Bosenex^® (Tablets) Instructions for Use

Marketing Authorization Holder

Rapharma, JSC (Russia)

ATC Code

C02KX01 (Bosentan)

Active Substance

Bosentan (Rec.INN registered by WHO)

Dosage Forms

	Bosenex®	Film-coated tablets, 62.5 mg: 40 or 56 pcs.
		Film-coated tablets, 125 mg: 40 or 56 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets pink in color, round, biconvex; on the cross-section, the core is white or almost white, a yellowish tint is allowed.

Excipients: corn starch, sodium starch glycolate type A (sodium carboxymethyl starch), pregelatinized starch, glyceryl dibehenate, povidone K90, magnesium stearate.

Film coating composition Opadry 21K220000 (hypromellose, titanium dioxide (E171), talc, ethylcellulose, glyceryl triacetate (triacetin), iron oxide yellow (E172), iron oxide red (E172)).

10 pcs. – blister packs (4) – cardboard packs.
14 pcs. – blister packs (4) – cardboard packs.

Film-coated tablets pink in color, round, biconvex; on the cross-section, the core is white or almost white, a yellowish tint is allowed.

Excipients: corn starch, sodium starch glycolate type A (sodium carboxymethyl starch), pregelatinized starch, glyceryl dibehenate, povidone K90, magnesium stearate.

Film coating composition Opadry 21K220000 (hypromellose, titanium dioxide (E171), talc, ethylcellulose, glyceryl triacetate (triacetin), iron oxide yellow (E172), iron oxide red (E172)).

10 pcs. – blister packs (4) – cardboard packs.
14 pcs. – blister packs (4) – cardboard packs.

Clinical-Pharmacological Group

Non-selective antagonist of endothelin receptors type ET_A and ET_B. Vasodilator

Pharmacotherapeutic Group

Vasodilating agent

Pharmacological Action

Non-selective antagonist of endothelin receptors type ET_A and ET_B. Vasodilator.

Bosentan reduces both pulmonary and systemic vascular resistance, leading to an increase in cardiac output without increasing heart rate.

The neurohormone endothelin-1 (ET-1) is one of the most potent vasoconstrictors, has the ability to induce fibrosis, cell proliferation, myocardial hypertrophy and remodeling, and also exhibits pro-inflammatory activity. These effects are caused by the binding of ET-1 to ET_A and ET_B receptors located in the endothelium and vascular smooth muscle cells. The concentration of ET-1 in tissues and blood plasma increases in some cardiovascular diseases and connective tissue pathology, including pulmonary arterial hypertension, scleroderma, acute and chronic heart failure, myocardial ischemia, arterial hypertension and atherosclerosis, which suggests the participation of ET-1 in the pathogenesis and development of these diseases. In pulmonary arterial hypertension and heart failure, in the absence of ET receptor antagonism, an increase in ET-1 concentration strictly correlates with the severity and prognosis of these diseases. Bosentan competes with ET-1 and other ET peptides for binding to ET_A and ET_B receptors, with a slightly higher affinity for ET_A receptors (Ki=4.1-43 nmol) compared to ET_B receptors (Ki=38-730 nmol).

Bosentan specifically blocks ET receptors and does not bind to other receptors.

Clinical studies have shown that in patients with pulmonary arterial hypertension, the use of bosentan is accompanied by an increase in cardiac index and is combined with a significant decrease in pulmonary artery pressure, pulmonary vascular resistance and mean right atrial pressure.

In patients with PAH FC III and Eisenmenger’s syndrome associated with congenital heart defects, when using bosentan at doses of 62.5 mg 2 times/day and 125 mg 2 times/day, no worsening of hypoxemia was noted after 16 weeks of therapy (oxygen saturation in blood plasma increased by 1%). The mean vascular resistance in the pulmonary artery significantly decreased, and exercise tolerance improved (the mean distance in the 6-minute walk test increased by 53 m).

A study of bosentan in patients with PAH FC III associated with HIV infection showed a significant increase in exercise tolerance.

The results of two clinical studies in adult patients with systemic scleroderma and limb ulcers (in the acute phase or in cases where ulcerative lesions were noted during the last year) showed that the use of bosentan is accompanied by a significant reduction in the number of new limb ulcers compared with placebo throughout the entire treatment period.

Pharmacokinetics

In healthy volunteers, the pharmacokinetics of bosentan are dose- and time-dependent. After oral administration, systemic exposure is proportional at doses up to 500 mg. When taken orally at a higher dose, the increase in C_max and AUC of bosentan relative to the dose taken is disproportionate and is achieved at a slower rate. The absolute bioavailability of bosentan after oral administration is approximately 50%; food intake does not affect bioavailability. C_max in blood plasma is reached after 3-5 hours.

The binding of bosentan to plasma proteins is 98%. Does not penetrate into red blood cells.

After a single IV administration of 250 mg of bosentan, V_d is 18 L, clearance is 8.2 L/h, T_1/2 is 5.4 hours.

Bosentan is metabolized in the liver with the participation of CYP2C9 and CYP3A4 isoenzymes to form 3 metabolites, only one of which has pharmacological activity. In patients with symptoms of cholestasis, the systemic exposure of this metabolite may increase.

Bosentan is an inducer of CYP2C9 and CYP3A4, and possibly CYP2C19 and P-glycoprotein. In vitro, Bosentan inhibits the effectiveness of the BSEP transporter (bile salt export pump), which excretes bile acids in hepatocyte cultures.

It is excreted with bile through the intestines; less than 3% of the dose is found in the urine.

In children over 2 years of age with pulmonary arterial hypertension, studies were conducted when taking the drug in doses, the value of which depended on body weight. The exposure of bosentan decreased over time along a curve characteristic of bosentan, since the substance is known for its properties to cause autoinduction of liver enzyme systems. The average AUC values in children were lower than in adults with pulmonary arterial hypertension. At steady state, systemic exposure in children weighing 10-20 kg, 20-40 kg and more than 40 kg was 43%, 67% and 75% of the level of systemic exposure in adults, respectively. The reasons for this difference are unclear and may be related to more active metabolism of bosentan in the liver and its excretion through the intestines with bile. Pharmacokinetic parameters show a decrease in systemic exposure compared to adult patients with pulmonary arterial hypertension, which may cause a decrease in effectiveness. The safety of using bosentan in high doses (more than 125 mg 2 times/day) in children has not been established.

The connection of this phenomenon with a negative effect on the liver has not been established. Gender and simultaneous IV administration of epoprostenol do not have a significant effect on the pharmacokinetics of bosentan.

In patients with severe renal impairment (creatinine clearance 15-30 ml/min), the concentration of bosentan in blood plasma decreases by approximately 10%. The concentration in the blood plasma of bosentan metabolites increases approximately 2 times compared to patients with preserved renal function. In patients with impaired renal function, no dose adjustment is required. Bosentan has not been used in patients undergoing hemodialysis. Given the physicochemical properties of bosentan and its high degree of binding to plasma proteins, significant removal of bosentan from the systemic circulation during hemodialysis is not expected.

Indications

Treatment of pulmonary arterial hypertension to improve exercise tolerance and clinical symptoms in patients of WHO functional class II-IV, adults and children over 3 years of age, including: primary (idiopathic and hereditary) pulmonary arterial hypertension; secondary pulmonary arterial hypertension against the background of scleroderma in the absence of significant interstitial lung damage; pulmonary arterial hypertension associated with congenital heart defects and, in particular, with hemodynamic disorders of the Eisenmenger’s syndrome type.

Reducing the number of new digital ulcers in adults with systemic scleroderma and progressive ulcerative lesions of the extremities.

ICD codes

Dosage Regimen

Depending on age, indications and treatment regimen, a single dose is 31.25-62.5 mg. Frequency of administration is 1-2 times/day. Maintenance dose is 62.5-250 mg/day. The duration of treatment is determined individually.

It is necessary to carefully evaluate the benefit/risk ratio, taking into account the negative dose-dependent effect of bosentan on the liver.

When discontinuing therapy, to reduce the risk of clinical deterioration of patients and prevent withdrawal syndrome, it is recommended to gradually reduce the dose of bosentan (reducing it by half over 3-7 days), while simultaneously starting alternative therapy.

Adverse Reactions

From the hematopoietic system common – anemia, decreased hemoglobin; uncommon – thrombocytopenia, neutropenia, leukopenia; frequency unknown – anemia or decreased hemoglobin when blood transfusion is necessary.

From the immune system common – hypersensitivity reactions, including dermatitis, skin itching and rash (9.9% vs. 9.1%, compared with placebo); anaphylactic and/or angioedema.

From the nervous system very common – headache (11.5% vs. 9.8%, compared with placebo).

From the cardiovascular system common – fainting, palpitations, decreased blood pressure (may be associated with the underlying disease), flushing of the skin of the face.

From the digestive system common – gastroesophageal reflux disease; uncommon – increased activity of liver transaminases, associated with hepatitis and/or jaundice; rare – liver cirrhosis, liver function failure. In the post-marketing period, there have been reports of rare cases of liver cirrhosis of unclear etiology with long-term use of bosentan in patients with severe concomitant diseases, simultaneously using numerous medications; in rare cases – liver function failure.

From the skin and subcutaneous tissues common – skin redness.

General disorders: very common – peripheral edema, fluid retention.

Contraindications

Moderate and severe liver dysfunction (7 or more points on the Child-Pugh scale); initial increase in the activity of liver transaminases (AST and/or ALT) more than 3 times the ULN; severe arterial hypotension (systolic blood pressure less than 85 mm Hg); simultaneous use of cyclosporine A; use in women of reproductive age who do not use reliable methods of contraception; children under 3 years of age (solid dosage form); hypersensitivity to bosentan.

Use in Pregnancy and Lactation

The use of bosentan during pregnancy is contraindicated.

It has not been established whether Bosentan is excreted in breast milk. Breastfeeding is not recommended during treatment with bosentan.

Special Precautions

Bosentan should be used with caution in severe arterial hypotension (systolic blood pressure less than 85 mm Hg), COPD, mild liver dysfunction (less than 7 points on the Child-Pugh scale); in pulmonary arterial hypertension FC I (insufficient clinical data on efficacy and safety of use).

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

An increase in AST and ALT activity associated with bosentan intake is dose-dependent. Changes in liver transaminase activity usually occur within the first 26 weeks of therapy, but can also occur later. The risk of liver dysfunction may also increase with the simultaneous use of bosentan with drugs that suppress the bile salt transport pump, such as rifampicin, glibenclamide and cyclosporine, although data on this are limited.

Monitoring of liver transaminase activity (AST and ALT) is necessary before starting therapy with bosentan, and then once a month during treatment.

If AST/ALT activity is 3-5 times higher, a repeat determination of AST/ALT activity should be performed; if an increase in AST and ALT activity is confirmed, the daily dose of bosentan should be reduced or discontinued; monitor liver transaminase activity every 2 weeks. If liver transaminase activity returns to the levels observed before the start of therapy, the possibility of continuing or resuming bosentan intake in the regimen indicated below is assessed.

If AST/ALT activity is 5-8 times higher, a repeat determination of AST/ALT activity should be performed; if an increase in AST and ALT activity is confirmed, Bosentan should be discontinued; monitor liver transaminase activity every 2 weeks. If liver transaminase activity returns to the levels observed before the start of therapy, the possibility of resuming bosentan intake in the regimen indicated below is assessed.

If AST/ALT activity is 8 times higher, therapy should be discontinued, resumption of bosentan intake is excluded.

If associated clinical symptoms of liver damage occur, i.e., in case of nausea, vomiting, fever, abdominal pain, jaundice, increased fatigue and apathy, with flu-like symptoms (arthralgia, myalgia, fever), bosentan therapy should be discontinued, resumption of intake is not recommended.

Bosentan therapy can be resumed only if the expected therapeutic effect of therapy outweighs the potential risk of developing adverse reactions, and if liver transaminase activity does not exceed the levels recorded before starting treatment with bosentan. Liver transaminase activity should be monitored 3 days after resuming therapy, then repeat the control, after which return to the regular monitoring schedule.

In placebo-controlled studies, the bosentan-associated decrease in hemoglobin is not progressive; hemoglobin stabilizes after the first 4-12 weeks of therapy. It is recommended to monitor this indicator before starting therapy, after 1 and 3 months of therapy and subsequently – once every 3 months. If a clinically significant decrease in hemoglobin is observed, patients should be further examined to determine the causes and the need for appropriate therapy.

Data from studies of the effect of bosentan on spermatogenesis do not exclude the possibility of the effect of endothelin receptor antagonists on spermatogenesis in men, and the absence of a systematic effect with long-term use does not contradict the results of toxicological studies of bosentan.

The possibility of concomitant veno-occlusive disease should be considered if signs of pulmonary edema appear in patients with pulmonary arterial hypertension while taking bosentan.

If clinically significant fluid retention in the body is noted during treatment, regardless of whether it is accompanied by weight gain or not, an examination should be carried out to clarify the cause of fluid retention in the body (use of bosentan or heart failure), and also assess the need to continue treatment with bosentan or discontinue it.

In pulmonary arterial hypertension as a result of severe COPD, the use of bosentan is accompanied by an increase in the rate of minute ventilation of the lungs and a decrease in oxygen saturation; among the side effects, shortness of breath was most often noted, the severity of which decreased when bosentan was discontinued.

In patients with diabetes mellitus, simultaneous use of bosentan and glibenclamide is not recommended due to the risk of increased liver transaminase activity. For the treatment of diabetes mellitus in patients receiving Bosentan, other oral hypoglycemic agents or insulin injections should be used.

Effect on ability to drive vehicles and mechanisms

Bosentan may cause dizziness, so during treatment, patients should exercise caution when driving vehicles and other potentially hazardous activities.

Drug Interactions

Bosentan is metabolized with the participation of the CYP2C9 and CYP3A4 isoenzymes.

Concomitant use with inhibitors of the CYP3A4 isoenzyme (e.g., ketoconazole) increases the plasma concentration of bosentan. The effect of CYP2C9 isoenzyme inhibition on the plasma concentration of bosentan has not been studied; caution is required with such combinations.

Concomitant use with fluconazole, which primarily inhibits the CYP2C9 isoenzyme and to a lesser extent the CYP3A4 isoenzyme, may be accompanied by an increase in the plasma concentration of bosentan; this combination is not recommended. For the same reason, concomitant use of bosentan and potent inhibitors of the CYP3A4 isoenzyme (such as ketoconazole, itraconazole, or ritonavir) and an inhibitor of the CYP2C9 isoenzyme (such as voriconazole) is not recommended.

Bosentan is an inducer of the CYP2C9 and CYP3A4 isoenzymes, and based on in vitro study data, it is also presumed to induce CYP2C19.

Therefore, when bosentan is used concomitantly with drugs whose metabolism is mediated by these isoenzymes, their plasma concentration decreases.

The possibility of reduced efficacy of drugs metabolized by the same isoenzymes should be considered.

Dose adjustment of concomitantly used drugs may be required after starting bosentan, changing its dose, or discontinuing it.

Concomitant use of bosentan and cyclosporine (a calcineurin inhibitor) is contraindicated.

With this combination, the minimum initial plasma concentration of bosentan increases 30-fold compared to the use of bosentan as monotherapy.

The C_ss of bosentan in plasma increases 3-4 times compared to the concentration of bosentan during monotherapy.

The possible mechanism of this interaction is the inhibition by cyclosporine of the transport protein responsible for the uptake of bosentan into hepatocytes.

The plasma concentration of cyclosporine decreases by almost 50%.

Clinical studies have not investigated the concomitant use of tacrolimus and sirolimus with bosentan, however, it is assumed that the plasma concentration of bosentan may increase similarly to cyclosporine.

The plasma concentration of tacrolimus and sirolimus may decrease when used concomitantly with bosentan.

Therefore, Bosentan should not be used concomitantly with tacrolimus or sirolimus.

If it is necessary to use this combination, monitoring of the patient’s condition and plasma concentrations of tacrolimus and sirolimus is mandatory.

Concomitant use of bosentan at a dose of 125 mg twice daily for 5 days reduces the plasma concentration of glibenclamide (a substrate of the CYP3A4 isoenzyme) by 40%, which may be accompanied by a significant decrease in the hypoglycemic effect of glibenclamide.

The plasma concentration of bosentan also decreases by 29%.

Furthermore, in patients receiving concomitant therapy, the risk of increased liver transaminase activity increases.

Both active substances, glibenclamide and Bosentan, have an inhibitory effect on the bile salt export pump, which may explain the increase in liver transaminase activity.

In this regard, Bosentan should not be used concomitantly with glibenclamide.

There are no data on possible drug interactions with other sulfonylurea derivatives.

Concomitant use of bosentan for 7 days at a dose of 125 mg twice daily and a single-dose oral contraceptive – a combined preparation containing 1 mg of norethisterone and 35 mcg of ethinylestradiol – resulted in a decrease in AUC for its components by 14% and 31%, respectively.

In individual female patients, the reduction in exposure to norethisterone and ethinylestradiol reached 56% and 66%, respectively.

Thus, hormonal contraception cannot be considered sufficiently effective, regardless of the route of administration of the drug – oral, injectable, transdermal, or as implants.

Concomitant use in healthy volunteers with bosentan at a dose of 500 mg twice daily for 6 days reduces the plasma concentration of S-warfarin (a substrate of the CYP2C9 isoenzyme) and R-warfarin (a substrate of the CYP3A4 isoenzyme) by 29% and 38%, respectively.

Experience with the concomitant use of bosentan and warfarin in patients with PAH was not accompanied by clinically significant changes in INR and warfarin dose (at the end of the study compared to baseline).

Furthermore, the frequency of warfarin dose adjustment during the study due to changes in INR or due to adverse events did not differ between patients receiving Bosentan or placebo.

No adjustment of the warfarin dose or other oral anticoagulants is required at the start of bosentan therapy, but mandatory monitoring of INR is recommended, especially at the start of bosentan use and during dose escalation.

Concomitant use of bosentan at a dose of 125 mg twice daily for 5 days reduces the plasma concentration of simvastatin (a substrate of the CYP3A4 isoenzyme) and its active form, beta-hydroxy acid, by 34% and 46%, respectively.

Concomitant use of simvastatin does not affect the plasma concentration of bosentan.

When simvastatin and bosentan are used together, monitoring of plasma cholesterol levels is recommended with subsequent adjustment of the simvastatin dose.

Concomitant use for 6 days of bosentan at a dose of 62.5 mg twice daily and ketoconazole, a potent inhibitor of the CYP3A4 isoenzyme, is accompanied by a 2-fold increase in the plasma concentration of bosentan.

No dose adjustment of bosentan is required.

An increase in the plasma concentration of bosentan is also expected with concomitant use of itraconazole and ritonavir, despite the lack of confirmation in in vivo studies.

Nevertheless, when bosentan is combined with a CYP3A4 inhibitor, in patients with reduced metabolism of the CYP2C9 isoenzyme, there is a risk of a significant increase in the concentration of bosentan, which may increase the frequency and severity of its side effects.

Concomitant use in healthy volunteers for 7 days of bosentan at a dose of 125 mg twice daily and rifampicin, which is an inducer of the CYP2C9 and CYP3A4 isoenzymes, reduced the plasma concentration of bosentan by 58%, and in some patients by 90%.

Consequently, a clinically significant reduction in the effect of bosentan is possible when used concomitantly with rifampicin; this combination is not recommended.

Data on concomitant use with other inducers of the CYP3A4 isoenzyme, such as carbamazepine, phenobarbital, phenytoin, as well as preparations containing St. John’s wort, are insufficient, nevertheless, it is highly likely that their concomitant use cannot exclude a significant reduction in the effectiveness of treatment with bosentan.

Concomitant use of bosentan at a dose of 125 mg twice daily and a combination of lopinavir+ritonavir 400+100 mg twice daily for 9.5 days in healthy volunteers resulted in a minimum initial plasma concentration of bosentan approximately 48 times higher compared to the concentration when using bosentan alone.

The C_ss of bosentan in plasma on day 9 was 5 times higher than when taking bosentan alone.

The mechanism of interaction is probably due to inhibition by ritonavir of the CYP3A4 isoenzyme and the transport protein responsible for the transport of bosentan into hepatocytes, leading to a decrease in the clearance of bosentan.

In patients simultaneously receiving Bosentan and drugs containing lopinavir+ritonavir or other boosted protease inhibitors, monitoring of bosentan tolerability is necessary.

When used concomitantly with bosentan for 9.5 days, the concentrations of lopinavir and ritonavir decrease to a clinically insignificant level (by approximately 14% and 17%, respectively).

Monitoring of the effectiveness of ongoing HIV therapy is necessary.

It is assumed that other boosted protease inhibitors in combination with ritonavir may have the same effect.

Due to the pronounced toxic effect on the liver of nevirapine, which may also enhance the adverse effect of bosentan on the liver, concomitant use of this combination is not recommended.

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.