1. Name Of The Medicinal Product
5 mg film-coated tablets
Volibris
10 mg film-coated tablets
Volibris
2. Qualitative And Quantitative Composition
5 mg film-coated tablets
Each tablet contains 5 mg of ambrisentan.
10 mg film-coated tablets
Each tablet contains 10 mg of ambrisentan.
Excipients
5 mg film-coated tablets
Each tablet contains lactose monohydrate (approximately 95 mg), Lecithin (Soya) (E322) (approximately 0.25 mg) and Allura red AC Aluminium Lake (E129) (approximately 0.11 mg).
10 mg film-coated tablets
Each tablet contains lactose monohydrate (approximately 90 mg), Lecithin (Soya) (E322) (approximately 0.25 mg) and Allura red AC Aluminium Lake (E129) (approximately 0.45 mg).
For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Film-coated tablet.
5 mg film-coated tablets
Pale-pink, square, convex, film-coated tablet with "GS" debossed on one side and "K2C" on the other side.
10 mg film-coated tablets
Deep-pink, oval, convex, film-coated tablet with "GS" debossed on one side and "KE3" on the other side.
4. Clinical Particulars
4.1 Therapeutic Indications
Volibris is indicated for the treatment of patients with pulmonary arterial hypertension (PAH) classified as WHO functional class II and III, to improve exercise capacity (see section 5.1). Efficacy has been shown in idiopathic PAH (IPAH) and in PAH associated with connective tissue disease.
4.2 Posology And Method Of Administration
Treatment must be initiated by a physician experienced in the treatment of PAH.
Posology
Volibris is to be taken orally at a dose of 5 mg once daily.
Some additional efficacy has been observed with 10 mg Volibris in patients with class III symptoms, however an increase in peripheral oedema has also been observed. Patients with PAH associated with connective tissue disease may require 10 mg Volibris for optimal efficacy. Confirm that the 5 mg dose is well tolerated before considering an increase in dose to 10 mg Volibris in these patients (see sections 4.4 and 4.8).
Limited data suggest that the abrupt discontinuation of Volibris is not associated with rebound worsening of PAH.
When co-administered with cyclosporine A, the dose of ambrisentan should be limited to 5 mg once daily and the patient should be carefully monitored (see sections 4.5 and 5.2).
Children and adolescents
Volibris is not recommended for use in patients below 18 years of age due to a lack of data on safety and efficacy.
Elderly
No dose adjustment is required in patients over the age of 65 (see section 5.2).
Patients with renal impairment
No dose adjustment is required in patients with renal impairment (see section 5.2). There is limited experience with Volibris in individuals with severe renal impairment (creatinine clearance <30 ml/min); initiate therapy cautiously in this subgroup and take particular care if the dose is increased to 10 mg Volibris.
Patients with hepatic impairment
Volibris has not been studied in individuals with severe hepatic impairment (with or without cirrhosis). Since the main routes of metabolism of ambrisentan are glucuronidation and oxidation with subsequent elimination in the bile, hepatic impairment would be expected to increase exposure (Cmax and AUC) to ambrisentan. Therefore Volibris should not be initiated in patients with severe hepatic impairment, or clinically significant elevated hepatic aminotransferases (greater than 3 times the Upper Limit of Normal (>3xULN); see sections 4.3 and 4.4).
Method of administration
It is recommended that the tablet is swallowed whole and it can be taken with or without food.
4.3 Contraindications
• Hypersensitivity to the active substance, to soya, or to any of the excipients (see sections 4.4 and 6.1).
• Pregnancy (see section 4.6).
• Women of child-bearing potential who are not using reliable contraception (see sections 4.4 and 4.6).
• Lactation (see section 4.6).
• Severe hepatic impairment (with or without cirrhosis) (see section 4.2).
• Baseline values of hepatic aminotransferases (aspartate aminotransferases (AST) and/or alanine aminotransferases (ALT)) >3xULN (see sections 4.2 and 4.4).
4.4 Special Warnings And Precautions For Use
Volibris has not been studied in a sufficient number of patients to establish the benefit/risk balance in WHO functional class I PAH.
The efficacy of Volibris as monotherapy has not been established in patients with WHO functional class IV PAH. Therapy that is recommended at the severe stage of the disease (e.g. epoprostenol) should be considered if the clinical condition deteriorates.
Liver function
Liver function abnormalities have been associated with PAH. 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 Volibris. Therefore hepatic aminotransferases (ALT and AST) should be evaluated prior to initiation of Volibris 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), Volibris therapy should be discontinued.
In patients without clinical symptoms of hepatic injury or of jaundice, re-initiation of Volibris may be considered following resolution of hepatic enzyme abnormalities. The advice of a hepatologist is recommended.
Haemoglobin concentration
Reductions in haemoglobin concentrations and haematocrit have been associated with ERAs including Volibris (see section 4.8). Most of these decreases were detected during the first 4 weeks of treatment and haemoglobin generally stabilised thereafter.
Initiation of Volibris is not recommended for patients with clinically significant anaemia. It is recommended that haemoglobin and/or haematocrit levels are measured during treatment with Volibris, for example at 1 month, 3 months and periodically thereafter in line with clinical practice. If a clinically significant decrease in haemoglobin or haematocrit is observed, and other causes have been excluded, dose reduction or discontinuation of treatment should be considered.
Fluid retention
Peripheral oedema has been observed with ERAs including ambrisentan. Most cases of peripheral oedema in clinical studies with ambrisentan were mild to moderate in severity, although it appeared to occur with greater frequency and severity in patients 65 years. Peripheral oedema was reported more frequently with 10 mg ambrisentan (see section 4.8).
Post-marketing reports of fluid retention occurring within weeks after starting ambrisentan have been received and, in some cases, have required intervention with a diuretic or hospitalisation for fluid management or decompensated heart failure. If patients have pre-existing fluid overload, this should be managed as clinically appropriate prior to starting ambrisentan.
If clinically significant fluid retention develops during therapy with ambrisentan, with or without associated weight gain, further evaluation should be undertaken to determine the cause, such as ambrisentan or underlying heart failure, and the possible need for specific treatment or discontinuation of ambrisentan therapy.
Women of child-bearing potential
Volibris treatment must not be initiated in women of child-bearing potential unless the result of a pre-treatment pregnancy test is negative and reliable contraception is practiced. If there is any doubt on what contraceptive advice should be given to the individual patient, consultation with a gynaecologist should be considered. Monthly pregnancy tests during treatment with Volibris are recommended (see sections 4.3 and 4.6).
Pulmonary veno-occlusive disease
Cases of pulmonary oedema have been reported with vasodilating agents, such as endothelin receptor antagonists, when used in patients with pulmonary veno-occlusive disease. Consequently, if PAH patients develop acute pulmonary oedema when treated with ambrisentan, the possibility of pulmonary veno-occlusive disease should be considered.
Concomitant use with other medicinal products
Rifampicin: Patients on ambrisentan therapy should be closely monitored when starting treatment with rifampicin (see sections 4.5 and 5.2).
Excipients
Volibris tablets contain lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Volibris tablets contain the azo colouring agent Allura red AC Aluminium Lake (E129), which can cause allergic reactions.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Ambrisentan does not inhibit or induce phase I or II drug metabolizing enzymes at clinically relevant concentrations in in vitro and in vivo non-clinical studies, suggesting a low potential for ambrisentan to alter the profile of medicinal products metabolized by these pathways.
The potential for ambrisentan to induce CYP3A4 activity was explored in healthy volunteers with results suggesting a lack of inductive effect of ambrisentan on the CYP3A4 isoenzyme.
Co-administration of ambrisentan with a phosphodiesterase inhibitor, either sildenafil or tadalafil (both substrates of CYP3A4) in healthy volunteers did not significantly affect the pharmacokinetics of the phosphodiesterase inhibitor or ambrisentan (see section 5.2).
Steady state administration of ketoconazole (a strong inhibitor of CYP3A4) did not result in a clinically significant increase in exposure to ambrisentan (see section 5.2).
Ambrisentan had no effects on the steady state pharmacokinetics and anti-coagulant activity of warfarin in a healthy volunteer study (see section 5.2). Warfarin also had no clinically significant effects on the pharmacokinetics of ambrisentan. In addition, in patients, ambrisentan had no overall effect on the weekly warfarin-type anticoagulant dose, prothrombin time (PT) and international normalized ratio (INR).Steady-state co-administration of ambrisentan and cyclosporine A resulted in a 2-fold increase in ambrisentan exposure in healthy volunteers. This may be due to the inhibition by cyclosporine A of transporters and metabolic enzymes involved in the pharmacokinetics of ambrisentan. Therefore the dose of ambrisentan should be limited to 5 mg once daily when co-administered with cyclosporine A (see section 4.2). Multiple doses of ambrisentan had no effect on cyclosporine A exposure, and no dose adjustment of cyclosporine A is warranted.
Co-administration of rifampicin (an inhibitor of OATP, a strong inducer of CYP3A and 2C19, and inducer of P-gp and uridine-diphospho-glucuronosyltransferases [UGTs]) was associated with a transient (approximately 2-fold) increase in ambrisentan exposure following initial doses in healthy volunteers. However, by day 8, steady state administration of rifampicin had no clinically relevant effect on ambrisentan exposure. Patients on ambrisentan therapy should be closely monitored when starting treatment with rifampicin (see sections 4.4 and 5.2).
In a clinical study in healthy volunteers, steady-state dosing with ambrisentan 10 mg once daily did not significantly affect the single-dose pharmacokinetics of the ethinyl estradiol and norethindrone components of a combined oral contraceptive (see section 5.2). Based on this pharmacokinetic study, ambrisentan would not be expected to significantly affect exposure to oestrogen- or progestogen- based contraceptives.
The efficacy and safety of Volibris when co-administered with other treatments for PAH (e.g. prostanoids and phosphodiesterase type V inhibitors) has not been specifically studied in controlled clinical trials in PAH patients (see section 5.1). Therefore, caution is recommended in the case of co-administration.
Effect of ambrisentan on xenobiotic transporters
In vitro, ambrisentan has no inhibitory effect on the P-glycoprotein (Pgp)-mediated efflux of digoxin and is a weak substrate for Pgp-mediated efflux. Additional in vitro studies in rat and human hepatocytes showed that ambrisentan did not inhibit sodium-taurocholate co-transporter (NTCP), organic anion export pump (OATP), bile salt export pump (BSEP) and multi-drug resistance protein isoform-2 (MRP2). In vitro studies in rat hepatocytes also showed that ambrisentan has no inductive effects on Pgp, BSEP or MRP2.
Steady-state administration of ambrisentan in healthy volunteers had no clinically relevant effects on the single-dose pharmacokinetics of digoxin, a substrate for Pgp (see section 5.2).
4.6 Pregnancy And Lactation
Pregnancy
Volibris is contraindicated in pregnancy (see section 4.3). Animal studies have shown that ambrisentan is teratogenic. There is no experience in humans.
Volibris treatment must not be initiated in women of child-bearing potential unless the result of a pre-treatment pregnancy test is negative and reliable contraception is practiced. Monthly pregnancy tests during treatment with Volibris are recommended.
Women receiving Volibris must be advised of the risk of foetal harm and alternative therapy initiated if pregnancy occurs (see sections 4.3, 4.4 and 5.3).
Lactation
It is not known whether ambrisentan is excreted in human breast milk. The excretion of ambrisentan in milk has not been studied in animals. Therefore lactation is contraindicated in patients taking Volibris (see section 4.3).
Male fertility
The development of testicular tubular atrophy in male animals has been linked to the chronic administration of ERAs, including ambrisentan (see section 5.3). The effect on male human fertility is not known. Chronic administration of ambrisentan was not associated with a change in plasma testosterone in clinical studies.
4.7 Effects On Ability To Drive And Use Machines
No studies on the effects on the ability to drive and use machines have been performed.
4.8 Undesirable Effects
Experience from clinical studies
Safety of Volibris has been evaluated in clinical trials of more than 483 patients with PAH (see section 5.1). Adverse drug reactions (ADR) identified from 12 week placebo controlled clinical trial data are listed below by system organ class and frequency. With longer observation in uncontrolled studies (mean observation of 79 weeks), the safety profile was similar to that observed in the short term studies. Frequencies are defined as: very common ( 1/10); common ( 1/100 to <1/10); uncommon (1/1,000 to <1/100); rare (1/10,000 to <1/1,000); very rare (<1/10,000). For dose-related adverse reactions the frequency category reflects the higher dose of Volibris. Frequency categories do not account for other factors including varying study duration, pre-existing conditions and baseline patient characteristics. Adverse reaction frequency categories assigned based on clinical trial experience may not reflect the frequency of adverse events occurring during normal clinical practice. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
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1 The frequency of headache appeared higher with 10 mg Volibris.
2 The incidence of nasal congestion was dose related during Volibris therapy.
3 Peripheral oedema was reported more frequently with 10 mg Volibris. In clinical studies peripheral oedema was reported more commonly and tended to be more severe in patients 65 years (see section 4.4).
Laboratory abnormalities
Decreased haemoglobin (see section 4.4).
The frequency of decreased haemoglobin (anaemia) was higher with 10 mg Volibris. Across the 12 week placebo controlled Phase III clinical studies, mean haemoglobin concentrations decreased for patients in the Volibris groups and were detected as early as week 4 (decrease by 0.83 g/dl); mean changes from baseline appeared to stabilise over the subsequent 8 weeks. A total of 17 patients (6.5%) in the Volibris treatment groups had decreases in haemoglobin of 15% from baseline and which fell below the lower limit of normal.
Post-marketing data
In addition to adverse reactions identified from clinical studies, the following adverse reactions were identified during post-approval use of Volibris. Frequencies are defined as: common (
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4Most of the reported cases of cardiac failure were associated with fluid retention.
5Cases of worsening dyspnoea of unclear aetiology have been reported shortly after starting Volibris therapy.
6Cases of autoimmune hepatitis, including cases of exacerbation of autoimmune hepatitis, and hepatic injury have been reported during ambrisentan therapy.
4.9 Overdose
There is no experience in PAH patients of Volibris at daily doses greater than 10 mg. In healthy volunteers, single doses of 50 and 100 mg (5 to 10 times the maximum recommended dose) were associated with headache, flushing, dizziness, nausea and nasal congestion.
Due to the mechanism of action, an overdose of Volibris could potentially result in hypotension (see section 5.3). In the case of pronounced hypotension, active cardiovascular support may be required. No specific antidote is available.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: other anti-hypertensives, ATC code: C02KX02.
Mechanism of action
Ambrisentan is an orally active, propanoic acid-class, ERA selective for the endothelin A (ETA) receptor. Endothelin plays a significant role in the pathophysiology of PAH.
− Ambrisentan is a potent (Ki 0.016 nM) and highly selective ETA antagonist (approximately 4000-fold more selective for ETA as compared to ETB).
− Ambrisentan blocks the ETA receptor subtype, localized predominantly on vascular smooth muscle cells and cardiac myocytes. This prevents endothelin-mediated activation of second messenger systems that result in vasoconstriction and smooth muscle cell proliferation.
− The selectivity of ambrisentan for the ETA over the ETB receptor is expected to retain ETB receptor mediated production of the vasodilators nitric oxide and prostacyclin.
Efficacy
Two randomised, double-blind, multi-centre, placebo controlled, Phase 3 pivotal studies were conducted (ARIES-1 and 2). ARIES-1 included 201 patients and compared Volibris 5 mg and 10 mg with placebo. ARIES-2 included 192 patients and compared Volibris 2.5 mg and 5 mg with placebo. In both studies, Volibris was added to patients' supportive/background medication, which could have included a combination of digoxin, anticoagulants, diuretics, oxygen and vasodilators (calcium channel blockers, ACE inhibitors). Patients enrolled had IPAH or PAH associated with connective tissue disease. The majority of patients had WHO functional Class II (38.4%) or Class III (55.0%) symptoms. Patients with pre-existent hepatic disease (cirrhosis or clinically significantly elevated aminotransferases) and patients using other targeted therapy for PAH (e.g. prostanoids) were excluded. Haemodynamic parameters were not assessed in these studies.
The primary endpoint defined for the Phase 3 studies was improvement in exercise capacity assessed by change from baseline in 6 minute walk distance (6MWD) at 12 weeks. In both studies, treatment with Volibris resulted in a significant improvement in 6MWD for each dose of Volibris.
The placebo-adjusted improvement in mean 6MWD at week 12 compared to baseline was 30.6 m (95% CI: 2.9 to 58.3; p=0.008) and 59.4 m (95% CI: 29.6 to 89.3; p<0.001) for the 5 mg group, in ARIES 1 and 2 respectively. The placebo-adjusted improvement in mean 6MWD at week 12 in patients in the 10 mg group in ARIES-1 was 51.4 m (95% CI: 26.6 to 76.2; p <0.001).
A pre-specified combined analysis of the Phase 3 studies (ARIES-C) was conducted. The placebo-adjusted mean improvement in 6MWD was 44.6 m (95% CI: 24.3 to 64.9; p<0.001) for the 5 mg dose, and 52.5 m (95% CI: 28.8 to 76.2; p<0.001) for the 10 mg dose.
In ARIES-2, Volibris (combined dose group) significantly delayed the time to clinical worsening of PAH compared to placebo (p<0.001), the hazard ratio demonstrated a 80% reduction (95% CI: 47% to 92%). The measure included: death, lung transplantation, hospitalisation for PAH, atrial septostomy, addition of other PAH therapeutic agents and early escape criteria. A statistically significant increase (3.41 ± 6.96) was observed for the combined dose group in the physical functioning scale of the SF-36 Health Survey compared with placebo (-0.20 ± 8.14, p=0.005). Treatment with Volibris led to a statistically significant improvement in Borg Dyspnea Index (BDI) at week 12 (placebo-adjusted BDI of -1.1 (95% CI: -1.8 to -0.4; p=0.019; combined dose group)).
Long term data
Patients enrolled into ARIES 1 and 2 were eligible to enter a long term open label extension study ARIES E (n=383).
The effect of Volibris on the outcome of the disease is unknown. The observed probability of survival at 1 year for subjects receiving Volibris (combined Volibris dose group) was 95% and at 2 years was 84%.
In an open label study (AMB222), Volibris was studied in 36 patients to evaluate the incidence of increased serum aminotransferase concentrations in patients who had previously discontinued other ERA therapy due to aminotransferase abnormalities. During a mean of 53 weeks of treatment with Volibris, none of the patients enrolled had a confirmed serum ALT >3xULN that required permanent discontinuation of treatment. Fifty percent of patients had increased from 5 mg to 10 mg Volibris during this time.
The cumulative incidence of serum aminotransferase abnormalities >3xULN in all Phase 2 and 3 studies (including respective open label extensions) was 17 of 483 subjects over a mean exposure duration of 79.5 weeks. This is an event rate of 2.3 events per 100 patient years of exposure for Volibris.
Other clinical information
An improvement in haemodynamic parameters was observed in patients with PAH after 12 weeks (n=29) in a Phase 2 study (AMB220). Treatment with Volibris resulted in an increase in mean cardiac index, a decrease in mean pulmonary artery pressure, and a decrease in mean pulmonary vascular resistance.
No clinically meaningful effects on the pharmacokinetics of ambrisentan or sildenafil were seen during a drug-drug interaction study in healthy volunteers, and the combination was well tolerated. The number of patients who received concomitant Volibris and sildenafil in ARIES-E and AMB222 was 22 patients (5.7%) and 17 patients (47%), respectively. No additional safety concerns were identified in these patients.
5.2 Pharmacokinetic Properties
Absorption
Ambrisentan is absorbed rapidly in humans. After oral administration, maximum plasma concentrations (Cmax) of ambrisentan typically occur around 1.5 hours post-dose under both fasted and fed conditions. Cmax and area under the plasma concentration-time curve (AUC) increase dose proportionally over the therapeutic dose range. Steady-state is generally achieved following 4 days of repeat dosing.
A food-effect study involving administration of ambrisentan to healthy volunteers under fasting conditions and with a high-fat meal indicated that the Cmax was decreased 12% while the AUC remained unchanged. This decrease in peak concentration is not clinically significant, and therefore ambrisentan can be taken with or without food.
Distribution
Ambrisentan is highly plasma protein bound. The in vitro plasma protein binding of ambrisentan was, on average, 98.8% and independent of concentration over the range of 0.2 – 20 microgram/ml. Ambrisentan is primarily bound to albumin (96.5%) and to a lesser extent to alpha1-acid glycoprotein.
The distribution of ambrisentan into red blood cells is low, with a mean blood:plasma ratio of 0.57 and 0.61 in males and females, respectively.
Metabolism
Ambrisentan is a non-sulphonamide (propanoic acid) ERA.
Ambrisentan is glucuronidated via several UGT isoenzymes (UGT1A9S, UGT2B7S and UGT1A3S) to form ambrisentan glucuronide (13%). Ambrisentan also undergoes oxidative metabolism mainly by CYP3A4 and to a lesser extent by CYP3A5 and CYP2C19 to form 4-hydroxymethyl ambrisentan (21%) which is further glucuronidated to 4-hydroxymethyl ambrisentan glucuronide (5%). The binding affinity of 4-hydroxymethyl ambrisentan for the human endothelin receptor is 65-fold less than ambrisentan. Therefore at concentrations observed in the plasma (approximately 4% relative to parent ambrisentan), 4-hydroxymethyl ambrisentan is not expected to contribute to pharmacological activity of ambrisentan.
In vitro data have shown that at therapeutic concentrations, ambrisentan does not inhibit UGT1A1, UGT1A6, UGT1A9, UGT2B7 or cytochrome P450 enzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A4. Additional in vitro studies showed that ambrisentan does not inhibit NTCP, OATP or BSEP. Furthermore, ambrisentan does not induce MRP2, Pgp or BSEP.
The effects of steady-state ambrisentan (10 mg once daily) on the pharmacokinetics and pharmacodynamics of a single dose of warfarin (25 mg), as measured by PT and INR, were investigated in 20 healthy volunteers. Ambrisentan did not have any clinically relevant effects on the pharmacokinetics or pharmacodynamics of warfarin. Similarly, co-administration with warfarin did not affect the pharmacokinetics of ambrisentan (see section 4.5).
The effect of 7-day dosing of sildenafil (20 mg three times daily) on the pharmacokinetics of a single dose of ambrisentan, and the effects of 7-day dosing of ambrisentan (10 mg once daily) on the pharmacokinetics of a single dose of sildenafil were investigated in 19 healthy volunteers. With the exception of a 13% increase in sildenafil Cmax following co-administration with ambrisentan, there were no other changes in the pharmacokinetic parameters of sildenafil, N-desmethyl-sildenafil and ambrisentan. This slight increase in sildenafil Cmax is not considered clinically relevant (see section 4.5).
The effects of steady-state ambrisentan (10 mg once daily) on the pharmacokinetics of a single dose of tadalafil, and the effects of steady-state tadalafil (40 mg once daily) on the pharmacokinetics of a single dose of ambrisentan were studied in 23 healthy volunteers. Ambrisentan did not have any clinically relevant effects on the pharmacokinetics of tadalafil. Similarly, co-administration with tadalafil did not affect the pharmacokinetics of ambrisentan (see section 4.5).
The effects of repeat dosing of ketoconazole (400 mg once daily) on the pharmacokinetics of a single dose of 10 mg ambrisentan were investigated in 16 healthy volunteers. Exposures of ambrisentan as measured by AUC(0-inf) and Cmax were increased by 35% and 20%, respectively. This change in exposure is unlikely to be of any clinical relevance and therefore Volibris may be co-administered with ketoconazole.
The effects of repeat dosing of cyclosporine A (100 – 150 mg twice daily) on the steady-state pharmacokinetics of ambrisentan (5 mg once daily), and the effects of repeat dosing of ambrisentan (5 mg once daily) on the steady-state pharmacokinetics of cyclosporine A (100 – 150 mg twice daily) were studied in healthy volunteers. The Cmax 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 AUC0-last and trough concentrations, and a 29% increase in digoxin Cmax. The increase in digoxin exposure observed in the presence of multiple doses of ambrisentan was not considered clinically relevant, and no dose adjustment of digoxin is warranted (see section 4.5).
The effects of 12 days dosing with ambrisentan (10 mg once daily) on the pharmacokinetics of a single dose of oral contraceptive containing ethinyl estradiol (35 μg) and norethindrone (1 mg) were studied in healthy female volunteers. The Cmax and AUC(0–
Elimination
Ambrisentan and its metabolites are eliminated primarily in the bile following hepatic and/or extra-hepatic metabolism. Approximately 22% of the administered dose is recovered in the urine following oral administration with 3.3% being unchanged ambrisentan. Plasma elimination half-life in humans ranges from 13.6 to 16.5 hours.
Special populations
Based on the results of a population pharmacokinetic analysis in healthy volunteers and patients with PAH, the pharmacokinetics of ambrisentan were not significantly influenced by gender or age (see section 4.2).
Renal impairment
Ambrisentan does not undergo significant renal metabolism or renal clearance (excretion). In a population pharmacokinetic analysis, creatinine clearance was found to be a statistically significant covariate affecting the oral clearance of ambrisentan. The magnitude of the decrease in oral clearance is modest (20-40%) in patients with moderate renal impairment and therefore is unlikely to be of any clinical relevance. However, caution should be used in patients with severe renal impairment (see section 4.2).
Hepatic impairment
The main routes of metabolism of ambrisentan are glucuronidation and oxidation with subsequent elimination in the bile and therefore hepatic impairment would be expected to increase exposure (Cmax and AUC) of ambrisentan. In a population pharmacokinetic analysis, the oral clearance was shown to be decreased as a function of increasing bilirubin levels. However, the magnitude of effect of bilirubin is modest (compared to the typical patient with a bilirubin of 0.6 mg/dl, a patient with an elevated bilirubin of 4.5 mg/dl would have approximately 30% lower oral clearance of ambrisentan). The pharmacokinetics of ambrisentan in patients with severe hepatic impairment (with or without cirrhosis) has not been studied. Therefore Volibris should not be initiated in patients with severe hepatic impairment or clinically significant elevated hepatic aminotransferases (>3xULN) (see sections 4.3 and 4.4).
5.3 Preclinical Safety Data
Due to the class primary pharmacologic effect, a large single dose of ambrisentan (i.e. an overdose) could lower arterial pressure and have the potential for causing hypotension and symptoms related to vasodilation.
Ambrisentan was not shown to be an inhibitor of bile acid transport or to produce overt hepatotoxicity.
Inflammation and changes in the nasal cavity epithelium have been seen in rodents after chronic administration at exposures below the therapeutic levels in humans. In dogs, slight inflammatory responses were observed following chronic high dose administration of ambrisentan at exposures greater than 20–fold that observed in patients.
Nasal bone hyperplasia of the ethmoid turbinates has been observed in the nasal cavity of rats treated with ambrisentan, at exposure levels 3-fold the clinical AUC. Nasal bone hyperplasia has not been observed with ambrisentan in mice or dogs. In the rat, hyperplasia of nasal turbinate bone is a recognised response to nasal inflammation, based on experience with other compounds.
Ambrisentan was clastogenic when tested at high concentrations in mammalian cells in vitro. No evidence for mutagenic or genotoxic effects of ambrisentan were seen in bacteria or in two in vivo rodent studies.
There were no treatment-related increases in the incidence of tumours in 2 year oral studies in rats and mice.
Testicular tubular atrophy, which was occasionally associated with aspermia, was observed in oral repeat dose toxicity and fertility studies with male rats and mice without safety margin. The testicular changes were not fully recoverable during the off-dose periods evaluated. However no testicular changes were observed in dog studies of up to 39 weeks duration at an exposure 35–fold that seen in humans based on AUC. 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, interventricular septal defects, trunk vessel defects, thyroid and thymus abnormalities, ossification of the basisphenoid bone and increased incidence of left umbilical artery were seen in the rat study. Teratogenicity is a suspected class effect of ERAs.
Administration of ambrisentan to female rats from late-pregnancy through lactation caused adverse events on maternal behaviour, reduced pup survival and impairment of the reproductive capability of the offspring (with observation of small testes at necropsy), at exposure 3-fold the AUC at the maximum recommended human dose.
6. Pharmaceutical Particulars
6.1 List Of Excipients
5 mg film-coated tablets
Tablet core
Lactose monohydrate
Microcrystalline cellulose
Croscarmellose sodium
Magnesium stearate
5 mg film-coated tablets
Film coat
Polyvinyl alcohol (Partially Hydrolysed)
Talc (E553b)
Titanium dioxide (E171)
Macrogol / PEG 3350
Lecithin (Soya) (E322)
Allura red AC Aluminium Lake (E129)
10 mg film-coated tablets
Tablet core
Lactose monohydrate
Microcrystalline cellulose
Croscarmellose sodium
Magnesium stearate
10 mg film-coated tablets
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
2 years.
6.4 Special Precautions For Storage
This medicinal product does not require any special storage conditions.
6.5 Nature And Contents Of Container
PVC/PVDC/aluminium foil blisters. Pack sizes of 10 or 30 film-coated tablets. Not all pack sizes may be marketed.
6.6 Special Precautions For Disposal And Other Handling
No special requirements.
7. Marketing Authorisation Holder
Glaxo Group Ltd
Greenford
Middlesex
UB6 0NN
United Kingdom
8. Marketing Authorisation Number(S)
5 mg film-coated tablets
EU/1/08/451/001
EU/1/08/451/002
10 mg film-coated tablets
EU/1/08/451/003
EU/1/08/451/004
9. Date Of First Authorisation/Renewal Of The Authorisation
21/04/2008
10. Date Of Revision Of The Text
18/08/2011
Detailed information on this medicinal product is available on the website of the European Medicines
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