45

46

CONTENTS

PREFACE

1. A BRIEF OVERVIEW OF PULMONARY ARTERIAL HYPERTENSION . . . . . . . . . . . . . . . . . . . . . 2

2. BIOLOGY OF THE ET SYSTEM . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

ET Biosynthesis

ET-Receptors

ETA- versus ETB-mediated eff ects

ET-Receptor Selectivity and its Vasoconstriction and Vasodilation Eff ects

ET-Receptor Selectivity and Fibrosis

3. CHEMISTRY OF AMBRISENTAN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

4. PHARMACODYNAMIC PROPERTIES OF AMBRISENTAN . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

5. PHARMACOKINETIC PROPERTIES OF AMBRISENTAN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

6. CLINICAL EFFICACY OF AMBRISENTAN IN PAH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

Ambrisentan for the Treatment of PAH (ARIES Studies 1 and 2)

Long-term Ambrisentan Therapy for the Treatment of PAH (ARIES-E)

ARIES-3: Ambrisentan Therapy in a Diverse Population of Patients with Pulmonary Hypertension

Ambrisentan Therapy in Patients with PAH Who Discontinued BosentanDue to Liver Function Test Abnormalities

7. INDICATIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

8. DOSAGE AND ADMINISTRATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

9. CONTRAINDICATIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

10. SPECIAL WARNINGS AND PRECAUTIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

11. DRUG INTERACTIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24

12. USE IN SPECIAL POPULATIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26

13. ADVERSE EVENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28

14. PLACE IN THERAPY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

15. FULL PRESCRIBING INFORMATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31

BIBLIOGRAPHY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41

1

PREFACE

Pulmonary arterial hypertension is a rare but devastating and life-threatening disease, with a profoundly poor prognosis and high mortality. The disease may present as

idiopathic pulmonary arterial hypertension, where no clear aetiology can be identifi ed, or as pulmonary arterial hypertension related to a variety of underlying conditions such as scleroderma, congenital heart diseases, HIV infection and others. The estimated incidence of idiopathic pulmonary arterial hypertension is 1–2 per 1,000,000 in the general population, with a mean age of 36 years and a greater incidence in females.

Research into the role of the endothelin system within the pulmonary circulation has led to a greater understanding of its eff ects on healthy pulmonary function, and of its pathological function and infl uence when increased concentrations are present. The research has led to the development of the endothelin-receptor antagonist class as a novel treatment strategy to target the deleterious eff ects of endothelins in pulmonary arterial hypertension.

Ambrisentan, an orally active, highly selective antagonist of the endothelin-1 type A receptor, is indicated for the treatment of pulmonary arterial hypertension. Ambrisentan is indicated for the treatment of pulmonary arterial hypertension (Group 1) in patients with the World Health Organization functional class II or III symptoms to improve the exercise capacity and delay clinical worsening.

Through a selective endothelin-receptor blockade, ambrisentan has been shown to signifi cantly improve exercise capacity, reduce dyspnoea scores, decrease the rate of clinical worsening and improve the exercise capacity, decrease the rate of clinical worsening and improve the World Health Organization functional class as well as haemodynamic measures. These benefi ts were maintained over time. Ambrisentan administration via an oral once-daily dosing regimen off ers patients a convenient and eff ective fi rst-line therapy for the treatment of pulmonary arterial hypertension.

February 2012

2

C H A P T E R 1

A BRIEF OVERVIEW OF PULMONARY ARTERIAL

HYPERTENSION

Pulmonary hypertension is an observation, not a single diagnosis or disease. It encompasses a diverse group of conditions that lead to elevated pulmonary pressures. It is defi ned clinically as an increase in the pulmonary vascular pressure that is caused by conditions that are associated with an increase in the pulmonary arterial pressure or both the arterial and venous pressure. Haemodynamically, it is defi ned as an increase in the mean pulmonary arterial pressure to >25 mmHg at rest or >30 mmHg during

exercise.

Pulmonary hypertension was previously classifi ed as either primary or secondary pulmonary hypertension, depending on the absence or presence of identifi able causes of increased pulmonary pressure. The 2008 World Symposium on Pulmonary Hypertension set forth a new classifi cation system that categorizes pulmonary hypertension on the basis of the following clinical criteria:

Updated clinical classifi cation of pulmonary hypertension (Dana Point, 2008)

1. Pulmonary arterial hypertension (PAH)

2. Pulmonary hypertension due to left heart disease

3. Pulmonary hypertension due to lung diseases and/or hypoxia

4. Chronic thromboembolic pulmonary hypertension

5. Pulmonary hypertension with unclear and/or multifactorial mechanisms

PAH (World Health Organization [WHO] Group I) is defi ned as a sustained elevation of pulmonary

arterial pressure to >25 mmHg at rest or to >30 mmHg with exercise, with a mean pulmonary-

capillary wedge pressure and left ventricular end-diastolic pressure of <15 mmHg.

PAH is a life-threatening and rare condition characterized by vasoconstriction and vascular remodelling resulting in a progressive increase in pulmonary vascular resistance (PVR) and pulmonary artery pressure (PAP), leading to right heart failure and death. Its prevalence is estimated at 15 cases per million people each year, with 2–3 times as many women versus men affl icted.

PAH may be idiopathic (IPAH), familial PAH (FPAH) or PAH associated (APAH) with various conditions, such as connective tissue disease, congenital systemic-to-pulmonary shunts, portal hypertension, drug and toxin use, and HIV infection.

PAH comprises a group of heterogeneous conditions that share comparable clinical and haemodynamic features and virtually identical pathological changes of the microcirculation of the lungs. The prevalence varies substantially depending on the type, aetiology and underlying condition.

3

1 Pulmonary arterial hypertension (PAH)

1.1 Idiopathic 1.2 Heritable 1.2.1 BMPR2 1.2.2 ALK1, endoglin (with or without hereditary haemorrhagic telangiectasia) 1.2.3 Unknown 1.3 Drugs and toxins induced 1.4 Associated with (APAH) 1.4.1 Connective tissue diseases 1.4.2 HIV infection 1.4.3 Portal hypertension 1.4.4 Congenital heart disease 1.4.5 Schistosomiasis 1.4.6 Chronic haemolytic anaemia 1.5 Persistent pulmonary hypertension of the newborn

The diagnosis of PAH should be considered in any patient with unexplained dyspnoea on exertion, fatigue or exercise limitation, those with clinical signs consistent with right-heart dysfunction (e.g., peripheral oedema, ascites), and patients with symptoms and having a process known to be associated with PAH and/or a family history of pulmonary hypertension.

The initial assessment of PAH is to determine whether pulmonary hypertension is present, with a non-invasive evaluation (screening echocardiogram). If there is evidence of pulmonary hypertension, then an invasive method (right-heart catheterization) is required to confi rm this fi nding and evaluate if it is haemodynamically consistent with PAH (i.e., increased pulmonary vascular resistance with normal wedge pressure). This method is also used to evaluate the severity of the disease.

The main vascular changes in PAH are vasoconstriction, smooth muscle cell and endothelial cell proliferation, and thrombosis. Advances in the understanding of the molecular mechanisms involved in this disease suggest that endothelial dysfunction plays a key role. Chronically impaired production of vasoactive mediators, such as nitric oxide and prostacyclin, along with prolonged over-expression of vasoconstrictors such as endothelin-1 (ET-1), not only aff ect vascular tone but also promote vascular remodelling. Thus, these substances represent logical pharmacological targets.

First-line treatment comprises general/supportive care, including supplemental oxygen (O2), diuretics, oral anticoagulants and avoidance of exacerbations. Patients should also be evaluated via acute vasoreactivity testing to determine if they are likely to respond to oral calcium channel blockers.

Patients who are not candidates for calcium channel blockers therapy or have not responded to it have a variety of treatment options depending on the severity of their disease. The options available are prostacyclin analogues, ET-receptor antagonists (ETRAs) and phosphodiesterase type 5 (PDE-5) inhibitors. Although none of them cure this devastating condition, the treatment options for patients with PAH have evolved, helping to prevent disease progression, prolong patient survival and improve their quality of life.

4

Figure 1

ETRAS

ET-1, a peptide produced primarily by vascular endothelial cells, is characterized as a powerful vasoconstrictor and mitogen for smooth muscle. ET-1 binds to two types of receptors, ETA and ETB; ETA-receptors are found in smooth muscle cells whereas ETB-receptors are localized on both the endothelial

cells and in smooth muscle cells. Activation of ETA- and ETB-receptors on smooth muscle cells mediates the vasoconstrictive and mitogenic eff ects of ET-1. Stimulation of ETB-receptors promotes ET-1 clearance and activation of nitric oxide and prostacyclin release. Currently, three diff erent ETRAs are available. Bosentan, the fi rst drug in this category is a dual ETRA whereas ambrisentan and sitaxsentan selectively block only the ETA-receptors.

PDE-5 INHIBITORS

These drugs are selective inhibitors of cyclic guanylate monophosphate (cGMP) PDE-5 that exert its pharmacological eff ect by increasing the intracellular concentration of cGMP. The increase of this nucleotide induces relaxation and antiproliferative eff ects on the vascular smooth muscle cells. PDE-5 is selectively abundant in the pulmonary circulation and PDE-5 gene expression and activity are increased in chronic pulmonary hypertension. Sildenafi l and tadalafi l are the PDE-5 inhibitors approved for use in PAH.

5

SYNTHETIC PROSTACYCLIN AND PROSTACYCLIN ANALOGUES

These drugs act mainly by relaxing the vascular smooth muscle cells (acute) and inhibiting platelet aggregation; however, the precise mechanism of action of prostacyclin administration in PAH is unknown and is likely to be multifactorial.

Though these drugs have contributed tremendously to the management of PAH, their usage has been limited due to drawbacks such as the route of administration, frequent dosing schedules and short half-lives.

However, PAH is a complex disorder and targeting a single pathway cannot be expected to be uniformly successful. Thus, combining substances with diff erent modes of action is expected to improve the symptoms, haemodynamics and survival rates in PAH patients.

6

C H A P T E R 2

BIOLOGY OF THE ET SYSTEM

ET BIOSYNTHESIS

The ETs are a family of 21 amino acid peptides produced by the vascular endothelial cells.

Figure 2

There are three ET isoforms termed ET-1, ET-2 and ET-3, which are encoded by three distinct genes. ET-1 is considered the predominant and more important pathophysiological isoform. It was fi rst isolated in 1988 by Yanagisawa as the most potent vasoconstrictor ever identifi ed. It is generated through the cleavage of prepro-ET-1 to big ET-1 and then to ET-1 by the action of ET-converting enzymes. Pre-clinical studies suggest that the lungs are the principal production site of ETs, with mRNA expression levels 5 times higher than any other organ studied. It is predominantly produced by the vascular endothelium and, to a lesser extent, by other cell types, including the pulmonary artery smooth muscles and the lung fi broblasts. The biosynthesis of ET is triggered by hypoxia, growth factors, cytokines, shear stress, thrombin and angiotensin II.

The lungs not only produce but also clear plasma ET from the circulation. The ETs are 100 times more potent than noradrenaline and 10 times more potent than angiotensin II.

ETA- VERSUS ET

B-MEDIATED EFFECTS

Within the mammalian cardiovascular system, ET-1 acts through two receptor subtypes — ETA and ETB. In the vasculature, ETA-receptors are located on smooth muscle cells and fi broblasts, whereas ETB-receptors are predominantly localized on ET cells and, to a lesser extent, on smooth muscle cells, fi broblasts and macrophages. Recent data using cultured transfected cell lines suggest that ETA- and ETB-receptors can form constitutive heterodimers (dimerization theory). Functionally, this means that ETB-receptors expressed on smooth muscle cells couple with ETA-receptors and the former adopt the function of the latter, such that ETB-receptors in heterodimers mediate vasoconstriction similar to ETA-receptors. Furthermore, it has been suggested that selective antagonism of one ET-receptor subtype only may result in compensation by the other receptor. This experimental hypothesis has been called ‘cross-talk’.

7

EXPERIMENTAL EVIDENCE

ET-Receptor Selectivity and its Vasoconstriction and Vasodilation Eff ects

Vasodilation is an important goal of therapeutic intervention for PAH. Theoretically, selective ETARAs should be more eff ective in achieving this than non-selective ETARAs/ETBRAs, given the role played by ETB-receptors in both vasodilation and ET-1 clearance. In animal models of PAH, however, positive dilatory eff ects have been observed with both selective ETA-receptor blockade and non-selective antagonism.

Since direct evaluation of the pulmonary circulation requires invasive procedures, the majority of the available data are extrapolated from human studies performed on blood vessels in the systemic circulation. Collectively, these studies indicate that (i) selective ETA-receptor blockade results in a robust vasodilator response and increased blood fl ow; and, (ii) selective ETB-receptor blockade results in vasoconstriction and reduced blood fl ow

ET-Receptor Selectivity and Fibrosis

Extra-vascular anti-mitotic and anti-fi brotic eff ects of ETRAs may result in greater effi cacy in scleroderma than therapies directed exclusively at the vasculature. Data from animal models using either ETA-selective or non-selective ETRAs demonstrate an amelioration of ET-1-related eff ects involving the reduction of the growth factor expression, extracellular matrix deposition and matrix metalloproteinase activity.

Subsequent in vitro data using lung fi broblasts indicate that ET-1 induces collagen matrix contraction through the ETA-receptor, but not the ETB-receptor. Furthermore, while there is evidence that ETB-receptors are linked to collagen production in vitro, in vivo animal data with ETARAs have shown that they eff ectively block the accumulation of collagen I, III and IV, normalize pro-collagen I and III mRNA, and abolish the eff ect of ET-1 on pro-collagen metabolism. Likewise, although there is evidence that under certain conditions ET-1 can act as a mitogen in vitro through both ETA- and ETB-receptor activation, ETB-receptors have been shown to inhibit vascular smooth muscle cells proliferation in vivo.

Under normal physiological conditions, the receptor types have broadly opposing functions. Activation of ETA-receptors mediates vasoconstriction, proliferation, hypertrophy, cell migration and fi brosis, whereas activation of ETB-receptors stimulates the release of the potent vasodilators (nitric oxide and prostacyclin), which exhibit anti-proliferative properties and prevents apoptosis. Importantly, ETB-receptors on the ET cells mediate the clearance of circulating ET-1 in the lungs, kidneys and liver, with up to 50% of mature ET-1 in healthy subjects and 40% in patients with PAH cleared via the pulmonary ETB-receptors. ET cell ETB-receptor activation also inhibits ET-converting enzyme-1, the enzyme that is required to produce mature ET-1.

Alterations in the distribution and number of ETA- and ETB-receptors in conditions such as PAH suggest that their roles in the disease state may diff er from those in normal physiology. For example, there are more ET-1-binding sites in the distal pulmonary vessels of patients with PAH, and ETB-receptors are also up regulated. ETB-receptors may not exclusively mediate pulmonary vasodilatation. Because of the eff ects of a sub-population of ETB-receptors located on the smooth muscle cells and fi broblasts, the spectrum of possible adverse eff ects of ETB-receptor stimulation in patients with pulmonary hypertension includes the induction of vasoconstriction, proliferation and fi brosis.

8

Figure 3

There are studies which suggest that increased ET concentration in the plasma and lung tissue serves as an important stimulus for sustained pulmonary vasoconstriction and excessive vascular remodelling in patients with PAH. Selective blockade of the ETA-receptor that mediate contractile and mitogenic eff ects on pulmonary arterial smooth muscle cells, while maintaining the function of the ETB-receptor that cause vasodilative eff ects and induce ET-1 clearance, is therefore a good strategy for designing therapeutic approaches for patients with PAH and may off er more benefi ts than non-selective ETARAs/ETBRAs.

Therefore there is a potential advantage to use a selective ETRA antagonist such as ambrisentan, which will selectively block the ETA-receptors, thereby sparing the vasodilative and anti-proliferative action of the ETB-receptors. The clinical advantage of this is yet to be determined.

9

C H A P T E R 3

CHEMISTRY OF AMBRISENTAN

In June 2007, the US Food and Drug Administration (FDA) approved ambrisentan for the once-daily treatment of PAH to improve exercise capacity and delay clinical worsening.

Ambrisentan, an orally active, highly selective antagonist of the ET-1 type A receptor, is indicated for the treatment of PAH. It has a low potential for drug–drug interactions and requires only once-daily administration.

Treatment for 3 months with ambrisentan 2.5–10 mg/day signifi cantly improved the exercise capacity, as determined by the distance walked in 6 minutes (6MWD; primary outcome measure), compared with placebo, in two double-blind, multicentre studies in patients with PAH. A decrease in dyspnoea and a delay in clinical worsening were among the improvements in secondary outcomes generally observed with ambrisentan versus placebo.

All available pre-registration and postmarketing data indicate that the drug poses only a very low risk of liver injury; hence, the ‘black box’ warning regarding potential liver injury has been removed.

Figure 4: Chemical structure of ambrisentan

10

C H A P T E R 4

PHARMACODYNAMIC PROPERTIES OF AMBRISENTAN

1. Ambrisentan is an orally active, diphenyl propionic acid derivative.

2. It is a potent antagonist of the ETA-receptor, and has a >4,000-fold higher selectivity for the ETA-receptor than the ETB-receptor. The ETA-receptors are located predominantly on vascular smooth muscle cells and mediate vasoconstriction and cell proliferation, whereas the ETB-receptors are found on both endothelial and vascular smooth muscle cells and primarily mediate vasodilation, antiproliferation and ET-1 clearance.

3. Cardiopulmonary haemodynamic parameters, as assessed by right-heart catheterization, were signifi cantly improved in patients with PAH who were treated (short- or long-term) with ambrisentan in clinical trials. Ambrisentan produced sustained, clinically relevant improvements in the mPAP (decreased by 8.2 mmHg from baseline [50.8 mmHg]), PVR (reduced by 297 dyn/s/cm-5 from baseline [856 dyn/s/cm-5]) and the cardiac index (increased by 0.5 L/min/m2 from baseline [2.5 L/min/m2]).

4. Right-heart catheterization data were analysed post hoc for a subset of 58 patients with moderate PAH who received ambrisentan 2.5, 5, or 10 mg once daily in the 2-year, open-label, uncontrolled extension (ARIES-E) of the 12-week ARIES (Ambrisentan in Pulmonary Arterial Hypertension, Randomized, Double-Blind, Placebo-Controlled, Multicenter Effi cacy) studies. Baseline right-heart catheterization data were assessed at various intervals before the fi rst dose of ambrisentan (median: 1.4 months); follow-up right-heart catheterization data were collected at various intervals after the fi rst dose of ambrisentan (median: 13.5 months). Ambrisentan produced sustained, clinically relevant improvements in the mPAP (decreased by 8.2 mmHg from baseline [50.8 mmHg]), PVR (reduced by 297 dyn/s/cm-5 from baseline [856 dyn/s/cm-5]) and the cardiac index (increased by 0.5 L/min/m2 from baseline [2.5 L/min/m2]).

5. Right-heart catheterization data were also evaluated retrospectively for a subset of 12 patients with PAH (from a single institution) who participated in the ARIES-1 and ARIES-E studies. Signifi cant improvements in the median mPAP, PVR and cardiac output were seen after 1 year of follow-up (all P=0.03 versus baseline); the improvement in PVR persisted after 2 years of follow-up.

11

C H A P T E R 5

PHARMACOKINETIC PROPERTIES OF AMBRISENTAN

1. Oral ambrisentan is rapidly absorbed, with the maximum plasma concentration (Cmax) reached at a median of ≈1.5–2 hours post-dose.

2. The absolute bioavailability of ambrisentan is unknown. Ambrisentan is 99% bound to plasma proteins and accumulates slightly at the steady state.

3. The distribution of ambrisentan into red blood cells is low, with a mean blood to plasma ratio of 0.57 and 0.61 in males and females, respectively.

4. The pharmacokinetics of ambrisentan is not aff ected to a clinically signifi cant extent by food.

5. The main route of ambrisentan metabolism is glucuronidation to form ambrisentan glucuronide. The drug also undergoes oxidative metabolism (by cytochrome P450 [CYP450] 3A4 and, to a lesser extent, CYP3A5 and CYP2C19) to form 4-hydroxymethyl ambrisentan, which is further glucuronidated to 4-hydroxymethyl ambrisentan glucuronide.

6. The main metabolite, 4-hydroxymethyl ambrisentan, has a 64-fold lower binding affi nity than the parent compound for the ETA receptor and is not pharmacologically active.

7. The elimination of ambrisentan (and its metabolites) is predominantly by non-renal pathways, with 66% of an orally administered dose being recovered in the faeces and 22.6% in the urine.

8. In patients with PAH, the mean oral clearance of ambrisentan is 19 mL/min. The mean terminal elimination half-life at the steady state was 15 and 13 hours with ambrisentan dosages of 5 and 10 mg/day, respectively.

9. Dosage adjustment is not needed in patients aged >65 years.

10. The results of a population pharmacokinetic analysis in patients with PAH and creatinine clearance between 20 and 150 mL/min suggest that mild or moderate renal impairment has no signifi cant infl uence on exposure to ambrisentan; hence, dosage adjustment is not required in these populations. However, there is limited or no experience with the drug in patients with severe renal impairment (creatinine clearance <30 mL/min).

11. The infl uence of hepatic impairment on the pharmacokinetics of ambrisentan has not been determined. Ambrisentan is not recommended in patients with moderate or severe hepatic impairment. The drug should not be initiated in patients with severe hepatic impairment or with clinically signifi cant elevated hepatic aminotransferases (>3 times the upper limit of normal [>3×ULN]).

Table 1

Pharmacokinetic profi le of ambrisentan 5 mg/day (n = 10) or 10 mg/day (n = 3) at steady state. Mean values

unless stated otherwise

5 mg 10 mgMaximum plasma concentration (Cmax) [ng/mL] 539 1147

Trough plasma concentration (ng/mL) 63 163Median time to Cmax (h) 1.5–2 1.5–2Area under the plasma concentration-time curve from time zero to 24 h (ng h/mL) 4804 12591Terminal elimination half life (h) 15 13

12

C H A P T E R 6

CLINICAL EFFICACY OF AMBRISENTAN IN PAH

AMBRISENTAN FOR THE TREATMENT OF PAH (ARIES STUDIES 1 AND 2)

ARIES-1 and ARIES-2 were concurrent, double-blind, placebo-controlled studies that randomized 202 and 192 patients with PAH, respectively, to placebo or ambrisentan (ARIES-1, 5 or 10 mg; ARIES-2, 2.5

or 5 mg) orally once daily for 12 weeks.

The primary endpoint for each study was as below:

1. Change in the 6MWD from baseline to week 12

2. Clinical worsening

3. WHO functional class

4. Short Form-36 health survey score

5. Borg dyspnoea score

6. B-type natriuretic peptide (BNP) plasma concentrations

In addition, a long-term extension study was performed (48 weeks).

Table 2: Baseline characteristics of the patients in ARIES-1 and ARIES-2

Characteristic ARIES - 1 ARIES - 2

Placebo

(n=67)

5 mg Ambrisentan

(n=67)

10 mg Ambrisentan

(n=67)

Placebo

(n=65)

2.5 mg Ambrisentan

(n=64)

5 mg Ambrisentan

(n=63)

Female sex, n (%) 59 (88) 56 (84) 53 (79) 44 (68) 48 (75) 51 (81)

Age, y 48 ±16 53 ±14 49 ±16 51 ±14 52 ±15 50 ±16

WHO functional class, n (%)

I 2 (3) 1 (2) 2 (3) 2 (3) 0 (0) 1 (2)

II 23 (34) 20 (30) 22 (33) 24 (37) 34 (53) 28 (44)

III 41 (61) 40 (60) 36 (54) 37 (57) 29 (45) 33 (52)

IV 1 (2) 6 (9) 7 (10) 2 (3) 1 (2) 1 (2)

Diagnosis, n (%)

Idiopathic PAH 43 (64) 42 (63) 41 (61) 42 (65) 42 (66) 41 (65)

Associated PAH

Connective tissue disease 21 (31) 19 (28) 22 (33) 22 (34) 19 (30) 21 (33)

HIV infection 2 (3) 3 (5) 2 (3) 1 (2) 2 (3) 1 (2)

Anorexigen use 1 (2) 2 (3) 2 (3) 0 (0) 1 (2) 0 (0)

6-min Walk distance, m 342 ±73 340 ±77 341±78 343±86 347±84 355±84

Mean pulmonary artery pressure,

mm Hg

50±15 47±13 51±16 51±13 48±14 48±14

Cardiac index, L • min-1 • m-2 2.5±0.8 2.5±0.9 2.6±0.7 2.4±0.7 2.5±0.7 2.4±0.8

Pulmonary vascular resistance,

dynes • s • cm-5

868±518 834±424 912±465 971±579 800±396 931±672

Right atrial pressure, mm Hg 8±5 8±5 9±6 7±5 8±5 8±5

B-type natriuretic peptide, ng/L† 138 (99-193) 121 (94-156) 146 (101-209) 126 (87-183) 125 (86-180) 84 (56-125)

SF-36 health survey physical

functioning scale

29.0±8.3 28.6±9.2 29.6±9.4 31.9±7.9 29.3±7.7 31.3±9.1

13

RESULTS

The 6MWD increased in all the ambrisentan groups; mean placebo-corrected treatment eff ects were 31 metres (P=0.008) and 51 metres (P<0.001) in ARIES-1 for 5 and 10 mg ambrisentan, respectively, and 32 metres (P=0.022) and 59 metres (P<0.001) in ARIES-2 for 2.5 and 5 mg ambrisentan, respectively.

Figure 5

Improvements in time to clinical worsening (ARIES-2), WHO functional class (ARIES-1), Short Form-36 score (ARIES-2), Borg dyspnoea score (both studies), and BNP (both studies) were observed.

Figure 6

No patient treated with ambrisentan developed aminotransferase concentrations >3×ULN. In 280 patients completing 48 weeks of treatment with ambrisentan monotherapy, the improvement from baseline in the 6MWD at 48 weeks was 39 metres.

Thus, it was observed that ambrisentan improves the exercise capacity in patients with PAH. Improvements were observed for several secondary end-points in each of the studies. Ambrisentan is well tolerated and is associated with a low risk of aminotransferase abnormalities.

14

LONG-TERM AMBRISENTAN THERAPY FOR THE TREATMENT OF PAH

This study evaluated the safety and effi cacy of ambrisentan for a period of 2 years in patients with PAH.

In the ARIES-1 and ARIES-2 studies, and the subsequent long-term extension protocol, the ARIES-E study, 383 patients received ambrisentan (2.5, 5 or 10 mg).

RESULTS

After 2 years of ambrisentan exposure, the mean change from baseline in the 6MWD was improved for the 5 mg (+23 metres; 95% confi dence interval [CI]: 9 to 38 metres) and 10 mg (+28 metres; 95% CI: 11 to 45 metres) groups.

Figure 7

Estimates of survival and freedom from clinical worsening for the combined dose group were 94% and 83%, respectively, at 1 year and 88% and 72%, respectively, at 2 years.

Figure 8

15

The annualized risk of aminotransferase (alanine aminotransferase [ALT] and/or aspartate aminotransferase [AST]) abnormalities >3×ULN was ≈2% per year; most of these events were mild and did not lead to discontinuation of the drug.

Figure 9

Ambrisentan treatment for 2 years was associated with sustained improvements in the exercise capacity and a low risk of clinical worsening and death in patients with PAH.

Ambrisentan was generally well tolerated and had a low risk of aminotransferase abnormalities over the 2-year study period.

ARIES-3: AMBRISENTAN THERAPY IN A DIVERSE POPULATION OF PATIENTS WITH

PAH

ARIES-3 was an open-label study evaluating the effi cacy and safety of ambrisentan in patients with PAH and pulmonary hypertension due to other non-PAH aetiologies. Patients received 5 mg ambrisentan once daily for 24 weeks. The primary endpoint was the change from baseline in the 6MWD at week 24.

Altogether, 224 patients were enrolled: 62% had PAH and 38% had pulmonary hypertension due to other aetiologies. All patients had the WHO functional class II (29%) and III (65%) symptoms at baseline, with a mean 6MWD of 317±84 metres and a median BNP level of 199 pg/mL. At baseline, 52% were receiving sildenafi l and/or prostanoid therapy.

The change from the baseline 6MWD at 24 weeks was +20.6 metres. The BNP decreased 25%, and signifi cant improvements in the Borg dyspnoea index and the WHO functional class were also observed.

Frequent adverse events were peripheral oedema (31%), headache (25%) and dyspnoea (15%). Aminotransferase concentrations >3×ULN were reported in 6 (2.7%) patients during the 24-week period.

Thus, it was concluded that ambrisentan was well tolerated and demonstrated clinical benefi ts in a broad population of patients with various pulmonary hypertension aetiologies and background pulmonary hypertension medications.

16

AMBRISENTAN THERAPY IN PATIENTS WITH PAH WHO DISCONTINUED BOSENTAN

DUE TO LIVER FUNCTION TEST ABNORMALITIES

Some ETRAs are associated with liver function test result abnormalities. However, ambrisentan has an incidence of serum aminotransferase levels >3×ULN, similar to that observed in PAH patients who are not receiving ETRAs. Because ambrisentan may provide benefi ts in PAH patients who have discontinued ETRA therapy due to liver function test abnormalities, the safety and effi cacy of ambrisentan in this patient population was evaluated.

Inclusion Criteria

1. Patients (12 to 75 years of age) with IPAH, FPAH, or APAH with connective tissue disease, congenital systemic-to-pulmonary shunts, anorexigen use or HIV infection, and who had previously discontinued bosentan therapy, or both, due to serum ALT and/or AST concentrations >3×ULN (liver function test result abnormalities) were eligible for this study.

2. Patients were required to have normal (<1×ULN) serum aminotransferase concentrations and a 6MWD ≥150 metres.

3. Patients receiving sildenafi l and/or a prostanoid (epoprostenol, treprostinil, iloprost) were required to have been receiving stable therapy for ≥4 weeks prior to screening.

4. Female patients were required to have a negative pregnancy test result, and to use a double method of contraception during and for at least 4 weeks following their participation.

Exclusion Criteria

1. Patients with pulmonary hypertension due to coronary artery disease, left-heart disease, interstitial lung disease, chronic obstructive pulmonary disease (COPD), veno-occlusive disease, chronic thrombotic and/or embolic disease or sleep apnoea, and portopulmonary hypertension.

2. Patients having a total lung capacity <70% of the predicted normal or a forced expiratory volume in 1 second (FEV1) <65% of the predicted normal; a haemoglobin concentration<10 g/dL or haematocrit <30%; or a resting arterial oxygen saturation <90% and refractory to treatment with oxygen supplementation.

Study Design

Patients who previously discontinued bosentan due to liver function test abnormalities received ambrisentan, 2.5 mg q.d. for 4 weeks, followed by 5 mg/day for 8 weeks.

17

Figure 10: Study design

The primary endpoint was the incidence of aminotransferase levels >3×ULN.

Secondary end points included the following:

1. Aminotransferase levels >5×ULN requiring drug discontinuation and >3×ULN requiring dose reduction

2. Changes in the 6MWD

3. Borg dyspnoea index

4. WHO functional class

5. Short Form-36 health survey score

Patients continued treatment beyond the 12-week endpoint with monthly monitoring of liver function tests.

RESULTS

1. No patient had an aminotransferase level >3×ULN that required ambrisentan discontinuation.

2. In 1 patient, there was a transient aminotransferase level >3×ULN that resolved following a temporary dose reduction. No additional aminotransferase levels >3×ULN were observed with long-term treatment (median exposure, 102 weeks), despite dose increases to 10 mg q.d. in more than half of the patients.

3. Signifi cant improvement was seen in the overall survival, 6MWD, Borg dyspnoea index scale and the WHO functional class.

18

Figure 11: Kaplan-Meier curve of the time to fi rst event. Time to fi rst event is defi ned as ALT or AST concentrations more than three times ULN. The symbol (+) on the curve indicates the time at which

subjects were censored.

Figure 12

Therefore, it was concluded by this study that ambrisentan treatment may be an option for patients who have discontinued bosentan therapy due to liver function test result abnormalities.

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C H A P T E R 7

INDICATIONS

Ambrisentan is indicated for the treatment of PAH (Group1) in patients with the WHO functional class II or III symptoms in order to improve the exercise capacity and delay clinical worsening.

20

C H A P T E R 8

DOSAGE AND ADMINISTRATION

Adults

Initiate treatment at 5 mg once daily with or without food, and consider increasing the dose to 10 mg once daily if 5 mg is tolerated.

Tablets may be administered with or without food. Tablets should not be split, crushed or chewed. Doses higher than 10 mg once daily have not been studied in patients with PAH.

Adolescents and Children

Ambrisentan is not recommended for use in patients <18 years of age due to a lack of data on safety and effi cacy.

Geriatric Use

No dose adjustment is required in patients aged ≥65 years.

Women of Childbearing Potential

Treat women of childbearing potential only after a negative pregnancy test and treat only women who are using two acceptable methods of contraception unless the patient has had a tubal sterilization or chooses to use a Copper T-380A IUD or LNg 20 IUS, in which case, no additional contraception is needed. Pregnancy tests should be obtained monthly in women of childbearing potential taking ambrisentan.

Pre-existing Hepatic Impairment

Ambrisentan is not recommended in patients with moderate or severe hepatic impairment. There is no information on the use of ambrisentan in patients with mild hepatic impairment; however, since the main routes of metabolism of ambrisentan are glucuronidation and oxidation with subsequent elimination in the bile, hepatic impairment would be expected to increase exposure (Cmax and AUC) to ambrisentan. Therefore ambrisentan should not be initiated in patients with severe hepatic impairment or clinically signifi cant elevated hepatic aminotransferases (>3×ULN).

Pre-existing Renal Impairment

No dose adjustment is required in patients with renal impairment. There is limited experience with ambrisentan in individuals with severe renal impairment (creatinine clearance <30 mL/min); initiate therapy cautiously in this subgroup and take particular care if the dose is increased to 10 mg.

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C H A P T E R 9

CONTRAINDICATIONS

Ambrisentan is contraindicated in patients with a history of hypersensitivity to the active substance, to soya or to any of the excipients.

Pregnancy Category X

Ambrisentan may cause foetal harm when administered to a pregnant woman. Ambrisentan was teratogenic at oral doses of ≥15 mg/kg/day in rats and ≥7 mg/kg/day in rabbits; it was not studied at lower doses. In both species, there were abnormalities of the lower jaw and hard and soft palate, malformation of the heart and great vessels, and failure of formation of the thymus and thyroid. Teratogenicity is a class eff ect of ETRAs. There are no data on the use of ambrisentan in pregnant women.

Ambrisentan is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a foetus. Pregnancy must be excluded before the initiation of treatment with ambrisentan and prevented during treatment and for 1 month after stopping treatment by the use of two acceptable methods of contraception. If the patient has had a tubal sterilization or chooses to use a Copper T-380A IUD or LNg 20 IUS for pregnancy prevention, no additional contraception is needed.

Ambrisentan is contraindicated in women of childbearing potential who are not using reliable contraception, and during lactation.

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C H A P T E R 1 0

SPECIAL WARNINGS AND PRECAUTIONS

Ambrisentan has not been studied in a suffi cient number of patients to establish the benefi t/risk balance in the WHO functional class IPAH.

The effi cacy of ambrisentan as monotherapy has not been established in patients with the 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.

Haematological Changes

Reductions in haemoglobin concentrations and haematocrit have been associated with ETRAs, including ambrisentan. Most of these decreases were detected during the fi rst few weeks of treatment and the haemoglobin level generally stabilized thereafter.

Marked decreases in haemoglobin (>15% decrease from baseline, resulting in a value below the lower limit of normal) were observed in 7% of all patients receiving ambrisentan (and 10% of patients receiving 10 mg), compared to 4% of patients receiving placebo. The cause of the decrease in haemoglobin is unknown, but it does not appear to result from haemorrhage or haemolysis. Therefore, the haemoglobin should be measured prior to the initiation of ambrisentan, at 1 month and periodically thereafter. Initiation of ambrisentan therapy is not recommended for patients with clinically signifi cant anaemia. If a clinically signifi cant decrease in haemoglobin is observed and other causes have been excluded, consider discontinuing ambrisentan.

Fluid Retention

Peripheral oedema has been observed with ETRAs, including ambrisentan. Most cases of peripheral oedema in clinical studies with ambrisentan were mild to moderate in severity, although it appeared to occur with greater frequency and severity in patients aged 65 years. Peripheral oedema was reported more frequently with 10 mg ambrisentan.

Postmarketing reports of fl uid retention occurring within weeks after starting ambrisentan have been received and, in some cases, have required intervention with a diuretic or hospitalization for fl uid management or decompensated heart failure. If patients have pre-existing fl uid overload, this should be managed as clinically appropriate prior to starting ambrisentan.

If clinically signifi cant fl uid 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 specifi c treatment or discontinuation of ambrisentan therapy.

Decreased Sperm Counts

In a 6-month study of another ETRA, bosentan, 25 male patients with the WHO functional class III and IV PAH and normal baseline sperm count were evaluated for eff ects on testicular function. There was a decline of at least 50% in the sperm count in 25% of the patients after 3 or 6 months of treatment with bosentan. One patient developed marked oligospermia at 3 months and the sperm count remained

23

low with two follow-up measurements over the subsequent 6 weeks. Bosentan was discontinued and after 2 months, the sperm count had returned to baseline levels. In 22 patients who completed 6 months of treatment, the sperm count remained within the normal range and no changes in sperm morphology, sperm motility or hormone levels were observed. Based on these fi ndings and preclinical data from ETRAs, it cannot be excluded that ETRAs such as ambrisentan have an adverse eff ect on spermatogenesis.

Pulmonary Veno-Occlusive Disease

If patients develop acute pulmonary oedema during initiation of therapy with vasodilating agents such as ambrisentan, the possibility of pulmonary veno-occlusive disease should be considered and, if confi rmed, ambrisentan should be discontinued.

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C H A P T E R 1 1

DRUG INTERACTIONS

Multiple-dose co-administration of ambrisentan and cyclosporine resulted in an approximately 2-fold increase in ambrisentan exposure in healthy volunteers; therefore, limit the dose of ambrisentan to 5 mg once daily when co-administered with cyclosporine.

In vitro Studies

Studies with human liver tissue indicate that ambrisentan is metabolized by CYP3A, CYP2C19 and uridine 5’-diphosphate glucuronosyltransferases ([UGTs]; 1A9S, 2B7S and 1A3S). In vitro studies suggest that ambrisentan is a substrate of organic anion transporting polypeptides (OATP1B1 and OATP1B3), and a substrate but not an inhibitor of P-glycoprotein (P-gp). Drug interactions might be expected because of these factors; however, a clinically relevant interaction has been demonstrated only with cyclosporine.

Ambrisentan does not inhibit or induce drug-metabolizing enzymes at clinically relevant concentrations.

In vivo Studies

The eff ects of other drugs on the ambrisentan pharmacokinetics and the eff ects of ambrisentan on the exposure to other drugs are shown in Figure 13 and Figure 14, respectively.

Figure 13: Eff ects of other drugs on ambrisentan pharmacokinetics* Omeprazole: Based on population pharmacokinetic (PK) analysis in PAH patients. ** Rifampin: AUC and Cmax were measured at the steady state. On day 3 of co-administration, a transient 2-fold increase in the AUC was noted that was no longer evident by day 7. Day 7 results are presented.

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Figure 14: Eff ects of ambrisentan on other drugs* Active metabolite of mycophenolate mofetil ** Cmax and AUC are shown; GMR (95% CI) for INR

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C H A P T E R 1 2

USE IN SPECIAL POPULATIONS

Renal Impairment

The impact of renal impairment on the pharmacokinetics of ambrisentan has been examined using a population pharmacokinetic approach in PAH patients with creatinine clearances ranging between 20 and 150 mL/min. There was no signifi cant impact of mild or moderate renal impairment on exposure to ambrisentan. Dose adjustment of ambrisentan in patients with mild or moderate renal impairment is, therefore, not required. There is no information on the exposure to ambrisentan in patients with severe renal impairment.

The impact of haemodialysis on the disposition of ambrisentan has not been investigated.

Hepatic Impairment

The infl uence of pre-existing hepatic impairment on the pharmacokinetics of ambrisentan has not been evaluated. Because there is in vitro and in vivo evidence of signifi cant metabolic and biliary contribution to the elimination of ambrisentan, hepatic impairment would be expected to have signifi cant eff ects on the pharmacokinetics of ambrisentan. Ambrisentan is not recommended in patients with moderate or severe hepatic impairment. There is no information on the use of ambrisentan in patients with mild, pre-existing impaired liver function; however, exposure to ambrisentan may be increased in these patients.

Pregnancy

Pregnancy Category X

Ambrisentan is contraindicated in pregnancy. Animal studies have shown that ambrisentan is teratogenic. There is no experience in humans.

Ambrisentan treatment must not be initiated in women of childbearing 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.

Women receiving ambrisentan must be advised of the risk of foetal harm and alternative therapy initiated if pregnancy occurs.

Lactation

It is not known whether ambrisentan is excreted in human milk. Breastfeeding while receiving ambrisentan is not recommended. A preclinical study in rats has shown decreased survival of newborn pups (mid and high doses) and eff ects on the testicle size and fertility of the pups (high dose) following maternal treatment with ambrisentan from late gestation through weaning. Doses tested were 17×, 51× and 170× (low, mid and high dose, respectively) the maximum oral human dose of 10 mg on a mg/mm2 basis.

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Paediatric Use

Safety and eff ectiveness of ambrisentan in paediatric patients have not been established.

Geriatric Use

In two placebo-controlled clinical studies of ambrisentan, 21% of the patients were ≥65 years old and 5% were ≥75 years old. The elderly (age ≥65 years) showed less improvement in walk distances with ambrisentan than younger patients did, but the results of such subgroup analyses must be interpreted cautiously. Peripheral oedema was more common in the elderly than in younger patients.

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C H A P T E R 1 3

ADVERSE EVENTS

Ambrisentan was generally well tolerated, with most adverse events being mild to moderate in intensity for all treatment groups. Peripheral oedema, headache and nasal congestion tended to be more frequent in patients treated with ambrisentan compared with placebo.

In the ARIES studies 1 and 2, none of the 261 patients receiving ambrisentan developed serum aminotransferase concentrations >3×ULN compared with 3 patients (2.3%) in the placebo groups. Moreover, the mean values for ALT, AST, total bilirubin and alkaline phosphatase did not increase from the baseline in the ambrisentan groups.

In the ARIES-E study, the most common adverse events encountered during the 2-year treatment period were peripheral oedema, headache, upper respiratory tract infection and dizziness.

Patients who had discontinued bosentan due to elevated liver enzymes and were switched to ambrisentan showed no liver function test abnormalities. No patient had an aminotransferase level >3×ULN that required ambrisentan discontinuation. No additional aminotransferase levels >3×ULN were observed with long-term treatment (median exposure, 102 weeks), despite dose increases to 10 mg q.d. in more than half of the patients.

Table 3

Most common adverse events leading to discontinuation of study, study drug or death through 2 years

Treatment Group2.5 mg (n=96) 5 mg (n = 190) 10 mg (n = 97) All (n = 383)

Right ventricular failure 3 (3.1) 7 (3.7) 5 (5.2) 15 (3.9)Pulmonary hypertension 7 (7.3) 4 (2.1) 3 (3.1) 14 (3.7)Acute respiratory failure 0 (0.0) 2 (1.1) 2 (2.1) 4 (1.0)Cardiac arrest 1 (1.0) 2 (1.1) 0 (0.0) 3 (0.8)Cardiorespiratory arrest 1 (1.0) 2 (1.1) 0 (0.0) 3 (0.8)Pneumonia 1 (1.0) 1 (0.5) 1 (1.0) 3 (0.8)Diarrhea 0 (0.0) 2 (1.1) 0 (0.0) 2 (0.5)Dyspnea exacerbated 1 (1.0) 1 (0.5) 0 (0.0) 2 (0.5)Hemorrhage intracranial 0 (0.0) 0 (0.0) 2 (2.1) 2 (0.5)Hepatic enzyme increased 1 (1.0) 0 (0.0) 1 (1.0) 2 (0.5)Hypoxia 0 (0.0) 0 (0.0) 2 (2.1) 2 (0.5)Multiorgan failure 1 (1.0) 1 (0.5) 0 (0.0) 2 (0.5)Pyrexia 0 (0.0) 2 (1.1) 0 (0.0) 2 (0.5)Respiratory arrest 1 (1.0) 0 (0.0) 1 (1.0) 2 (0.5)Sudden death 0 (0.0) 1 (0.5) 1 (1.0) 2 (0.5)Syncope 2 (2.1) 0 (0.0) 0 (0.0) 2 (0.5)Vomiting 0 (0.0) 2 (1.1) 0 (0.0) 2 (0.5)

The following could be the possible explanation for decreased liver toxicity observed with ambrisentan:

Ambrisentan is a propanoic acid derivative whereas bosentan is a sulphonamide-based structure. This structural variance confers diff ering off -target binding affi nities to the hepatic transporters. Therefore, ambrisentan has a lesser uptake in the liver cells than compared to bosentan and, thus, reduced liver toxicity.

Bosentan, but not ambrisentan, inhibits human hepatic transporters, which provides a potential mechanism for the increased hepatotoxicity observed for these agents in a clinical setting.

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C H A P T E R 1 4

PLACE IN THERAPY

The diagnosis and management of PAH has evolved substantially in the past decade, before which it was considered to be untreatable and fatal. Earlier diagnosis, advanced understanding of the pathogenic and molecular pathways and a growing armamentarium of drugs have all assisted in changing the course of this challenging disease.

The guidelines recommend that all patients with PAH undergo acute vasoreactivity testing to evaluate the response to vasodilators. For patients who show a favourable response, treatment with calcium channel blockers should be initiated. However, if the response is inadequate, treatment with other vasodilators (prostacyclin analogues, ETRAs or PDE-5 inhibitors) is recommended for patients with New York Heart Association (NYHA) class II, III or IV symptoms. Patients who do not respond to initial monotherapy or who initially benefi t but then deteriorate on a single agent should be initiated with a combination of vasodilators.

Ambrisentan, the selective ETRA, received approval in 2007 from the US FDA. The approved indication was for the use in PAH (group 1) patients with the WHO functional class II or III symptoms. It may be especially useful in patients with IPAH and PAH associated with connective tissue disease, scleroderma, HIV and Eisenmenger’s syndrome. Data available from the ARIES-E study suggest that ambrisentan can be safely used as a long-term therapy in PAH patients.

Also, with the recent safety data available, ambrisentan can be used in PAH patients who have discontinued bosentan due to liver function test abnormalities.

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Table 4: Treatment algorithm for PAH patients

CCB=calcium channel blockers; FC=functional class; BAS=

31

C H A P T E R 1 5

FULL PRESCRIBING INFORMATION

For the use of a Registered Cardiologist only

Ambrisentan Tablets

WARNING: CONTRAINDICATED IN PREGNANCY

Ambrisentan is very likely to produce serious birth defects if used by pregnant women, as this eff ect has been seen consistently when it is administered to animals. Pregnancy must, therefore, be excluded before the initiation of treatment with ambrisentan, and prevented during treatment and for 1 month after stopping treatment by the use of two acceptable methods of contraception unless the patient has had a tubal sterilization or chooses to use a Copper T-380A IUD or LNg 20 IUS, in which case no additional contraception is needed. Monthly pregnancy tests should also be obtained.

COMPOSITION

ENDOBLOC 5

Each tablet contains:Ambrisentan … 5 mg

ENDOBLOC 10

Each tablet contains:Ambrisentan… 10 mg

DOSAGE FORM

Tablet

PHARMACOLOGY

Pharmacodynamics

Ambrisentan is an orally active, propanoic acid-class, endothelin-receptor antagonist (ETRA), selective for the endothelin-A (ETA)-receptor. ET plays a signifi cant role in the pathophysiology of pulmonary arterial hypertension (PAH). Ambrisentan is a potent (Ki 0.016 nM) and highly selective ETA-antagonist (approximately 4,000-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 ET-mediated activation of second messenger systems that result in vasoconstriction and smooth muscle cell proliferation. The selectivity of ambrisentan for the ETA-receptor over the ETB-receptor is expected to retain ETB-receptor-mediated production of the vasodilators, nitric oxide and prostacyclin.

In a randomized, positive- and placebo-controlled, parallel-group study, healthy subjects received

32

either ambrisentan10 mg daily followed by a single dose of 40 mg, placebo followed by a single dose of moxifl oxacin 400 mg or placebo alone. Ambrisentan 10 mg daily had no signifi cant eff ect on the QTc interval. The 40 mg dose of ambrisentan increased the mean QTc at the tmax by 5 ms with an upper 95% confi dence limit (95% CI) of 9 ms. In patients receiving ambrisentan 5–10 mg daily and not taking metabolic inhibitors, no signifi cant QT prolongation is expected.

Pharmacokinetics

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. The Cmax and the 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-eff ect study involving the administration of ambrisentan to healthy volunteers under fasting conditions and with a high-fat meal indicated that the Cmax was decreased by 12% while the AUC remained unchanged. This decrease in peak concentration is not clinically signifi cant 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 to 20 mcg/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 to plasma ratio of 0.57 and 0.61 in males and females, respectively.

Metabolism

Ambrisentan is a non-sulphonamide (propanoic acid) ETRA. Ambrisentan is glucuronidated via several uridine 5’-diphosphate glucuronosyltransferase (UGT) isoenzymes (UGT1A9S, UGT2B7S and UGT1A3S) to form ambrisentan glucuronide (13%). Ambrisentan also undergoes oxidative metabolism mainly by cytochrome (CY) P3A4 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 affi nity of 4-hydroxymethyl ambrisentan for the human ET-receptor is 65-fold less than ambrisentan. Therefore, at concentrations observed in the plasma (approximately 4% relative to the parent ambrisentan), 4-hydroxymethyl ambrisentan is not expected to contribute to the pharmacological activity of ambrisentan.

In vitro data have shown that at therapeutic concentrations, ambrisentan does not inhibit UGT1A1, UGT1A6, UGT1A9, UGT2B7 or the CYP450 enzymes, 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A4. Additional in vitro studies showed that ambrisentan does not inhibit NTCP, organic anion transporting polypeptides (OATP) or BSEP. Furthermore, ambrisentan does not induce MRP2, P-glycoprotein (P-gp) or BSEP.

Elimination

Ambrisentan and its metabolites are eliminated primarily in the bile following hepatic and/or extra-hepatic metabolism. Approximately 22% of the administered dose is recovered in the urine following oral administration, with 3.3% being unchanged ambrisentan. Plasma elimination half-life in humans

33

ranges from 13.6 to 16.5 hours.

INDICATIONS

Ambrisentan is indicated for the treatment of PAH (World Health Organization [WHO] Group I) in patients with the WHO functional class II or III symptoms in order to improve exercise capacity and delay clinical worsening.

DOSAGE AND ADMINISTRATION

Adults

Initiate treatment at 5 mg once daily with or without food, and consider increasing the dose to 10 mg once daily if 5 mg is tolerated.

Tablets may be administered with or without food. Tablets should not be split, crushed or chewed. Doses higher than 10 mg once daily have not been studied in patients with PAH.

Adolescents and Children

Ambrisentan is not recommended for use in patients <18 years of age due to a lack of data on safety and effi cacy.

Geriatric Use

No dose adjustment is required in patients aged ≥65 years.

Women of Childbearing Potential

Treat women of childbearing potential only after a negative pregnancy test and treat only women who are using two acceptable methods of contraception unless the patient has had a tubal sterilization or chooses to use a Copper T-380A IUD or LNg 20 IUS, in which case, no additional contraception is needed. Pregnancy tests should be obtained monthly in women of childbearing potential taking ambrisentan.

Pre-existing Hepatic Impairment

Ambrisentan is not recommended in patients with moderate or severe hepatic impairment. There is no information on the use of ambrisentan in patients with mild hepatic impairment; however, since the main routes of metabolism of ambrisentan are glucuronidation and oxidation with subsequent elimination in the bile, hepatic impairment would be expected to increase exposure (Cmax and AUC) to ambrisentan. Therefore ambrisentan should not be initiated in patients with severe hepatic impairment or clinically signifi cant elevated hepatic aminotransferases (greater than 3 times the upper limit of normal [>3×ULN]).

Pre-existing Renal Impairment

No dose adjustment is required in patients with renal impairment. There is limited experience with ambrisentan in individuals with severe renal impairment (creatinine clearance <30 mL/min); initiate therapy cautiously in this subgroup and take particular care if the dose is increased to 10 mg.

CONTRAINDICATIONS

Ambrisentan is contraindicated in patients with a history of hypersensitivity to the active substance, to soya or to any of the excipients.

34

Ambrisentan may cause foetal harm when administered to a pregnant woman. Ambrisentan was teratogenic at oral doses of ≥15 mg/kg/day in rats and ≥7 mg/kg/day in rabbits; it was not studied at lower doses. In both species, there were abnormalities of the lower jaw and hard and soft palate, malformation of the heart and great vessels, and failure of formation of the thymus and thyroid. Teratogenicity is a class eff ect of ETRAs. There are no data on the use of ambrisentan in pregnant women.

Ambrisentan is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a foetus. Pregnancy must be excluded before the initiation of treatment with ambrisentan and prevented during treatment and for 1 month after stopping treatment by the use of two acceptable methods of contraception. If the patient has had a tubal sterilization or chooses to use a Copper T-380A IUD or LNg 20 IUS for pregnancy prevention, no additional contraception is needed.

Ambrisentan is contraindicated in women of childbearing potential who are not using reliable contraception, and lactation.

WARNINGS AND PRECAUTIONS

Ambrisentan has not been studied in a suffi cient number of patients to establish the benefi t/risk balance in the WHO functional class I PAH.

The effi cacy of ambrisentan as monotherapy has not been established in patients with the 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.

Haematological Changes

Reductions in haemoglobin concentrations and haematocrit have been associated with ETRAs, including ambrisentan. Most of these decreases were detected during the fi rst few weeks of treatment and the haemoglobin level generally stabilized thereafter.

Marked decreases in haemoglobin (>15% decrease from baseline, resulting in a value below the lower limit of normal) were observed in 7% of all patients receiving ambrisentan (and 10% of patients receiving 10 mg), compared to 4% of patients receiving placebo. The cause of the decrease in haemoglobin is unknown, but it does not appear to result from haemorrhage or haemolysis. Therefore, the haemoglobin should be measured prior to the initiation of ambrisentan, at 1 month and periodically thereafter. Initiation of ambrisentan therapy is not recommended for patients with clinically signifi cant anaemia. If a clinically signifi cant decrease in haemoglobin is observed and other causes have been excluded, consider discontinuing ambrisentan.

Fluid Retention

Peripheral oedema has been observed with ETRAs, including ambrisentan. Most cases of peripheral oedema in clinical studies with ambrisentan were mild to moderate in severity, although it appeared to occur with greater frequency and severity in patients aged 65 years. Peripheral oedema was reported more frequently with 10 mg ambrisentan.

Postmarketing reports of fl uid retention occurring within weeks after starting ambrisentan have been received and, in some cases, have required intervention with a diuretic or hospitalization for fl uid management or decompensated heart failure. If patients have pre-existing fl uid overload, this should be managed as clinically appropriate prior to starting ambrisentan.

35

If clinically signifi cant fl uid 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 specifi c treatment or discontinuation of ambrisentan therapy.

Decreased Sperm Counts

In a 6-month study of another ETRA, bosentan, 25 male patients with the WHO functional class III and IV PAH and normal baseline sperm count were evaluated for eff ects on testicular function. There was a decline of at least 50% in the sperm count in 25% of the patients after 3 or 6 months of treatment with bosentan. One patient developed marked oligospermia at 3 months and the sperm count remained low with two follow-up measurements over the subsequent 6 weeks. Bosentan was discontinued and after 2 months, the sperm count had returned to baseline levels. In 22 patients who completed 6 months of treatment, the sperm count remained within the normal range and no changes in sperm morphology, sperm motility or hormone levels were observed. Based on these fi ndings and preclinical data from ETRAs, it cannot be excluded that ETRAs such as ambrisentan have an adverse eff ect on spermatogenesis.

Pulmonary Veno-Occlusive Disease

If patients develop acute pulmonary oedema during initiation of therapy with vasodilating agents such as ambrisentan, the possibility of pulmonary veno-occlusive disease should be considered and, if confi rmed, ambrisentan should be discontinued.

Drug Interactions

Multiple-dose co-administration of ambrisentan and cyclosporine resulted in an approximately 2-fold increase in ambrisentan exposure in healthy volunteers; therefore, limit the dose of ambrisentan to 5 mg once daily when co-administered with cyclosporine.

In vitro Studies

Studies with human liver tissue indicate that ambrisentan is metabolized by CYP3A, CYP2C19 and UGTs (1A9S, 2B7S and 1A3S). In vitro studies suggest that ambrisentan is a substrate of OATP1B1 and OATP1B3, and a substrate but not an inhibitor of P-gp. Drug interactions might be expected because of these factors; however, a clinically relevant interaction has been demonstrated only with cyclosporine.

Ambrisentan does not inhibit or induce drug-metabolizing enzymes at clinically relevant concentrations.

In vivo Studies

The eff ects of other drugs on the ambrisentan pharmacokinetics and the eff ects of ambrisentan on the exposure to other drugs are shown in Figure 1 and Figure 2, respectively.

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Figure 15: Eff ects of other drugs on ambrisentan pharmacokinetics* Omeprazole: Based on population pharmacokinetic (PK) analysis in PAH patients. ** Rifampin: AUC and Cmax were measured at the steady state. On day 3 of co-administration, a transient 2-fold increase in the AUC was noted that was no longer evident by day 7. Day 7 results are presented.

On day 3 of co-administration, a transient 2-fold increase in the AUC was noted that was no longer evident by day 7. Day 7 results are presented.

Figure 16: Eff ects of ambrisentan on other drugs* Active metabolite of mycophenolate mofetil ** Cmax and AUC are shown; GMR (95% CI) for INR

Renal Impairment

The impact of renal impairment on the pharmacokinetics of ambrisentan has been examined using a population pharmacokinetic approach in PAH patients with creatinine clearances ranging between 20

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and 150 mL/min. There was no signifi cant impact of mild or moderate renal impairment on exposure to ambrisentan. Dose adjustment of ambrisentan in patients with mild or moderate renal impairment is, therefore, not required. There is no information on the exposure to ambrisentan in patients with severe renal impairment.

The impact of haemodialysis on the disposition of ambrisentan has not been investigated.

Hepatic Impairment

The infl uence of pre-existing hepatic impairment on the pharmacokinetics of ambrisentan has not been evaluated. Because there is in vitro and in vivo evidence of signifi cant metabolic and biliary contribution to the elimination of ambrisentan, hepatic impairment would be expected to have signifi cant eff ects on the pharmacokinetics of ambrisentan. Ambrisentan is not recommended in patients with moderate or severe hepatic impairment. There is no information on the use of ambrisentan in patients with mild, pre-existing impaired liver function; however, exposure to ambrisentan may be increased in these patients.

Pregnancy

Pregnancy Category X

Ambrisentan is contraindicated in pregnancy. Animal studies have shown that ambrisentan is teratogenic. There is no experience in humans.

Ambrisentan treatment must not be initiated in women of childbearing 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.

Women receiving ambrisentan must be advised of the risk of foetal harm and alternative therapy initiated if pregnancy occurs.

Lactation

It is not known whether ambrisentan is excreted in human milk. Breastfeeding while receiving ambrisentan is not recommended. A preclinical study in rats has shown decreased survival of newborn pups (mid and high doses) and eff ects on the testicle size and fertility of the pups (high dose) following maternal treatment with ambrisentan from late gestation through weaning. Doses tested were 17×, 51× and 170× (low, mid and high dose, respectively) the maximum oral human dose of 10 mg on a mg/mm2 basis.

Paediatric Use

Safety and eff ectiveness of ambrisentan in paediatric patients have not been established.

Geriatric Use

In two placebo-controlled clinical studies of ambrisentan, 21% of the patients were ≥65 years old and 5% were ≥75 years old. The elderly (age ≥65 years) showed less improvement in walk distances with ambrisentan than younger patients did, but the results of such subgroup analyses must be interpreted cautiously. Peripheral oedema was more common in the elderly than in younger patients.

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UNDESIRABLE EFFECTS

Experience from Clinical Studies

The safety of ambrisentan has been evaluated in clinical trials of more than 483 patients with PAH. Adverse drug reactions identifi ed from 12-week, placebo-controlled, clinical trial data are listed below by system organ class and frequency. With longer observation in uncontrolled studies (mean observation of 79 weeks), the safety profi le was similar to that observed in the short-term studies. Frequencies were defi ned as follows: 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); and, very rare (<1/10,000). For dose-related adverse reactions, the frequency category refl ects 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 refl ect the frequency of adverse events occurring during normal clinical practice. Within each frequency grouping, undesirable eff ects are presented in order of decreasing seriousness.

Cardiac Disorders

Common: Palpitation.

Blood and Lymphatic System Disorders

Common: Anaemia (decreased haemoglobin, decreased haematocrit).

Nervous System Disorders

Very common: Headache (including sinus headache, migraine1).

Respiratory, Thoracic and Mediastinal Disorders

Common: Upper respiratory (e.g., nasal,2 sinus) congestion, sinusitis, nasopharyngitis, rhinitis.

Gastrointestinal Disorders

Common: Abdominal pain, constipation.

Vascular Disorders

Common: Flushing.

General Disorders and Administration Site Conditions

Very common: Peripheral oedema, fl uid retention.3

Common: Chest pain/discomfort.

Immune System Disorders

Uncommon: Hypersensitivity reactions (e.g., angio-oedema, rash, pruritus).

1 The frequency of headache appeared higher with 10 mg ambrisentan. 2 The incidence of nasal congestion was dose-related during ambrisentan therapy. 3 Peripheral oedema was reported more frequently with 10 mg ambrisentan. In clinical studies, peripheral oedema was reported more commonly and tended to be more severe in patients aged ≥65 years.

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Laboratory Abnormalities

Decreased Haemoglobin

The frequency of decreased haemoglobin (anaemia) was higher with 10 mg ambrisentan. Across the 12-week, placebo-controlled, Phase III 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 stabilize 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, which fell below the lower limit of normal.

Use in Patients with Prior ETRA-Related Serum Liver Enzyme Abnormalities

In an uncontrolled, open-label study, 36 patients who had previously discontinued ETRAs due to aminotransferase elevations >3×ULN were treated with ambrisentan. All patients had to have normal aminotransferase levels on entry to this study. Prior elevations were predominantly moderate, with 64% of the ALT elevations <5×ULN, but 9 patients had elevations >8×ULN. In 8 patients who had been re-challenged with bosentan and/or the investigational ETRA, all 8 had a recurrence of aminotransferase abnormalities that required discontinuation of ETRA therapy. Of the 36 patients, 25 were also receiving prostanoid and/or phosphodiesterase type 5 (PDE-5) inhibitor therapy. There was early discontinuation by 2 patients (including one of the patients with a prior 8×ULN elevation). Of the remaining 34 patients, 1 patient experienced a mild aminotransferase elevation at 12 weeks on ambrisentan 5 mg, which was resolved by decreasing the dosage to 2.5 mg; this did not recur with later escalations to 10 mg. With a median follow-up of 13 months and with 50% of patients increasing the dose of ambrisentan to 10 mg, no patients were discontinued for aminotransferase elevations.

While the uncontrolled study design does not provide information about what would have occurred with re-administration of previously used ETRAs or show that ambrisentan led to fewer aminotransferase elevations than would have been seen with those drugs, the study indicates that ambrisentan may be tried in patients who have experienced asymptomatic aminotransferase elevations on other ETRAs after aminotransferase levels have returned to normal.

Postmarketing Data

In addition to adverse reactions identifi ed from clinical studies, the following adverse reactions were identifi ed during post-approval use of ambrisentan. Frequencies were defi ned as follows: common (1/100 to <1/10); uncommon (1/1,000 to <1/100); and, not known (cannot be estimated from the available data).

Nervous System Disorders

Not known: Dizziness.

Cardiac Disorders

Not known: Cardiac failure.4

Vascular Disorders

4 Most of the reported cases of cardiac failure were associated with fl uid retention.

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Not known: Syncope, hypotension.

Respiratory, Thoracic and Mediastinal Disorders

Not known: Dyspnoea.5

Gastrointestinal Disorders

Not known: Syncope, hypotension.

Hepatobiliary Disorders

Common: Hepatic transaminases increased.

Uncommon: Hepatic injury and autoimmune hepatitis.6

Immune System Disorders

Hypersensitivity reactions (e.g., angio-oedema, rash).

Others

Anaemia, nausea, and vomiting.

Elevations of liver aminotransferases (alanine aminotransferase [ALT] and/or aspartate aminotransferase [AST]) have been reported with ambrisentan use; in most cases, alternative causes of the liver injury could be identifi ed (heart failure, hepatic congestion, hepatitis, alcohol use, hepatotoxic medications). Other ETRAs have been associated with elevations of aminotransferases, hepatotoxicity and cases of liver failure. Discontinue ambrisentan if >5×ULN or if elevations are accompanied by bilirubin >2×ULN or by signs or symptoms of liver dysfunction and other causes are excluded. Because these reactions were reported voluntarily from a population of uncertain size, it is not possible to reliably estimate the frequency or establish a causal relationship to drug exposure.

OVERDOSAGE

There is no experience with overdosage of ambrisentan. The highest single dose of ambrisentan administered to healthy volunteers was 100 mg and the highest daily dose administered to patients with PAH was 10 mg once daily. In healthy volunteers, single doses of 50 mg and 100 mg (5 to 10 times the maximum recommended dose) were associated with headache, fl ushing, dizziness, nausea and nasal congestion.

Massive overdosage could potentially result in hypotension. In the case of pronounced hypotension, active cardiovascular support may be required. No specifi c antidote is available.

INCOMPATIBILITY

SHELF-LIFE

STORAGE AND HANDLING INSTRUCTIONS

PACKAGING INFORMATION

BRAND NAME Tablets

5 Cases of worsening dyspnoea of unclear aetiology have been reported shortly after starting ambrisentan therapy.6 Cases of autoimmune hepatitis, including cases of exacerbation of autoimmune hepatitis, and hepatic injury have been reported during ambrisentan therapy.

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BIBLIOGRAPHY

1. European Heart Journal 2009; 30: 2493–2537

2. CHEST 2001; 120: 1562–1569

3. Am J Cardiovasc Drugs 2011; 11: 215–226

4. Circulation 2008; 117: 3010–3019

5. J Am Coll Cardiol 2009; 54: 1971–1981

6. CHEST 2009; 135: 122–129

7. Can. J. Physiol. Pharmacol. 2010; 88: 682–691

8. Am J Respir Crit Care Med 179; 2009: A3357

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Notes

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