafil, and the effects of steady-state tadalafil (40 mg once daily) on the pharmacokinetics of a
single dose of ambrisentan were studied in 23 healthy volunteers. Ambrisentan did not have any
clinically relevant effects on the pharmacokinetics of tadalafil. Similarly, co-administration with
tadalafil did not affect the pharmacokinetics of ambrisentan (see section 4.5).
The effects of repeat dosing of ketoconazole (400 mg once daily) on the pharmacokinetics of a single
dose of 10 mg ambrisentan were investigated in 16 healthy volunteers. Exposures of ambrisentan as
measured by AUC
(0-inf)
and C
max
were increased by 35% and 20%, respectively. This change in
exposure is unlikely to be of any clinical relevance and therefore Volibris may be co-administered
with ketoconazole.
The effects of repeat dosing of cyclosporine A (100 – 150 mg twice daily) on the steady-state
pharmacokinetics of ambrisentan (5 mg once daily), and the effects of repeat dosing of ambrisentan (5
mg once daily) on the steady-state pharmacokinetics of cyclosporine A (100 – 150 mg twice daily)
were studied in healthy volunteers. The C
max
and AUC(0-
τ
) of ambrisentan increased (48% and 121%,
respectively) in the presence of multiple doses of cyclosporine A. Based on these changes, the dose of
ambrisentan should be limited to 5 mg once daily when co-administered with cyclosporine A (see
section 4.2). However, multiple doses of ambrisentan had no clinically relevant effect on cyclosporine
A exposure, and no dose adjustment of cyclosporine A is warranted.
The effects of acute and repeat dosing of rifampicin (600 mg once daily) on the steady-state
pharmacokinetics of ambrisentan (10 mg once daily) were studied in healthy volunteers. Following
initial doses of rifampicin, a transient increase in ambrisentan AUC(0–
τ
) (121% and 116% after first
and second doses of rifampicin, respectively) was observed, presumably due to a rifampicin-mediated
OATP inhibition. However, there was no clinically relevant effect on ambrisentan exposure by day 8,
following administration of multiple doses of rifampicin. Patients on ambrisentan therapy should be
closely monitored when starting treatment with rifampicin (see sections 4.4 and 4.5).
The effects of repeat dosing of ambrisentan (10 mg) on the pharmacokinetics of single dose digoxin
were studied in 15 healthy volunteers. Multiple doses of ambrisentan resulted in slight increases in
digoxin AUC
0-last
and trough concentrations, and a 29% increase in digoxin C
max
. The increase in
11
digoxin exposure observed in the presence of multiple doses of ambrisentan was not considered
clinically relevant, and no dose adjustment of digoxin is warranted (see section 4.5).
The effects of 12 days dosing with ambrisentan (10 mg once daily) on the pharmacokinetics of a
single dose of oral contraceptive containing ethinyl estradiol (35 μg) and norethindrone (1 mg) were
studied in healthy female volunteers. The C
max
and AUC
(0–∞)
were slightly decreased for ethinyl
estradiol (8% and 4%, respectively), and slightly increased for norethindrone (13% and 14 %,
respectively). These changes in exposure to ethinyl estradiol or norethindrone were small and are
unlikely to be clinically significant (see section 4.5).
Elimination
Ambrisentan and its metabolites are eliminated primarily in the bile following hepatic and/or extra-
hepatic metabolism. Approximately 22% of the administered dose is recovered in the urine following
oral administration with 3.3% being unchanged ambrisentan. Plasma elimination half-life in humans
ranges from 13.6 to 16.5 hours.
Special populations
Based on the results of a population pharmacokinetic analysis in healthy volunteers and patients with
PAH, the pharmacokinetics of ambrisentan were not significantly influenced by gender or age (see
section 4.2).
Renal impairment
Ambrisentan does not undergo significant renal metabolism or renal clearance (excretion). In a
population pharmacokinetic analysis, creatinine clearance was found to be a statistically significant
covariate affecting the oral clearance of ambrisentan. The magnitude of the decrease in oral clearance
is modest (20-40%) in patients with moderate renal impairment and therefore is unlikely to be of any
clinical relevance. However, caution should be used in patients with severe renal impairment (see
section 4.2).
Hepatic impairment
The main routes of metabolism of ambrisentan are glucuronidation and oxidation with subsequent
elimination in the bile and therefore hepatic impairment would be expected to increase exposure (C
max
and AUC) of ambrisentan. In a population pharmacokinetic analysis, the oral clearance was shown to
be decreased as a function of increasing bilirubin levels. However, the magnitude of effect of bilirubin
is modest (compared to the typical patient with a bilirubin of 0.6 mg/dl, a patient with an elevated
bilirubin of 4.5 mg/dl would have approximately 30% lower oral clearance of ambrisentan). The
pharmacokinetics of ambrisentan in patients with severe hepatic impairment (with or without
cirrhosis) has not been studied. Therefore Volibris should not be initiated in patients with severe
hepatic impairment or clinically significant elevated hepatic aminotransferases (>3xULN) (see
sections 4.3 and 4.4).
5.3 Preclinical safety data
Due to the class primary pharmacologic effect, a large single dose of ambrisentan (i.e. an overdose)
could lower arterial pressure and have the potential for causing hypotension and symptoms related to
vasodilation.
Ambrisentan was not shown to be an inhibitor of bile acid transport or to produce overt hepatotoxicity.
Inflammation and changes in the nasal cavity epithelium have been seen in rodents after chronic
administration at exposures below the therapeutic levels in humans. In dogs, slight inflammatory
12
responses were observed following chronic high dose administration of ambrisentan at exposures
greater than 20–fold that observed in patients.
Nasal bone hyperplasia of the ethmoid turbinates has been observed in the nasal cavity of rats treated
with ambrisentan, at exposure levels 3-fold the clinical AUC. Nasal bone hyperplasia has not been
observed with ambrisentan in mice or dogs. In the rat, hyperplasia of nasal turbinate bone is a
recognised response to nasal inflammation, based on experience with other compounds.
Ambrisentan was clastogenic when tested at high concentrations in mammalian cells
in vitro
. No
evidence for mutagenic or genotoxic effects of ambrisentan were seen in bacteria or in two
in vivo
rodent studies.
There were no treatment-related increases in the incidence of tumours in 2 year oral studies in rats and
mice.
Testicular tubular atrophy, which was occasionally associated with aspermia, was observed in oral
repeat dose toxicity and fertility studies with male rats and mice without safety margin. The testicular
changes were not fully recoverable during the off-dose periods evaluated. However no testicular
changes were observed in dog studies of up to 39 weeks duration at an exposure 35–fold that seen in
humans based on AUC. The effect of ambrisentan on male human fertility is not known.
Ambrisentan has been shown to be teratogenic in rats and rabbits. Abnormalities of the lower jaw,
tongue, and/or palate were seen at all doses tested. In addition, interventricular septal defects, trunk
vessel defects, thyroid and thymus abnormalities, ossification of the basisphenoid bone and increased
incidence of left umbilical artery were seen in the rat study. Teratogenicity is a suspected class effect
of ERAs.
Administration of ambrisentan to female rats from late-pregnancy through lactation caused adverse
events on maternal behaviour, reduced pup survival and impairment of the reproductive capability of
the offspring (with observation of small testes at necropsy), at exposure 3-fold the AUC at the
maximum recommended human dose.
6.
6.1 List of excipients
Tablet core
Lactose monohydrate
Microcrystalline cellulose
Croscarmellose sodium
Magnesium stearate
Film coat
Polyvinyl alcohol (Partially Hydrolysed)
Talc (E553b)
Titanium dioxide (E171)
Macrogol / PEG 3350
Lecithin (Soya) (E322)
Allura red AC Aluminium Lake (E129)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
13
2 years.
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5
Nature and contents of container
PVC/PVDC/aluminium foil blisters. Pack sizes of 10 or 30 film-coated tablets. Not all pack sizes may
be marketed.
6.6 Special precautions for disposal
No special requirements.
7.
Glaxo Group Ltd
Greenford
Middlesex
UB6 0NN
United Kingdom
8.
EU/1/08/451/001
EU/1/08/451/002
9.
Date of first authorisation: 21 April 2008
{MM/YYYY}
Detailed information on this product is available on the website of the European Medicines Agency
http://www.ema.europa.eu
.
14
1.
Volibris 10 mg film-coated tablets
2.
Each tablet contains 10 mg of ambrisentan.
Excipients
Each tablet contains lactose monohydrate (approximately 90 mg), Lecithin (Soya) (E322)
(approximately 0.25 mg) and Allura red AC Aluminium Lake (E129) (approximately 0.45 mg).
For a full list of excipients, see section 6.1.
3.
Film-coated tablet.
Deep-pink, oval, convex, film-coated tablet with “GS” debossed on one side and “KE3” on the other
side.
4.
Volibris is indicated for the treatment of patients with pulmonary arterial hypertension (PAH)
classified as WHO functional class II and III, to improve exercise capacity (see section 5.1). Efficacy
has been shown in idiopathic PAH (IPAH) and in PAH associated with connective tissue disease.
Treatment must be initiated by a physician experienced in the treatment of PAH.
Posology
Volibris is to be taken orally at a dose of 5 mg once daily.
Some additional efficacy has been observed with 10 mg Volibris in patients with class III symptoms,
however an increase in peripheral oedema has also been observed. Patients with PAH associated with
connective tissue disease may require 10 mg Volibris for optimal efficacy. Confirm that the 5 mg dose
is well tolerated before considering an increase in dose to 10 mg Volibris in these patients (see
sections 4.4 and 4.8).
Limited data suggest that the abrupt discontinuation of Volibris is not associated with rebound
worsening of PAH.
When co-administered with cyclosporine A, the dose of ambrisentan should be limited to 5 mg once
daily and the patient should be carefully monitored (see sections 4.5 and 5.2).
Children and adolescents
15
Volibris is not recommended for use in patients below 18 years of age due to a lack of data on safety
and efficacy.
Elderly
No dose adjustment is required in patients over the age of 65 (see section 5.2).
Patients with renal impairment
No dose adjustment is required in patients with renal impairment (see section 5.2). There is limited
experience with Volibris in individuals with severe renal impairment (creatinine clearance
<30 ml/min); initiate therapy cautiously in this subgroup and take particular care if the dose is
increased to 10 mg Volibris.
Patients with hepatic impairment
Volibris has not been studied in individuals with severe hepatic impairment (with or without
cirrhosis). Since the main routes of metabolism of ambrisentan are glucuronidation and oxidation with
subsequent elimination in the bile, hepatic impairment would be expected to increase exposure (C
max
and AUC) to ambrisentan. Therefore Volibris should not be initiated in patients with severe hepatic
impairment, or clinically significant elevated hepatic aminotransferases (greater than 3 times the
Upper Limit of Normal (>3xULN); see sections 4.3 and 4.4).
Method of administration
It is recommended that the tablet is swallowed whole and it can be taken with or without food.
• Hypersensitivity to the active substance, to soya, or to any of the excipients (see sections 4.4 and
6.1).
• Pregnancy (see section 4.6).
• Women of child-bearing potential who are not using reliable contraception (see sections 4.4 and 4.6).
• Lactation (see section 4.6).
• Severe hepatic impairment (with or without cirrhosis) (see section 4.2).
• Baseline values of hepatic aminotransferases (aspartate aminotransferases (AST) and/or alanine
aminotransferases (ALT))>3xULN (see sections 4.2 and 4.4).
Volibris has not been studied in a sufficient number of patients to establish the benefit/risk balance in
WHO functional class I PAH.
The efficacy of Volibris as monotherapy has not been established in patients with WHO functional
class IV PAH. Therapy that is recommended at the severe stage of the disease (e.g. epoprostenol)
should be considered if the clinical condition deteriorates.
Liver function
Liver function abnormalities have been associated with PAH. Hepatic enzyme elevations potentially
related to therapy have been observed with endothelin receptor antagonists (ERAs) (see section 5.1).
16
Therefore hepatic aminotransferases (ALT and AST) should be evaluated prior to initiation of
Volibris. Volibris treatment should not be initiated in patients with baseline values of ALT and/or
AST>3xULN (see section 4.3).
Monthly monitoring of ALT and AST is recommended. If patients develop sustained, unexplained,
clinically significant ALT and/or AST elevation, or if ALT and/or AST elevation is accompanied by
signs or symptoms of hepatic injury (e.g. jaundice), Volibris therapy should be discontinued.
In patients without clinical symptoms of hepatic injury or of jaundice, re-initiation of Volibris may be
considered following resolution of hepatic enzyme abnormalities. The advice of a hepatologist is
recommended.
Haemoglobin concentration
Reductions in haemoglobin concentrations and haematocrit have been associated with ERAs including
Volibris (see section 4.8). Most of these decreases were detected during the first 4 weeks of treatment
and haemoglobin generally stabilised thereafter.
Initiation of Volibris is not recommended for patients with clinically significant anaemia. It is
recommended that haemoglobin and/or haematocrit levels are measured during treatment with
Volibris, for example at 1 month, 3 months and periodically thereafter in line with clinical practice. If
a clinically significant decrease in haemoglobin or haematocrit is observed, and other causes have
been excluded, dose reduction or discontinuation of treatment should be considered.
Fluid retention
Peripheral oedema has been observed with ERAs including ambrisentan. Most cases of peripheral
oedema in clinical studies with ambrisentan were mild to moderate in severity, although it appeared to
occur with greater frequency and severity in patients ≥65 years. Peripheral oedema was reported more
frequently with 10 mg ambrisentan (see section 4.8).
Post-marketing reports of fluid retention occurring within weeks after starting ambrisentan have been
received and, in some cases, have required intervention with a diuretic or hospitalisation for fluid
management or decompensated heart failure. If patients have pre-existing fluid overload, this should
be managed as clinically appropriate prior to starting ambrisentan.
If clinically significant fluid retention develops during therapy with ambrisentan, with or without
associated weight gain, further evaluation should be undertaken to determine the cause, such as
ambrisentan or underlying heart failure, and the possible need for specific treatment or discontinuation
of ambrisentan therapy.
Women of child-bearing potential
Volibris treatment must not be initiated in women of child-bearing potential unless the result of a pre-
treatment pregnancy test is negative and reliable contraception is practiced. If there is any doubt on
what contraceptive advice should be given to the individual patient, consultation with a gynaecologist
should be considered. Monthly pregnancy tests during treatment with Volibris are recommended (see
sections 4.3 and 4.6).
Pulmonary veno-occlusive disease
Cases of pulmonary oedema have been reported with vasodilating agents, such as endothelin receptor
antagonists, when used in patients with pulmonary veno-occlusive disease. Consequently, if PAH
patients develop acute pulmonary oedema when treated with ambrisentan, the possibility of pulmonary
veno-occlusive disease should be considered.
17
Concomitant use with other medicinal products
Rifampicin
: Patients on ambrisentan therapy should be closely monitored when starting treatment with
rifampicin (see sections 4.5 and 5.2).
Excipients
Volibris tablets contain lactose monohydrate. Patients with rare hereditary problems of galactose
intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this
medicine.
Volibris tablets contain the azo colouring agent Allura red AC Aluminium Lake (E129), which can
cause allergic reactions.
Ambrisentan does not inhibit or induce phase I or II drug metabolizing enzymes at clinically relevant
concentrations in
in vitro
and
in vivo
non-clinical studies, suggesting a low potential for ambrisentan
to alter the profile of medicinal products metabolized by these pathways.
The potential for ambrisentan to induce CYP3A4 activity was explored in healthy volunteers with
results suggesting a lack of inductive effect of ambrisentan on the CYP3A4 isoenzyme.
Co-administration of ambrisentan with a phosphodiesterase inhibitor, either sildenafil or tadalafil (both
substrates of CYP3A4) in healthy volunteers did not significantly affect the pharmacokinetics of the
phosphodiesterase inhibitor or ambrisentan (see section 5.2).
Steady-state administration of ketoconazole (a strong inhibitor of CYP3A4) did not result in a
clinically significant increase in exposure to ambrisentan (see section 5.2).
Ambrisentan had no effects on the steady-state pharmacokinetics and anti-coagulant activity of
warfarin in a healthy volunteer study (see section 5.2). Warfarin also had no clinically significant
effects on the pharmacokinetics of ambrisentan. In addition, in patients, ambrisentan had no overall
effect on the weekly warfarin-type anticoagulant dose, prothrombin time (PT) and international
normalized ratio (INR).
Steady-state co-administration of ambrisentan and cyclosporine A resulted in a 2-fold increase in
ambrisentan exposure in healthy volunteers. This may be due to the inhibition by cyclosporine A of
transporters and metabolic enzymes involved in the pharmacokinetics of ambrisentan. Therefore the
dose of ambrisentan should be limited to 5 mg once daily when co-administered with cyclosporine A
(see section 4.2). Multiple doses of ambrisentan had no effect on cyclosporine A exposure, and no
dose adjustment of cyclosporine A is warranted.
Co-administration of rifampicin (an inhibitor of OATP, a strong inducer of CYP3A and 2C19, and
inducer of P-gp and uridine-diphospho-glucuronosyltransferases [UGTs]) was associated with a
transient (approximately 2-fold) increase in ambrisentan exposure following initial doses in healthy
volunteers. However, by day 8, steady state administration of rifampicin had no clinically relevant
effect on ambrisentan exposure. Patients on ambrisentan therapy should be closely monitored when
starting treatment with rifampicin (see sections 4.4 and 5.2).
In a clinical study in healthy volunteers, steady-state dosing with ambrisentan 10 mg once daily did
not significantly affect the single-dose pharmacokinetics of the ethinyl estradiol and norethindrone
components of a combined oral contraceptive (see section 5.2). Based on this pharmacokinetic study,
ambrisentan would not be expected to significantly affect exposure to oestrogen- or progestogen-
based contraceptives.
18
The efficacy and safety of Volibris when co-administered with other treatments for PAH (e.g.
prostanoids and phosphodiesterase type V inhibitors) has not been specifically studied in controlled
clinical trials in PAH patients (see section 5.1). Therefore, caution is recommended in the case of co-
administration.
Effect of ambrisentan on xenobiotic transporters
In vitro
, ambrisentan has no inhibitory effect on the P-glycoprotein (Pgp)-mediated efflux of digoxin
and is a weak substrate for Pgp-mediated efflux. Additional
in vitro
studies in rat and human
hepatocytes showed that ambrisentan did not inhibit sodium-taurocholate co-transporter (NTCP),
organic anion export pump (OATP), bile salt export pump (BSEP) and multi-drug resistance protein
isoform-2 (MRP2).
In vitro
studies in rat hepatocytes also showed that ambrisentan has no inductive
effects on Pgp, BSEP or MRP2.
Steady-state administration of ambrisentan in healthy volunteers had no clinically relevant effects on
the single-dose pharmacokinetics of digoxin, a substrate for Pgp (see section 5.2).
Pregnancy
Volibris is contraindicated in pregnancy (see section 4.3). Animal studies have shown that
ambrisentan is teratogenic. There is no experience in humans.
Volibris treatment must not be initiated in women of child-bearing potential unless the result of a pre-
treatment pregnancy test is negative and reliable contraception is practiced. Monthly pregnancy tests
during treatment with Volibris are recommended.
Women receiving Volibris must be advised of the risk of foetal harm and alternative therapy initiated
if pregnancy occurs (see sections 4.3, 4.4 and 5.3).
Lactation
It is not known whether ambrisentan is excreted in human breast milk. The excretion of ambrisentan in
milk has not been studied in animals. Therefore lactation is contraindicated in patients taking Volibris
(see section 4.3).
Male fertility
The development of testicular tubular atrophy in male animals has been linked to the chronic
administration of ERAs, including ambrisentan (see section 5.3). The effect on male human fertility is
not known. Chronic administration of ambrisentan was not associated with a change in plasma
testosterone in clinical studies.
No studies on the effects on the ability to drive and use machines have been performed.
Safety of Volibris has been evaluated in clinical trials of more than 483 patients with PAH (see section
5.1). Adverse drug reactions (ADR) identified from 12 week placebo controlled clinical trial data are
listed below by system organ class and frequency. With longer observation in uncontrolled studies
19
(mean observation of 79 weeks), the safety profile was similar to that observed in the short term
studies. Frequencies are defined as: very common (≥ 1/10); common (≥ 1/100 to <1/10); uncommon
(≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000). For dose-related adverse
reactions the frequency category reflects the higher dose of Volibris. Frequency categories do not
account for other factors including varying study duration, pre-existing conditions and baseline patient
characteristics. Adverse reaction frequency categories assigned based on clinical trial experience may
not reflect the frequency of adverse events occurring during normal clinical practice. Within each
frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Cardiac disorders
Palpitation
Common
Blood and lymphatic system disorders
Anaemia (decreased haemoglobin, decreased haematocrit)
Common
Nervous system disorders
Headache (including sinus headache, migraine)
1
Very
common
Respiratory, thoracic and mediastinal disorders
Upper respiratory (e.g. nasal
2
, sinus) congestion, sinusitis,
nasopharyngitis, rhinitis
Common
Gastrointestinal disorders
Abdominal pain
Common
Constipation
Common
Vascular disorders
Flushing
Common
General disorders and administration site conditions
Peripheral oedema, fluid retention
3
Very
common
Chest pain/discomfort
Common
Immune system disorders
Hypersensitivity reactions (e.g. angioedema, rash, pruritus) Uncommon
1
The frequency of headache appeared higher with 10 mg Volibris.
2
The incidence of nasal congestion was dose related during Volibris therapy.
3
Peripheral oedema was reported more frequently with 10 mg Volibris. In clinical studies peripheral
oedema was reported more commonly and tended to be more severe in patients ≥65 years (see section
4.4).
Laboratory abnormalities
Decreased haemoglobin (see section 4.4).
The frequency of decreased haemoglobin (anaemia) was higher with 10 mg Volibris. Across the
12 week placebo controlled Phase III clinical studies, mean haemoglobin concentrations decreased for
patients in the Volibris groups and were detected as early as week 4 (decrease by 0.83 g/dl); mean
20
changes from baseline appeared to stabilise over the subsequent 8 weeks. A total of 17 patients (6.5%)
in the Volibris treatment groups had decreases in haemoglobin of ≥15% from baseline and which fell
below the lower limit of normal.
Post-marketing data
In addition to adverse reactions identified from clinical studies, the following adverse reactions were
identified during post-approval use of Volibris. Frequencies are defined as: ‘not known’ (cannot be
estimated from the available data).
Nervous system disorders
Dizziness
Not known
Cardiac disorders
Cardiac failure
4
Not known
Vascular disorders
Syncope, hypotension
Not known
Respiratory, thoracic and mediastinal disorders
Dyspnoea
5
Not known
Gastrointestinal disorders
Nausea, vomiting, diarrhoea
Not known
Hepatobiliary disorders
Hepatic transaminases increased Common
4
Most of the reported cases of cardiac failure were associated with fluid retention.
5
Cases of worsening dyspnoea of unclear aetiology have been reported shortly after starting Volibris
therapy.
There is no experience in PAH patients of Volibris at daily doses greater than 10 mg. In healthy
volunteers, single doses of 50 and 100 mg (5 to 10 times the maximum recommended dose) were
associated with headache, flushing, dizziness, nausea and nasal congestion.
Due to the mechanism of action, an overdose of Volibris could potentially result in hypotension (see
section 5.3). In the case of pronounced hypotension, active cardiovascular support may be required.
No specific antidote is available.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: other anti-hypertensives, ATC code: C02KX02
Mechanism of action
Ambrisentan is an orally active, propanoic acid-class, ERA selective for the endothelin A (ET
A
)
receptor. Endothelin plays a significant role in the pathophysiology of PAH.
•
Ambrisentan is a potent (Ki 0.016 nM) and highly selective ET
A
antagonist (approximately
4000-fold more selective for ET
A
as compared to ET
B
).
21
•
Ambrisentan blocks the ET
A
receptor subtype, localized predominantly on vascular smooth
muscle cells and cardiac myocytes. This prevents endothelin-mediated activation of second
messenger systems that result in vasoconstriction and smooth muscle cell proliferation.
•
The selectivity of ambrisentan for the ET
A
over the ET
B
receptor is expected to retain ET
B
receptor mediated production of the vasodilators nitric oxide and prostacyclin.
Efficacy
Two randomised, double-blind, multi-centre, placebo controlled, Phase 3 pivotal studies were
conducted (ARIES-1 and 2). ARIES-1 included 201 patients and compared Volibris 5 mg and 10 mg
with placebo. ARIES-2 included 192 patients and compared Volibris 2.5 mg and 5 mg with placebo.
In both studies, Volibris was added to patients’ supportive/background medication, which could have
included a combination of digoxin, anticoagulants, diuretics, oxygen and vasodilators (calcium
channel blockers, ACE inhibitors). Patients enrolled had IPAH or PAH associated with connective
tissue disease. The majority of patients had WHO functional Class II (38.4%) or Class III (55.0%)
symptoms. Patients with pre-existent hepatic disease (cirrhosis or clinically significantly elevated
aminotransferases) and patients using other targeted therapy for PAH (e.g. prostanoids) were
excluded. Haemodynamic parameters were not assessed in these studies.
The primary endpoint defined for the Phase 3 studies was improvement in exercise capacity assessed
by change from baseline in 6 minute walk distance (6MWD) at 12 weeks. In both studies, treatment
with Volibris resulted in a significant improvement in 6MWD for each dose of Volibris.
The placebo-adjusted improvement in mean 6MWD at week 12 compared to baseline was 30.6 m
(95% CI: 2.9 to 58.3; p=0.008) and 59.4 m (95% CI: 29.6 to 89.3; p<0.001) for the 5 mg group, in
ARIES 1 and 2 respectively. The placebo-adjusted improvement in mean 6MWD at week 12 in
patients in the 10 mg group in ARIES-1 was 51.4 m (95% CI: 26.6 to 76.2; p <0.001).
A pre-specified combined analysis of the Phase 3 studies (ARIES-C) was conducted. The placebo-
adjusted mean improvement in 6MWD was 44.6 m (95% CI: 24.3 to 64.9; p<0.001) for the 5 mg dose,
and 52.5 m (95% CI: 28.8 to 76.2; p<0.001) for the 10 mg dose.
In ARIES-2, Volibris (combined dose group) significantly delayed the time to clinical worsening of
PAH compared to placebo (p<0.001), the hazard ratio demonstrated a 80% reduction (95% CI: 47% to
92%). The measure included: death, lung transplantation, hospitalisation for PAH, atrial septostomy,
addition of other PAH therapeutic agents and early escape criteria. A statistically significant increase
(3.41 ± 6.96) was observed for the combined dose group in the physical functioning scale of the SF-36
Health Survey compared with placebo (-0.20 ± 8.14, p=0.005). Treatment with Volibris led to a
statistically significant improvement in Borg Dyspnea Index (BDI) at week 12 (placebo-adjusted BDI
of -1.1 (95% CI: -1.8 to -0.4; p=0.019; combined dose group)).
Long term data
Patients enrolled into ARIES 1 and 2 were eligible to enter a long term open label extension study
ARIES E (n=383).
The effect of Volibris on the outcome of the disease is unknown. The observed probability of survival
at 1 year for subjects receiving Volibris (combined Volibris dose group) was 95% and at 2 years was
84%.
In an open label study (AMB222), Volibris was studied in 36 patients to evaluate the incidence of
increased serum aminotransferase concentrations in patients who had previously discontinued other
ERA therapy due to aminotransferase abnormalities. During a mean of 53 weeks of treatment with
Volibris, none of the patients enrolled had a confirmed serum ALT>3xULN that required permanent
22
discontinuation of treatment. Fifty percent of patients had increased from 5 mg to 10 mg Volibris
during this time.
The cumulative incidence of serum aminotransferase abnormalities>3xULN in all Phase 2 and 3
studies (including respective open label extensions) was 17 of 483 subjects over a mean exposure
duration of 79.5 weeks. This is an event rate of 2.3 events per 100 patient years of exposure for
Volibris.
Other clinical information
An improvement in haemodynamic parameters was observed in patients with PAH after 12 weeks
(n=29) in a Phase 2 study (AMB220). Treatment with Volibris resulted in an increase in mean cardiac
index, a decrease in mean pulmonary artery pressure, and a decrease in mean pulmonary vascular
resistance.
No clinically meaningful effects on the pharmacokinetics of ambrisentan or sildenafil were seen
during a drug-drug interaction study in healthy volunteers, and the combination was well tolerated.
The number of patients who received concomitant Volibris and sildenafil in ARIES-E and AMB222
was 22 patients (5.7%) and 17 patients (47%), respectively. No additional safety concerns were
identified in these patients.
5.2 Pharmacokinetic properties
Absorption
Ambrisentan is absorbed rapidly in humans. After oral administration, maximum plasma
concentrations (C
max
) of ambrisentan typically occur around 1.5 hours post-dose under both fasted and
fed conditions. C
max
and area under the plasma concentration-time curve (AUC) increase dose
proportionally over the therapeutic dose range. Steady-state is generally achieved following 4 days of
repeat dosing.
A food-effect study involving administration of ambrisentan to healthy volunteers under fasting
conditions and with a high-fat meal indicated that the C
max
was decreased 12% while the AUC
remained unchanged. This decrease in peak concentration is not clinically significant, and therefore
ambrisentan can be taken with or without food.
Distribution
Ambrisentan is highly plasma protein bound. The
in vitro
plasma protein binding of ambrisentan was,
on average, 98.8% and independent of concentration over the range of 0.2 – 20 microgram/ml.
Ambrisentan is primarily bound to albumin (96.5%) and to a lesser extent to alpha
1
-acid glycoprotein.
The distribution of ambrisentan into red blood cells is low, with a mean blood:plasma ratio of 0.57 and
0.61 in males and females, respectively.
Metabolism
Ambrisentan is a non-sulphonamide (propanoic acid) ERA.
Ambrisentan is glucuronidated via several UGT isoenzymes (UGT1A9S, UGT2B7S and UGT1A3S)
to form ambrisentan glucuronide (13%). Ambrisentan also undergoes oxidative metabolism mainly by
CYP3A4 and to a lesser extent by CYP3A5 and CYP2C19 to form 4-hydroxymethyl ambrisentan
(21%) which is further glucuronidated to 4-hydroxymethyl ambrisentan glucuronide (5%). The
binding affinity of 4-hydroxymethyl ambrisentan for the human endothelin receptor is 65-fold less
than ambrisentan. Therefore at concentrations observed in the plasma (approximately 4% relative to
23
parent ambrisentan), 4-hydroxymethyl ambrisentan is not expected to contribute to pharmacological
activity of ambrisentan.
In vitro
data have shown that at therapeutic concentrations, ambrisentan does not inhibit UGT1A1,
UGT1A6, UGT1A9, UGT2B7 or cytochrome P450 enzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6,
2E1 and 3A4. Additional
in vitro
studies showed that ambrisentan does not inhibit NTCP, OATP or
BSEP. Furthermore, ambrisentan does not induce MRP2, Pgp or BSEP.
The effects of steady-state ambrisentan (10 mg once daily) on the pharmacokinetics and
pharmacodynamics of a single dose of warfarin (25 mg), as measured by PT and INR, were
investigated in 20 healthy volunteers. Ambrisentan did not have any clinically relevant effects on the
pharmacokinetics or pharmacodynamics of warfarin. Similarly, co-administration with warfarin did
not affect the pharmacokinetics of ambrisentan (see section 4.5).
The effect of 7-day dosing of sildenafil (20 mg three times daily) on the pharmacokinetics of a single
dose of ambrisentan, and the effects of 7-day dosing of ambrisentan (10 mg once daily) on the
pharmacokinetics of a single dose of sildenafil were investigated in 19 healthy volunteers. With the
exception of a 13% increase in sildenafil C
max
following co-administration with ambrisentan, there
were no other changes in the pharmacokinetic parameters of sildenafil, N-desmethyl-sildenafil and
ambrisentan. This slight increase in sildenafil C
max
is not considered clinically relevant (see section
4.5).
The effects of steady-state ambrisentan (10 mg once daily) on the pharmacokinetics of a single dose of
tadalafil, and the effects of steady-state tadalafil (40 mg once daily) on the pharmacokinetics of a
single dose of ambrisentan were studied in 23 healthy volunteers. Ambrisentan did not have any
clinically relevant effects on the pharmacokinetics of tadalafil. Similarly, co-administration with
tadalafil did not affect the pharmacokinetics of ambrisentan (see section 4.5).
The effects of repeat dosing of ketoconazole (400 mg once daily) on the pharmacokinetics of a single
dose of 10 mg ambrisentan were investigated in 16 healthy volunteers. Exposures of ambrisentan as
measured by AUC
(0-inf)
and C
max
were increased by 35% and 20%, respectively. This change in
exposure is unlikely to be of any clinical relevance and therefore Volibris may be co-administered
with ketoconazole.
The effects of repeat dosing of cyclosporine A (100 – 150 mg twice daily) on the steady-state
pharmacokinetics of ambrisentan (5 mg once daily), and the effects of repeat dosing of ambrisentan (5
mg once daily) on the steady-state pharmacokinetics of cyclosporine A (100 – 150 mg twice daily)
were studied in healthy volunteers. The C
max
and AUC(0-
τ
) of ambrisentan increased (48% and 121%,
respectively) in the presence of multiple doses of cyclosporine A. Based on these changes, the dose of
ambrisentan should be limited to 5 mg once daily when co-administered with cyclosporine A (see
section 4.2). However, multiple doses of ambrisentan had no clinically relevant effect on cyclosporine
A exposure, and no dose adjustment of cyclosporine A is warranted.
The effects of acute and repeat dosing of rifampicin (600 mg once daily) on the steady-state
pharmacokinetics of ambrisentan (10 mg once daily) were studied in healthy volunteers. Following
initial doses of rifampicin, a transient increase in ambrisentan AUC(0–
τ
) (121% and 116% after first
and second doses of rifampicin, respectively) was observed, presumably due to a rifampicin-mediated
OATP inhibition. However, there was no clinically relevant effect on ambrisentan exposure by day 8,
following administration of multiple doses of rifampicin. Patients on ambrisentan therapy should be
closely monitored when starting treatment with rifampicin (see sections 4.4 and 4.5).
The effects of repeat dosing of ambrisentan (10 mg) on the pharmacokinetics of single dose digoxin
were studied in 15 healthy volunteers. Multiple doses of ambrisentan resulted in slight increases in
digoxin AUC
0-last
and trough concentrations, and a 29% increase in digoxin C
max
. The increase in
24
digoxin exposure observed in the presence of multiple doses of ambrisentan was not considered
clinically relevant, and no dose adjustment of digoxin is warranted (see section 4.5).
The effects of 12 days dosing with ambrisentan (10 mg once daily) on the pharmacokinetics of a
single dose of oral contraceptive containing ethinyl estradiol (35 μg) and norethindrone (1 mg) were
studied in healthy female volunteers. The C
max
and AUC
(0–∞)
were slightly decreased for ethinyl
estradiol (8% and 4%, respectively), and slightly increased for norethindrone (13% and 14 %,
respectively). These changes in exposure to ethinyl estradiol or norethindrone were small and are
unlikely to be clinically significant (see section 4.5).
Elimination
Ambrisentan and its metabolites are eliminated primarily in the bile following hepatic and/or extra-
hepatic metabolism. Approximately 22% of the administered dose is recovered in the urine following
oral administration with 3.3% being unchanged ambrisentan. Plasma elimination half-life in humans
ranges from 13.6 to 16.5 hours.
Special populations
Based on the results of a population pharmacokinetic analysis in healthy volunteers and patients with
PAH, the pharmacokinetics of ambrisentan were not significantly influenced by gender or age (see
section 4.2).
Renal impairment
Ambrisentan does not undergo significant renal metabolism or renal clearance (excretion). In a
population pharmacokinetic analysis, creatinine clearance was found to be a statistically significant
covariate affecting the oral clearance of ambrisentan. The magnitude of the decrease in oral clearance
is modest (20-40%) in patients with moderate renal impairment and therefore is unlikely to be of any
clinical relevance. However, caution should be used in patients with severe renal impairment (see
section 4.2).
Hepatic impairment
The main routes of metabolism of ambrisentan are glucuronidation and oxidation with subsequent
elimination in the bile and therefore hepatic impairment would be expected to increase exposure (C
max
and AUC) of ambrisentan. In a population pharmacokinetic analysis, the oral clearance was shown to
be decreased as a function of increasing bilirubin levels. However, the magnitude of effect of bilirubin
is modest (compared to the typical patient with a bilirubin of 0.6 mg/dl, a patient with an elevated
bilirubin of 4.5 mg/dl would have approximately 30% lower oral clearance of ambrisentan). The
pharmacokinetics of ambrisentan in patients with severe hepatic impairment (with or without
cirrhosis) has not been studied. Therefore Volibris should not be initiated in patients with severe
hepatic impairment or clinically significant elevated hepatic aminotransferases (>3xULN) (see
sections 4.3 and 4.4).
5.3 Preclinical safety data
Due to the class primary pharmacologic effect, a large single dose of ambrisentan (i.e. an overdose)
could lower arterial pressure and have the potential for causing hypotension and symptoms related to
vasodilation.
Ambrisentan was not shown to be an inhibitor of bile acid transport or to produce overt hepatotoxicity.
Inflammation and changes in the nasal cavity epithelium have been seen in rodents after chronic
administration at exposures below the therapeutic levels in humans. In dogs, slight inflammatory
25
responses were observed following chronic high dose administration of ambrisentan at exposures
greater than 20–fold that observed in patients.
Nasal bone hyperplasia of the ethmoid turbinates has been observed in the nasal cavity of rats treated
with ambrisentan, at exposure levels 3-fold the clinical AUC. Nasal bone hyperplasia has not been
observed with ambrisentan in mice or dogs. In the rat, hyperplasia of nasal turbinate bone is a
recognised response to nasal inflammation, based on experience with other compounds.
Ambrisentan was clastogenic when tested at high concentrations in mammalian cells
in vitro
. No
evidence for mutagenic or genotoxic effects of ambrisentan were seen in bacteria or in two
in vivo
rodent studies.
There were no treatment-related increases in the incidence of tumours in 2 year oral studies in rats and
mice.
Testicular tubular atrophy, which was occasionally associated with aspermia, was observed in oral
repeat dose toxicity and fertility studies with male rats and mice without safety margin. The testicular
changes were not fully recoverable during the off-dose periods evaluated. However no testicular
changes were observed in dog studies of up to 39 weeks duration at an exposure 35–fold that seen in
humans based on AUC. The effect of ambrisentan on male human fertility is not known.
Ambrisentan has been shown to be teratogenic in rats and rabbits. Abnormalities of the lower jaw,
tongue, and/or palate were seen at all doses tested. In addition, interventricular septal defects, trunk
vessel defects, thyroid and thymus abnormalities, ossification of the basisphenoid bone and increased
incidence of left umbilical artery were seen in the rat study. Teratogenicity is a suspected class effect
of ERAs.
Administration of ambrisentan to female rats from late-pregnancy through lactation caused adverse
events on maternal behaviour, reduced pup survival and impairment of the reproductive capability of
the offspring (with observation of small testes at necropsy), at exposure 3-fold the AUC at the
maximum recommended human dose.
6.
6.1 List of excipients
Tablet core
Lactose monohydrate
Microcrystalline cellulose
Croscarmellose sodium
Magnesium stearate
Film coat
Polyvinyl alcohol (Partially Hydrolysed)
Talc (E553b)
Titanium dioxide (E171)
Macrogol / PEG 3350
Lecithin (Soya) (E322)
Allura red AC Aluminium Lake (E129)
6.2 Incompatibilities
Not applicable.
26
6.3 Shelf life
2 years.
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5
Nature and contents of container
PVC/PVDC/aluminium foil blisters. Pack sizes of 10 or 30 film-coated tablets. Not all pack sizes may
be marketed.
6.6 Special precautions for disposal
No special requirements.
7.
Glaxo Group Ltd
Greenford
Middlesex
UB6 0NN
United Kingdom
8.
EU/1/08/451/003
EU/1/08/451/004
9.
Date of first authorisation: 21 April 2008
{MM/YYYY}
Detailed information on this product is available on the website of the European Medicines Agency
http://www.ema.europa.eu
.
27
ANNEX II
A.
MANUFACTURING AUTHORISATION HOLDER
RESPONSIBLE FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
28
A. MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer responsible for batch release
Glaxo Wellcome GmbH & Co. KG
Industriestrasse 32-36
D-23843 Bad Oldesloe
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
The MAH shall set up a post-marketing surveillance study as per the synopsis in the EU-Risk
Management Plan. Details of the implementation of the post-marketing surveillance study should be
agreed with the National Competent Authorities in each member state and put in place prior to
marketing of the product.
The MAH must agree the details of a controlled distribution system with the National Competent
Authorities and must implement such programme nationally to ensure that prior to prescribing (and
where appropriate and in agreement with the National Competent Authority, dispensing) all health
care professionals who intend to prescribe (and where appropriate, dispense) Volibris have been
provided with the following:
•
Product information (Summary of Product Characteristics (SPC) and Package Leaflet)
•
Healthcare professional information regarding Volibris
•
Pre-prescription checklist for physicians
•
Information about the post marketing surveillance study
•
Information booklets for patients
•
Information booklets for male partners of female patients with child-bearing potential
•
Patient reminder cards
•
Pregnancy reporting forms
•
Adverse drug reaction reporting forms
Health care Professional information
The healthcare professional information regarding Volibris should contain the following key elements:
Obligations of health care professionals in relation to the prescribing of Volibris:
•
That patients should be capable of complying with the requirements for the safe use of
Volibris.
•
The need to provide comprehensive advice and counselling to patients.
•
The need to provide patients with the appropriate information booklet(s) and patient reminder
card.
•
Should consider monthly prescription of 30 day supply to ensure that patients and key test
results are reviewed prior to further prescription.
29
•
That the safety database of Volibris is limited and physicians are encouraged to enrol patients
in a post marketing surveillance study.
•
To report suspected adverse reactions and pregnancy.
That Volibris is teratogenic
•
Volibris is contraindicated in pregnancy and in women of child-bearing potential who are not
using reliable contraception.
•
That women receiving Volibris should be advised of the risk of foetal harm.
•
Guidance for identifying women of child-bearing potential and the actions the physician
should take if unsure.
For women with child-bearing potential:
•
Exclusion of pregnancy prior to treatment initiation and monthly pregnancy testing during
treatment.
•
The need to advise women (even if a woman has amenorrhoea) on the use of reliable
contraception during treatment and for one month following permanent discontinuation of
treatment.
•
Definition of reliable contraception and the need to seek expert advice if unsure what is
suitable for an individual patient.
•
That if a woman of child-bearing potential needs to change or stop her method of
contraception she should inform the physician prescribing her contraception that she is taking
Volibris.
•
That if a women of child-bearing potential needs to change or stop her method of
contraception she should inform the physician prescribing Volibris.
•
That the patient should contact her doctor immediately if pregnancy is suspected and that
alternative therapy should be initiated if pregnancy confirmed.
•
The need to refer patients who become pregnant to a physician specialised or experienced in
teratology and its diagnosis for evaluation and advice.
•
To report all cases of pregnancy occurring during therapy.
That Volibris is potentially hepatotoxic
•
Contraindication in patients with severe hepatic impairment (with or without cirrhosis) and in
patients with baseline values of hepatic aminotransferases (AST and/or ALT)>3X ULN.
•
Hepatic aminotransferases (ALT and/or AST) should be evaluated prior to initiation of
ambrisentan.
•
During therapy, monthly monitoring of ALT and AST is recommended.
•
Discontinuation of ambrisentan therapy if patients develop sustained, unexplained clinically
significant ALT and/or AST elevation or if ALT and/or AST elevation is accompanied by
signs or symptoms of hepatic injury (e.g. jaundice).
•
In subjects without clinical symptoms of hepatic injury or jaundice, reinitiation of ambrisentan
may be considered following resolution of hepatic enzyme abnormalities. The advice of a
hepatologist is recommended.
That treatment with Volibris often causes a decrease in haemoglobin and haematocrit
•
Initiation of Volibris is not recommended for patients with clinically significant anaemia.
•
Patients taking Volibris should have their haemoglobin and/or haematocrit levels measured
regularly.
•
If tests show a clinically significant decrease in haemoglobin or haematocrit, and other causes
have been excluded, consider reducing the dose of Volibris, or stopping treatment.
That treatment with Volibris causes peripheral oedema and fluid retention
30
•
If a patient develops clinically significant peripheral oedema, with or without associated
weight gain, carry out further evaluation to determine the cause and if appropriate consider
discontinuation of Volibris.
That chronic administration of Volibris in animals has been linked to testicular tubular atrophy
and impaired fertility
. The effect of Volibris on human testicular function and male fertility is not
known.
That Volibris should be initiated with caution in patients with severe renal impairment.
That hypersensitivity reactions, although uncommon, have been reported with Volibris.
Physician checklist
The physician pre-prescription checklist will highlight the contraindications to the use of ambrisentan
and important pre-prescription assessments including:
•
Liver function tests.
•
Determination of child-bearing potential in female patients.
•
Pregnancy test if female patient with child-bearing potential.
•
That women of child-bearing potential are on reliable contraception.
Patient information
The information for patients should include the following information:
•
That Volibris may cause serious birth defects in unborn babies conceived before, during, or
within a month after stopping treatment.
•
That Volibris cannot be initiated if patient is pregnant.
•
Women with child-bearing potential must have a pregnancy test immediately prior to the first
prescription and at monthly intervals whilst taking Volibris.
•
The need to ensure that women of child-bearing potential are using reliable contraception and
that patients should inform their doctors of any possibility of pregnancy before a new
prescription is issued.
•
That if a women of child-bearing potential needs to change or stop her method of
contraception she should inform the physician prescribing her contraception that she is taking
Volibris.
•
That if a women of child-bearing potential needs to change or stop her method of
contraception she should inform the physician prescribing Volibris.
•
The need for female patients to contact their treating doctor immediately if they suspect that
they might be pregnant.
•
The need for the patient to discuss with her doctor if she is planning to become pregnant.
•
That Volibris may cause liver injury.
•
That because of the potential for liver injury and anaemia, patients should have regular blood
tests and also tell their doctor if experiencing any symptoms of liver injury.
•
That the patient should not give Volibris to any other person.
•
That the patient should tell their doctor about any adverse event.
Booklet for male partners of women with child-bearing potential
The information for male partners of women with child-bearing potential should include the following
information:
31
•
That Volibris may cause serious birth defects in unborn babies conceived before, during, or
within a month after stopping treatment.
•
The need to ensure that women of child-bearing potential are using reliable contraception.
•
That Volibris cannot be taken if a woman is or might become pregnant.
Patient reminder card
This should include key messages regarding the need for regular blood and pregnancy tests and
provide spaces for the dates of appointments and the results of tests.
•
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 3.1 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, any
updated RMP should be submitted at the same time as the following 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.
32
ANNEX III
LABELLING AND PACKAGE LEAFLET
33
A. LABELLING
34
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON
1.
Volibris 5 mg film-coated tablets
ambrisentan
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each tablet contains 5 mg ambrisentan
3.
LIST OF EXCIPIENTS
Contains lactose, lecithin (soya) (E322) and Allura red AC Aluminium Lake (E129). See leaflet for
further information
4.
10 film-coated tablets.
30 film-coated tablets.
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
For oral use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
35
9.
SPECIAL STORAGE CONDITIONS
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Glaxo Group Ltd
Greenford
Middlesex UB6 0NN
United Kingdom
EU/1/08/451/001
EU/1/08/451/002
13. BATCH NUMBER
LOT
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Volibris 5 mg
36
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON
1.
Volibris 10 mg film-coated tablets
ambrisentan
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each tablet contains 10 mg ambrisentan
3.
LIST OF EXCIPIENTS
Contains lactose, lecithin (soya) (E322) and Allura red AC Aluminium Lake (E129). See leaflet for
further information
4.
10 film-coated tablets.
30 film-coated tablets.
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
For oral use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
37
9.
SPECIAL STORAGE CONDITIONS
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Glaxo Group Ltd
Greenford
Middlesex UB6 0NN
United Kingdom
EU/1/08/451/003
EU/1/08/451/004
13. BATCH NUMBER
LOT
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Volibris 10 mg
38
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
Blister Pack
1.
Volibris 5 mg tablets
ambrisentan
2.
Glaxo Group Ltd
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
LOT
5.
OTHER
39
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
Blister Pack
1.
Volibris 10 mg tablets
ambrisentan
2.
Glaxo Group Ltd
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
LOT
5.
OTHER
40
B. PACKAGE LEAFLET
41
PACKAGE LEAFLET: INFORMATION FOR THE USER
Volibris 5 mg film-coated tablets
Volibris 10 mg film-coated tablets
ambrisentan
Read all of this leaflet carefully before you start taking this medicine.
•
Keep this leaflet. You may need to read it again.
•
If you have any further questions, ask your doctor or 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 pharmacist.
In this leaflet
:
1. What Volibris is and what it is used for
2. Before you take Volibris
3. How to take Volibris
4. Possible side effects
5.
How to store Volibris
6.
Further information
1.
WHAT VOLIBRIS IS AND WHAT IT IS USED FOR
Volibris is used to treat pulmonary arterial hypertension (PAH). PAH is high blood pressure in the
blood vessels (the pulmonary arteries) that carry blood from the heart to the lungs. In people with
PAH, these arteries get narrower, so the heart has to work harder to pump blood through them. This
causes people to feel tired, dizzy and short of breath.
Volibris widens the pulmonary arteries, making it easier for the heart to pump blood through them.
This lowers the blood pressure and relieves the symptoms.
2.
BEFORE YOU TAKE VOLIBRIS
Don't take Volibris:
•
if you are
allergic
(hypersensitive) to ambrisentan, soya, or any of the other ingredients of
Volibris (listed in Section 6).
•
if you are pregnant,
if you are
planning to become pregnant,
or if you
could become
pregnant
because you are not using reliable birth control (contraception). Please read the
information under ‘Pregnancy and Breast feeding’.
•
if you are
breast feeding
.
•
if you
have liver disease
. Talk to your doctor, who will decide whether Volibris is suitable for
you.
•
if you
are under 18 years old
.
If any of these apply to you:
→ Tell your doctor
and don’t take Volibris.
42
Take special care with Volibris:
•
if you have anaemia
(a reduced number of red blood cells).
→ Tell your doctor,
who will decide whether Volibris is suitable for you.
You will need regular blood tests
Before you start taking Volibris, and at regular intervals while you’re taking it, your doctor will take
blood tests to check:
•
whether you have anaemia (a reduced number of red blood cells)
•
whether your liver is working properly.
→
It is important that you have these regular blood tests for as long as you are taking Volibris.
Signs that your liver may not be working properly include:
•
loss of appetite
•
feeling sick (nausea)
•
being sick (vomiting)
•
high temperature (fever)
•
pain in your stomach (abdomen)
•
yellowing of your skin or the whites of your eyes (jaundice)
•
dark-coloured urine
•
itching of your skin.
If you notice any of these signs:
→ Tell your doctor immediately.
Taking other medicines
Tell your doctor or pharmacist if you’re taking any other medicines, if you’ve taken any
recently, or if you start taking new ones –
these include herbal medicines or other medicines you
bought without a prescription.
Your doctor may need to adjust your dose of Volibris if you start taking cyclosporine A (a medicine
used after transplant or to treat psoriasis).
→ Tell your doctor or pharmacist
if you are taking this.
Pregnancy
Volibris may harm unborn babies conceived before, during or soon after treatment.
→ If it is possible you could become pregnant, use a reliable form of birth control
(contraception)
while you’re taking Volibris. Talk to your doctor about this.
→ Don’t take Volibris if you are pregnant or planning to become pregnant.
→
If you become pregnant or think that you may be pregnant
while you’re taking Volibris,
see
your doctor immediately.
If you are a woman who could become pregnant, your doctor will ask you to take a pregnancy
test
before you start taking Volibris and regularly while you are taking Volibris.
43
If you are a man taking Volibris, it is possible that Volibris may lower your sperm count.
Talk to
your doctor if you have any questions or concerns about this.
Breast-feeding
It is not known if Volibris is transferred to breast milk.
→
Don’t breast feed while you're taking Volibris.
Talk to your doctor about this.
Driving and using machines
It is not known whether Volibris affects your ability to drive or use machines. However, it can cause
side effects such as headaches (listed in Section 4), and the symptoms of your condition can also make
you less fit to drive.
→ Don’t drive or operate machines if you’re feeling unwell.
Important information about some of the ingredients of Volibris
Volibris tablets contain small amounts of a sugar called lactose. If you have an intolerance to lactose
or any other sugars:
→ Contact your doctor
before taking Volibris.
Volibris tablets contain a colouring called Allura red AC Aluminium Lake (E129) which can cause
allergic reactions (see Section 4).
3.
HOW TO TAKE VOLIBRIS
Always take Volibris exactly as your doctor has told you to.
Check with your doctor or pharmacist
if you’re not sure.
How much Volibris to take
The usual dose of Volibris is one 5 mg tablet, once a day. Your doctor may decide to increase your
dose to 10 mg, once a day.
If you take cyclosporine A, do not take more than one 5 mg tablet of Volibris, once a day.
How to take Volibris
It is best to take your tablet at the same time each day. Swallow the tablet whole, with a glass of water,
do not chew or break the tablet. You can take Volibris with or without food.
Taking out a tablet
These tablets come in special packaging to prevent children removing them.
1.
Separate one tablet:
tear along the cutting lines to separate one “pocket” from the strip.
44
2. Peel back the outer layer:
starting at the coloured corner, lift and peel over the pocket.
3. Push out the tablet:
gently push one end of the tablet through the foil layer.
If you take more Volibris than you should
If you accidentally take too much Volibris:
→ Ask your doctor or pharmacist for advice.
If you forget to take Volibris
If you forget a dose of Volibris, just take the tablet as soon as you remember, then carry on as before.
Don’t take two doses at the same time to make up for a forgotten dose.
Don't stop taking Volibris without your doctor's advice.
Volibris is a treatment that you will need to keep on taking to control your PAH.
→Don’t stop taking Volibris unless you have agreed this with your doctor.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Volibris can cause side effects, although not everybody gets them.
Very common side effects
These may affect
more than one in 10
people:
•
swelling (oedema), especially of the ankles and feet. If you notice this side effect,
tell your
doctor
.
•
headache.
Common side effects
These may affect
up to one in 10
people:
•
anaemia (a reduced number of red blood cells), which can cause tiredness, weakness,
shortness of breath, and generally feeling unwell
•
a runny or blocked nose, congestion or pain in the sinuses
•
constipation
•
pain in your stomach (abdomen)
•
chest pain or discomfort
45
•
flushing (redness of the skin)
•
palpitations (fast or irregular heart beats)
•
abnormal blood test results for liver function.
Uncommon side effects
These may affect
up to one in 100
people:
•
Allergic reactions. You may notice a rash or itching and swelling (usually of the face, lips,
tongue or throat), which may cause difficulty in breathing or swallowing.
→
Tell your doctor straight away
if you get these effects or if they happen suddenly after taking
Volibris.
Some patients may have the following side effects:
•
heart failure (associated with swelling/fluid retention)
•
worsening shortness of breath shortly after starting Volibris.
•
fainting or dizziness
•
low blood pressure
•
feeling sick or being sick (nausea or vomiting)
•
diarrhoea
It is important to have regular blood tests
, to check for anaemia and that your liver is working
properly.
Make sure that you have also read the information in Section 2
under ‘You will need
regular blood tests’ and ‘Signs that your liver may not be working properly’.
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 pharmacist.
5.
HOW TO STORE VOLIBRIS
Keep out of the reach and sight of children.
Do not use Volibris after the expiry date which is stated on pack and blister.
The expiry date means the last day of the month shown.
This medicine does not require any special storage conditions.
Medicines should not be disposed of in wastewater or household waste. Ask your pharmacist how to
dispose of medicines you no longer require. These measures will help to protect the environment.
6.
FURTHER INFORMATION
What Volibris contains
The active substance is ambrisentan (5 mg or 10 mg).
The other ingredients are: lactose monohydrate, microcrystalline cellulose, croscarmellose sodium,
magnesium stearate, polyvinyl alcohol, talc (E553b), titanium dioxide (E171), macrogol/polyethylene
glycol 3350, lecithin (soya) (E322) and Allura red AC Aluminium Lake (E129).
46
What Volibris looks like and contents of the pack
Volibris 5 mg tablet is a pale pink, square, convex tablet engraved with ‘GS’ on one face and ‘K2C’
on the other.
Volibris 10 mg tablet is a deep pink, oval, convex tablet engraved with ‘GS’ on one face and ‘KE3’ on
the other.
Volibris is supplied as 5 mg and 10 mg film-coated tablets in blister packs of 10 or 30 tablets.
Not all pack sizes may be marketed.
Marketing Authorisation Holder
Glaxo Group Ltd
Greenford
Middlesex UB6 0NN
United Kingdom
Manufacturer
Glaxo Wellcome GmbH & Co. KG
Bad Oldesloe
Germany
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
België/Belgique/Belgien
GlaxoSmithKline s.a./n.v.
Tél/Tel: + 32 (0)2 656 21 11
Luxembourg/Luxemburg
GlaxoSmithKline s.a./n.v.
Belgique/Belgien
Tél/Tel: + 32 (0)2 656 21 11
България
ГлаксоСмитКлайн ЕООД
Teл.: + 359 2 953 10 34
Magyarország
GlaxoSmithKline Kft.
Tel.: + 36 1 225 5300
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
GlaxoSmithKline BV
Tel: + 31 (0)30 6938100
nlinfo@gsk.com
Deutschland
GlaxoSmithKline GmbH & Co. KG
Tel.: + 49 (0)89 36044 8701
produkt.info@gsk.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
47
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
GlaxoSmithKline, S.A.
Tel: + 34 902 202 700
es-ci@gsk.com
Portugal
GlaxoSmithKline – Produtos Farmacêuticos, Lda.
Tel: + 351 21 412 95 00
FI.PT@gsk.com
France
Laboratoire GlaxoSmithKline
Tél: + 33 (0)1 39 17 84 44
diam@gsk.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
GlaxoSmithKline S.p.A.
Tel: + 39 (0)45 9218 111
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
Latvija
GlaxoSmithKline Latvia SIA
Tel: + 371 67312687
lv-epasts@gsk.com
United Kingdom
GlaxoSmithKline UK
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 web site:
http://www.ema.europa.eu
. There are also links to other websites about rare diseases and treatments.
48
Source: European Medicines Agency
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