Ranclir

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT RANCLIR (RANCLEER)

Composition:

Active substance: bosentan;

One tablet contains 62.5 mg or 125 mg of bosentan (as bosentan monohydrate);

Excipients: maize starch, pregelatinized starch, sodium starch glycolate, povidone K-30, magnesium stearate, glycerol dibehenate; coating composition (Oparay 21K520019 yellow): hypromellose, titanium dioxide (E 171), triacetin, talc, ethylcellulose, yellow iron oxide (E 172), hypromellose, red iron oxide (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

62.5 mg: film-coated, light pink to pink, round, biconvex tablets, embossed with "62.5" on one side and smooth on the other.

125 mg: film-coated, light pink to pink, oval, biconvex tablets, embossed with "125" on one side and smooth on the other.

Pharmacotherapeutic group.

Antihypertensive agents for the treatment of pulmonary arterial hypertension. Bosentan.

ATC code C02K X01.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Bosentan is a dual endothelin receptor antagonist, structurally similar to both endothelin A and B receptors (ETA and ETB). Bosentan reduces both pulmonary and systemic vascular resistance, thereby increasing cardiac output without increasing heart rate.

The neurohormone endothelin-1 (ET-1) is one of the most potent vasoconstrictors and has the ability to induce fibrosis, cellular proliferation, hypertrophy, and myocardial remodeling, as well as exhibits anti-inflammatory activity. These effects are mediated by binding of endothelin to ETA and ETB receptors located on endothelial cells and vascular smooth muscle cells. The concentration of ET-1 in tissues and plasma is elevated in certain cardiovascular diseases and connective tissue disorders, including pulmonary arterial hypertension (PAH), scleroderma, acute and chronic heart failure, myocardial ischemia, systemic hypertension, and atherosclerosis, suggesting a role of ET-1 in the pathogenesis and progression of these conditions. In PAH and heart failure, in the absence of endothelin receptor antagonism, elevated ET-1 levels strongly correlate with disease severity and prognosis.

Bosentan competes with ET-1 and other endothelin peptides for binding to ETA and ETB receptors, with slightly higher affinity for ETA receptors (Ki 4.1–43 nM) than for ETB receptors (Ki 38–730 nM). Bosentan specifically blocks endothelin receptors and does not bind to other receptors.

Efficacy

Animal models

In animals with pulmonary hypertension, chronic oral administration of bosentan reduced pulmonary vascular resistance, pulmonary hypertrophy, and right ventricular hypertrophy. In an animal model of pulmonary fibrosis, bosentan reduced collagen deposition in the lungs.

Efficacy in adult patients with PAH

Treatment with bosentan (initial dose of 62.5 mg twice daily for 4 weeks, followed by 125 mg twice daily) resulted in a significant improvement in exercise capacity.

An increase in cardiac index and significant reductions in pulmonary arterial pressure, pulmonary vascular resistance (PVR), and mean right atrial pressure were observed in patients with PAH treated with bosentan.

Bosentan treatment was associated with a reduction in PAH symptoms. Measurements of dyspnea during walking demonstrated improvement in patients receiving bosentan.

Pharmacokinetics.

Pharmacokinetics of bosentan have been primarily studied in healthy volunteers. Available data suggest that the exposure to bosentan in adult patients with PAH is approximately twice higher than in healthy adult volunteers.

In healthy volunteers, the pharmacokinetics of bosentan are dose- and time-dependent. Clearance and volume of distribution decrease with increasing intravenous dose and with increasing time.

After oral administration, systemic exposure is dose-proportional up to 500 mg. At higher oral doses, increases in maximum concentration (Cmax) and area under the concentration–time curve (AUC) are less than proportional to the dose and occur at a slower rate.

Absorption

In healthy volunteers, the absolute bioavailability of bosentan is approximately 50% and is independent of food intake. Cmax is reached within 3–5 hours.

Distribution

Bosentan is highly bound (98%) to plasma proteins, primarily albumin. Bosentan does not penetrate into erythrocytes.

The volume of distribution, approximately 18 L, is determined after intravenous administration of a 250 mg dose.

Metabolism and elimination

After a single intravenous dose of 250 mg, clearance is 8.2 L/h, and the elimination half-life (t½) is 5.4 hours.

With repeated dosing, plasma concentrations of bosentan gradually decrease to 50–65% compared to those observed after a single dose. This reduction is likely due to autoinduction of hepatic metabolic enzymes. Steady-state conditions are achieved within 3–5 days.

Bosentan is eliminated via bile, metabolized in the liver by the CYP2C9 and CYP3A4 isoenzymes, and excreted in bile; less than 3% of an orally administered dose is recovered in urine.

Bosentan forms three metabolites, only one of which is pharmacologically active. This active metabolite is primarily excreted unchanged in bile. In adult patients, exposure to the active metabolite is higher than in healthy adult volunteers. In patients with signs of cholestasis, exposure to the active metabolite may be increased.

Bosentan is an inducer of CYP2C9 and CYP3A4, and possibly of CYP2C19 and P-glycoprotein. In vitro studies have shown that bosentan inhibits hepatocyte bile acid efflux.

Bosentan does not exert significant inhibitory effects on the isoenzymes CYP1A2, 2A6, 2B6, 2C8, 2C9, 2D6, 2E1, and 3A4. Therefore, it is unlikely that bosentan increases plasma concentrations of drugs metabolized by these isoenzymes.

Pharmacokinetics in special patient populations

Based on study results, bosentan pharmacokinetics are not expected to depend on sex, body weight, race, or age in adult patients.

Children

In children, AUC values were 43%, 67%, and 75% of those in adults at body weights of 10–20 kg, 20–40 kg, and >40 kg, respectively. Plasma concentrations of bosentan in children reach plateau at lower doses than in adults. Doses exceeding 2 mg/kg do not result in increased AUC in children.

The pharmacokinetics of bosentan in patients with Child–Pugh class B and C hepatic impairment have not been studied, and bosentan is contraindicated in these patient groups. No dose adjustment of bosentan is required in patients with severe renal impairment (creatinine clearance 15–30 mL/min).

Clinical characteristics.

Indications.

Treatment of World Health Organization (WHO) functional class III pulmonary arterial hypertension to improve exercise tolerance and clinical symptoms in patients. Efficacy has been demonstrated in the following conditions:

• Primary (idiopathic and hereditary) pulmonary arterial hypertension;
• Secondary pulmonary arterial hypertension associated with scleroderma without significant interstitial lung disease;
• Pulmonary arterial hypertension associated with congenital systemic-to-pulmonary shunts and Eisenmenger syndrome.

Some improvement has also been demonstrated in patients with WHO functional class II pulmonary arterial hypertension.

For reduction of the number of new digital ulcers in adult patients with systemic sclerosis and progressive ulcerative lesions of the extremities (fingers and toes).

Contraindications.

Hypersensitivity to bosentan or to any of the excipients of the medicinal product.

Moderate or severe hepatic impairment (Child-Pugh class B or C).

Elevated liver aminotransferase activity [aspartate aminotransferase (AST) and alanine aminotransferase (ALT)] more than 3 times the upper limit of normal.

Concomitant use of cyclosporine A.

Pregnancy.

It is contraindicated in women of childbearing potential who are not using reliable contraceptive methods.

Interaction with other medicinal products and other forms of interaction.

Interaction studies have been conducted only in adults.

Bosentan is an inducer of cytochrome P450 (CYP) isoenzymes CYP2C9 and CYP3A4.

In vitro laboratory data also indicate induction of CYP2C19. Therefore, plasma concentrations of drugs metabolized by these isoenzymes may be reduced when co-administered with bosentan. The possibility of reduced efficacy of such medicinal products should be considered. Dose adjustments or changes in concomitant therapy with bosentan may be required at the start of treatment.

Bosentan is metabolized by CYP2C9 and CYP3A4. Inhibition of these isoenzymes may increase bosentan plasma concentrations (see "ketoconazole" below). The effect of CYP2C9 inhibitors on bosentan concentration has not been studied; therefore, such combinations should be used with caution.

Fluconazole and other inhibitors such as CYP2C9 and CYP3A4. Concomitant use with fluconazole, which primarily inhibits CYP2C9 and to a lesser extent CYP3A4, may lead to a significant increase in bosentan plasma concentration. Therefore, this combination is not recommended. For the same reason, concomitant use of potent CYP3A4 inhibitors (such as ketoconazole, itraconazole, or ritonavir) and CYP2C9 inhibitors (such as voriconazole) with bosentan is not recommended.

Cyclosporine A. Concomitant use of bosentan and cyclosporine A (a calcineurin inhibitor) is contraindicated. When used in combination, the initial concentration of bosentan was approximately 30 times higher than with bosentan monotherapy. At steady state, bosentan plasma concentration was 3–4 times higher than with bosentan alone. The likely mechanism of this interaction is inhibition by cyclosporine of the transporter protein responsible for hepatic uptake of bosentan. Cyclosporine A (a CYP3A4 substrate) blood concentration decreased by approximately 50%. This is most likely due to induction of CYP3A4 by bosentan.

Tacrolimus, sirolimus. There are no data on concomitant use of tacrolimus or sirolimus with bosentan. Combined use of tacrolimus or sirolimus with bosentan may lead to increased bosentan plasma concentration, similar to the interaction with cyclosporine A. Concomitant use of bosentan may reduce plasma concentrations of tacrolimus and sirolimus; therefore, their combined use is not recommended. Patients requiring concomitant use of bosentan with tacrolimus or sirolimus should be closely monitored, with blood concentration monitoring of these drugs.

Glibenclamide. Concomitant use with bosentan at a dose of 125 mg twice daily for 5 days reduces plasma concentration of glibenclamide (a CYP3A4 substrate) by 40%, which may significantly reduce its hypoglycemic effect. Plasma concentration of bosentan is also reduced by 29%. In addition, increased incidence of elevated liver transaminase activity has been observed in patients receiving concomitant therapy. Both glibenclamide and bosentan inhibit bile acid metabolism, which may explain the increased liver transaminase activity. This combination should not be used. There are no data on interaction with other sulfonylureas.

Rifampicin. Concomitant use of bosentan at a dose of 125 mg twice daily with rifampicin, a potent inducer of CYP2C9 and CYP3A4, for 7 days resulted in a 58% reduction in bosentan plasma concentration. This reduction may reach up to 90% in individual cases. As a result, the expected therapeutic effect of bosentan is significantly reduced when co-administered with rifampicin. Concomitant use of bosentan and rifampicin is not recommended. There are insufficient data on other CYP3A4 inducers (e.g., carbamazepine, phenobarbital, phenytoin, and St. John's wort), but their concomitant use is expected to reduce systemic exposure to bosentan. Clinically significant reduction in efficacy cannot be excluded.

Lopinavir/ritonavir (and other protease inhibitors). Concomitant use of bosentan at a dose of 125 mg twice daily with lopinavir/ritonavir 400/100 mg twice daily for 9.5 days in healthy volunteers led to a 48-fold increase in bosentan plasma concentration compared to bosentan alone. On day 9, bosentan plasma concentration was approximately 5 times higher than with bosentan monotherapy. This interaction is most likely due to ritonavir inhibition of CYP3A4 and the transporter protein responsible for hepatic uptake of bosentan, thereby reducing bosentan elimination. Monitoring of bosentan tolerability should be performed when co-administered with lopinavir/ritonavir or other protease inhibitors.

After 9.5 days of concomitant use, plasma concentrations of lopinavir and ritonavir decreased slightly (by approximately 14% and 17%, respectively). Monitoring of HIV therapy efficacy is required. Similar effects are possible when bosentan is used with other protease inhibitors.

Other antiretroviral agents. Due to lack of data, no specific recommendations can be made regarding other antiretroviral agents. Because of the pronounced hepatotoxicity of nevirapine, which may increase bosentan toxicity, this combination is not recommended.

Hormonal contraceptives. Concomitant use of bosentan at a dose of 125 mg twice daily for 7 days with a single dose of an oral contraceptive containing 1 mg norethisterone and 35 µg ethinylestradiol led to a 14% and 31% reduction in AUC of norethisterone and ethinylestradiol, respectively. However, the reduction in contraceptive effect of norethisterone and ethinylestradiol in individual patients was 56% and 66%, respectively. Therefore, use of hormonal contraceptives alone, regardless of route of administration (oral, injectable, transdermal, or implanted), is not considered a reliable method of contraception.

Warfarin. Concomitant use of warfarin with bosentan at a dose of 500 mg twice daily for 6 days reduced plasma concentrations of S-warfarin (CYP2C9 substrate) and R-warfarin (CYP3A4 substrate) by 29% and 38%, respectively. During clinical trials of concomitant bosentan and warfarin use in patients with PAH, no clinically significant changes in international normalized ratio (INR) were observed, and no dose adjustments of warfarin were required (baseline compared to end of clinical trials). Additionally, the frequency of warfarin dose adjustments during the trials due to INR changes or adverse effects was similar in patients receiving bosentan and placebo. When using warfarin and similar oral anticoagulants, dose adjustment is not required at the initiation of bosentan therapy, but INR monitoring should be performed, especially at the beginning of bosentan treatment and during titration.

Simvastatin. Concomitant use with bosentan at a dose of 125 mg twice daily for 5 days reduces plasma concentrations of simvastatin (a CYP3A4 substrate) and its active metabolite beta-hydroxy acid by 34% and 46%, respectively. Bosentan plasma concentration was not altered by concomitant use with simvastatin. Cholesterol levels should be monitored and appropriate dose adjustments made.

Ketoconazole. Concomitant use of bosentan at a dose of 62.5 mg twice daily with ketoconazole, a potent CYP3A4 inhibitor, increases bosentan plasma concentration by approximately 2-fold. Dose adjustment of bosentan is not required. A similar increase in bosentan plasma concentration is expected when used with other strong CYP3A4 inhibitors (itraconazole, ritonavir). However, when combined with a CYP3A4 inhibitor in patients with reduced CYP2C9 metabolism, there is a risk of increased bosentan plasma concentration, potentially leading to dangerous adverse effects.

Epoprostenol. Limited study data in which 10 children received a combination of bosentan and epoprostenol indicate that after single and multiple dosing, Cmax and AUC values of bosentan were similar in patients receiving and not receiving continuous epoprostenol infusion.

Sildenafil. Concomitant use of bosentan at a dose of 125 mg twice daily (steady state) with sildenafil at a dose of 80 mg three times daily (steady state) for 6 days in healthy volunteers resulted in a 63% reduction in sildenafil AUC and a 50% increase in bosentan AUC. Therefore, this combination should be used with caution.

Tadalafil: bosentan (125 mg twice daily) reduced systemic exposure to tadalafil (40 mg once daily) by 42% and Cmax by 27% after multiple concomitant dosing. Tadalafil did not affect the exposure (AUC and Cmax) of bosentan or its metabolites.

Digoxin. Concomitant use of bosentan at a dose of 500 mg twice daily with digoxin for 7 days reduced AUC, Cmax, and Cmin of digoxin by 12%, 9%, and 23%, respectively. The mechanism of this interaction may be related to induction of P-glycoprotein. This interaction is not clinically significant.

Pediatric patients

Interaction studies have been conducted only in adult patients.

Special precautions for use.

The efficacy of bosentan has not been established in patients with severe pulmonary arterial hypertension (PAH). Transition to therapies recommended for severe stages of the disease (e.g., epoprostenol) should be considered if the clinical condition worsens.

The benefit-risk ratio of bosentan use has not been established in patients with WHO functional class I PAH.

Treatment with the medicinal product should only be initiated when the patient's systemic systolic arterial pressure is above 85 mm Hg.

The effect of bosentan on healing of digital ulcers has not been established.

Liver function

Bosentan-associated elevations in liver aminotransferases (i.e., AST and/or ALT) are dose-dependent. Changes in liver enzyme levels usually occur within the first 26 weeks of treatment but may also appear later (see section "Adverse reactions"). This increase in liver enzymes may be partly related to competitive inhibition of bile salt export from hepatocytes; however, other mechanisms not fully elucidated are likely involved in the development of liver dysfunction. Accumulation of bosentan in hepatocytes leading to cytolytic damage with potential for severe liver injury, or an immunological mechanism, cannot be excluded. The risk of liver dysfunction may also be increased when bosentan is used concomitantly with medicinal products that are inhibitors of the bile salt export pump, such as rifampicin, glyburide, and cyclosporine A (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction"), although data in this regard are limited.

Liver aminotransferase levels must be measured before starting treatment and monthly thereafter throughout the treatment period. Additionally, liver aminotransferase levels should be measured 2 weeks after any dose increase of the medicinal product.

Recommendations in case of elevated ALT/AST levels

ALT/AST levels Treatment and monitoring recommendations

3 and ≤ 5 × ULN The result should be confirmed by repeat testing of liver enzymes; if confirmed, an individual decision should be made on whether to continue treatment, possibly at a lower dose, or discontinue the medicinal product (see section "Dosage and administration"). Monitoring of aminotransferase levels should continue at least every 2 weeks. If aminotransferase levels return to pre-treatment values, consideration should be given to continuing or resuming treatment with the medicinal product according to the conditions described below.

5 and ≤ 8 × ULN The result should be confirmed by repeat testing of liver enzymes; if confirmed, treatment with the medicinal product should be discontinued and aminotransferase levels should be monitored at least every 2 weeks. If aminotransferase levels return to pre-treatment values, consideration should be given to resuming treatment with the medicinal product according to the conditions described below.

8 × ULN Treatment with the medicinal product must be discontinued, and re-initiation should not be considered.

If clinical symptoms associated with liver injury occur, namely: nausea, vomiting, fever, abdominal pain, jaundice, pathological somnolence or increased fatigue, or flu-like symptoms (arthralgia, myalgia, fever) – treatment with the medicinal product must be discontinued and re-initiation should not be considered.

Resumption of treatment with the medicinal product

Resumption of treatment with the medicinal product should only be considered if the potential benefit outweighs the potential risks and if liver aminotransferase levels have returned to pre-treatment values. Hepatologist consultation is recommended. Treatment should be resumed according to the recommendations in section "Dosage and administration". Aminotransferase levels must be monitored 3 days after resuming treatment, followed by monitoring every 2 weeks for the next 2 weeks, and thereafter according to the recommendations outlined above.

Hemoglobin concentration

Bosentan has been shown to reduce hemoglobin concentration in whole blood. In placebo-controlled studies, bosentan treatment did not cause progressive hemoglobin reduction; levels stabilized after the first 4–12 weeks of therapy. Monitoring of this parameter is recommended before starting therapy, monthly during the first 4 months, and then every 3 months. If a clinically significant decrease in hemoglobin concentration is observed, further patient evaluation should be performed to determine the cause and need for appropriate therapy. During post-marketing surveillance, cases of anemia requiring red blood cell transfusion have been reported.

Women of childbearing potential

Given that bosentan may reduce the efficacy of hormonal contraceptives, the risk of worsening PAH associated with pregnancy, and the teratogenic effects observed in animals:

• Treatment with bosentan in women of childbearing potential may only be initiated if they are using reliable contraceptive methods and have a negative pregnancy test prior to starting treatment;
• Hormonal contraceptives cannot be used as the sole method of contraception during bosentan treatment;
• Monthly pregnancy testing is recommended during treatment to allow for early detection of pregnancy.

Pulmonary veno-occlusive disease

Cases of pulmonary edema have been reported in patients with pulmonary veno-occlusive disease receiving vasodilators (mainly prostacyclins). The possibility of associated obliterative disease should be considered if signs of pulmonary edema occur during bosentan treatment in patients with PAH. Rare cases of pulmonary edema have been reported in patients previously treated with bosentan in whom pulmonary veno-occlusive disease was suspected.

PAH in patients with concomitant left ventricular dysfunction

No specific studies have been conducted in patients with PAH and concomitant left ventricular dysfunction. However, 1611 patients (804 receiving bosentan and 807 receiving placebo) with severe chronic heart failure (CHF) were treated for an average of 1.5 years in a placebo-controlled study. This study demonstrated an increased number of hospitalizations due to CHF during the first 4–8 weeks of bosentan treatment, possibly due to fluid retention. In this study, fluid retention was associated with initial weight gain, decreased hemoglobin concentration, and increased incidence of leg edema. At the end of this study, no difference was observed in overall hospitalization due to heart failure or mortality between patients receiving bosentan and those receiving placebo. Patients should be monitored for signs of fluid retention (e.g., weight gain), especially if they also have severe systolic dysfunction. If such signs are detected, diuretic therapy should be initiated or the dose increased if the patient is already receiving diuretics. Diuretic treatment should be considered before initiating bosentan therapy in patients with signs of fluid retention.

PAH associated with HIV infection

Clinical experience with bosentan in patients with PAH associated with HIV infection who are receiving antiretroviral agents is limited. Interaction studies between bosentan and lopinavir+ritonavir in healthy volunteers showed increased plasma concentrations of bosentan, with maximum levels observed during the first 4 days of treatment. When prescribing bosentan to patients receiving protease inhibitors, careful monitoring of bosentan tolerability is required, especially at the beginning of treatment, due to the risk of arterial hypotension, and liver function should be checked. An increased risk of hepatotoxicity and hematological adverse effects cannot be excluded when bosentan is used in combination with antiretroviral agents. Monitoring of HIV therapy efficacy is necessary, as bosentan may induce CYP450 enzymes, potentially affecting the efficacy of antiretroviral therapy.

Secondary PAH related to chronic obstructive pulmonary disease (COPD)

During the study, minute ventilation increased and oxygen saturation decreased. The most common adverse effect was dyspnea, which resolved after discontinuation of bosentan therapy.

Use with other medicinal products

Concomitant use of bosentan with cyclosporine A is contraindicated. Concomitant use of bosentan with glyburide, fluconazole, and rifampicin is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Concomitant use of bosentan with a CYP3A4 inhibitor and a CYP2C9 inhibitor should be avoided.

Use during pregnancy or breastfeeding.

Pregnancy

Animal studies indicate reproductive toxicity (teratogenic, embryotoxic). There are no reliable data on the use of bosentan in pregnant women. The potential risk to humans has not been established. Bosentan is contraindicated during pregnancy.

Use in women of childbearing potential

Before initiating treatment with the medicinal product, women of childbearing potential must be confirmed not to be pregnant, and must be advised on reliable contraceptive methods. Patients prescribed the medicinal product should be informed that due to possible pharmacokinetic interactions, bosentan may lead to reduced efficacy of hormonal contraceptives. Therefore, women of childbearing potential should not use hormonal contraceptives (including oral, injectable, implant, or transdermal patch forms) as the sole method of contraception—additional or alternative reliable contraceptive methods should be used. In case of any doubts regarding individual contraceptive use, gynecological consultation is recommended. Due to the potential inefficacy of hormonal contraception during bosentan treatment and the risk of PAH worsening during pregnancy, monthly pregnancy testing is recommended during bosentan treatment to ensure early detection of pregnancy.

Period of breastfeeding

It is unknown whether bosentan is excreted in breast milk; therefore, breastfeeding is not recommended during treatment with the medicinal product.

Fertility

Animal studies have demonstrated testicular effects. In a study evaluating the effect of bosentan on testicular function in male patients with PAH, reduced sperm concentration of at least 42% compared to baseline was observed in 8 out of 24 patients after 3 or 6 months of bosentan treatment. Therefore, a negative effect of bosentan on spermatogenesis in men cannot be excluded. A long-term effect on fertility in males cannot be excluded after bosentan treatment.

Ability to influence reaction speed when driving or operating machinery.

Studies on the effect of the medicinal product on the ability to drive or operate machinery have not been conducted. However, bosentan may cause arterial hypotension with symptoms such as dizziness or faintness, which may affect the ability to drive or operate machinery.

Method of Administration and Dosage

Dosage

Pulmonary Arterial Hypertension (PAH)

Treatment must be initiated and monitored by a physician experienced in the management of PAH.

Adults

In adult patients, treatment with bosentan should be initiated at a dose of 62.5 mg twice daily for 4 weeks, followed by an increase to the maintenance dose of 125 mg twice daily. These recommendations also apply to re-initiation of bosentan after interruption of treatment.

In case of clinical worsening (e.g., a decrease in the 6-minute walk distance of at least 10% compared to previous assessments), despite treatment with bosentan for at least 8 weeks (with the target dose administered for at least 4 weeks), alternative treatment options should be considered. However, some patients who do not respond after 8 weeks of bosentan treatment may show a positive response after an additional 4–8 weeks of therapy.

In cases of late clinical worsening despite bosentan treatment (after several months of therapy), treatment should be re-evaluated. Some patients may not respond adequately to the dose of 125 mg bosentan twice daily, but their exercise capacity may improve when the dose is increased to 250 mg twice daily. A careful benefit-risk assessment of such use is required, considering that hepatotoxicity is dose-dependent.

Experience with abrupt discontinuation of bosentan in PAH patients is limited. No rebound effects have been observed. However, to avoid clinical worsening due to a potential rebound effect, the dose should be tapered gradually (reduce the dose by half over a period of 3 to 7 days). Close monitoring of the patient is recommended during the discontinuation period.

Discontinuation of bosentan should be performed gradually, with concomitant initiation of alternative therapy.

Systemic Sclerosis with Progressive Digital Ulceration (Fingers and Toes)

Treatment must be initiated and monitored by a physician experienced in the management of systemic sclerosis.

Adults

Bosentan treatment should be initiated at a dose of 62.5 mg twice daily for 4 weeks, followed by an increase to the maintenance dose of 125 mg twice daily. These recommendations also apply to re-initiation of bosentan after interruption of treatment.

Controlled clinical experience in patients with these symptoms is limited to 6 months.

The patient’s response to treatment and the need for continued therapy should be continuously assessed, with careful evaluation of the benefit-risk ratio of the drug, considering the dose-dependent impact on hepatotoxicity.

Special Patient Populations

Patients with Hepatic Impairment

Bosentan is contraindicated in patients with moderate or severe hepatic impairment. Dose adjustment is not required in patients with mild hepatic impairment (Child–Pugh class A).

Patients with Renal Impairment

Dose adjustment is not required in patients with renal impairment.

Dose adjustment is also not required in patients undergoing dialysis.

Elderly Patients

Dose adjustment is not required for patients aged 65 years and older.

Method of Administration

Tablets should be taken orally in the morning and evening, independent of food intake, with water.

Children

Pulmonary Arterial Hypertension

Pharmacokinetic data in pediatric patients indicate that plasma concentrations of bosentan in children aged 1–15 years with pulmonary arterial hypertension are on average lower than in adults and do not increase with bosentan doses exceeding 2 mg/kg body weight or with increasing the dosing frequency from twice to three times daily (see section "Pharmacokinetics"). It is considered that increasing the dose or dosing frequency will not provide additional clinical benefit.

Based on pharmacokinetic data in children aged 1 year and older, the recommended initial and maintenance dose is 2 mg/kg in the morning and evening.

In neonates with persistent pulmonary hypertension of the newborn, no benefit of bosentan has been demonstrated when added to standard therapy. No dosage recommendations can be provided (see sections "Pharmacodynamics" and "Pharmacokinetics").

This pharmaceutical form is not recommended for children under 12 years of age.

Systemic Sclerosis with Active Digital Ulceration

Safety and efficacy data for the use of the drug in patients under 18 years of age are lacking. Pharmacokinetic data on bosentan use in young children with systemic sclerosis are not available.

Overdose

Bosentan has been administered as a single dose of up to 2400 mg to healthy volunteers and at doses up to 2000 mg daily for 2 months to patients with conditions other than pulmonary hypertension. The most commonly reported adverse reaction was mild to moderate headache.

Severe overdose may lead to pronounced arterial hypotension, requiring active cardiovascular support. During post-marketing surveillance, an overdose of 10,000 mg of bosentan was reported in a male adolescent. Symptoms included nausea, vomiting, dizziness, increased sweating, and blurred vision. He fully recovered within 24 hours with supportive management of blood pressure. Bosentan is not dialyzable.

Adverse Reactions

In studies conducted across various therapeutic indications, a total of 2486 patients received bosentan at daily doses ranging from 100 mg to 2000 mg, and 1838 patients received placebo. The average duration of treatment was 45 weeks. Adverse reactions occurred in at least 1% of patients receiving bosentan, with an incidence at least 0.5% higher than in the placebo group. The most common adverse reactions were headache (11.5%), edema/fluid retention (13.2%), liver function abnormalities (10.9%), and anemia/decreased hemoglobin (9.9%).

Treatment with bosentan was associated with dose-dependent increases in liver aminotransferase levels and decreases in hemoglobin concentration.

Adverse reactions observed during clinical studies and post-marketing experience with bosentan are classified according to their frequency: very common (> 1/10); common (> 1/100, < 1/10); uncommon (> 1/1000, < 1/100); rare (> 1/10,000, < 1/1000); very rare (< 1/10,000); not known (cannot be estimated from available data).

Within each frequency category, adverse reactions are listed in order of decreasing severity.

1 Data obtained after discontinuation of the drug; frequency determined based on statistical modeling of data from placebo-controlled clinical trials.

2 Hypersensitivity reactions were reported in 9.9% of patients receiving bosentan and in 9.1% of patients receiving placebo.

3 Headache was reported in 11.5% of patients receiving bosentan and in 9.8% of patients receiving placebo.

4 These types of reactions may also be related to the underlying disease.

5 Edema or fluid retention was reported in 13.2% of patients receiving bosentan and in 10.9% of patients receiving placebo.

During the post-marketing surveillance period, isolated cases of liver cirrhosis have been reported after long-term bosentan therapy in patients with multiple concomitant diseases and receiving concomitant medications. Rare cases of hepatic failure have also been reported. Therefore, monthly monitoring of liver function is required during bosentan treatment.

Shelf life.

2 years.

Storage conditions.

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

Keep out of reach of children.

Packaging.

No. 15: 15 tablets in a blister; 1 blister per cardboard box;

No. 30: 15 tablets in a blister; 2 blisters per cardboard box;

No. 100: 100 tablets in a bottle; 1 bottle per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Sun Pharmaceutical Industries Limited.

Manufacturer's address and place of business.

Industrial Area 3, Dewas, 455001, India.