VOLIBRIS 10 MG

Israel - English - Ministry of Health

Buy It Now

Active ingredient:
AMBRISENTAN
Available from:
GLAXO SMITH KLINE (ISRAEL) LTD
ATC code:
C02KX02
Pharmaceutical form:
FILM COATED TABLETS
Composition:
AMBRISENTAN 10 MG
Administration route:
PER OS
Prescription type:
Required
Manufactured by:
PATHEON INC., CANADA
Therapeutic area:
AMBRISENTAN
Therapeutic indications:
Volibris is indicated for treatment of pulmonary arterial hypertension (PAH) in adult patients of WHO Functional Class (FC) II to III, including use in combination treatment with tadalafil.Efficacy has been shown in idiopathic PAH (IPAH) and in PAH associated with connective tissue disease.
Authorization number:
140 09 31884 00
Authorization date:
2014-01-31

Documents in other languages

Patient Information leaflet Patient Information leaflet - Arabic

21-01-2021

Patient Information leaflet Patient Information leaflet - Hebrew

06-10-2019

Page 1 of 19

The format of this leaflet was determined by the Ministry of Health and its content was checked and

approved in March 2016

was updated according to the guidelines of the Ministry of Health in January 2019

Volibris 5 mg

Volibris 10 mg

1.

NAME OF THE MEDICINAL PRODUCT

Volibris 5 mg

Volibris 10 mg

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Volibris 5 mg:

Each tablet contains 5 mg of ambrisentan.

Excipient(s) with known effect:

Each tablet contains approximately 95 mg of lactose (as monohydrate), approximately 0.25 mg of

lecithin (soya) (E322) and approximately 0.11 mg of Allura red AC Aluminium Lake (E129).

Volibris 10 mg

Each tablet contains 10 mg of ambrisentan.

Excipient(s) with known effect:

Each tablet contains approximately 90 mg lactose (as monohydrate), approximately 0.25 mg of

lecithin (soya) (E322) and approximately 0.45 mg of Allura red AC Aluminium Lake (E129).

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Film-coated tablet

Volibris 5 mg

:

Pale-pink, square, convex, film-coated tablet with “GS” debossed on one side and “K2C” on the other

side.

Volibris 10

Deep-pink, oval, convex, film-coated tablet with “GS” debossed on one side and “KE3” on the other

side.

Page 2 of 19

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Volibris is indicated for treatment of pulmonary arterial hypertension (PAH) in adult patients of WHO

Functional Class (FC) II to III, including use in combination treatment with tadalafil

.

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

Volibris 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, Volibris 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.

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).

WARNING: EMBRYO-FETAL TOXICITY

Do not administer Volibris to a pregnant female because it may cause fetal harm

[see

Contraindications (

) and

Fertility, pregnancy and lactation

Females of reproductive potential: Exclude pregnancy before the start of treatment,

monthly during treatment, and 1 month after stopping treatment. Prevent pregnancy

during treatment and for one month after stopping treatment by using acceptable

methods of contraception

[see

Fertility, pregnancy and lactation

The marketing of Volibris is subject to a Risk Evaluation and Mitigation Strategy

(REMS) Program. Each patient should recieve a Patient alert card, emphasizing the risks

of embryo fetal toxicity.

Page 3 of 19

Special populations

Elderly patients

No dose adjustment is required in patients over the age of 65 (see section 5.2).

Patients with renal impairment

No dose adjustment is required in patients with renal impairment (see section 5.2). There is limited

experience with 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.

Patients with 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 (C

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 clinical 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, to soya, 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).

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.

Page 4 of 19

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 hemoglobin 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.

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

Page 5 of 19

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

Volibris treatment must not be initiated in women of child-bearing potential unless the result of a pre-

treatment pregnancy test is negative and reliable contraception is practiced. If there is any doubt on

what contraceptive advice should be given to the individual patient, consultation with a gynaecologist

should be considered. Monthly pregnancy tests during treatment with 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

Volibris tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the

Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Volibris tablets contain the azo colouring agent Allura red AC Aluminium Lake (E129), which can

cause allergic reactions.

Volibris tablets contain lecithin derived from soya. If a patient is hypersensitive to soya, ambrisentan

must not be used (see section 4.3).

Volibris tablets contain less than 1 mmol sodium (23 mg), which is 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

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

(see section 4.2). Multiple doses of ambrisentan had no effect on cyclosporine A exposure, and no

dose adjustment of cyclosporine A is warranted.

Page 6 of 19

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 drugs. 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).

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

Page 7 of 19

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).

Male fertility

The development of testicular tubular atrophy in male animals has been linked to the chronic

administration of ERAs, including ambrisentan (see section 5.3). 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 1200 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

(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

Page 8 of 19

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)

Common

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 common

Very common

Very common

Dizziness

Common

Very common

Very common

Eye disorders

Blurred vision, visual impairment

Not known

Common

Common

Ear and labyrinth disorders

Tinnitus

Common

Sudden hearing loss

Uncommon

Cardiac disorders

Cardiac failure

Common

Common

Common

Palpitation

Common

Very common

Very common

Page 9 of 19

Vascular disorders

Hypotension

Common

Common

Common

Flushing

Common

Common

Very common

Syncope

Uncommon

Common

Common

Respiratory, thoracic and mediastinal disorders

Epistaxis

Common

Common

Common

Dyspnoea

Common

Very common

Very common

Upper respiratory (e.g. nasal, sinus)

congestion, sinusitis,

nasopharyngitis, rhinitis

Common

Nasopharyngitis

Very common

Very common

Sinusitis, rhinitis

Common

Common

Nasal congestion

Very common

Very common

Gastrointestinal disorders

Nausea, vomiting, diarrhoea

Common

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)

Uncommon

3, 8

Autoimmune hepatitis (see section

4.4)

Uncommon

Hepatic transaminases increased

Common

Skin and subcutaneous tissue disorders

Rash

Common

Common

General disorders and administration site conditions

Peripheral oedema, fluid retention

Very common

Very common

Very common

Chest pain/discomfort

Common

Common

Very common

Page 10 of 19

Asthenia

Common

Common

Common

Fatigue

Common

Very common

Very common

NR – not reported

See section ‘

Description of selected adverse reactions

’.

The frequency of headache appeared higher with 10 mg ambrisentan.

Data derived from routine pharmacovigilance surveillance and frequencies based on placebo-

controlled clinical trial experience.

Data derived from routine pharmacovigilance surveillance

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.

Cases of worsening dyspnoea of unclear aetiology have been reported shortly after starting

ambrisentan therapy.

The incidence of nasal congestion was dose related during ambrisentan therapy.

Cases of autoimmune hepatitis, including cases of exacerbation of autoimmune hepatitis, and hepatic

injury have been reported during ambrisentan therapy.

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.

Any suspected adverse events should be reported to the Ministry of Health according to the National

Regulation by using an online form

https://forms.gov.il/forms/Resources/DowloadSetup/AGFormsDownloadToolbar.htm?formid=AdversEffectMedic@moh.gov.il

Additionally, you should also report to GSK Israel (

il.safety@gsk.com

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.

Page 11 of 19

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 (ET

receptor. Endothelin plays a significant role in the pathophysiology of PAH.

Ambrisentan is a potent (Ki 0.016 nM) and highly selective ET

antagonist (approximately

4000-fold more selective for ET

as compared to ET

Ambrisentan blocks the ET

receptor subtype, localized predominantly on vascular smooth

muscle cells and cardiac myocytes. This prevents endothelin-mediated activation of second

messenger systems that result in vasoconstriction and smooth muscle cell proliferation.

The selectivity of ambrisentan for the ET

over the ET

receptor is expected to retain ET

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)).

Page 12 of 19

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.

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 3mm 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 multicenter, 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.

Page 13 of 19

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 drugs 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.

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

Table 1

Ambrisentan +

Tadalafil

(N=253)

Monotherapy

Pooled

(N=247)

Ambrisentan

monotherapy

(N=126)

Tadalafil

monotherapy

(N=121)

Time to First Clinical Failure Event (Adjudicated)

Page 14 of 19

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

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

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

Page 15 of 19

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 (C

) of ambrisentan typically occur around 1.5 hours post-dose under both fasted and

fed conditions. C

and area under the plasma concentration-time curve (AUC) increase dose

proportionally over the therapeutic dose range. Steady-state is generally achieved following 4 days of

repeat dosing.

A food-effect study involving administration of ambrisentan to healthy volunteers under fasting

conditions and with a high-fat meal indicated that the C

was decreased 12% while the AUC

remained unchanged. This decrease in peak concentration is not clinically significant, and therefore

ambrisentan can be taken with or without food.

Distribution

Ambrisentan is highly plasma protein bound. The

in vitro

plasma protein binding of ambrisentan was,

on average, 98.8% and independent of concentration over the range of 0.2 – 20 microgram/ml.

Ambrisentan is primarily bound to albumin (96.5%) and to a lesser extent to alpha

-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 C

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

pharmacokinetics or pharmacodynamics of warfarin. Similarly, co-administration with warfarin did

not affect the pharmacokinetics of ambrisentan (see section 4.5).

Page 16 of 19

The effect of 7-day dosing of sildenafil (20 mg three times daily) on the pharmacokinetics of a single

dose of ambrisentan, and the effects of 7-day dosing of ambrisentan (10 mg once daily) on the

pharmacokinetics of a single dose of sildenafil were investigated in 19 healthy volunteers. With the

exception of a 13% increase in sildenafil C

following co-administration with ambrisentan, there

were no other changes in the pharmacokinetic parameters of sildenafil, N-desmethyl-sildenafil and

ambrisentan. This slight increase in sildenafil C

is not considered clinically relevant (see section

4.5).

The effects of steady-state ambrisentan (10 mg once daily) on the pharmacokinetics of a single dose of

tadalafil, and the effects of steady-state tadalafil (40 mg once daily) on the pharmacokinetics of a

single dose of ambrisentan were studied in 23 healthy volunteers. Ambrisentan did not have any

clinically relevant effects on the pharmacokinetics of tadalafil. Similarly, co-administration with

tadalafil did not affect the pharmacokinetics of ambrisentan (see section 4.5).

The effects of repeat dosing of ketoconazole (400 mg once daily) on the pharmacokinetics of a single

dose of 10 mg ambrisentan were investigated in 16 healthy volunteers. Exposures of ambrisentan as

measured by AUC

(0-inf)

and C

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 C

and AUC(0-

) 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–

) (121% and 116% after first

and second doses of rifampicin, respectively) was observed, presumably due to a rifampicin-mediated

OATP inhibition. However, there was no clinically relevant effect on ambrisentan exposure by day 8,

following administration of multiple doses of rifampicin. Patients on ambrisentan therapy should be

closely monitored when starting treatment with rifampicin (see sections 4.4 and 4.5).

The effects of repeat dosing of ambrisentan (10 mg) on the pharmacokinetics of single dose digoxin

were studied in 15 healthy volunteers. Multiple doses of ambrisentan resulted in slight increases in

digoxin AUC

0-last

and trough concentrations, and a 29% increase in digoxin C

. 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 C

and AUC

(0–∞)

were slightly decreased for ethinyl

estradiol (8% and 4%, respectively), and slightly increased for norethindrone (13% and 14 %,

respectively). These changes in exposure to ethinyl estradiol or norethindrone were small and are

unlikely to be clinically significant (see section 4.5).

Elimination

Ambrisentan and its metabolites are eliminated primarily in the bile following hepatic and/or extra-

hepatic metabolism. Approximately 22% of the administered dose is recovered in the urine following

Page 17 of 19

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 (C

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.

Page 18 of 19

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 monohydrate

Microcrystalline cellulose

Croscarmellose sodium

Magnesium stearate

Film coat

Polyvinyl alcohol (partially hydrolysed)

Talc (E553b)

Titanium dioxide (E171)

Macrogol / PEG 3350

Lecithin (soya) (E322)

Allura red AC Aluminium Lake (E129)

6.2

Incompatibilities

Not applicable.

6.3

Shelf life

The expiry date of the product is indicated on the label and packaging.

Page 19 of 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/aluminium foil blisters.

Pack size: 30 film-coated tablets.

7.

MANUFACTURER

Patheon Inc., Mississauga, Canada.

8.

LICENSE HOLDER AND IMPORTER

GlaxoSmithKline (Israel) Ltd., 25 Basel St., Petach Tikva.

9.

LICENSE NUMBER(S)

Volibris 5 mg: 140-08-31883

Volibris 10 mg: 140-09-31884

Vol DR v8

Trade marks are owned by or licensed to the GSK group of companies

©2018 GSK group of companies or its licensor

: ךיראת

ץרמ

2019

:ןודנה

Volibris 5 mg, 10mg

/

סירבילוו

5

,ג"מ

10

ג"מ

Ambrisentan 5 mg, 10 mg

Film Coated Tablets

ה/דבכנ ה/אפור

,ה/דבכנ ת/חקור

תרבח

ג

ןיילקתימסוסקל

מ"עב לארשי

GSK)

(

לש ןכרצלו אפורל םינולעה ןוכדע לע עידוהל תשקבמ

סירבילוו

5

ו ג"מ

-

10

ג"מ

ה

רישכתל המושרה היוותה

:לארשיב

Volibris is indicated for treatment of pulmonary arterial hypertension (PAH) in adult patients of WHO Functional

Class (FC) II to III, including use in combination treatment with tadalafil.

Efficacy has been shown in idiopathic PAH (IPAH) and in PAH associated with connective tissue disease.

ע

:אפורל ןולעב םיאבה םיפיעסב ושענ םייתוהמ םינוכד

4.4

Special warnings and precautions for use

Volibris tablets contain less than 1

mmol sodium (23

mg), which is essentially

sodium-free

.

4.6

Fertility, pregnancy and lactation

Women of childbearing potential

Women shouldn’t take this medicine if they are planning a pregnancy.

Women patients of reproductive potential must have a negative pregnancy test prior to initiation of

treatment, monthly pregnancy test during treatment, and 1 month after stopping treatment with Volibris.

Advise patients to contact their healthcare provider if they become pregnant or suspect they may be

pregnant. Perform a pregnancy test if pregnancy is suspected for any reason. For positive pregnancy

tests, counsel patient on the potential risk to the foetus and patient options.

Women of childbearing potential should have a negative pregnancy test before starting treatment with

Volibris.

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.

prescriber should document a negative urine or serum pregnancy test performed during the first 5 days

of a normal menstrual period and at least 11 days after the last unprotected act of sexual intercourse.

Contraception

Women patients of reproductive potential must use effective methods of contraception during treatment

with Volibris and for 1 month after stopping treatment with Volibris. The prescriber must guide patients

to choose one highly effective form of contraception (intrauterine device (IUD) or tubal sterilization) or

a combination of methods (hormone method with a barrier method or two barrier methods). If a

partner’s vasectomy is the chosen method of contraception, a hormone or barrier method must be used

along with this method. Counsel patients on pregnancy planning and prevention, including emergency

contraception, or designate counseling by another healthcare provider trained in contraceptive

counseling.

You should recommend patients to use a reliable method of birth control to help them lower their risk of

problems with pulmonary arterial hypertension.

4.8

Undesirable effects

Skin and subcutaneous tissue disorders

Rash

Common

Very common

Common

5.3

Preclinical safety data

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.

ע

ושענ םייתוהמ םינוכד

ב

םיפיעס

ה

אב

י

ם

ב

: ןכרצל ןולע

2

.

הפורתב שומיש ינפל

מ תוחפ הליכמ וז הפורת

-

1mmol

) ןרתנ

23

.ןרתנ תלוטנכ תבשחנ ןכ לעו ,הילבט לכב (ג"מ

4

תועפות .

יאוול

...

תפורת) ליפאלאדאט םע בולישב

PAH

(תרחא

:הלעמ םושרל ףסונב

(רועה לש תוימומדא) הקמסה

תואקה

החירפ

.הזחב תוחונ יא/באכ

...

האר םיפרוצמ ןכרצל ןולעו אפורל ןולע

םינכדועמ

ארקמ

םינוכדעל

םינמוסמה

תפסות

הרמחה

בתכ

לוחכ

ןמוסמ

בוהצב

רקרמ

תפסות

בתכ לוחכ

עדימ רסוהש

קוחמ םודא בתכ

ןולעה

אפורל

ןולעהו

ןכרצל

וחלשנ

םוסרפל

רגאמב

תופורתה

רתאבש

דרשמ

תואירבה

https://www.old.health.gov.il/units/pharmacy/trufot/index.asp?safa=h

ןתינו םיספדומ םלבקל

לע

תרבחל הינפ ידי לזב 'חר ןיילקתימסוסקלג

:ןופלטב הוקת חתפ

03-9297100

,הכרבב

ןזור תירש

הנוממ תחקור

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