Endobloc

Ambrisentan (Ambrisentan) Instructions
Common name: Ambrisentan
Trade name: Vanrex
Full names: Ambrisentan, Vanrex, Ambrisentan, Volibris, Endobloc

Indications:
Indicated for the treatment of patients with pulmonary arterial hypertension (WHO group 1) with WHO grade II or III symptoms to improve exercise capacity and delay clinical deterioration.

Usage and dosage:
1. Adult dosage
(1) The starting dose is 5 mg orally once a day on an empty stomach or after meals; if tolerated, it may be adjusted to 10 mg once a day.
(2) The tablets can be taken on an empty stomach or after meals. Tablets should not be broken in half, crushed, or chewed. No studies have been conducted in patients with pulmonary hypertension at doses higher than 10 mg once daily. Liver function should be monitored before starting treatment with this drug and during treatment.

2. Women of childbearing age
Women can only receive treatment if they have a negative pregnancy test and are using 2 suitable contraceptive methods for contraception. However, if the patient has undergone fallopian tube ligation or chooses to use T-shaped copper 380AIUD or LNg20IUS for contraception, no additional contraceptive measures are required. Women of childbearing potential who are receiving this medicine should have monthly pregnancy tests.

3. Existing liver damage

There are currently no studies on the impact of existing liver damage on the pharmacokinetics of ambrisentan. Because both in vivo and in vitro evidence suggests that ambrisentan clearance is largely dependent on hepatic metabolism and biliary excretion, hepatic impairment is expected to have a significant impact on the pharmacokinetics of ambrisentan. Vanrex is not recommended for patients with moderate or severe hepatic impairment. There are currently no data on the use of ambrisentan in patients with mild hepatic impairment; however, ambrisentan exposure may be elevated in such patients.

4. Increased liver transaminases
Other endothelin receptor antagonists (ERAs) are associated with elevated transaminases (AST, ALT), hepatotoxicity, and cases of liver failure. Patients who develop liver injury after starting varexin should be fully investigated for the cause of the liver injury. If the transaminase elevation is >5xULN or the transaminase elevation is accompanied by bilirubin >2xULN, or is accompanied by symptoms or signs of liver insufficiency, and other causes can be ruled out, discontinue this product.

5. Combined use with cyclosporine A
When used in combination with cyclosporine A, the dosage of this product should be controlled within 5 mg once a day.

Adverse reactions:
> 10%
Peripheral edema (17%)
Headache (15%)

1-10%
Nasal congestion (6%)
Papitations (5%)
Constipation (4%)
Breathing Difficulties (4%)
Flushing (4%)
Abdominal pain (3%)
Nasopharyngitis (3%)
Sinusitis (3%)

Postmarketing Reports
Anemia
Dizziness
Fatigue
Fluid retention
Heart failure (related to fluid retention)
Nausea
vomiting
Elevated liver transaminases (ALT, AST)
Allergies (such as angioedema, rash)
Symptomatic hypotension
Hepatotoxicity
Liver failure

Contraindications:
1. Pregnancy Class X:
(1) Use of this product in pregnant women may cause fetal damage. Ambrisentan is teratogenic at oral doses of ≥15 mg/kg/day in rats and ≥7 mg/kg/day in rabbits; there are currently no studies on lower doses. Malformations of the jaw, hard and soft palate, as well as the heart and great vessels, as well as disorders of the thymus and thyroid gland are observed in both species. Teratogenicity is one of the effects of endothelin receptor antagonists. There are currently no data on the use of this product in pregnant women.
(2) This product is prohibited for use by women who are or may be pregnant. If this drug is used during pregnancy, or if pregnancy occurs while taking this drug, the patient should be informed of the possible harm to the fetus.
(3) For women of childbearing potential, pregnancy must be ruled out before starting treatment, and 2 suitable contraceptive methods should be used during treatment and within 1 month after treatment. However, if the patient has undergone fallopian tube ligation or chooses to use T-type copper 380AIUD or LNg20IUS for contraception, no additional contraceptive measures are required. It is also recommended that the ginseng test be reviewed every month during the medication period until 4 weeks after stopping treatment.

2. Idiopathic pulmonary fibrosis: Ambrisentan is contraindicated in patients with idiopathic pulmonary fibrosis with or without secondary pulmonary hypertension.

3. Severe liver function impairment: It is prohibited for those allergic to ambrisentan, soybean or any of the excipients in ambrisentan tablets.

Notes:
1. A doctor with extensive experience in treating pulmonary hypertension should decide whether to start treatment with this drug, and the treatment process should be strictly monitored. The medical information leaflet for this product should be read before prescribing this product and the patient should be informed of the precautions for taking this product. Before starting treatment with this product, patients should read the Medical Information Leaflet (For Patients) for this product.
2. Studies have not been conducted in a sufficient number of patients to weigh the benefits and risks of this product in the treatment of WHO grade I pulmonary hypertension. The efficacy of this product as monotherapy has not been established in patients with WHO grade IV pulmonary hypertension.
3. Women of childbearing age: Pregnancy must be ruled out before starting treatment. Pregnancy testing should be performed before the first treatment with this product and every month during treatment. Confirm that a pregnancy test has been completed before dispensing the medication. If you become pregnant while taking this product or within 30 days after stopping this product, contact your prescribing physician.
4. This product has potential adverse reactions of liver damage, hematological changes, fluid retention, decreased sperm count, and pulmonary veno-occlusive disease. The excipients contain lactose monohydrate.
5. Medication for pregnant and lactating women:
(1) Pregnant patients: Pregnancy category X.
(2) Nursing mothers: It is unclear whether ambrisentan will be secreted with breast milk. Breastfeeding while taking this product is not recommended. A preclinical study in rats showed that feeding ambrisentan to dams from late gestation to weaning resulted in decreased survival of newborn mice (moderate to high doses) and affected testicular size and maturity (high doses). The doses detected were 17, 51 and 170 times the maximum human oral dose (10 mg) (low, medium and high doses respectively), in units of mg/mm2.
6. Medication in children: The safety and effectiveness of this product in pediatric patients have not yet been established.
7. Elderly use: In two placebo-controlled clinical studies on this product, 21% of patients were ≥65 years old, and 5% of patients were ≥75 years old. Elderly patients (≥65 years of age) showed less improvement in walking distance with treatment than younger patients, but the results of such subgroup analyzes must be interpreted with caution. Peripheral edema is more common in older patients than in younger patients.
8. Overdose: There is currently no experience with overdose of this product. The maximum single dose of this product used in healthy volunteers is 100 mg, and in patients with pulmonary arterial hypertension, 10 mg once daily. In healthy volunteers, single doses of 50 mg and 100 mg (5 to 10 times the maximum recommended dose) were associated with headache, facial redness, dizziness, nausea, and nasal congestion. Severe overdose may result in hypotension requiring therapeutic intervention.

Storage:
Avoid light and keep in a sealed container.

Mechanism of action:
1. In vitro studies: Studies using human liver tissue have shown that ambrisentan is metabolized by CYP3A, CYP2C19, 5’-bisphosphoglucosyltransferases (UGTs), 1A9S, 2B7S and 1A3S. In vitro experiments suggest that ambrisentan is a substrate of organic anion transporter (OATP) and a substrate (not an inhibitor) of P-gp.
2. In vivo studies:
(1) The combined use of ambrisentan with the following drugs will not lead to clinically significant changes in ambrisentan exposure: ketoconazole, omeprazole, sildenafil, sildenafil or tadala Non, rifampin.
(2) The combined use of ambrisentan will not cause changes in the exposure of the following drugs: warfarin, digoxin, sildenafil, sildenafil or tadalafil, ethinyl estradiol/norethindrone, and cyclosporine A.
3. A clinical trial in healthy subjects showed that the steady-state dose of 10 mg ambrisentan did not significantly affect the single-dose pharmacokinetics of ethinyl estradiol or norethindrone in the combined oral contraceptive pill (Ortho-Novum 1/35). Based on this pharmacokinetic study, ambrisentan is not expected to affect the exposure of estrogen or progesterone contraceptives.
4. After combined use with cyclosporine A (an inhibitor of P-gp and OATP), the steady-state plasma concentration of ambrisentan in healthy volunteers increased by 2 times. Therefore, if used in combination with cyclosporine A, the dosage of ambrisentan should be controlled to no more than 5 mg once daily. No clinically significant effects of ambrisentan on cyclosporine A exposure were observed.
5. After the first combined use of ambrisentan and rifampicin (an inhibitor of OATP, a strong inducer of CYP3A and 2C19, and an inducer of P-gp and UGTs) in healthy volunteers, the exposure of ambrisentan increased transiently (about 2 times). However, stable dosing of rifampicin had no clinically relevant effect on ambrisentan exposure by day 7 post-dose. Therefore, no dosage adjustment of ambrisentan is required when used concomitantly with rifampicin.

Efficacy and safety:
A total of 15 patients with idiopathic pulmonary hypertension (10 cases) and connective tissue disease-related pulmonary hypertension (5 cases) were prospectively selected. Ambrisentan 2.5 mg or 5 mg was taken orally once a day for 12 weeks. Six-minute walking distance, WHO functional class of pulmonary hypertension, echocardiography and plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) values ​​were evaluated before ambrisentan treatment and at 12 weeks of treatment. Results: After 12 weeks of ambrisentan treatment, the patient's six-minute walking distance increased from (376.5±108.2) m to (460.3±95.7) m (P =0.021), and the pulmonary artery systolic pressure measured by echocardiography decreased from (85.0±33.3) mmHg to (70.5±30.5) mmHg (P =0.015). NT-proBNP decreased from (1947.5±2469.8) pg/ml to (430.3±652.4) pg/ml (P=0.009), and the WHO pulmonary hypertension functional classification of 4 patients was improved (P>0.05). No patient withdrew from the study due to serious adverse reactions. Conclusion: Ambrisentan can improve exercise tolerance, WHO pulmonary hypertension functional classification, reduce pulmonary artery systolic pressure, significantly reduce NTproBNP levels in patients with pulmonary hypertension, and is safe and well tolerated.
In summary, the endothelin antagonist-ambrisentan can continuously improve the symptoms of patients with pulmonary arterial hypertension in terms of short-term effects and long-term efficacy and safety.