Ambrisentan (Tablets) Instructions for Use

ATC Code

C02KX02 (Ambrisentan)

Active Substance

Ambrisentan (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Endothelin receptor antagonist

Pharmacotherapeutic Group

Antihypertensive agents; other antihypertensive agents; antihypertensive agents for the treatment of pulmonary arterial hypertension

Pharmacological Action

Antagonist of type A endothelin receptors (ET_A), characterized by high affinity and selectivity for these receptors.

Endothelin-1 (ET-1) is a potent autocrine and paracrine peptide. In vascular smooth muscle and endothelium, the effects of endothelin-1 are mediated by two types of endothelin receptors – ET_A and ET_B. Activation of ET_A receptors primarily causes vasoconstriction and cell proliferation; activation of ET_B receptors primarily causes vasodilation, an antiproliferative effect, and promotes ET-1 clearance.

In patients with pulmonary arterial hypertension, plasma ET-1 concentration is increased 10-fold and correlates with increased right atrial pressure and disease severity. ET-1 and ET-1 mRNA concentrations are increased 9-fold in the lung tissue of patients with pulmonary arterial hypertension, predominantly in the pulmonary artery endothelium. These data suggest that ET-1 may play a critical role in the pathogenesis and progression of pulmonary arterial hypertension.

Pharmacokinetics

The pharmacokinetics of ambrisentan in healthy volunteers is characterized by linear dose-dependency. After oral administration, Ambrisentan is absorbed, with C_max reached approximately 2 hours after administration. The AUC in plasma for the metabolite 4-hydroxymethyl ambrisentan is approximately 4% of the parent compound’s AUC. Food intake does not affect bioavailability.

Plasma protein binding is high – 99%. C_ss averages 15% of C_max. The accumulation factor is about 1.2 after long-term use.

In vitro studies have shown that Ambrisentan is a substrate of P-glycoprotein. In vivo inversion of S-ambrisentan to R-ambrisentan is negative.

The T_1/2 of ambrisentan is 15 hours. The effective T_1/2 of ambrisentan is about 9 hours. The mean oral clearance is 38 ml/min and 19 ml/min in healthy volunteers and patients with pulmonary arterial hypertension, respectively. It is eliminated primarily by non-renal routes, however, the relative role of metabolism and biliary elimination has not been sufficiently characterized.

Indications

Treatment of pulmonary arterial hypertension to improve exercise tolerance and delay the progression of clinical symptoms. Studies have established efficacy primarily in patients with symptoms corresponding to functional class II-III and idiopathic or hereditary etiology (64%) or pulmonary arterial hypertension associated with connective tissue diseases (32%).

ICD codes

Dosage Regimen

Initiate treatment at 5 mg administered orally once daily.

Do not split tablets. Take with or without food.

If the 5 mg dose is well tolerated, consider increasing the dose to 10 mg once daily.

The maximum recommended dose is 10 mg once daily.

Doses exceeding 10 mg daily are not recommended for pulmonary arterial hypertension.

For patients receiving concomitant cyclosporine, limit the ambrisentan dose to 5 mg once daily.

No dosage adjustment is required for patients with mild to moderate renal impairment.

Use with caution in patients with mild hepatic impairment; no dosage recommendation exists for this population.

Contraindicated in patients with severe hepatic impairment.

Monitor hemoglobin before initiation, at one month, and periodically thereafter.

Discontinue treatment if signs of hepatic injury or pulmonary veno-occlusive disease occur.

Adverse Reactions

Respiratory system: nasal congestion (nasal mucosal edema), sinusitis.

Digestive system: possible increase in ALT and AST activity (in most such cases, patients had other reasons that could cause impaired liver function, including heart failure, liver enlargement, hepatitis, alcoholism, hepatotoxic drugs).

General reactions: peripheral edema, flushing.

Contraindications

Idiopathic pulmonary fibrosis with or without secondary pulmonary hypertension, severe hepatic insufficiency (10 points or more on the Child-Pugh scale), increase in hepatic transaminase activity more than 3 times the upper limit of normal (ULN); pregnancy (established or planned); children and adolescents under 18 years of age; hypersensitivity to ambrisentan.

Use in Pregnancy and Lactation

Contraindicated in established pregnancy and planned pregnancy, because Ambrisentan has a teratogenic effect.

Pregnancy should be excluded before starting treatment.

Women of childbearing potential should use effective contraceptive measures during treatment and for 1 month after its completion. If pregnancy occurs during therapy, the woman should be informed about the potential risk to the fetus.

It is not known whether Ambrisentan is excreted in human breast milk. If it is necessary to use ambrisentan during lactation, breastfeeding should be discontinued.

Special Precautions

Ambrisentan is not recommended for use in patients with clinically significant anemia. If a clinically significant decrease in hemoglobin concentration is observed during treatment and other causes of this effect are excluded, Ambrisentan should be discontinued.

For symptoms of fluid retention, therapy with diuretics is administered. If symptoms of fluid retention continue to worsen, an examination and appropriate therapy should be carried out; if necessary, Ambrisentan should be discontinued. Hospitalization is necessary in case of decompensated heart failure.

Peripheral edema was observed more frequently and was more severe in elderly patients.

If pulmonary veno-occlusive disease develops during the use of ambrisentan, it should be discontinued.

Hemoglobin concentration should be monitored before starting treatment, after 1 month of treatment, and then periodically.

No dose adjustment is required for patients with mild or moderate renal impairment. There are no data on use in patients with severe renal impairment. The effect of hemodialysis on the distribution of ambrisentan has not been studied.

There are no data on the use of ambrisentan in mild hepatic impairment; it should be borne in mind that in such cases, an increase in the bioavailability of ambrisentan is possible. Ambrisentan should be discontinued if during treatment there is an increase in transaminase activity of more than 3 times the ULN or an increase in bilirubin concentration of more than 2 times the ULN, or if symptoms of liver dysfunction occur.

It cannot be excluded that endothelin receptor antagonists, including Ambrisentan, may have an undesirable effect on spermatogenesis.

Drug Interactions

With repeated co-administration of ambrisentan and cyclosporine, the bioavailability of ambrisentan increased approximately 2-fold in healthy volunteers, therefore, with this combination, the dose of ambrisentan should be reduced to 5 mg once daily.

The following drugs, when taken concomitantly, did not have a significant effect on the C_max and AUC of ambrisentan: mycophenolate mofetil, omeprazole, ketoconazole, rifampin, ritonavir, sildenafil, tacrolimus, tadalafil, warfarin (no dose adjustment required).

When taken concomitantly, Ambrisentan did not cause significant changes in the C_max and AUC of the following drugs: cyclosporine, digoxin, ethinyl estradiol, norethindrone, mycophenolic acid, ritonavir, sildenafil, desmethylsildenafil, tadalafil, warfarin, S-warfarin, R-warfarin (no dose adjustment required).

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.