Ambrisentan Mylan

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
 
 



 

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1. NAME OF THE MEDICINAL PRODUCT 
 
Ambrisentan Mylan 5 mg film-coated tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each tablet contains 5 mg of ambrisentan. 
 
Excipients with known effect 
 
Each tablet contains approximately 26 mg of lactose and 10 micrograms of Allura red AC Aluminium 
lake 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Film-coated tablet (tablet) 
 
Pink, round, biconvex film-coated tablet with ‘M’ debossed on one side and ‘AN’ on the other, 
approximately 5.7 mm in diameter. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Ambrisentan Mylan is indicated for the treatment of pulmonary arterial hypertension (PAH) in adult 
patients of WHO Functional Class (FC) II to III, including use in combination treatment (see 
section 5.1). Efficacy has been shown in idiopathic PAH (IPAH) and in PAH associated with 
connective tissue disease. 
 
4.2 Posology and method of administration 
 
Treatment must be initiated by a physician experienced in the treatment of PAH. 
 
Posology 
 
Ambrisentan monotherapy 
 
Ambrisentan Mylan is to be taken orally to begin at a dose of 5 mg once daily and may be increased to 
10 mg daily depending upon clinical response and tolerability. 
 
Ambrisentan in combination with tadalafil 
 
When used in combination with tadalafil, Ambrisentan Mylan should be titrated to 10 mg once daily. 
 
In the AMBITION study, patients received 5 mg ambrisentan daily for the first 8 weeks before up 
titrating to 10 mg, dependent on tolerability (see section 5.1). When used in combination with tadalafil, 
patients were initiated with 5 mg ambrisentan and 20 mg tadalafil. Dependent on tolerability the dose 
of tadalafil was increased to 40 mg after 4 weeks and the dose of ambrisentan was increased to 10 mg 
after 8 weeks. More than 90% of patients achieved this. Doses could also be decreased depending on 
tolerability. 
 



 

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Limited data suggest that the abrupt discontinuation of ambrisentan 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). 
 
Special populations 
 
Elderly 
 
No dose adjustment is required in patients over the age of 65 (see section 5.2). 
 
Renal impairment 
 
No dose adjustment is required in patients with renal impairment (see section 5.2). There is limited 
experience with ambrisentan in individuals with severe renal impairment (creatinine clearance 
<30 ml/min); therapy should be initiated cautiously in this subgroup and particular care taken if the 
dose is increased to 10 mg ambrisentan. 
 
Hepatic impairment 
 
Ambrisentan has not been studied in individuals with 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 might be expected to increase exposure (Cmax 
and AUC) to ambrisentan. Therefore, ambrisentan must 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). 
 
Paediatric population 
 
The safety and efficacy of ambrisentan in children and adolescents aged below 18 years has not been 
established. No data are available (see section 5.3 regarding data available in juvenile animals). 
 
Method of administration 
 
It is recommended that the tablet is swallowed whole and it can be taken with or without food. It is 
recommended that the tablet should not be split, crushed or chewed. 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 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). 
 
Breast-feeding (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). 
 
Idiopathic pulmonary fibrosis (IPF), with or without secondary pulmonary hypertension (see 
section 5.1). 
 



 

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4.4 Special warnings and precautions for use 
 
Ambrisentan 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 ambrisentan 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. Cases consistent with autoimmune 
hepatitis, including possible exacerbation of underlying autoimmune hepatitis, hepatic injury and 
hepatic enzyme elevations potentially related to therapy have been observed with ambrisentan (see 
sections 4.8 and 5.1). Therefore, hepatic aminotransferases (ALT and AST) should be evaluated prior 
to initiation of ambrisentan and treatment should not be initiated in patients with baseline values of 
ALT and/or AST >3xULN (see section 4.3). 
 
Patients should be monitored for signs of hepatic injury and 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), ambrisentan therapy should be discontinued. 
 
In patients without clinical symptoms of hepatic injury or of jaundice, re-initiation of ambrisentan 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 endothelin 
receptor antagonists (ERAs) including ambrisentan. Most of these decreases were detected during the 
first 4 weeks of treatment and haemoglobin generally stabilised thereafter. Mean decreases from 
baseline (ranging from 0.9 to 1.2 g/dL) in haemoglobin concentrations persisted for up to 4 years of 
treatment with ambrisentan in the long-term open-label extension of the pivotal Phase 3 clinical 
studies. In the post-marketing period, cases of anaemia requiring blood cell transfusion have been 
reported (see section 4.8). 
 
Initiation of ambrisentan is not recommended for patients with clinically significant anaemia. It is 
recommended that haemoglobin and/or haematocrit levels are measured during treatment with 
ambrisentan, 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. The incidence of 
anaemia was increased when ambrisentan was dosed in combination with tadalafil (15% adverse event 
frequency), compared to the incidence of anaemia when ambrisentan and tadalafil were given as 
monotherapy (7% and 11%, respectively). 
 
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 may occur 
with greater frequency and severity in patients ≥65 years. Peripheral oedema was reported more 
frequently with 10 mg ambrisentan in short-term clinical studies (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. 



 

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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. The incidence of peripheral oedema was increased when ambrisentan was 
dosed in combination with tadalafil (45% adverse event frequency), compared to the incidence of 
peripheral oedema when ambrisentan and tadalafil were given as monotherapy (38% and 28%, 
respectively). The occurrence of peripheral oedema was highest within the first month of treatment 
initiation. 
 
Women of child-bearing potential 
 
Ambrisentan Mylan 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 ambrisentan are 
recommended (see sections 4.3 and 4.6). 
 
Pulmonary veno-occlusive disease 
 
Cases of pulmonary oedema have been reported with vasodilating medicinal products, such as ERAs, 
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. 
 
Concomitant use with other medicinal products 
 
Patients on ambrisentan therapy should be closely monitored when starting treatment with rifampicin 
(see sections 4.5 and 5.2). 
 
Excipients 
 
Ambrisentan Mylan 5 mg film-coated tablets contain lactose. Patients with rare hereditary problems of 
galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this 
medicinal product. 
 
Ambrisentan Mylan 5 mg film-coated tablets contain the azo-colouring agent Allura red AC 
Aluminium Lake (E129), which may cause allergic reactions. 
 
Ambrisentan Mylan 5 mg film-coated tablets contains less than 1 mmol sodium (23 mg) per tablet, that 
is to say essentially ‘sodium-free’ 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Ambrisentan does not inhibit or induce phase I or II drug metabolising 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 metabolised 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. 
 
Cyclosporine A 
 
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 



 

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(see section 4.2). Multiple doses of ambrisentan had no effect on cyclosporine A exposure, and no 
dose adjustment of cyclosporine A is warranted. 
 
Rifampicin 
 
Co-administration of rifampicin (an inhibitor of Organic Anion Transporting Polypeptide [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). 
 
Phosphodiesterase inhibitors 
 
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). 
 
Other targeted PAH treatments 
 
The efficacy and safety of ambrisentan when co-administered with other treatments for PAH (e.g. 
prostanoids and soluble guanylate cyclase stimulators) has not been specifically studied in controlled 
clinical trials in PAH patients (see section 5.1). No specific drug-drug interactions with soluble 
guanylate cyclase stimulators or prostanoids are anticipated based on the known biotransformation 
data (see section 5.2). However, no specific drug-drug interactions studies have been conducted with 
these active substances. Therefore, caution is recommended in the case of co-administration. 
 
Oral contraceptives 
 
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. 
 
Warfarin 
 
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 
normalised ratio (INR). 
 
Ketoconazole 
 
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). 
 
Effect of ambrisentan on xenobiotic transporters 
 
In vitro, ambrisentan has no inhibitory effect on human transporters at clinically relevant 
concentrations, including the P-glycoprotein (Pgp), breast cancer resistance protein (BCRP), multi-
drug resistance related protein 2 (MRP2), bile salt export pump (BSEP), organic anion transporting 
polypeptides (OATP1B1 and OATP1B3) and the sodium-dependent taurocholate co-transporting 
polypeptide (NTCP). 
 



 

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Ambrisentan is a substrate for Pgp-mediated efflux. 
 
In vitro studies in rat hepatocytes also showed that ambrisentan did not induce Pgp, BSEP or MRP2 
protein expression. 
 
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). 
 
4.6 Fertility, pregnancy and lactation 
 
Women of childbearing potential 
 
Ambrisentan 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 ambrisentan are recommended. 
 
Pregnancy 
 
Ambrisentan is contraindicated in pregnancy (see section 4.3). Animal studies have shown that 
ambrisentan is teratogenic. There is no experience in humans. 
 
Women receiving ambrisentan 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). 
 
Breast-feeding 
 
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 breast-feeding is contraindicated in patients taking 
ambrisentan (see section 4.3). 
 
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). Although no clear evidence of a 
detrimental effect of ambrisentan long-term exposure on sperm count was found in ARIES-E study, 
chronic administration of ambrisentan was associated with changes in markers of spermatogenesis. A 
decrease in plasma inhibin-B concentration and an increase in plasma FSH concentration were 
observed. The effect on male human fertility is not known but a deterioration of spermatogenesis 
cannot be excluded. Chronic administration of ambrisentan was not associated with a change in plasma 
testosterone in clinical studies. 
 
4.7 Effects on ability to drive and use machines 
 
Ambrisentan has minor or moderate influence on the ability to drive and use machines. The clinical 
status of the patient and the adverse reaction profile of ambrisentan (such as hypotension, dizziness, 
asthenia, fatigue) should be borne in mind when considering the patient's ability to perform tasks that 
require judgement, motor or cognitive skills (see section 4.8). Patients should be aware of how they 
might be affected by ambrisentan before driving or using machines. 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
 
The safety of ambrisentan has been evaluated as monotherapy and/or in combination in clinical trials 
of more than 1,200 patients with PAH (see section 5.1). Adverse reactions identified from 12-week 
placebo-controlled clinical trial data are included below by system organ class and frequency. 
Information from longer term non-placebo-controlled studies (ARIES-E and AMBITION 



 

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(combination with tadalafil)) is also included below. No previously unknown adverse reactions were 
identified with long-term treatment or for ambrisentan in combination with tadalafil. With longer 
observation in uncontrolled studies (mean observation of 79 weeks), the safety profile was similar to 
that observed in the short- term studies. Routine pharmacovigilance data are also presented. 
 
Peripheral oedema, fluid retention and headache (including sinus headache, migraine) were the most 
common adverse reactions observed with ambrisentan. The higher dose (10 mg) was associated with a 
higher incidence of these adverse reactions, and peripheral oedema tended to be more severe in 
patients ≥65 years in short-term clinical studies (see section 4.4). 
 
Tabulated list of adverse reactions 
 
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) and not known (cannot be estimated 
from available data). For dose-related adverse reactions the frequency category reflects the higher dose 
of ambrisentan. 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, adverse reactions are presented in 
order of decreasing seriousness. 
 
 Ambrisentan (ARIES-C and post 

marketing) 
Ambrisentan 
(AMBITION 
and ARIES-E) 

Combination 
with tadalafil 
(AMBITION) 

Blood and lymphatic system disorders 
Anaemia (decreased 
haemoglobin, decreased 
haematocrit) 

Common1 Very common Very common 

 
Immune system disorders  
Hypersensitivity 
reactions (e.g. 
angioedema, rash, 
pruritus) 

Uncommon Common Common 

 
Nervous system disorders 
Headache (including 
sinus headache, 
migraine) 

Very common2 Very common Very common 

Dizziness Common3 Very common Very common
 
Eye disorders  
Blurred vision, visual 
impairment 

Not known4 Common Common 

 
Ear and labyrinth disorders  
Tinnitus NR NR Common
Sudden hearing loss NR NR Uncommon
 
Cardiac disorders  
Cardiac failure Common5 Common Common
Palpitation Common Very common Very common
 



 

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 Ambrisentan (ARIES-C and post 
marketing) 

Ambrisentan 
(AMBITION 
and ARIES-E) 

Combination 
with tadalafil 
(AMBITION) 

Vascular disorders  
Hypotension Common3 Common Common
Flushing Common Common Very common
Syncope Uncommon3 Common Common
 
Respiratory, thoracic and mediastinal disorders 
Epistaxis Common3 Common Common
Dyspnoea Common3,6 Very common Very common
Upper respiratory (e.g. 
nasal, sinus) congestion, 
sinusitis, 
nasopharyngitis, rhinitis

Common7   

Nasopharyngitis  Very common Very common
Sinusitis, rhinitis  Common Common
Nasal congestion  Very common Very common
 
Gastrointestinal disorders 
Nausea, vomiting, 
diarrhoea 

Common3   

Nausea  Very common Very common
Vomiting  Common Very common
Diarrhoea  Very common Very common
Abdominal pain Common Common Common
Constipation Common Common Common
 
Hepatobiliary disorders 
Hepatic injury (see 
section 4.4) 

Uncommon3, 8 NR NR 

Autoimmune hepatitis 
(see section 4.4) 

Uncommon3, 8 NR NR 

Hepatic transaminases 
increased 

Common3 NR NR 

 
Skin and subcutaneous tissue disorders 
Rash NR Common9 Common9

 
General disorders and administration site conditions 
Peripheral oedema, fluid 
retention 

Very common Very common Very common 

Chest pain/discomfort Common Common Very common
Asthenia Common3 Common Common
Fatigue Common3 Very common Very common
NR – not reported 
1 See section ‘Description of selected adverse reactions’. 
2 The frequency of headache appeared higher with 10 mg ambrisentan. 
3 Data derived from routine pharmacovigilance surveillance and frequencies based on placebo 

controlled clinical trial experience. 



 

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4 Data derived from routine pharmacovigilance surveillance 
5 Most of the reported cases of cardiac failure were associated with fluid retention. Data derived from 

routine pharmacovigilance surveillance, frequencies based on statistical modelling of placebo 
controlled clinical trial data. 

6 Cases of worsening dyspnoea of unclear aetiology have been reported shortly after starting 
ambrisentan therapy. 

7 The incidence of nasal congestion was dose related during ambrisentan therapy. 
8 Cases of autoimmune hepatitis, including cases of exacerbation of autoimmune hepatitis, and 

hepatic injury have been reported during ambrisentan therapy. 
9 Rash includes rash erythematous, rash generalised, rash papular and rash pruritic 
 
Description of selected adverse reactions 
 
Decreased haemoglobin 
 
In the post-marketing period, cases of anaemia requiring blood cell transfusion have been reported (see 
section 4.4). The frequency of decreased haemoglobin (anaemia) was higher with 10 mg ambrisentan. 
Across the 12 week placebo controlled Phase 3 clinical studies, mean haemoglobin concentrations 
decreased for patients in the ambrisentan groups and were detected as early as week 4 (decrease by 
0.83 g/dL); mean changes from baseline appeared to stabilise over the subsequent 8 weeks. A total of 
17 patients (6.5%) in the ambrisentan treatment groups had decreases in haemoglobin of ≥15% from 
baseline and which fell below the lower limit of normal. 
 
Reporting of suspected adverse reactions 
 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
There is no experience in PAH patients of ambrisentan 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 ambrisentan 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. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Anti-hypertensives, other anti-hypertensives, ATC code: C02KX02 
 
Mechanism of action 
 
Ambrisentan is an orally active, propanoic acid-class, ERA selective for the endothelin A (ETA) 
receptor. Endothelin plays a significant role in the pathophysiology of PAH. 
 
Ambrisentan is a potent (Ki 0.016 nM) and highly selective ETA antagonist (approximately 4000-fold 
more selective for ETA as compared to ETB). 
Ambrisentan blocks the ETA 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. 



 

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The selectivity of ambrisentan for the ETA over the ETB receptor is expected to retain ETB receptor 
mediated production of the vasodilators nitric oxide and prostacyclin. 
 
Clinical efficacy and safety 
 
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 ambrisentan 5 mg and 
10 mg with placebo. ARIES-2 included 192 patients and compared ambrisentan 2.5 mg and 5 mg with 
placebo. In both studies, ambrisentan 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 (PAH-CTD). 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 ambrisentan resulted in a significant improvement in 6MWD for each dose of ambrisentan. 
 
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, ambrisentan (combined dose group) significantly delayed the time to clinical worsening 
of PAH compared to placebo (p<0.001), the hazard ratio demonstrated an 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 ambrisentan 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 combined mean exposure was approximately 145 ± 80 weeks, and the 
maximum exposure was approximately 295 weeks. The main primary endpoints of this study were the 
incidence and severity of adverse events associated with long-term exposure to ambrisentan, including 
serum LFTs. The safety findings observed with long-term ambrisentan exposure in this study were 
generally consistent with those observed in the 12 week placebo-controlled studies. 
 
The observed probability of survival for subjects receiving ambrisentan (combined ambrisentan dose 
group) at 1, 2 and 3 years was 93%, 85% and 79% respectively. 
 
In an open label study (AMB222), ambrisentan 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 
ambrisentan, 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 
ambrisentan during this time. 
 



 

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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 
ambrisentan. In the ARIES-E open label long term extension study, the 2 year risk of developing 
serum aminotransferase elevations >3xULN in patients treated with ambrisentan was 3.9%. 
 
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 ambrisentan resulted in an increase in mean 
cardiac index, a decrease in mean pulmonary artery pressure, and a decrease in mean pulmonary 
vascular resistance. 
 
Decrease in systolic and diastolic blood pressures has been reported with ambrisentan therapy. In 
placebo controlled clinical trials of 12 weeks duration mean reduction in systolic and diastolic blood 
pressures from base line to end of treatment were 3 mm Hg and 4.2 mm Hg respectively. The mean 
decreases in systolic and diastolic blood pressures persisted for up to 4 years of treatment with 
ambrisentan in the long-term open label ARIES E study. 
 
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 ambrisentan 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. 
 
Clinical efficacy in combination with tadalafil 
 
A multicentre, double-blind, active comparator, event-driven, Phase 3 outcome study 
(AMB112565/AMBITION) was conducted to assess the efficacy of initial combination of ambrisentan 
and tadalafil vs. monotherapy of either ambrisentan or tadalafil alone, in 500 treatment naive PAH 
patients, randomised 2:1:1, respectively. No patients received placebo alone. The primary analysis was 
combination group vs. pooled monotherapy groups. Supportive comparisons of combination therapy 
group vs. the individual monotherapy groups were also made. Patients with significant anaemia, fluid 
retention or rare retinal diseases were excluded according to the investigators' criteria. Patients with 
ALT and AST values >2xULN at baseline were also excluded. 
 
At baseline, 96% of patients were naive to any previous PAH-specific treatment, and the median time 
from diagnosis to entry into the study was 22 days. Patients started on ambrisentan 5 mg and tadalafil 
20 mg and were titrated to 40 mg tadalafil at week 4 and 10 mg ambrisentan at week 8, unless there 
were tolerability issues. The median double-blind treatment duration for combination therapy was 
greater than 1.5 years. 
 
The primary endpoint was the time to first occurrence of a clinical failure event, defined as: 
– death, or 
– hospitalisation for worsening PAH, 
– disease progression;   
– unsatisfactory long-term clinical response. 
 
The mean age of all patients was 54 years (SD 15; range 18–75 years of age). Patients WHO FC at 
baseline was II (31%) and FC III (69%). Idiopathic or heritable PAH was the most common aetiology 
in the study population (56%), followed by PAH due to connective tissue disorders (37%), PAH 
associated with medicines and toxins (3%), corrected simple congenital heart disease (2%), and HIV 
(2%). Patients with WHO FC II and III had a mean baseline 6MWD of 353 metres. 
 



 

13 

Outcome endpoints 
 
Treatment with combination therapy resulted in a 50% risk reduction (hazard ratio [HR] 0.502; 
95% CI: 0.348 to 0.724; p=0.0002) of the composite clinical failure endpoint up to final assessment 
visit when compared to the pooled monotherapy group [Figure 1 and Table 1]. The treatment effect 
was driven by a 63% reduction in hospitalisations on combination therapy, was established early and 
was sustained. Efficacy of combination therapy on the primary endpoint was consistent on the 
comparison to individual monotherapy and across the subgroups of age, ethnic origin, geographical 
region, aetiology (iPAH/hPAH and PAH-CTD). The effect was significant for both FC II and FC III 
patients. 
 
Figure 1 
 

 
 



 

14 

Table 1 
 

 Ambrisentan + Tadalafil 
Monotherapy 
Pooled 

Ambrisentan 
monotherapy 

Tadalafil 
monotherapy 

 (N=253) (N=247) (N=126) (N=121) 
Time to First Clinical Failure Event (Adjudicated)   
Clinical failure, no. 
(%)   46 (18%) 77 (31%) 43 (34) 34 (28) 

Hazard ratio 
(95% CI)  

0.502 
(0.348, 0.724)

0.477 
(0.314, 0.723)

0.528 
(0.338, 0.827)

P-value, Log-rank 
test  0.0002 0.0004 0.0045 

Component as First Clinical Failure Event (Adjudicated)   
Death (all-cause) 9 (4%) 8 (3%) 2 (2) 6 (5) 
Hospitalisation for 
worsening PAH 10 (4%) 30 (12%) 18 (14) 12 (10) 

Disease 
progression 10 (4%) 16 (6%) 12 (10) 4 (3) 

Unsatisfactory 
long-term clinical 
response 

17 (7%) 23 (9%) 11 (9) 12 (10) 

Time to First Hospitalisation for Worsening PAH (Adjudicated)   
First 
hospitalisation, 
no. (%) 

19 (8%) 44 (18%) 27 (21%) 17 (14%) 

Hazard ratio 
(95% CI)  0.372 0.323 0.442 

P-value, Log-rank 
test  0.0002 <0.0001 0.0124 

 
Secondary endpoints 
 
Secondary endpoints were tested: 
 
Table 2 
 
Secondary Endpoints 
(change from baseline to 
week 24) 

Ambrisentan + 
Tadalafil 

Monotherapy 
pooled 

Difference and 
Confidence 
Interval

p-value 

NT-proBNP 
(% reduction) -67.2 -50.4 

% difference -
33.8; 
95% CI:   
-44.8, -20.7

p<0.0001 

  
% subjects achieving a 
satisfactory clinical 
response at week 24 

39 29 
Odds ratio 1.56; 
95% CI: 1.05, 
2.32 

p=0.026 

6MWD (metres, median 
change) 49.0 23.8 

22.75m; 95% CI: 
12.00, 33.50 p<0.0001 

 



 

15 

Idiopathic Pulmonary Fibrosis 
 
A study of 492 patients (ambrisentan N=329, placebo N=163) with idiopathic pulmonary fibrosis (IPF), 
11% of which had secondary pulmonary hypertension (WHO group 3), has been conducted, but was 
terminated early when it was determined that the primary efficacy endpoint could not be met 
(ARTEMIS-IPF study). Ninety events (27%) of IPF progression (including respiratory 
hospitalisations) or death were observed in the ambrisentan group compared to 28 events (17%) in the 
placebo group. Ambrisentan is therefore contraindicated for patients with IPF with or without 
secondary pulmonary hypertension (see section 4.3). 
 
5.2 Pharmacokinetic properties 
 
Absorption 
 
Ambrisentan is absorbed rapidly in humans. After oral administration, maximum plasma 
concentrations (Cmax) of ambrisentan typically occur around 1.5 hours post-dose under both fasted and 
fed conditions. Cmax 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 Cmax 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 alpha1-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. 
 
Biotransformation 
 
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 
parent ambrisentan), 4-hydroxymethyl ambrisentan is not expected to contribute to pharmacological 
activity of ambrisentan. 
 
In vitro data indicate that ambrisentan at 300 μM resulted in less than 50% inhibition of UGT1A1, 
UGT1A6, UGT1A9, UGT2B7 (up to 30%) or of cytochrome P450 enzymes 1A2, 2A6, 2B6, 2C8, 2C9, 
2C19, 2D6, 2E1 and 3A4 (up to 25%). In vitro, ambrisentan has no inhibitory effect on human 
transporters at clinically relevant concentrations, including Pgp, BCRP, MRP2, BSEP, OATP1B1, 
OATP1B3 and NTCP. Furthermore, ambrisentan did not induce MRP2, Pgp or BSEP protein 
expression in rat hepatocytes. Taken together, the in vitro data suggest ambrisentan at clinically 
relevant concentrations (plasma Cmax up to 3.2 μM) would not be expected to have an effect on 
UGT1A1, UGT1A6, UGT1A9, UGT2B7 or cytochrome P450 enzymes 1A2, 2A6, 2B6, 2C8, 2C9, 
2C19, 2D6, 2E1, 3A4 or transport via BSEP, BCRP, Pgp, MRP2, OATP1B1/3, or NTCP. 
 



 

16 

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 Cmax 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 Cmax 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 Cmax were increased by 35% and 20%, respectively. This change in 
exposure is unlikely to be of any clinical relevance and therefore ambrisentan 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 Cmax 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 AUC0-last and trough concentrations, and a 29% increase in digoxin Cmax. The increase in 
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 Cmax 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). 
 



 

17 

Elimination 
 
Ambrisentan and its metabolites are eliminated primarily in the bile following hepatic and/or 
extrahepatic 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 might be expected to increase exposure (Cmax 
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 hepatic impairment (with or without cirrhosis) has 
not been studied. Therefore, ambrisentan 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 
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. 
 



 

18 

There was no evidence of carcinogenic potential in 2 year oral studies in rats and mice. There was a 
small increase in mammary fibroadenomas, a benign tumor, in male rats at the highest dose only. 
Systemic exposure to ambrisentan in male rats at this dose (based on steady-state AUC) was 6-fold 
that achieved at the 10 mg/day clinical dose. 
 
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. In male rats, there were no effects of ambrisentan on sperm motility at all 
doses tested (up to 300 mg/kg/day). A slight (<10%) decrease in the percentage of morphologically 
normal sperms was noted at 300 mg/kg/day but not at 100 mg/kg/day (>9-fold clinical exposure at 
10 mg/day). 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, the rat study showed an increased 
incidence of interventricular septal defects, trunk vessel defects, thyroid and thymus abnormalities, 
ossification of the basisphenoid bone, and the occurrence of the umbilical artery located on the left 
side of the urinary bladder instead of the right side. 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. 
 
In juvenile rats administered ambrisentan orally once daily during postnatal day 7 to 26, 36 or 62, a 
decrease in brain weight (−3% to -8%) with no morphologic or neurobehavioral changes occurred after 
breathing sounds, apnoea and hypoxia were observed. These effects occurred at exposures 
approximately 1.8 to 7 times human paediatric exposures at 10 mg (age 9 to 15 years), based on AUC. 
The clinical relevance of this finding to the paediatric population is not fully understood. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Tablet core 
Lactose 
Microcrystalline cellulose (E460i) 
Croscarmellose sodium 
Magnesium stearate (E570) 
 
Film coat 
Poly(vinyl alcohol)(partly hydrolysed) 
Titanium dioxide (E171) 
Macrogol 
Talc (E553b) 
Allura red AC Aluminium Lake (E129) 
Indigo Carmine Aluminium Lake (E132). 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
3 years 



 

19 

 
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 blisters 
Pack sizes of 30 film-coated tablets and unit dose blisters of 30x1 or 60x1 film-coated tablets 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal and other handling 
 
Any unused medicinal product or waste material should be disposed of in accordance with the local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Mylan S.A.S. 
117 Allée des Parcs  
69800 Saint-Priest 
France 
  
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/19/1368/001 
EU/1/19/1368/002 
EU/1/19/1368/005 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 
Date of latest renewal: 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 
 



 

20 

1. NAME OF THE MEDICINAL PRODUCT 
 
Ambrisentan Mylan 10 mg film-coated tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each tablet contains 10 mg of ambrisentan. 
 
Excipients with known effect 
 
Each tablet contains approximately 52 mg of lactose and 20 micrograms of Allura red AC Aluminium 
lake 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Film-coated tablet (tablet) 
 
Pink, capsule shaped, biconvex film-coated tablet with ‘M’ debossed on one side and ‘AN1’ on the 
other, approximately 9.9 mm long and 4.8 mm wide. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Ambrisentan Mylan is indicated for the treatment of pulmonary arterial hypertension (PAH) in adult 
patients of WHO Functional Class (FC) II to III, including use in combination treatment (see 
section 5.1). Efficacy has been shown in idiopathic PAH (IPAH) and in PAH associated with 
connective tissue disease. 
 
4.2 Posology and method of administration 
 
Treatment must be initiated by a physician experienced in the treatment of PAH. 
 
Posology 
 
Ambrisentan monotherapy 
 
Ambrisentan Mylan is to be taken orally to begin at a dose of 5 mg once daily and may be increased to 
10 mg daily depending upon clinical response and tolerability. 
 
Ambrisentan in combination with tadalafil 
 
When used in combination with tadalafil, Ambrisentan Mylan should be titrated to 10 mg once daily. 
 
In the AMBITION study, patients received 5 mg ambrisentan daily for the first 8 weeks before up 
titrating to 10 mg, dependent on tolerability (see section 5.1). When used in combination with tadalafil, 
patients were initiated with 5 mg ambrisentan and 20 mg tadalafil. Dependent on tolerability the dose 
of tadalafil was increased to 40 mg after 4 weeks and the dose of ambrisentan was increased to 10 mg 
after 8 weeks. More than 90% of patients achieved this. Doses could also be decreased depending on 
tolerability. 
 



 

21 

Limited data suggest that the abrupt discontinuation of ambrisentan 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). 
 
Special populations 
 
Elderly 
 
No dose adjustment is required in patients over the age of 65 (see section 5.2). 
 
Renal impairment 
 
No dose adjustment is required in patients with renal impairment (see section 5.2). There is limited 
experience with ambrisentan in individuals with severe renal impairment (creatinine clearance 
<30 ml/min); therapy should be initiated cautiously in this subgroup and particular care taken if the 
dose is increased to 10 mg ambrisentan. 
 
Hepatic impairment 
 
Ambrisentan has not been studied in individuals with 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 might be expected to increase exposure (Cmax 
and AUC) to ambrisentan. Therefore, ambrisentan must 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). 
 
Paediatric population 
 
The safety and efficacy of ambrisentan in children and adolescents aged below 18 years has not been 
established. No data are available (see section 5.3 regarding data available in juvenile animals). 
 
Method of administration 
 
It is recommended that the tablet is swallowed whole and it can be taken with or without food. It is 
recommended that the tablet should not be split, crushed or chewed. 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 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). 
 
Breast-feeding (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). 
 
Idiopathic pulmonary fibrosis (IPF), with or without secondary pulmonary hypertension (see 
section 5.1). 
 



 

22 

4.4 Special warnings and precautions for use 
 
Ambrisentan 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 ambrisentan 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. Cases consistent with autoimmune 
hepatitis, including possible exacerbation of underlying autoimmune hepatitis, hepatic injury and 
hepatic enzyme elevations potentially related to therapy have been observed with ambrisentan (see 
sections 4.8 and 5.1). Therefore, hepatic aminotransferases (ALT and AST) should be evaluated prior 
to initiation of ambrisentan and treatment should not be initiated in patients with baseline values of 
ALT and/or AST >3xULN (see section 4.3). 
 
Patients should be monitored for signs of hepatic injury and 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), ambrisentan therapy should be discontinued. 
 
In patients without clinical symptoms of hepatic injury or of jaundice, re-initiation of ambrisentan 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 endothelin 
receptor antagonists (ERAs) including ambrisentan. Most of these decreases were detected during the 
first 4 weeks of treatment and haemoglobin generally stabilised thereafter. Mean decreases from 
baseline (ranging from 0.9 to 1.2 g/dL) in haemoglobin concentrations persisted for up to 4 years of 
treatment with ambrisentan in the long-term open-label extension of the pivotal Phase 3 clinical 
studies. In the post-marketing period, cases of anaemia requiring blood cell transfusion have been 
reported (see section 4.8). 
 
Initiation of ambrisentan is not recommended for patients with clinically significant anaemia. It is 
recommended that haemoglobin and/or haematocrit levels are measured during treatment with 
ambrisentan, 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. The incidence of 
anaemia was increased when ambrisentan was dosed in combination with tadalafil (15% adverse event 
frequency), compared to the incidence of anaemia when ambrisentan and tadalafil were given as 
monotherapy (7% and 11%, respectively). 
 
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 may occur 
with greater frequency and severity in patients ≥65 years. Peripheral oedema was reported more 
frequently with 10 mg ambrisentan in short-term clinical studies (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. 



 

23 

 
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. The incidence of peripheral oedema was increased when ambrisentan was 
dosed in combination with tadalafil (45% adverse event frequency), compared to the incidence of 
peripheral oedema when ambrisentan and tadalafil were given as monotherapy (38% and 28%, 
respectively). The occurrence of peripheral oedema was highest within the first month of treatment 
initiation. 
 
Women of child-bearing potential 
 
Ambrisentan Mylan 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 ambrisentan are 
recommended (see sections 4.3 and 4.6). 
 
Pulmonary veno-occlusive disease 
 
Cases of pulmonary oedema have been reported with vasodilating medicinal products, such as ERAs, 
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. 
 
Concomitant use with other medicinal products 
 
Patients on ambrisentan therapy should be closely monitored when starting treatment with rifampicin 
(see sections 4.5 and 5.2). 
 
Excipients 
 
Ambrisentan Mylan 10 mg film-coated tablets contain lactose. Patients with rare hereditary problems 
of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take 
this medicinal product. 
 
Ambrisentan Mylan 10 mg film-coated tablets contain the azo-colouring agent Allura red AC 
Aluminium Lake (E129), which may cause allergic reactions. 
 
Ambrisentan Mylan 10 mg film-coated tablets contains less than 1 mmol sodium (23 mg) per tablet, 
that is to say essentially ‘sodium-free’ 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Ambrisentan does not inhibit or induce phase I or II drug metabolising 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 metabolised 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. 
 
Cyclosporine A 
 
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 



 

24 

(see section 4.2). Multiple doses of ambrisentan had no effect on cyclosporine A exposure, and no 
dose adjustment of cyclosporine A is warranted. 
 
Rifampicin 
 
Co-administration of rifampicin (an inhibitor of Organic Anion Transporting Polypeptide [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). 
 
Phosphodiesterase inhibitors 
 
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). 
 
Other targeted PAH treatments 
 
The efficacy and safety of ambrisentan when co-administered with other treatments for PAH (e.g. 
prostanoids and soluble guanylate cyclase stimulators) has not been specifically studied in controlled 
clinical trials in PAH patients (see section 5.1). No specific drug-drug interactions with soluble 
guanylate cyclase stimulators or prostanoids are anticipated based on the known biotransformation 
data (see section 5.2). However, no specific drug-drug interactions studies have been conducted with 
these active substances. Therefore, caution is recommended in the case of co-administration. 
 
Oral contraceptives 
 
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. 
 
Warfarin 
 
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 
normalised ratio (INR). 
 
Ketoconazole 
 
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). 
 
Effect of ambrisentan on xenobiotic transporters 
 
In vitro, ambrisentan has no inhibitory effect on human transporters at clinically relevant 
concentrations, including the P-glycoprotein (Pgp), breast cancer resistance protein (BCRP), multi-
drug resistance related protein 2 (MRP2), bile salt export pump (BSEP), organic anion transporting 
polypeptides (OATP1B1 and OATP1B3) and the sodium-dependent taurocholate co-transporting 
polypeptide (NTCP). 
 



 

25 

Ambrisentan is a substrate for Pgp-mediated efflux. 
 
In vitro studies in rat hepatocytes also showed that ambrisentan did not induce Pgp, BSEP or MRP2 
protein expression. 
 
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). 
 
4.6 Fertility, pregnancy and lactation 
 
Women of childbearing potential 
 
Ambrisentan 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 ambrisentan are recommended. 
 
Pregnancy 
 
Ambrisentan is contraindicated in pregnancy (see section 4.3). Animal studies have shown that 
ambrisentan is teratogenic. There is no experience in humans. 
 
Women receiving ambrisentan 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). 
 
Breast-feeding 
 
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 breast-feeding is contraindicated in patients taking 
ambrisentan (see section 4.3). 
 
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). Although no clear evidence of a 
detrimental effect of ambrisentan long-term exposure on sperm count was found in ARIES-E study, 
chronic administration of ambrisentan was associated with changes in markers of spermatogenesis. A 
decrease in plasma inhibin-B concentration and an increase in plasma FSH concentration were 
observed. The effect on male human fertility is not known but a deterioration of spermatogenesis 
cannot be excluded. Chronic administration of ambrisentan was not associated with a change in plasma 
testosterone in clinical studies. 
 
4.7 Effects on ability to drive and use machines 
 
Ambrisentan has minor or moderate influence on the ability to drive and use machines. The clinical 
status of the patient and the adverse reaction profile of ambrisentan (such as hypotension, dizziness, 
asthenia, fatigue) should be borne in mind when considering the patient's ability to perform tasks that 
require judgement, motor or cognitive skills (see section 4.8). Patients should be aware of how they 
might be affected by ambrisentan before driving or using machines. 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
 
The safety of ambrisentan has been evaluated as monotherapy and/or in combination in clinical trials 
of more than 1,200 patients with PAH (see section 5.1). Adverse reactions identified from 12 week 
placebo controlled clinical trial data are included below by system organ class and frequency. 
Information from longer term non-placebo-controlled studies (ARIES-E and AMBITION 



 

26 

(combination with tadalafil)) is also included below. No previously unknown adverse reactions were 
identified with long-term treatment or for ambrisentan in combination with tadalafil. With longer 
observation in uncontrolled studies (mean observation of 79 weeks), the safety profile was similar to 
that observed in the short- term studies. Routine pharmacovigilance data are also presented. 
 
Peripheral oedema, fluid retention and headache (including sinus headache, migraine) were the most 
common adverse reactions observed with ambrisentan. The higher dose (10 mg) was associated with a 
higher incidence of these adverse reactions, and peripheral oedema tended to be more severe in 
patients ≥65 years in short-term clinical studies (see section 4.4). 
 
Tabulated list of adverse reactions 
 
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) and not known (cannot be estimated 
from available data). For dose-related adverse reactions the frequency category reflects the higher dose 
of ambrisentan. 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, adverse reactions are presented in 
order of decreasing seriousness. 
 
 Ambrisentan (ARIES-C and post 

marketing) 
Ambrisentan 
(AMBITION 
and ARIES-E) 

Combination 
with tadalafil 
(AMBITION) 

Blood and lymphatic system disorders 
Anaemia (decreased 
haemoglobin, decreased 
haematocrit) 

Common1 Very common Very common 

 
Immune system disorders  
Hypersensitivity 
reactions (e.g. 
angioedema, rash, 
pruritus) 

Uncommon Common Common 

 
Nervous system disorders 
Headache (including 
sinus headache, 
migraine) 

Very common2 Very common Very common 

Dizziness Common3 Very common Very common
 
Eye disorders  
Blurred vision, visual 
impairment 

Not known4 Common Common 

 
Ear and labyrinth disorders  
Tinnitus NR NR Common
Sudden hearing loss NR NR Uncommon
 
Cardiac disorders  
Cardiac failure Common5 Common Common
Palpitation Common Very common Very common
 



 

27 

 Ambrisentan (ARIES-C and post 
marketing) 

Ambrisentan 
(AMBITION 
and ARIES-E) 

Combination 
with tadalafil 
(AMBITION) 

Vascular disorders  
Hypotension Common3 Common Common
Flushing Common Common Very common
Syncope Uncommon3 Common Common
 
Respiratory, thoracic and mediastinal disorders 
Epistaxis Common3 Common Common
Dyspnoea Common3,6 Very common Very common
Upper respiratory (e.g. 
nasal, sinus) congestion, 
sinusitis, 
nasopharyngitis, rhinitis

Common7   

Nasopharyngitis  Very common Very common
Sinusitis, rhinitis  Common Common
Nasal congestion  Very common Very common
 
Gastrointestinal disorders 
Nausea, vomiting, 
diarrhoea 

Common3   

Nausea  Very common Very common
Vomiting  Common Very common
Diarrhoea  Very common Very common
Abdominal pain Common Common Common
Constipation Common Common Common
 
Hepatobiliary disorders 
Hepatic injury (see 
section 4.4) 

Uncommon3, 8 NR NR 

Autoimmune hepatitis 
(see section 4.4) 

Uncommon3, 8 NR NR 

Hepatic transaminases 
increased 

Common3 NR NR 

 
Skin and subcutaneous tissue disorders 
Rash NR Common9 Common9

 
General disorders and administration site conditions 
Peripheral oedema, fluid 
retention 

Very common Very common Very common 

Chest pain/discomfort Common Common Very common
Asthenia Common3 Common Common
Fatigue Common3 Very common Very common
NR – not reported 
1 See section ‘Description of selected adverse reactions’. 
2 The frequency of headache appeared higher with 10 mg ambrisentan. 
3 Data derived from routine pharmacovigilance surveillance and frequencies based on placebo 

controlled clinical trial experience. 



 

28 

4 Data derived from routine pharmacovigilance surveillance 
5 Most of the reported cases of cardiac failure were associated with fluid retention. Data derived from 

routine pharmacovigilance surveillance, frequencies based on statistical modelling of placebo 
controlled clinical trial data. 

6 Cases of worsening dyspnoea of unclear aetiology have been reported shortly after starting 
ambrisentan therapy. 

7 The incidence of nasal congestion was dose related during ambrisentan therapy. 
8 Cases of autoimmune hepatitis, including cases of exacerbation of autoimmune hepatitis, and 

hepatic injury have been reported during ambrisentan therapy. 
9 Rash includes rash erythematous, rash generalised, rash papular and rash pruritic 
 
Description of selected adverse reactions 
 
Decreased haemoglobin 
 
In the post-marketing period, cases of anaemia requiring blood cell transfusion have been reported (see 
section 4.4). The frequency of decreased haemoglobin (anaemia) was higher with 10 mg ambrisentan. 
Across the 12 week placebo-controlled Phase 3 clinical studies, mean haemoglobin concentrations 
decreased for patients in the ambrisentan groups and were detected as early as week 4 (decrease by 
0.83 g/dL); mean changes from baseline appeared to stabilise over the subsequent 8 weeks. A total of 
17 patients (6.5%) in the ambrisentan treatment groups had decreases in haemoglobin of ≥15% from 
baseline and which fell below the lower limit of normal. 
 
Reporting of suspected adverse reactions 
 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
There is no experience in PAH patients of ambrisentan 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 ambrisentan 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. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Anti-hypertensives, other anti-hypertensives, ATC code: C02KX02 
 
Mechanism of action 
 
Ambrisentan is an orally active, propanoic acid-class, ERA selective for the endothelin A (ETA) 
receptor. Endothelin plays a significant role in the pathophysiology of PAH. 
 
Ambrisentan is a potent (Ki 0.016 nM) and highly selective ETA antagonist (approximately 4000-fold 
more selective for ETA as compared to ETB). 
Ambrisentan blocks the ETA 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. 



 

29 

The selectivity of ambrisentan for the ETA over the ETB receptor is expected to retain ETB receptor 
mediated production of the vasodilators nitric oxide and prostacyclin. 
 
Clinical efficacy and safety 
 
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 ambrisentan 5 mg and 
10 mg with placebo. ARIES-2 included 192 patients and compared ambrisentan 2.5 mg and 5 mg with 
placebo. In both studies, ambrisentan 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 (PAH-CTD). 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 6minute walk distance (6MWD) at 12 weeks. In both studies, treatment 
with ambrisentan resulted in a significant improvement in 6MWD for each dose of ambrisentan. 
 
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, ambrisentan (combined dose group) significantly delayed the time to clinical worsening 
of PAH compared to placebo (p<0.001), the hazard ratio demonstrated an 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 ambrisentan 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 combined mean exposure was approximately 145 ± 80 weeks, and the 
maximum exposure was approximately 295 weeks. The main primary endpoints of this study were the 
incidence and severity of adverse events associated with long-term exposure to ambrisentan, including 
serum LFTs. The safety findings observed with long-term ambrisentan exposure in this study were 
generally consistent with those observed in the 12 week placebo-controlled studies. 
 
The observed probability of survival for subjects receiving ambrisentan (combined ambrisentan dose 
group) at 1, 2 and 3 years was 93%, 85% and 79% respectively. 
 
In an open label study (AMB222), ambrisentan 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 
ambrisentan, 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 
ambrisentan during this time. 
 



 

30 

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 
ambrisentan. In the ARIES-E open label long term extension study, the 2 year risk of developing 
serum aminotransferase elevations >3xULN in patients treated with ambrisentan was 3.9%. 
 
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 ambrisentan resulted in an increase in mean 
cardiac index, a decrease in mean pulmonary artery pressure, and a decrease in mean pulmonary 
vascular resistance. 
 
Decrease in systolic and diastolic blood pressures has been reported with ambrisentan therapy. In 
placebo controlled clinical trials of 12 weeks duration mean reduction in systolic and diastolic blood 
pressures from base line to end of treatment were 3 mm Hg and 4.2 mm Hg respectively. The mean 
decreases in systolic and diastolic blood pressures persisted for up to 4 years of treatment with 
ambrisentan in the long-term open label ARIES E study. 
 
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 ambrisentan 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. 
 
Clinical efficacy in combination with tadalafil 
 
A multicentre, double-blind, active comparator, event-driven, Phase 3 outcome study 
(AMB112565/AMBITION) was conducted to assess the efficacy of initial combination of ambrisentan 
and tadalafil vs. monotherapy of either ambrisentan or tadalafil alone, in 500 treatment naive PAH 
patients, randomised 2:1:1, respectively. No patients received placebo alone. The primary analysis was 
combination group vs. pooled monotherapy groups. Supportive comparisons of combination therapy 
group vs. the individual monotherapy groups were also made. Patients with significant anaemia, fluid 
retention or rare retinal diseases were excluded according to the investigators' criteria. Patients with 
ALT and AST values >2xULN at baseline were also excluded. 
 
At baseline, 96% of patients were naive to any previous PAH-specific treatment, and the median time 
from diagnosis to entry into the study was 22 days. Patients started on ambrisentan 5 mg and tadalafil 
20 mg and were titrated to 40 mg tadalafil at week 4 and 10 mg ambrisentan at week 8, unless there 
were tolerability issues. The median double-blind treatment duration for combination therapy was 
greater than 1.5 years. 
 
The primary endpoint was the time to first occurrence of a clinical failure event, defined as: 
– death, or 
– hospitalisation for worsening PAH, 
– disease progression;   
– unsatisfactory long-term clinical response. 
 
The mean age of all patients was 54 years (SD 15; range 18–75 years of age). Patients WHO FC at 
baseline was II (31%) and FC III (69%). Idiopathic or heritable PAH was the most common aetiology 
in the study population (56%), followed by PAH due to connective tissue disorders (37%), PAH 
associated with medicines and toxins (3%), corrected simple congenital heart disease (2%), and HIV 
(2%). Patients with WHO FC II and III had a mean baseline 6MWD of 353 metres. 
 



 

31 

Outcome endpoints 
 
Treatment with combination therapy resulted in a 50% risk reduction (hazard ratio [HR] 0.502; 
95% CI: 0.348 to 0.724; p=0.0002) of the composite clinical failure endpoint up to final assessment 
visit when compared to the pooled monotherapy group [Figure 1 and Table 1]. The treatment effect 
was driven by a 63% reduction in hospitalisations on combination therapy, was established early and 
was sustained. Efficacy of combination therapy on the primary endpoint was consistent on the 
comparison to individual monotherapy and across the subgroups of age, ethnic origin, geographical 
region, aetiology (iPAH/hPAH and PAH-CTD). The effect was significant for both FC II and FC III 
patients. 
 
Figure 1 
 

 
 



 

32 

Table 1 
 

 Ambrisentan + Tadalafil 
Monotherapy 
Pooled 

Ambrisentan 
monotherapy 

Tadalafil 
monotherapy 

 (N=253) (N=247) (N=126) (N=121) 
Time to First Clinical Failure Event (Adjudicated)   
Clinical failure, 
no. (%)   46 (18%) 77 (31%) 43 (34) 34 (28) 

Hazard ratio 
(95% CI)  

0.502 
(0.348, 0.724)

0.477 
(0.314, 0.723)

0.528 
(0.338, 0.827)

P-value, Log-rank 
test  0.0002 0.0004 0.0045 

Component as First Clinical Failure Event (Adjudicated)   
Death (all-cause) 9 (4%) 8 (3%) 2 (2) 6 (5) 
Hospitalisation for 
worsening PAH 10 (4%) 30 (12%) 18 (14) 12 (10) 

Disease 
progression 10 (4%) 16 (6%) 12 (10) 4 (3) 

Unsatisfactory 
long-term clinical 
response 

17 (7%) 23 (9%) 11 (9) 12 (10) 

Time to First Hospitalisation for Worsening PAH (Adjudicated)   
First 
hospitalisation, no 
(%)   

19 (8%) 44 (18%) 27 (21%) 17 (14%) 

Hazard ratio 
(95% CI)  0.372 0.323 0.442 

P-value, Log-rank 
test  0.0002 <0.0001 0.0124 

 
Secondary endpoints 
 
Secondary endpoints were tested: 
 
Table 2 
 
Secondary Endpoints 
(change from baseline to 
week 24) 

Ambrisentan + 
Tadalafil 

Monotherapy 
pooled 

Difference and 
Confidence 
Interval

p-value 

NT-proBNP 
(% reduction) −67.2 −50.4 

% difference -
33.8; 95% 
CI: -44.8, -20.7 

p<0.0001 

  
% subjects achieving a 
satisfactory clinical 
response at week 24 

39 29 
Odds ratio 1.56; 
95% 
CI: 1.05, 2.32 

p=0.026 

6MWD (metres, median 
change) 49.0 23.8 

22.75 m; 95% 
CI: 12.00, 33.50 p<0.0001 

 
Idiopathic Pulmonary Fibrosis 
 
A study of 492 patients (ambrisentan N=329, placebo N=163) with idiopathic pulmonary fibrosis (IPF), 
11% of which had secondary pulmonary hypertension (WHO group 3), has been conducted, but was 



 

33 

terminated early when it was determined that the primary efficacy endpoint could not be met 
(ARTEMIS-IPF study). Ninety events (27%) of IPF progression (including respiratory 
hospitalisations) or death were observed in the ambrisentan group compared to 28 events (17%) in the 
placebo group. Ambrisentan is therefore contraindicated for patients with IPF with or without 
secondary pulmonary hypertension (see section 4.3). 
 
5.2 Pharmacokinetic properties 
 
Absorption 
 
Ambrisentan is absorbed rapidly in humans. After oral administration, maximum plasma 
concentrations (Cmax) of ambrisentan typically occur around 1.5 hours post-dose under both fasted and 
fed conditions. Cmax 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 Cmax 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 alpha1-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. 
 
Biotransformation 
 
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 
parent ambrisentan), 4-hydroxymethyl ambrisentan is not expected to contribute to pharmacological 
activity of ambrisentan. 
 
In vitro data indicate that ambrisentan at 300 μM resulted in less than 50% inhibition of UGT1A1, 
UGT1A6, UGT1A9, UGT2B7 (up to 30%) or of cytochrome P450 enzymes 1A2, 2A6, 2B6, 2C8, 2C9, 
2C19, 2D6, 2E1 and 3A4 (up to 25%). In vitro, ambrisentan has no inhibitory effect on human 
transporters at clinically relevant concentrations, including Pgp, BCRP, MRP2, BSEP, OATP1B1, 
OATP1B3 and NTCP. Furthermore, ambrisentan did not induce MRP2, Pgp or BSEP protein 
expression in rat hepatocytes. Taken together, the in vitro data suggest ambrisentan at clinically 
relevant concentrations (plasma Cmax up to 3.2 μM) would not be expected to have an effect on 
UGT1A1, UGT1A6, UGT1A9, UGT2B7 or cytochrome P450 enzymes 1A2, 2A6, 2B6, 2C8, 2C9, 
2C19, 2D6, 2E1, 3A4 or transport via BSEP, BCRP, Pgp, MRP2, OATP1B1/3, or NTCP. 
 
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 



 

34 

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 Cmax 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 Cmax 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 Cmax were increased by 35% and 20%, respectively. This change in 
exposure is unlikely to be of any clinical relevance and therefore ambrisentan 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 Cmax 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 AUC0-last and trough concentrations, and a 29% increase in digoxin Cmax. The increase in 
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 Cmax 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 
extrahepatic metabolism. Approximately 22% of the administered dose is recovered in the urine 



 

35 

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 might be expected to increase exposure (Cmax 
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 hepatic impairment (with or without cirrhosis) has 
not been studied. Therefore, ambrisentan 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 
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 was no evidence of carcinogenic potential in 2 year oral studies in rats and mice. There was a 
small increase in mammary fibroadenomas, a benign tumor, in male rats at the highest dose only. 
Systemic exposure to ambrisentan in male rats at this dose (based on steady-state AUC) was 6-fold 
that achieved at the 10 mg/day clinical dose. 



 

36 

 
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. In male rats, there were no effects of ambrisentan on sperm motility at all 
doses tested (up to 300 mg/kg/day). A slight (<10%) decrease in the percentage of morphologically 
normal sperms was noted at 300 mg/kg/day but not at 100 mg/kg/day (>9-fold clinical exposure at 
10 mg/day). 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, the rat study showed an increased 
incidence of interventricular septal defects, trunk vessel defects, thyroid and thymus abnormalities, 
ossification of the basisphenoid bone, and the occurrence of the umbilical artery located on the left 
side of the urinary bladder instead of the right side. 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. 
 
In juvenile rats administered ambrisentan orally once daily during postnatal day 7 to 26, 36 or 62, a 
decrease in brain weight (−3% to -8%) with no morphologic or neurobehavioral changes occurred after 
breathing sounds, apnoea and hypoxia were observed. These effects occurred at exposures 
approximately 1.8 to 7 times human paediatric exposures at 10 mg (age 9 to 15 years), based on AUC. 
The clinical relevance of this finding to the paediatric population is not fully understood. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Tablet core 
Lactose 
Microcrystalline cellulose (E460i) 
Croscarmellose sodium 
Magnesium stearate (E570) 
 
Film coat 
Poly(vinyl alcohol) (partly hydrolysed) 
Titanium dioxide (E171) 
Macrogol 
Talc (E553b) 
Allura red AC Aluminium Lake (E129) 
Indigo Carmine Aluminium Lake (E132). 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
3 years 
 
6.4 Special precautions for storage 
 
This medicinal product does not require any special storage conditions. 



 

37 

 
6.5 Nature and contents of container 
 
PVC/PVdC blisters 
Pack sizes of 30 film-coated tablets and unit dose blisters of 30x1 or 60x1 film-coated tablets 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal and other handling 
 
Any unused medicinal product or waste material should be disposed of in accordance with the local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Mylan S.A.S. 
117 Allée des Parcs  
69800 Saint-Priest 
France 
  
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/19/1368/003 
EU/1/19/1368/004 
EU/1/19/1368/006 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 
Date of latest renewal: 
 
10. DATE OF REVISION OF THE TEXT 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 
 



 

38 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE 
 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
AUTHORISATION 

 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
 



 

39 

A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer(s) responsible for batch release 
 
Generics (UK) Limited, 
Potters Bar, 
Hertfordshire, 
EN6 1TL, 
United Kingdom 
 
or 
 
McDermott Laboratories t/a Gerard Laboratories, 
35/36 Baldoyle Industrial Estate, 
Grange Road, 
Dublin 13, 
Ireland 
 
or 
 
Mylan Hungary Kft, Mylan utca 1, 
2900 Komárom, 
Hungary 
 
The printed package leaflet of the medicinal product must state the name and address of the 
manufacturer responsible for the release of the concerned batch. 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2) 
 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
 Periodic Safety Update Reports 
 
The requirements for submission of periodic safety update reports for this medicinal product are set 
out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 
2001/83/EC and any subsequent updates published on the European medicines web-portal. 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
 Risk Management Plan (RMP) 
 
The MAH shall perform the required pharmacovigilance activities and interventions detailed in the 
agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent 
updates of the RMP. 
 
An updated RMP should be submitted: 

 At the request of the European Medicines Agency; 



 

40 

 Whenever the risk management system is modified, especially as the result of new information 
being received that may lead to a significant change to the benefit/risk profile or as the result of 
an important (pharmacovigilance or risk minimisation) milestone being reached. 

 
 Additional risk minimisation measures 
 
The MAH will agree the distribution plan with the National Competent Authorities before the product 
launch in each territory and will ensure that all patients taking Ambrisentan Mylan have been provided 
with the relevant educational materials. 
 

 Patient Reminder Card 
 
Patient reminder card should include the following messages 

 That Ambrisentan Mylan is teratogenic in animals 
 That pregnant women must not take Ambrisentan Mylan 
 That women of reproductive potential must use effective contraception 
 The need for monthly pregnancy tests 
 The need for regular monitoring of liver function because Ambrisentan Mylan may cause liver 

injury. 
 



 

41 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
 
 



 

42 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 
 
 



 

43 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Ambrisentan Mylan 5 mg film-coated tablets 
 
ambrisentan 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 5 mg ambrisentan 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose and Allura red AC Aluminium Lake (E129). See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
30 film-coated tablets 
30x1 film-coated tablets. 
60x1 film-coated tablets. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
 



 

44 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Mylan S.A.S. 
117 Allée des Parcs  
69800 Saint-Priest 
France  
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/19/1368/001  
EU/1/19/1368/002  
EU/1/19/1368/005 
  
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
 
15. INSTRUCTIONS ON USE 
 
 
 
16. INFORMATION IN BRAILLE 
 
Ambrisentan Mylan 5 mg film-coated tablets 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 
 



 

45 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Ambrisentan Mylan 10 mg film-coated tablets 
 
ambrisentan 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 10 mg ambrisentan 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose and Allura red AC Aluminium Lake (E129). See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
30 film-coated tablets 
30x1 film-coated tablets. 
60x1 film-coated tablets. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
 



 

46 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Mylan S.A.S. 
117 Allée des Parcs  
69800 Saint-Priest 
France  
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/19/1368/003  
EU/1/19/1368/004  
EU/1/19/1368/006 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
 
15. INSTRUCTIONS ON USE 
 
 
 
16. INFORMATION IN BRAILLE 
 
Ambrisentan Mylan 10 mg film-coated tablets 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 
 



 

47 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
Blisters 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Ambrisentan Mylan 5 mg film-coated tablets 
 
ambrisentan 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Mylan S.A.S 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
 
 



 

48 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
Blisters 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Ambrisentan Mylan 10 mg film-coated tablets 
 
ambrisentan 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Mylan S.A.S 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
 
 



 

49 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 
 
 



 

50 

Package leaflet: Information for the user 
 

Ambrisentan Mylan 5 mg film-coated tablets 
Ambrisentan Mylan 10 mg film-coated tablets 

 
ambrisentan 

 
Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you. 
– Keep this leaflet. You may need to read it again. 
– If you have any further questions, ask your doctor, pharmacist or nurse. 
– This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 
– If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible 

side effects not listed in this leaflet. See section 4. 
 
 
What is in this leaflet 
 
1. What Ambrisentan Mylan is and what it is used for 
2. What you need to know before you take Ambrisentan Mylan 
3. How to take Ambrisentan Mylan 
4. Possible side effects 
5. How to store Ambrisentan Mylan 
6. Contents of the pack and other information 
 
 
1. What Ambrisentan Mylan is and what it is used for 
 
Ambrisentan Mylan contains the active substance ambrisentan. It belongs to a group of medicines 
called other antihypertensives (used to treat high blood pressure). 
 
It is used to treat pulmonary arterial hypertension (PAH) in adults. 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. 
 
Ambrisentan Mylan widens the pulmonary arteries, making it easier for the heart to pump blood 
through them. 
This lowers the blood pressure and relieves the symptoms. 
 
Ambrisentan Mylan may also be used in combination with other medicines used to treat PAH. 
 
 
2. What you need to know before you take Ambrisentan Mylan 
 
Do not take Ambrisentan Mylan: 
– if you are allergic to ambrisentan or any of the other ingredients of this medicine (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’ 

– if you are breast feeding. Read the information under ‘Breast-feeding’ 
– if you have liver disease. Talk to your doctor, who will decide whether this medicine is suitable 

for you 
– if you have scarring of the lungs, of unknown cause (idiopathic pulmonary fibrosis). 
 



 

51 

Warnings and precautions 
 
Talk to your doctor, pharmacist or nurse before taking this medicine if you have: 
 liver problems 
 anaemia (a reduced number of red blood cells) 
 swelling in the hands, ankles or feet caused by fluid (peripheral oedema) 
 lung disease where the veins in the lungs are blocked (pulmonary veno-occlusive disease). 
 
Your doctor will decide whether Ambrisentan Mylan is suitable for you. 
 
You will need regular blood tests 
Before you start taking Ambrisentan Mylan, and at regular intervals while you’re taking it, your doctor 
will take blood tests to check: 
 
 whether you have anaemia 
 whether your liver is working properly. 
 
→ It is important that you have these regular blood tests for as long as you are taking Ambrisentan 
Mylan. 
 
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. 
 
Children and adolescents 
 
Ambrisentan Mylan is not recommended for children and adolescents aged under 18 years as the 
safety and effectiveness is not known in this age group. 
 
Other medicines and Ambrisentan Mylan 
 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. 
 
Your doctor may need to adjust your dose of Ambrisentan Mylan if you start taking cyclosporine A (a 
medicine used after transplant or to treat psoriasis). 
 
If you’re taking rifampicin (an antibiotic used to treat serious infections) your doctor will monitor you 
when you first start taking Ambrisentan Mylan. 
 
If you’re taking other medicines used to treat PAH (e.g. iloprost, epoprostenol, sildenafil) your doctor 
may need to monitor you. 
 
→ Tell your doctor or pharmacist if you are taking any of these medicines. 
 



 

52 

Pregnancy 
 
Ambrisentan Mylan 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 Ambrisentan Mylan. Talk to your doctor about this. 
 
→ Don’t take Ambrisentan Mylan if you are pregnant or planning to become pregnant. 
 
→ If you become pregnant or think that you may be pregnant while you’re taking Ambrisentan 
Mylan, 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 Ambrisentan Mylan and regularly while you are taking this medicine. 
 
Breast-feeding 
 
It is not known if Ambrisentan Mylan is transferred to breast milk. 
 
→ Don’t breast-feed while you’re taking Ambrisentan Mylan. Talk to your doctor about this. 
 
Fertility 
 
If you are a man taking Ambrisentan Mylan, it is possible that this medicine may lower your sperm 
count. Talk to your doctor if you have any questions or concerns about this. 
 
Driving and using machines 
 
Ambrisentan Mylan may cause side effects, such as low blood pressure, dizziness, tiredness (see 
section 4), that may affect your ability to drive or use machines. The symptoms of your condition can 
also make you less fit to drive or use machines. 
 
→ Don’t drive or use machines if you’re feeling unwell. 
 
Ambrisentan Mylan tablets contains lactose and Allura red (E129) 
 
Ambrisentan Mylan tablets contain small amounts of a sugar called lactose. If you have been told by 
your doctor that you have an intolerance to some sugars: 
 
→ Contact your doctor before taking this medicinal product. 
 
Ambrisentan Mylan tablets contain a colouring agent called Allura red AC Aluminium Lake (E129) 
which may cause allergic reactions. 
 
This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-
free’. 
 
 
3. How to take Ambrisentan Mylan 
 
Always take this medicine exactly as your doctor or pharmacist has told you. Check with your 
doctor or pharmacist if you are not sure. 
 
How much Ambrisentan Mylan to take 
The usual dose of Ambrisentan Mylan is one 5 mg tablet, once a day. Your doctor may decide to 
increase your dose to 10 mg, once a day. 
 



 

53 

If you take cyclosporine A, do not take more than one 5 mg tablet of Ambrisentan Mylan once a day. 
 
How to take Ambrisentan Mylan 
It is best to take your tablet at the same time each day. Swallow the tablet whole, with a glass of water, 
do not split, crush or chew the tablet. You can take Ambrisentan Mylan with or without food. 
 
If you take more Ambrisentan Mylan than you should 
If you take too many tablets you may be more likely to have side effects, such as headache, flushing, 
dizziness, nausea (feeling sick), or low blood pressure that could cause light-headedness: 
 
→ Ask your doctor or pharmacist for advice if you take more tablets than prescribed. 
 
If you forget to take Ambrisentan Mylan 
If you forget a dose of Ambrisentan Mylan, 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 Ambrisentan Mylan without your doctor’s advice 
Ambrisentan Mylan is a treatment that you will need to keep on taking to control your PAH. 
 
→Don’t stop taking Ambrisentan Mylan unless you have agreed this with your doctor. 
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Conditions you and your doctor need to look out for: 
 
Allergic reactions 
 
This is a common side effect that may affect up to one in 10 people. 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. 
 
Swelling (oedema), especially of the ankles and feet 
 
This is a very common side effect that may affect more than one in 10 people. 
 
Heart failure 
 
This is due to the heart not pumping out enough blood, causing shortness of breath, extreme tiredness 
and swelling in the ankles and legs. This is a common side effect that may affect up to one in 10 
people. 
 
Anaemia (reduced number of red blood cells) 
 
This is a blood disorder which can cause tiredness, weakness, shortness of breath, and generally 
feeling unwell. Sometimes this requires a blood transfusion. This is a very common side effect that 
may affect more than one in 10 people 
 
Hypotension (low blood pressure) 
 
This can cause light-headedness. This is a common side effect that may affect up to one in 10 people. 



 

54 

 
→ Tell your doctor straight away if you get these effects or if they happen suddenly after taking 
Ambrisentan Mylan. 
 
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’. 
 
Other side effects include 
 
Very common side effects: 
 
 headache 
 dizziness 
 palpitations (fast or irregular heart-beats) 
 worsening shortness of breath shortly after starting Ambrisentan Mylan 
 a runny or blocked nose, congestion or pain in the sinuses 
 feeling sick (nausea) 
 diarrhoea 
 feeling tired 
 
In combination with tadalafil (another PAH medicine) in addition to the above: 
 
 flushing (redness of the skin) 
 being sick (vomiting) 
 chest pain/discomfort. 
 
Common side effects: 
 
 blurry or other changes to vision 
 fainting 
 abnormal blood test results for liver function 
 a runny nose 
 constipation 
 pain in your stomach (abdomen) 
 chest pain or discomfort 
 flushing (redness of the skin) 
 being sick (vomiting) 
 feeling weak 
 nose bleed 
 rash 
 
In combination with tadalafil 
 
In addition to the above, except abnormal blood test results for liver function: 
 ringing in the ears (tinnitus) only when taking the combination treatment. 
 
Uncommon side effects: 
 
 liver injury 
 inflammation of the liver caused by the body’s own defences (autoimmune hepatitis) 
 
In combination with tadalafil 
 
 sudden hearing loss. 



 

55 

 
Reporting of side effects 
 
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 
effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V. By reporting side effects you can help provide more information on the 
safety of this medicine. 
 
 
5. How to store Ambrisentan Mylan 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the carton after EXP. 
 
The expiry date refers to the last day of that month. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Ambrisentan Mylan contains 
 
The active substance is ambrisentan. 
Each film-coated tablet contains 5 mg or 10 mg. 
 
The other ingredients are lactose, see section 2, ‘Ambrisentan Mylan contains lactose’, 
microcrystalline cellulose (E460i), sodium croscarmellose, magnesium stearate (E570), polyvinyl 
alcohol part hydrolysed, titanium dioxide (E171), macrogol/PEG, talc (E553b), Allura red (E129), see 
section 2 ‘Ambrisentan Mylan contains Allura red (E129)’, Indigo carmine (E132) 
 
What Ambrisentan Mylan looks like and contents of the pack 
 
Ambrisentan Mylan 5 mg film-coated tablet (tablet) is a pink round biconvex tablet engraved with ‘M’ 
on one side and ‘AN’ on the other side. 
 
Ambrisentan Mylan 10 mg film-coated tablet (tablet) is a pink, capsule shaped tablet engraved with 
‘M’ on one side of the tablet and ‘AN1’ on the other side. 
 
Ambrisentan Mylan is supplied as 5 mg and 10 mg film-coated tablets in packs of 30 tablets and unit 
dose blister packs of 30x1 tablets or 60 x1 tablets. 
 
Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder 
 
Mylan S.A.S. 
117 Allée des Parcs 
69800 Saint-Priest 
France 
 
Manufacturer 
 
Generics (UK) Limited, Potters Bar, Hertfordshire, EN6 1TL, United Kingdom 
 



 

56 

McDermott Laboratories t/a Gerard Laboratories, 35/36 Baldoyle Industrial Estate, Grange Road, 
Dublin 13, Ireland 
 
Mylan Hungary Kft, Mylan utca 1, 2900 Komárom, Hungary 
 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien 
Mylan bvba/sprl 
Tél/Tel: + 32 (0)2 658 61 00 
 

Lietuva 
BGP Products UAB 
Tel: +370 5 205 1288 

България 
Майлан ЕООД 
Тел: +359 2 44 55 400 
 

Luxembourg/Luxemburg 
Mylan bvba/sprl 
Tel: + 32 (0)2 658 61 00 
(Belgique/Belgien) 

Česká republika 
Mylan Healthcare CZ  
s.r.o. 
Tel: + 420 222 004 400 
 

Magyarország 
Mylan EPD Kft 
Tel: + 36 1 465 2100 
 

Danmark 
Mylan Denmark ApS 
 
Tlf: + 45 28116932 
 

Malta 
V.J. Salomone Pharma Ltd 
Tel: + 356 21 22 01 74 
 

Deutschland 
Mylan Healthcare GmbH 
Tel: + 49 800 0700 800 
 

Nederland 
Mylan BV 
Tel: +31 (0)20 426 3300 

Eesti 
BGP Products Switzerland GmbH Eesti filiaal 
Tel: + 372 6363 052 
 

Norge 
Mylan Healthcare Norge AS 
Tel: + 47 66 75 33 00 

Ελλάδα 
Generics Pharma Hellas ΕΠΕ 
Τηλ: +30 210 993 6410 
 

Österreich 
Arcana Arzneimittel GmbH 
Tel: +43 1 416 2418 

España 
Mylan Pharmaceuticals, S.L 
Tel: + 34 900 102 712 
 

Polska 
Mylan Healthcare Sp. z.o.o. 
Tel: + 48 22 546 64 00 

France 
Mylan S.A.S 
Tél : +33 4 37 25 75 00 
 

Portugal 
Mylan, Lda. 
Tel: + 351 21 412 72 56 

Hrvatska 
Mylan Hrvatska d.o.o. 
Tel: +385 1 23 50 599 
 
Ireland 
Mylan Ireland Limited 
Tel:  +353 (0) 87 1694982 

România 
BGP Products SRL 
Tel: +40 372 579 000  
 
Slovenija 
Mylan Healthcare d.o.o. 
Tel: + 386 1 236 31 80 



 

57 

Ísland 
Icepharma hf 
Tel: +354 540 8000 
 
 

Slovenská republika 
Mylan s.r.o. 
Tel: +421 2 32 199 100 
 

Italia 
Mylan Italia S.r.l. 
Tel: + 39 02 612 46921 
 

Suomi/Finland 
Mylan Finland OY 
Puh/Tel: +358 20 720 9555 

Κύπρος 
Varnavas Hadjipanayis Ltd  
. 
Τηλ: +357 2220 7723 
 

Sverige 
Mylan AB  
Tel: + 46 855 522 750 
 

Latvija 
Mylan Healthcare SIA   
Tel: +371 676 055 80 
 

United Kingdom 
Generics [UK] Ltd 
Tel: +44 1707 853000 

 
 
This leaflet was last revised in. 
 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. 
 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETINGAUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE ANDEFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET