Ambrisentan generis

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT AMBRISENTAN GENERIS (AMBRISENTAN GENERIS)

Composition:

Active substance: ambrisentan;

One film-coated tablet contains ambrisentan 5 mg or 10 mg;

Excipients:

Tablets of 5 mg: magnesium stearate, sodium croscarmellose, lactose monohydrate, microcrystalline cellulose 102;
Coating OPADRY® II 85G94065 PINK: polyvinyl alcohol, titanium dioxide (E 171), talc, soy lecithin, macrogol 3350, Allura Red AC aluminum lake (E 129);

Tablets of 10 mg: magnesium stearate, sodium croscarmellose, lactose monohydrate, microcrystalline cellulose 102;
OPADRY® II 85G94101 RED: polyvinyl alcohol, titanium dioxide (E 171), talc, soy lecithin, macrogol 3350, Allura Red AC aluminum lake (E 129).

Pharmaceutical form. Film-coated tablets.

Main physicochemical characteristics:

5 mg: pale pink, square-shaped, approximately 6.9 mm, biconvex film-coated tablets, embossed with "AS" on one side and "5" on the other;

10 mg: deep pink, oval-shaped, approximately 9.8 × 4.9 mm, biconvex film-coated tablets, embossed with "AS" on one side and "10" on the other.

Pharmacotherapeutic group

Medicinal products used in cardiovascular therapy. Antihypertensive agents. Other antihypertensive agents. Antihypertensive agents for the treatment of pulmonary arterial hypertension. ATC code C02K X02.

Pharmacological Properties

Pharmacodynamics

Mechanism of action

Ambrisentan is an orally active agent of the propanoic acid class, a selective endothelin receptor type A (ETA) antagonist (ERA). Endothelin plays a significant role in the pathophysiology of pulmonary arterial hypertension (PAH). Ambrisentan is a selective antagonist of the ET_A receptor (approximately 4,000-fold more selective for ET_A than for ET_B). Ambrisentan blocks the ET_A receptor subtype, predominantly located on vascular smooth muscle cells and cardiac myocytes. This prevents endothelin-mediated activation of secondary messenger systems, which leads to vasoconstriction and smooth muscle cell proliferation.

The selectivity of ambrisentan for the ET_A receptor over the ET_B receptor is expected to preserve ET_B receptor-mediated production of vasodilatory nitric oxide and prostacyclin.

Clinical efficacy and safety

Two randomized, double-blind, placebo-controlled, multicenter Phase 3 trials (ARIES-1 and ARIES-2) were conducted. 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 background therapies, which could include combinations of digoxin, anticoagulants, diuretics, oxygen, and vasodilators (calcium channel blockers, ACE inhibitors). Enrolled patients had idiopathic PAH (IPAH) or PAH associated with connective tissue disease (PAH-CTD). The majority of patients had symptoms classified as WHO functional class (FC) II (38.4%) or III (55%). Patients with pre-existing liver disease (cirrhosis or clinically significant elevated aminotransferases) and patients receiving other targeted PAH therapies (e.g., prostacyclins) were excluded. Hemodynamic 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 the 6-minute walk distance (6MWD) at 12 weeks. In both studies, treatment with ambrisentan resulted in significant improvement in 6MWD for each ambrisentan dose.

The placebo-corrected mean improvement in 6MWD at week 12 from baseline was 30.6 m (95% CI: 2.9–58.3; p = 0.008) and 59.4 m (95% CI: 29.6–89.3; p < 0.001) for the 5 mg dose in ARIES-1 and ARIES-2, respectively. The placebo-corrected mean improvement in 6MWD at week 12 in the 10 mg group in ARIES-1 was 51.4 m (95% CI: 26.6–76.2; p < 0.001).

A pre-specified pooled analysis of the Phase 3 studies (ARIES-C) was conducted. The placebo-corrected mean improvement in 6MWD was 44.6 m (95% CI: 24.3–64.9; p < 0.001) for the 5 mg dose and 52.5 m (95% CI: 28.8–76.2; p < 0.001) for the 10 mg dose. In the ARIES-2 study, ambrisentan (combined dose) significantly delayed time to clinical worsening of PAH compared to placebo (p < 0.001), with a hazard ratio indicating an 80% risk reduction (95% CI: 47–92%). The composite endpoint included: death, lung transplantation, hospitalization due to PAH, atrial septostomy, addition of other PAH therapies, and early withdrawal criteria. A statistically significant improvement (3.41 ± 6.96) was observed in the physical functioning domain of the SF-36 Health Survey in the combined dose group compared to placebo (-0.20 ± 8.14; p = 0.005). Treatment with ambrisentan led to a statistically significant improvement in the Borg dyspnea index (BDI) at week 12 (placebo-corrected BDI was -1.1 [95% CI: -1.8 to -0.4; p = 0.019; combined dose group]).

Long-term data

Patients enrolled in ARIES-1 and ARIES-2 were eligible to participate in the long-term open-label extension study ARIES-E (n = 383). The overall mean exposure was approximately 145 ± 80 weeks, with a maximum exposure of approximately 295 weeks. The primary endpoints of this study were the frequency and severity of adverse reactions associated with long-term exposure to ambrisentan, including serum liver function tests (LFTs). The safety data obtained during long-term exposure to ambrisentan in this study were generally consistent with those observed in the 12-week placebo-controlled studies.

The observed probability of patient survival 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 evaluated in 36 patients to assess the incidence of serum aminotransferase elevation in patients who had previously discontinued another ERA therapy due to aminotransferase abnormalities. Over a mean treatment duration of 53 weeks with ambrisentan, none of the patients had a confirmed serum ALT level > 3×ULN requiring permanent discontinuation of treatment. Fifty percent of patients increased their ambrisentan dose from 5 mg to 10 mg during this period. The cumulative incidence of serum aminotransferase abnormalities > 3×ULN across all Phase 2 and 3 studies (including corresponding open-label extensions) was 17 out of 483 subjects over a mean exposure duration of 79.5 weeks. This corresponds to an incidence rate of 2.3 cases per 100 patient-years of ambrisentan exposure. In the long-term open-label extension study ARIES-E, the 2-year risk of developing serum aminotransferase elevation > 3×ULN in patients receiving ambrisentan was 3.9%.

Other clinical information

In a Phase 2 study (AMB220) in patients with PAH, improvements in hemodynamic parameters were observed after 12 weeks (n = 29). Treatment with ambrisentan led to an increase in mean cardiac index, a reduction in mean pulmonary artery pressure, and a reduction in mean pulmonary vascular resistance. During ambrisentan therapy, decreases in systolic and diastolic blood pressure were reported. In the 12-week placebo-controlled clinical studies, the mean reduction in systolic and diastolic blood pressure from baseline to end of treatment was 3 mm Hg and 4.2 mm Hg, respectively. In the long-term open-label study ARIES-E, the mean reduction in systolic and diastolic blood pressure was maintained over 4 years of ambrisentan treatment. In a drug interaction study in healthy volunteers, no clinically significant effect on the pharmacokinetics of ambrisentan or sildenafil was observed, and this combination was well tolerated. The number of patients who received ambrisentan and sildenafil concomitantly in the ARIES-E and AMB222 studies was 22 (5.7%) and 17 (47%), respectively. No additional safety concerns were observed in these patients.

Clinical efficacy in combination with tadalafil

To evaluate the efficacy of initial combination therapy with ambrisentan and tadalafil compared to monotherapy with either ambrisentan or tadalafil alone, a multicenter, double-blind, active-comparator-controlled, event-driven Phase 3 outcomes study (AMB112565/AMBITION) was conducted in 500 patients with PAH, randomized 2:1:1, respectively. No patient received placebo. The primary comparison was combination therapy versus pooled monotherapy groups. Additional supportive comparisons were made between the combination therapy group and each monotherapy group individually. Patients with significant anemia, fluid retention, or rare retinal disorders were excluded according to study criteria. Patients with baseline ALT or AST levels > 2×ULN were also excluded. At baseline, 96% of patients had not received prior specific PAH therapy, and the mean time from diagnosis to study entry was 22 days. Patients initiated treatment with ambrisentan 5 mg and tadalafil 20 mg, with dose titration to tadalafil 40 mg at week 4 and ambrisentan 10 mg at week 8, if tolerated. The mean duration of double-blind treatment in the combination therapy group was over 1.5 years.

The primary endpoint was time to first occurrence of clinical failure, defined as:

• death, or
• hospitalization due to worsening PAH;
• disease progression;
• unsatisfactory long-term clinical response.

The mean age of all patients was 54 years (SD 15; range 18–75 years). WHO FC distribution at baseline was FC II (31%) and FC III (69%). Idiopathic or heritable PAH was the most common etiology in the study population (56%), followed by PAH associated with connective tissue diseases (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 m.

Outcome endpoints

Treatment with combination therapy resulted in a 50% reduction in risk (hazard ratio [HR] 0.502; 95% CI: 0.348–0.724; p = 0.0002) of the composite clinical failure endpoint at the final assessment visit compared to the pooled monotherapy group. The treatment effect was driven by a 63% reduction in hospitalizations with combination therapy, which was established early and sustained. The efficacy of combination therapy on the primary endpoint was consistent when compared to individual monotherapies and across subgroups by age, ethnicity, geographic region, and etiology (IPAH/hPAH and PAH-CTD). The effect was significant in both FC II and FC III patients.

Table 1

	Ambientan + tadalafil (N = 253)	Combined monotherapy (N = 247)	Ambrisentan monotherapy (N = 126)	Tadalafil monotherapy (N = 121)
Time to first clinical failure (defined)
No clinical failure (%)	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 (resolved)
Death (from all causes)	9 (4 %)	8 (3 %)	2 (2 %)	6 (5 %)
Hospitalization due to PAH exacerbation	10 (4 %)	30 (12 %)	18 (14 %)	12 (10 %)
Disease progression	10 (4 %)	16 (6 %)	12 (10 %)	4 (3 %)
Inadequate long-term clinical response	17 (7 %)	23 (9 %)	11 (9 %)	12 (10 %)
Time to first hospitalization due to worsening PAH (defined)
No first hospitalization (%)	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

The secondary endpoints were tested:

Table 2

Secondary endpoints (change from baseline to week 24)	Ambrisentan + tadalafil	Combined monotherapy	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
% of patients achieving a satisfactory clinical response at week 24	39	29	Odds ratio 1.56; 95% CI: 1.05; 2.32	p = 0.026
6MWD (m, mean change)	49.0	8	22.75 m; 95% CI: 12.00; 33.50	p < 0.0001

Idiopathic Pulmonary Fibrosis

A study of 492 patients (ambrisentan N = 329, placebo N = 163) with idiopathic pulmonary fibrosis (IPF), 11% of whom had secondary pulmonary hypertension (WHO Group 3), was conducted. However, the study was terminated early when it was determined that the primary efficacy endpoint could not be achieved (ARTEMIS-IPF study). Progression of IPF (including respiratory hospitalizations) or death occurred in 90 patients (27%) in the ambrisentan group compared to 28 patients (17%) in the placebo group. Therefore, ambrisentan is contraindicated in patients with IPF, with or without secondary pulmonary hypertension (see section "Special warnings and precautions for use").

Pediatric patients

Study AMB112529

The safety and tolerability of once-daily ambrisentan administered for 24 weeks were evaluated in an open-label, uncontrolled study involving 41 pediatric patients with PAH aged 8 to 18 years (median: 13 years). The etiology of PAH was idiopathic (n = 26; 63%), persistent congenital PAH despite surgical repair (n = 11; 27%), secondary to connective tissue disease (n = 1; 2%), or familial (n = 3; 7.3%). Among the 11 patients with congenital heart disease, 9 had ventricular septal defects, 2 had atrial septal defects, and 1 had a persistent patent ductus arteriosus. Patients were classified as WHO Functional Class (FC) II (n = 32; 78%) or FC III (n = 9; 22%) at initiation of study drug. At study initiation, patients were receiving PAH therapy (most commonly PDE5i monotherapy [n = 18; 44%], combination therapy with PDE5i and prostanoids [n = 8; 20%], or prostanoid monotherapy [n = 1; 2%]); they continued their PAH therapy during the study. Patients were divided into two dosing groups: ambrisentan 2.5 mg or 5 mg once daily (low dose, n = 21) and ambrisentan 2.5 mg or 5 mg once daily titrated to 5 mg, 7.5 mg, or 10 mg depending on body weight (high dose, n = 20). Overall, 20 patients across both dosing groups were titrated after 2 weeks based on clinical response and tolerability; 37 patients completed the study; 4 patients discontinued. There was no dose trend observed regarding the effect of ambrisentan on the primary measure of exercise capacity (6MWD). The mean change from baseline at 24 weeks in 6MWD for patients in the low- and high-dose groups with baseline and 24-week measurements was +55.14 m (95% CI: 4.32–105.95) in 18 patients and +26.25 m (95% CI: -4.59 to 57.09) in 18 patients, respectively. The mean change from baseline at 24 weeks in 6MWD for 36 patients (both doses combined) was +40.69 m (95% CI: 12.08–69.31). These results were consistent with those observed in adults. At 24 weeks, 95% and 100% of patients in the low- and high-dose groups, respectively, remained stable (functional class unchanged or improved). Kaplan-Meier estimate of freedom from clinical worsening of PAH (death [all causes], lung transplantation, or hospitalization due to worsening PAH or PAH-related deterioration) at 24 weeks was 86% and 85% in the low- and high-dose groups, respectively.

Hemodynamics were measured in 5 patients (low-dose group). The mean increase in cardiac index compared to baseline was +0.94 L/min/m², the mean reduction in mean pulmonary arterial pressure was -2.2 mmHg, and the mean reduction in PVR was -277 dyn·s/cm⁵ (-3.46 mmHg/L/min).

In pediatric patients with PAH receiving ambrisentan for 24 weeks, the mean geometric reduction from baseline in NT-pro-BNP was 31% in the low-dose group (2.5 and 5 mg) and 28% in the high-dose group (5 mg, 7.5 mg, and 10 mg).

Study AMB114588

Long-term data were obtained from 38 of the 41 pediatric patients with PAH aged 8 to 18 years who received ambrisentan in the 24-week randomized study. The majority of subjects who transitioned into this long-term extension of ambrisentan had idiopathic or heritable PAH (68%) according to baseline of AMB112529. The mean duration of exposure (± standard deviation) to ambrisentan treatment was approximately 4 ± 2.5 years (range: 3 months to 10 years). Patients could receive additional PAH therapy if needed during the open-label extension, and the dose of ambrisentan could be adjusted down to 2.5 mg. Overall, 66% of patients continuing in the study remained on the same ambrisentan dose they were receiving in AMB112529.

Clinical worsening was defined as death (all causes), listing for lung transplantation or atrial septostomy, or worsening of PAH leading to hospitalization, change in ambrisentan dose, addition or change in dose of existing targeted PAH therapy, increase in WHO functional class; 20% decrease in 6MWD, or signs/symptoms of right heart failure. At the same time points, overall 71% of patients had no worsening of PAH, while clinical worsening of PAH based on at least one criterion occurred in 11 participants (29%) across all 4 dose groups, with more than one clinical worsening criterion in 5 of the 11 participants (45%). Kaplan-Meier survival estimates were 94.74% and 92.11% at 3 and 4 years after initiation of treatment, respectively. Changes from baseline in AMB112529 to the end of the extension study showed a mean increase in 6MWD of 58.4 ± 88 meters (17% improvement compared to baseline) for all dose groups.

In study AMB114588, all 4 WHO functional classes (I, II, III, and IV) were represented among participants, more than half of whom were in class II (n = 22; 58%), with the remainder in class I (n = 9; 24%), III (n = 6; 16%), or IV (n = 1; 3%). Changes from baseline in AMB112529 to the end of the extension study (N = 29) demonstrated improvement (45%) or no change (55%) with no worsening of WHO functional class, along with a mean increase in 6MWD of 17%, respectively.

Pharmacokinetics

Absorption

Ambrisentan is rapidly absorbed in humans. After oral administration, peak plasma concentration (Cmax) of ambrisentan is typically achieved approximately 1.5 hours after dosing, both in the fasting state and after food intake. Cmax and area under the concentration-time curve (AUC) increase proportionally with dose over the therapeutic dose range. Steady state is typically achieved after 4 days of repeated dosing. A food-effect study involving administration of ambrisentan to healthy volunteers in the fasting state and with a high-fat meal showed that Cmax is reduced by 12%, while AUC remains unchanged. This reduction in peak concentration is not clinically significant; therefore, ambrisentan can be administered with or without food.

Distribution

Ambrisentan is highly bound to plasma proteins. In vitro, the binding of ambrisentan to plasma proteins averaged 98.8% and was independent of concentration over the range of 0.2–20 µg/mL. Ambrisentan binds predominantly to albumin (96.5%) and to a lesser extent to alpha-1-acid glycoprotein.

Distribution of ambrisentan into erythrocytes is low, with a mean blood-to-plasma ratio of 0.57 and 0.61 in men and women, respectively.

Biological transformation

Ambrisentan is a non-sulfonamide (propanoic acid) ERA. Ambrisentan undergoes glucuronidation by several UGT isoenzymes (UGT1A9S, UGT2B7S, and UGT1A3S), forming ambrisentan glucuronide (13%). Ambrisentan also undergoes oxidative metabolism, primarily by CYP3A4 and to a lesser extent by CYP3A5 and CYP2C19, forming 4-hydroxymethylambrisentan (21%), which is further glucuronidated to 4-hydroxymethylambrisentan glucuronide (5%). The binding affinity of 4-hydroxymethylambrisentan for the human endothelin receptor is 65-fold lower than that of ambrisentan. Thus, at plasma concentrations observed (approximately 4% relative to parent ambrisentan), 4-hydroxymethylambrisentan is not expected to contribute to the pharmacological activity of ambrisentan.

In vitro data indicate that ambrisentan at a concentration of 300 µM caused less than 50% inhibition of UGT1A1, UGT1A6, UGT1A9, UGT2B7 (up to 30%), or cytochrome P450 enzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4 (up to 25%). In vitro, ambrisentan does not inhibit human transporters at clinically relevant concentrations, including P-glycoprotein (P-gp), BCRP, MRP2, BSEP, OATP1B1, OATP1B3, and NTCP. Additionally, ambrisentan did not induce expression of MRP2, Pgp, or BSEP proteins in rat hepatocytes. Collectively, in vitro data suggest that ambrisentan at clinically relevant concentrations (plasma Cmax up to 3.2 µM) will not affect 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 effect of steady-state ambrisentan (10 mg once daily) on the pharmacokinetics and pharmacodynamics of a single dose of warfarin (25 mg), measured by PT and INR, was evaluated in 20 healthy volunteers. Ambrisentan had no clinically significant effect on the pharmacokinetics or pharmacodynamics of warfarin. Similarly, coadministration with warfarin did not affect the pharmacokinetics of ambrisentan (see section "Interaction with other medicinal products and other forms of interaction").

The effect of 7-day administration of sildenafil (20 mg three times daily) on the pharmacokinetics of a single dose of ambrisentan, and the effect of 7-day administration of ambrisentan (10 mg once daily) on the pharmacokinetics of a single dose of sildenafil, were evaluated in 19 healthy volunteers. Except for a 13% increase in Cmax of sildenafil after coadministration with ambrisentan, no other changes in pharmacokinetic parameters of sildenafil, N-desmethylsildenafil, or ambrisentan were observed. This minor increase in sildenafil Cmax is not considered clinically significant (see section "Special warnings and precautions for use"). The effect of steady-state ambrisentan (10 mg once daily) on the pharmacokinetics of a single dose of tadalafil and the effect of steady-state tadalafil (40 mg once daily) on the pharmacokinetics of a single dose of ambrisentan were evaluated in 23 healthy volunteers. Ambrisentan had no clinically significant effect on the pharmacokinetics of tadalafil. Similarly, coadministration with tadalafil did not affect the pharmacokinetics of ambrisentan (see section "Special warnings and precautions for use").

The effect of repeated ketoconazole (400 mg once daily) on the pharmacokinetics of a single 10 mg dose of ambrisentan was evaluated in 16 healthy volunteers. Exposure to ambrisentan, measured by AUC (0-inf) and Cmax, increased by 35% and 20%, respectively. This change in exposure is unlikely to have any clinical significance; therefore, ambrisentan may be used concomitantly with ketoconazole.

The effect of repeated administration of cyclosporine A (100–150 mg twice daily) on the pharmacokinetics of ambrisentan (5 mg once daily) at steady state, and the effect of repeated administration of ambrisentan (5 mg once daily) on the steady-state pharmacokinetics of cyclosporine A (100–150 mg twice daily), was evaluated in healthy volunteers. Cmax and AUC(0–∞) of ambrisentan increased (by 48% and 121%, respectively) when multiple doses of cyclosporine A were administered. Based on these changes, when coadministered with cyclosporine A, ambrisentan should be limited to a dose of 5 mg once daily in adult patients or children with body weight ≥ 50 kg; for children with body weight ≥ 20 to < 50 kg, the dose should be limited to 2.5 mg once daily (see section "Special warnings and precautions for use"). However, multiple doses of ambrisentan had no clinically significant effect on cyclosporine A exposure; therefore, dose adjustment of cyclosporine A is not warranted.

The effect of single and repeated administration of rifampicin (600 mg once daily) on the steady-state pharmacokinetics of ambrisentan (10 mg once daily) was evaluated in healthy volunteers. Following initial doses of rifampicin, a transient increase in AUC(0–∞) of ambrisentan was observed (121% and 116% after the first and second dose of rifampicin, respectively), likely due to rifampicin-mediated inhibition of OATP. However, there was no clinically significant effect on ambrisentan exposure on day 8 after multiple doses of rifampicin. Patients receiving ambrisentan therapy should be closely monitored at the initiation of rifampicin treatment (see sections "Interaction with other medicinal products and other forms of interaction" and "Special warnings and precautions for use").

The effect of repeated administration of ambrisentan (10 mg) on the pharmacokinetics of a single dose of digoxin was evaluated in 15 healthy volunteers. Multiple doses of ambrisentan resulted in a slight increase in AUC 0-last and minimum concentration of digoxin and a 29% increase in Cmax of digoxin. The increase in digoxin exposure observed with multiple doses of ambrisentan was not considered clinically significant; therefore, dose adjustment of digoxin is not warranted (see section "Special warnings and precautions for use").

The effect of 12-day administration of ambrisentan (10 mg once daily) on the pharmacokinetics of a single dose of an oral contraceptive containing ethinylestradiol (35 µg) and norethindrone (1 mg) was evaluated in healthy volunteers. Cmax and AUC (0–∞) were slightly decreased for ethinylestradiol (8% and 4%, respectively) and slightly increased for norethindrone (13% and 14%, respectively). These changes in ethinylestradiol or norethindrone exposure were minor and unlikely to be clinically significant (see section "Interaction with other medicinal products and other forms of interaction").

Elimination

Ambrisentan and its metabolites are primarily eliminated via bile following hepatic and/or extrahepatic metabolism. Approximately 22% of the administered dose is recovered in urine after oral administration, with 3.3% as unchanged ambrisentan. The elimination half-life from human plasma ranges from 13.6 to 16.5 hours.

Special patient populations

Adults (sex, age)

According to results from population pharmacokinetic analyses in healthy volunteers and patients with PAH, sex or age did not have a significant effect on the pharmacokinetics of ambrisentan (see section "Dosage and administration").

Pediatric patients

Pharmacokinetic data in children are limited. Pharmacokinetics were studied in pediatric patients aged 8 to 18 years in one clinical study (AMB112529). The pharmacokinetics of ambrisentan after oral administration in pediatric patients aged 8 to 18 years with PAH were generally consistent with those in adults after accounting for body weight. The modeled pediatric steady-state exposures (AUCss) for low and high doses across all body weight groups were within the 5th and 95th percentiles of historical adult exposures at low dose (5 mg) or high dose (10 mg), respectively.

Renal impairment

Ambrisentan does not undergo significant renal metabolism or renal clearance. In a population pharmacokinetic analysis, creatinine clearance was identified as a statistically significant covariate affecting oral clearance of ambrisentan. The magnitude of reduction in oral clearance is minor (20–40%) in patients with moderate renal impairment and is unlikely to have any clinical significance. However, ambrisentan should be used with caution in patients with severe renal impairment (see section "Special warnings and precautions for use").

Hepatic impairment

The primary metabolic pathways of ambrisentan are glucuronidation and oxidation, followed by biliary excretion; therefore, hepatic impairment may lead to increased exposure (Cmax and AUC) to ambrisentan. Population pharmacokinetic analysis has shown that oral clearance decreases as a function of increasing bilirubin levels. However, the magnitude of the bilirubin effect is moderate (compared to a typical patient with bilirubin level of 0.6 mg/dL, a patient with 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) have not been studied. Therefore, treatment with ambrisentan should not be initiated in patients with severe hepatic impairment or clinically significant elevation of liver aminotransferases (> 3xULN) (see sections "Contraindications" and "Special warnings and precautions for use").

Clinical Characteristics

Indications

• The medicinal product is indicated for the treatment of pulmonary arterial hypertension in adult patients with WHO functional class II–III, including use in combination therapy.
• Efficacy has been demonstrated in idiopathic pulmonary arterial hypertension and pulmonary arterial hypertension associated with connective tissue disease.

Contraindications

• Hypersensitivity to the active substance, to soy, or to any of the excipients.
• Pregnancy.
• Use in women who are not using reliable contraception.
• Breastfeeding.
• Severe hepatic impairment (with or without cirrhosis).
• Baseline levels of liver aminotransferases (aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT)) more than 3 times the upper limit of normal (> 3xULN).
• Idiopathic pulmonary fibrosis with or without secondary pulmonary hypertension.

Interaction with other medicinal products and other types of interactions

In preclinical in vitro and in vivo studies, ambrisentan did not inhibit or induce phase I or phase II drug metabolism enzymes at clinically relevant concentrations, indicating a low potential for ambrisentan to alter the profile of drugs metabolized through these pathways.

The potential of ambrisentan to induce CYP3A4 activity was evaluated in healthy volunteers; results showed no inductive effect of ambrisentan on the CYP3A4 isoenzyme.

Cyclosporine A

Concomitant administration of ambrisentan and cyclosporine A at steady state resulted in a 2-fold increase in ambrisentan exposure in healthy volunteers. This may be related to inhibition by cyclosporine A of transporters and metabolic enzymes involved in the pharmacokinetics of ambrisentan. Therefore, when ambrisentan is used concomitantly with cyclosporine A, the dose of ambrisentan in adult patients or children with body weight ≥ 50 kg should be limited to 5 mg once daily; for children with body weight ≥ 20 to < 50 kg, the dose should be limited to 2.5 mg once daily (see section "Dosage and administration"). Multiple doses of ambrisentan did not affect cyclosporine A exposure, so dose adjustment of cyclosporine A is not required.

Rifampicin

Concomitant use of rifampicin (an inhibitor of organic anion transporting polypeptide [OATP], a strong inducer of CYP3A and 2C19, and an inducer of P-gp and uridine-diphosphate-glucuronosyltransferases [UGT]) was associated with a transient (approximately 2-fold) increase in ambrisentan exposure after initial doses in healthy volunteers. However, by day 8 of rifampicin administration at steady state, there was no clinically significant effect on ambrisentan exposure. Patients receiving ambrisentan therapy should be closely monitored when initiating treatment with rifampicin (see sections "Pharmacokinetics" and "Special precautions for use").

Phosphodiesterase inhibitors

Concomitant administration of ambrisentan with a phosphodiesterase inhibitor, sildenafil, or tadalafil (both substrates of CYP3A4) in healthy volunteers did not significantly affect the pharmacokinetics of the phosphodiesterase inhibitor or ambrisentan (see section "Pharmacokinetics").

Other targeted therapies for PAH

The efficacy and safety of ambrisentan when used concomitantly with other medicinal products for the treatment of PAH (e.g., prostanoinds and soluble guanylate cyclase stimulators) have not been specifically studied in controlled clinical trials in patients with PAH (see section "Pharmacodynamics"). Based on known data of biotransformation, no specific interactions between ambrisentan and soluble guanylate cyclase stimulators or prostanoinds are expected (see section "Pharmacokinetics"). However, no specific interaction studies with these medicinal products have been conducted. Therefore, caution is recommended when using them concomitantly.

Oral contraceptives

In a clinical study involving healthy volunteers, steady-state dosing of ambrisentan 10 mg once daily did not significantly affect the pharmacokinetics of a single dose of the components ethinylestradiol and norethindrone of a combined oral contraceptive (see section "Pharmacokinetics"). Based on this pharmacokinetic study, ambrisentan is not expected to significantly affect the exposure of estrogen- or progestogen-based contraceptives.

Warfarin

In a study involving healthy volunteers, ambrisentan did not affect steady-state pharmacokinetics or anticoagulant activity of warfarin (see section "Pharmacokinetics"). Warfarin also had no clinically significant effect on the pharmacokinetics of ambrisentan. Furthermore, in patients, ambrisentan had no overall effect on weekly warfarin dose, prothrombin time (PT), or international normalized ratio (INR).

Ketoconazole

Concomitant use of ketoconazole (a potent inhibitor of CYP3A4) at steady state did not result in a clinically significant increase in ambrisentan exposure (see section "Pharmacokinetics").

Effect of ambrisentan on xenobiotic transporters

In vitro, ambrisentan does not exert inhibitory effects on human transporters at clinically relevant concentrations, including P-gp, breast cancer resistance protein (BCRP), multidrug resistance-associated protein 2 (MRP2), bile salt export pump (BSEP), organic anion transporting polypeptides (OATP1B1 and OATP1B3), and sodium-taurocholate cotransporting polypeptide (NTCP).

Ambrisentan is a substrate for P-gp-mediated efflux.

In vitro studies in rat hepatocytes also showed that ambrisentan does not induce expression of P-gp, BSEP, or MRP2 proteins.

Administration of ambrisentan at steady state in healthy volunteers had no clinically significant effect on the pharmacokinetics of a single dose of digoxin, a P-gp substrate (see section "Pharmacokinetics").

Paediatric patients

Interaction studies have been performed only in adults.

Special precautions for use

Ambrisentan has not been studied in a sufficient number of patients to establish a benefit-risk ratio in WHO FC I PAH.

The efficacy of ambrisentan as monotherapy in patients with WHO FC IV PAH has not been established. Therapy recommended for severe disease (e.g., epoprostenol) should be considered if clinical status worsens.

Liver function

Impaired liver function is associated with PAH. Cases of autoimmune hepatitis, including possible exacerbation of underlying autoimmune hepatitis, liver injury, and elevation of liver enzymes potentially related to therapy, have been observed with ambrisentan (see sections "Pharmacodynamics" and "Adverse reactions"). Therefore, liver aminotransferases (ALT and AST) should be assessed before initiating ambrisentan therapy, and treatment should not be initiated in patients with baseline ALT and/or AST levels > 3 × ULN (see section "Contraindications").

Patients should be monitored for signs of liver injury, and monthly monitoring of ALT and AST is recommended. If patients develop persistent, unexplained, clinically significant elevations in ALT and/or AST, or if such elevations are accompanied by signs or symptoms of liver injury (e.g., jaundice), ambrisentan therapy should be discontinued. Reinitiation of ambrisentan may be considered in patients without clinical symptoms of liver injury or jaundice after normalization of liver enzyme abnormalities. Hepatology consultation is recommended.

Haemoglobin concentration

Decreases in haemoglobin concentration and haematocrit have been associated with endothelin receptor antagonists (ERAs), including ambrisentan. Most of these decreases occurred within the first 4 weeks of treatment, after which haemoglobin levels generally stabilized. The mean decrease from baseline (0.9 to 1.2 g/dL) in haemoglobin concentration persisted over 4 years of ambrisentan treatment in long-term open-label extensions of the main phase 3 clinical trials. Cases of anaemia requiring blood transfusion have been reported in the post-marketing period (see section "Special precautions for use").

Initiation of ambrisentan therapy is not recommended in patients with clinically significant anaemia. Haemoglobin and/or haematocrit levels should be measured during ambrisentan treatment, e.g., at 1 month, 3 months, and periodically thereafter, according to clinical practice. If clinically significant decreases in haemoglobin or haematocrit are observed and other causes are excluded, dose reduction or discontinuation of therapy should be considered. The incidence of anaemia was increased with ambrisentan in combination with tadalafil (adverse reaction rate 15%) compared to ambrisentan and tadalafil as monotherapy (7% and 11%, respectively).

Fluid retention

Peripheral oedema has been observed with ERAs, including ambrisentan. Most cases of peripheral oedema in ambrisentan clinical trials were mild to moderate in severity, although it may occur more frequently and severely in patients aged ≥ 65 years. Peripheral oedema was more frequently observed with 10 mg ambrisentan in short-term clinical studies (see section "Special precautions for use"). Post-marketing reports have described fluid retention occurring within several weeks after starting ambrisentan, in some cases requiring intervention with diuretics or hospitalization for fluid reduction or decompensated heart failure. Any pre-existing fluid overload should be resolved prior to initiating ambrisentan, according to clinical judgment. If clinically significant fluid retention develops during ambrisentan therapy, with or without associated weight gain, further evaluation is required to determine the cause (e.g., ambrisentan or underlying heart failure) and possible need for specific treatment or discontinuation of ambrisentan. The incidence of peripheral oedema was increased with ambrisentan in combination with tadalafil (adverse reaction rate 45%) compared to ambrisentan and tadalafil monotherapy (38% and 28%, respectively). The occurrence of peripheral oedema was highest during the first month of treatment.

Women of childbearing potential

Ambrisentan therapy must not be initiated in women of childbearing potential unless a negative pregnancy test result prior to treatment and use of reliable contraception have been confirmed. If there is any uncertainty regarding the appropriate contraceptive method for an individual patient, consultation with a gynaecologist should be considered. Monthly pregnancy testing is recommended during ambrisentan therapy (see sections "Contraindications" and "Use in pregnancy or lactation").

Pulmonary veno-occlusive disease

Cases of pulmonary oedema have been reported when vasodilating medicinal products such as ERAs are used in patients with pulmonary veno-occlusive disease. Therefore, if patients with PAH develop acute pulmonary oedema during ambrisentan therapy, pulmonary veno-occlusive disease should be considered.

Concomitant use with other medicinal products

Patients receiving ambrisentan therapy should be closely monitored when initiating treatment with rifampicin (see sections "Pharmacokinetics" and "Interaction with other medicinal products and other forms of interaction").

Disposal of unused medicinal product or waste

Any unused medicinal products or waste materials should be disposed of in accordance with local requirements.

Important information on excipients

Lactose. This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

Lecithin (soy). This medicinal product contains lecithin derived from soy. Ambrisentan should not be used in patients with hypersensitivity to soy (see section "Special precautions for use").

Sodium. This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, i.e., essentially "sodium-free".

Allura red AC aluminium lake. The tablets contain the azo dye Allura red AC aluminium lake (E 129), which may cause allergic reactions.

Use in pregnancy or lactation

Women of childbearing potential

Ambrisentan therapy must not be initiated in women of childbearing potential unless a negative pregnancy test result prior to treatment and use of reliable contraception have been confirmed. Monthly pregnancy testing is recommended during ambrisentan therapy.

Pregnancy

Ambrisentan is contraindicated during pregnancy (see section "Special precautions for use"). Animal studies have shown that ambrisentan is teratogenic. There is no experience with such effects in humans. Women receiving ambrisentan should be informed of the risk of fetal harm and alternative therapy should be initiated if pregnancy occurs (see sections "Contraindications" and "Special precautions for use").

Lactation

It is unknown whether ambrisentan is excreted in human breast milk. Excretion of ambrisentan in animal milk has not been studied. Therefore, breastfeeding is contraindicated in patients taking ambrisentan (see section "Special precautions for use").

Male fertility

Testicular tubular atrophy in male animals has been associated with long-term use of ERAs, including ambrisentan. Although ARIES-E did not show clear evidence of harmful effects of long-term ambrisentan use on sperm count, chronic administration of ambrisentan was associated with changes in markers of spermatogenesis. Decreased plasma inhibin-B concentration and increased plasma FSH concentration were observed. The effect on male fertility is unknown, but impairment of spermatogenesis cannot be excluded. In clinical trials, long-term use of ambrisentan was not associated with changes in plasma testosterone levels.

Ability to influence reaction speed when driving or operating machinery

Ambrisentan has a minor or moderate influence on the ability to drive or operate machinery. When assessing a patient's ability to perform tasks requiring judgment, motor, or cognitive skills, the patient's clinical status and the adverse reaction profile of ambrisentan (such as arterial hypotension, dizziness, asthenia, fatigue) should be taken into account (see section "Adverse reactions"). Patients should be aware of how ambrisentan may affect them before driving or operating machinery.

Method of Administration and Dosage

The medicinal product is intended for oral administration. The tablet should be swallowed whole and may be taken independently of food intake. The tablet is not recommended to be crushed or chewed. Treatment should be initiated by a physician experienced in the management of pulmonary arterial hypertension (PAH).

Dosage

Ambrisentan Monotherapy

The medicinal product should be administered orally, starting at a dose of 5 mg once daily, which may be increased to 10 mg once daily based on clinical response and patient tolerability.

Ambrisentan in Combination with Tadalafil

When used in combination with tadalafil, the dose of ambrisentan should be titrated to 10 mg once daily. In the AMBITION study, patients received 5 mg of ambrisentan daily for the first 8 weeks before increasing the dose to 10 mg based on tolerability (see section "Pharmacodynamics"). When used in combination with tadalafil, patients started with 5 mg of ambrisentan and 20 mg of tadalafil. Depending on tolerability, the tadalafil dose was increased to 40 mg after 4 weeks, and the ambrisentan dose to 10 mg after 8 weeks. More than 90% of patients achieved this regimen. Doses may also be reduced depending on tolerability.

Limited data suggest that abrupt discontinuation of ambrisentan is not associated with rebound worsening of PAH.

Ambrisentan in Combination with Cyclosporine A

In adults, when co-administered with cyclosporine A, the dose of ambrisentan should be limited to 5 mg once daily, and patients should be closely monitored (see sections "Pharmacokinetics" and "Interaction with Other Medicinal Products and Other Forms of Interaction").

Special Patient Populations

Elderly Patients

Dose adjustment is not required for patients aged 65 years and older (see section "Pharmacokinetics").

Patients with Renal Impairment

Dose adjustment is not required for patients with renal impairment (see section "Pharmacokinetics"). Experience with ambrisentan in patients with severe renal impairment (creatinine clearance < 30 mL/min) is limited; therapy should be initiated cautiously in this subgroup and with particular caution if the dose is increased to 10 mg of ambrisentan.

Patients with Hepatic Impairment

Ambrisentan has not been studied in individuals with hepatic impairment (with or without cirrhosis). Since the primary metabolic pathways of ambrisentan are glucuronidation and oxidation, followed by biliary excretion, hepatic impairment may lead to increased exposure (Cmax and AUC) to ambrisentan. Therefore, ambrisentan therapy should not be initiated in patients with severe hepatic impairment or with clinically significant elevations in liver aminotransferases (more than 3 times the upper limit of normal (> 3xULN); see sections "Contraindications" and "Special Warnings and Precautions for Use").

Children

The medicinal product at this dosage strength is not indicated for use in children.

Overdose

Symptoms. In healthy volunteers, single doses of 50 mg and 100 mg (5–10 times the maximum recommended dose) were associated with headache, flushing, dizziness, nausea, and nasal congestion. Due to its mechanism of action, ambrisentan overdose may potentially lead to arterial hypotension.

Treatment. In cases of pronounced arterial hypotension, active cardiovascular support may be required. There is no specific antidote.

Adverse Reactions

Short description of the safety profile

Peripheral edema (37%) and headache (28%) were the most commonly observed adverse reactions during treatment with ambrisentan. The higher dose (10 mg) was associated with a higher incidence of these adverse reactions, and peripheral edema was more severe in patients aged ≥ 65 years in short-term clinical studies (see section "Special precautions for use").

Serious adverse reactions associated with ambrisentan include anemia (decreased hemoglobin, decreased hematocrit) and hepatotoxicity.

Decreases in hemoglobin and hematocrit concentrations (10%) have been associated with endothelin receptor antagonists (ERAs), including ambrisentan. Most of these decreases occurred within the first 4 weeks of treatment, after which hemoglobin levels generally stabilized (see section "Special precautions for use").

Elevations in liver enzymes (2%), liver injury, and autoimmune hepatitis, including exacerbation of underlying disease, have been observed with ambrisentan (see sections "Pharmacodynamics" and "Special precautions for use").

All adverse reactions are listed by system organ class and frequency: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000), and frequency not known (cannot be estimated from available data).

For dose-dependent adverse reactions, the frequency category reflects the higher dose of ambrisentan. Within each frequency group, adverse reactions are listed in order of decreasing severity.

System organ class	Frequency	Adverse reaction
Blood and lymphatic system disorders	Very common	Anemia (decreased hemoglobin, decreased hematocrit)1
Immune system disorders	Common	Hypersensitivity reactions (e.g., angioneurotic edema, rash, pruritus)
Nervous system disorders	Very common	Headache (including sinus headache, migraine)2, dizziness
Eye disorders	Common	Blurred vision, visual disturbance
Ear and labyrinth disorders	Common	Tinnitus3
	Uncommon	Sudden hearing loss3
Cardiac disorders	Very common	Palpitations, flushing5
	Common	Heart failure4, arterial hypotension, syncope
Respiratory, thoracic and mediastinal disorders	Very common	Dyspnea6, upper airway congestion (e.g., nose, sinuses)7, nasopharyngitis7
	Common	Nosebleed, rhinitis7, sinusitis7
Gastrointestinal disorders	Very common	Nausea, diarrhea, vomiting5
	Common	Abdominal pain, constipation
Hepatobiliary disorders	Common	Elevated liver transaminases
	Uncommon	Liver injury (see section "Special precautions"), autoimmune hepatitis (see section "Special precautions")
Skin and subcutaneous tissue disorders	Common	Rash8
General disorders and administration site conditions	Very common	Peripheral edema, fluid retention, chest pain/discomfort5, fatigue
	Common	Asthenia

1 See section "Description of selected adverse reactions".

2 Headache frequency was higher with 10 mg ambrisentan.

3 Cases occurred only in the placebo-controlled clinical study of ambrisentan in combination with tadalafil.

4 Most reported cases of heart failure were associated with fluid retention.

5 Frequencies were observed in the placebo-controlled clinical study of ambrisentan in combination with tadalafil. A lower frequency was observed with ambrisentan monotherapy.

6 Cases of worsening dyspnoea of unclear aetiology were reported shortly after initiation of ambrisentan therapy.

7 Nasopharyngitis frequency was dose-dependent during ambrisentan therapy.

8 Rash includes erythematous rash, generalized rash, papular rash, and pruritic rash.

Description of selected adverse reactions

Decreased haemoglobin

During the post-marketing period, cases of anaemia requiring blood transfusions have been reported (see section "Special precautions for use"). The frequency of decreased haemoglobin (anaemia) was higher with 10 mg ambrisentan. During 12-week placebo-controlled phase 3 clinical studies, mean haemoglobin concentrations decreased in patients in the ambrisentan groups and were observed as early as week 4 (decrease of 0.83 g/dL); mean changes from baseline stabilized over the subsequent 8 weeks. Overall, 17 patients (6.5%) in the ambrisentan treatment groups experienced a decrease in haemoglobin of ≥ 15% from baseline, which fell below the lower limit of normal.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows ongoing monitoring of the benefit-risk balance of the medicine. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life

3 years.

Storage conditions

Store at temperatures not exceeding 25 °C in the original packaging.

Keep out of reach and sight of children.

Packaging

10 tablets in a blister pack, 3 blisters in a cardboard box.

Prescription status

Prescription only.

Manufacturer

Responsible for batch release.

APL Swift Services (Malta) Limited.

Manufacturing, primary packaging, secondary packaging.

APL Healthcare Limited.

Manufacturer's address and location of operations

Xf26, Hal Far Industrial Estate, Qasam Industrial Hal Far, Birzebbugia, BBG 3000, Malta.

Unit IV Plot No 16, APIIC Multi Product Special Economic Zone, Manakuru Village Naidupeta Mandal Tirupati District, Naidupeta, Andhra Pradesh, 524421, India.