Silkay 125

Bosentan monohydrate.

Each film coated tablet contains: Bosentan monohydrate eq. to Bosentan 125 mg.

Pharmacology: Bosentan is a dual endothelin receptor antagonist (ERA) with affinity for both endothelin A and B (ET_A and ET_B) receptors. Bosentan decreases both pulmonary and systemic vascular resistance resulting in increased cardiac output without increasing heart rate.
The neurohormone endothelin-1 (ET-1) is one of the most potent vasoconstrictors known and can also promote fibrosis, cell proliferation, cardiac hypertrophy and remodelling, and is pro-inflammatory. These effects are mediated by endothelin binding to ET_A and ET_B receptors located in the endothelium and vascular smooth muscle cells. ET-1 concentrations in tissues and plasma are increased in several cardiovascular disorders and connective tissue diseases, including PAH, scleroderma, acute and chronic heart failure, myocardial ischemia, systemic hypertension and atherosclerosis, suggesting a pathogenic role of ET-1 in these diseases. In PAH and heart failure, in the absence of endothelin receptor antagonism, elevated ET-1 concentrations are strongly correlated with the severity and prognosis of these diseases.
Bosentan competes with the binding of ET-1 and other ET peptides to both ET_A and ET_B receptors, with a slightly higher affinity for ET_A receptors (K_i = 4.1-43 nanomolar) than for ET_B receptors (K_i = 38-730 nanomolar). Bosentan specifically antagonizes ET receptors and does not bind to other receptors.
Pharmacokinetics: Absorption: In healthy individual, the absolute bioavailability of Bosentan is approximately 50% and is not affected by food. The maximum plasma concentrations are attained within 3-5 hours.
Distribution: Bosentan is highly bound (> 98%) to plasma proteins, mainly albumin. Bosentan does not penetrate into erythrocytes.
A volume of distribution (V_ss) of about 18 liters was determined after an intravenous dose of 250 mg.
Biotransformation and elimination: After a single intravenous dose of 250 mg, the clearance was 8.2 L/h. The terminal elimination half-life (t_½) is 5.4 hours.
Upon multiple dosing, plasma concentrations of Bosentan decrease gradually to 50-65% of those seen after single dose administration. This decrease is probably due to auto-induction of metabolizing liver enzymes. Steady-state conditions are reached within 3-5 days.
Bosentan is eliminated by biliary excretion following metabolism in the liver by the cytochrome P450 isoenzymes, CYP2C9 and CYP3A4. Less than 3% of an administered oral dose is recovered in urine.
Bosentan forms three metabolites and only one of these is pharmacologically active. This metabolite is mainly excreted unchanged via the bile. In adult patients, the exposure to the active metabolite is greater than in healthy individual. In patients with evidence of the presence of cholestasis, the exposure to the active metabolite may be increased.
Bosentan is an inducer of CYP2C9 and CYP3A4 and possibly also of CYP2C19 and the P-glycoprotein. Bosentan inhibits the bile salt export pump in hepatocyte cultures.
Bosentan had no relevant inhibitory effect on the CYP isoenzymes tested (CYP1A2, 2A6, 2B6, 2C8, 2C9, 2D6, 2E1, 3A4). Consequently, Bosentan is not expected to increase the plasma concentrations of medicinal products metabolized by these isoenzymes.
Pharmacokinetics in special populations: Based on the investigated range of each variable, it is not expected that the pharmacokinetics of Bosentan will be influenced by gender, body weight, race, or age in the adult population to any relevant extent.
Children: Due to limited data in children below 2 years of age, pharmacokinetics remains not well characterized in this age category.
In pediatric patients more than 2 years of age, it appears that the exposure to Bosentan reaches plateau at lower doses in pediatric patients than in adults, and that doses higher than 2 mg/Kg twice daily (4 mg/Kg twice daily or 2 mg/Kg three times daily) will not result in greater exposure to Bosentan in pediatric patients.
Hepatic impairment: In patients with mildly impaired liver function (Child-Pugh class A) no relevant changes in the pharmacokinetics have been observed. The steady-state AUC of Bosentan was 9% higher and the AUC of the active metabolite, Ro 48-5033, was 33% higher in patients with mild hepatic impairment than in healthy individuals.
The impact of moderately impaired liver function (Child-Pugh class B) on the pharmacokinetics of Bosentan and its primary metabolite Ro 48-5033 was investigated and data indicates a marked increase in the exposure to Bosentan and its primary metabolite, though the number of patients included was limited and with high variability.
The pharmacokinetics of Bosentan have not been studied in patients with Child-Pugh class C hepatic impairment. Bosentan is contraindicated in patients with moderate to severe hepatic impairment, i.e., Child-Pugh class B or C.
Renal impairment: In patients with severe renal impairment (creatinine clearance 15-30 mL/min), plasma concentrations of Bosentan decreased by approximately 10%. Plasma concentrations of Bosentan metabolites increased about 2-fold in these patients as compared with individuals with normal renal function. No dose adjustment is required in patients with renal impairment. There is no specific clinical experience in patients undergoing dialysis. Based on physicochemical properties and the high degree of protein binding, Bosentan is not expected to be removed from the circulation by dialysis to any significant extent.

Treatment of pulmonary arterial hypertension (PAH) in patients of WHO functional Class II-IV.
Consideration for use: Patients with WHO Class II symptoms showed reduction in the rate of clinical deterioration and a trend for improvement in walk distance. Physicians should consider whether these benefits are sufficient to offset the risk of liver injury in WHO Class II patients, which may preclude future use as their disease progresses.

General: Bosentan treatment should be initiated at a dose of 62.5 mg twice daily for 4 weeks and then increased to the maintenance dose of 125 mg twice daily. Doses above 125 mg twice daily did not appear to confer additional benefit sufficient to offset the increased risk of liver injury.
Tablets should be administered morning and evening with or without food. In the case of clinical deterioration (e.g. decrease in 6-minute walk test distance by at least 10% compared with pre-treatment measurement) despite Bosentan treatment for at least 8 weeks (target dose for at least 4 weeks), alternative therapies should be considered. However, some patients who show no response after 8 weeks of treatment with Bosentan may respond favorably after an additional 4 to 8 weeks of treatment. In the case of late clinical deterioration despite treatment with Bosentan (i.e. after several months of treatment), the treatment should be re-assessed. Some patients not responding well to 125 mg twice daily of Bosentan may slightly improve their exercise capacity when the dose is increased to 250 mg twice daily. A careful benefit/risk assessment should be made, taking into consideration that the liver toxicity is dose dependent.
Required monitoring: Liver aminotransferase levels must be measured prior to initiation of treatment and then monthly. If elevated aminotransferase levels are seen, changes in monitoring and treatment must be initiated.
Dosage adjustment and monitoring in patients developing aminotransferase abnormalities: The table 1 as follows summarizes the dosage adjustment and monitoring recommendations for patients who develop aminotransferase elevations > 3 x ULN during therapy with Bosentan. If liver aminotransferase elevations are accompanied by clinical symptoms of liver injury (such as nausea, vomiting, fever, abdominal pain, jaundice, or unusual lethargy or fatigue) or increases in bilirubin > 2 x ULN, treatment with Bosentan should be stopped. There is no experience with the re-introduction of Bosentan in these circumstances. (See Table 1.)

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Use in women of childbearing potential: Initiate treatment in females of child-bearing potential only after a negative pregnancy and only in females who are using two reliable methods of contraception. Females who have had a tubal sterilization or a Copper T 380A IUD of LNg 20 IUS inserted do not require other forms of contraception. Effective contraception must be practiced throughout treatment and for one month after stopping Bosentan. Females should seek contraceptive advice as needed from a gynecologist or similar expert. Urine or serum pregnancy tests should be obtained monthly in females of childbearing potential taking Bosentan.
Dosage adjustment in renally impaired patients: The effect of renal impairment on the pharmacokinetics of Bosentan is small and does not require dosing adjustment.
Dosage adjustment in geriatric patients: Clinical studies of Bosentan did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects.
Dosage adjustment in hepatically impaired patients: Because there is in vitro and in vivo evidence that the main route of excretion of Bosentan is biliary, liver impairment could be expected to increase exposure (C_max and AUC) of Bosentan.
Mild liver impairment was shown not to impact the pharmacokinetics of Bosentan. The influence of moderate or severe liver impairment on the pharmacokinetics of Bosentan has not been evaluated. There are no specific data to guide dosing in hepatically impaired patients. (See Precautions); caution should be exercised in patients with mildly impaired liver function. Bosentan should generally be avoided in patients with moderate or severe liver impairment.
Dosage adjustment in children: Safety and efficacy in pediatric patients have not been established.
Dosage adjustment in patients with low body weight: In patients with a body weight below 40 Kg but who are over 12 years of age, the recommended initial and maintenance dose is 62.5 mg twice daily. There is limited information about the safety and efficacy of Bosentan in children between ages of 12 and 18 years.
Discontinuation of treatment: There is limited experience with abrupt discontinuation of Bosentan. No evidence for acute rebound has been observed. Nevertheless, to avoid the potential for clinical deterioration, gradual dose reduction (62.5 mg twice daily for 3 to 7 days) should be considered.

The most common adverse reaction of Bosentan when administered as a single dose of up to 2,400 mg for 2 months in patients with a disease other than pulmonary hypertension was headache of mild to moderate intensity.
Massive overdose may result in pronounced hypotension requiring active cardiovascular support. An overdose of 10,000 mg of Bosentan may experience symptoms of nausea, vomiting, hypotension, dizziness, sweating and blurred vision. Note: Bosentan is not removed through dialysis.

Hypersensitivity to the active substance or to any of the excipients;
Moderate to severe hepatic impairment, i.e. Child-Pugh class B or C;
Baseline values of liver aminotransferases, i.e. aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT), greater than 3 × the upper limit of normal (ULN);
Concomitant use of cyclosporine A;
Pregnancy;
Women of childbearing potential who are not using reliable methods of contraception.

The efficacy of Bosentan has not been established in patients with severe PAH. Transfer to a therapy that is recommended at the severe stage of the disease (e.g. Epoprostenol) should be considered if the clinical condition deteriorates.
The benefit/risk balance of Bosentan has not been established in patients with WHO class I functional status of PAH.
Bosentan should only be initiated if the systemic systolic blood pressure is higher than 85 mmHg.
Bosentan has not been shown to have a beneficial effect on the healing of existing digital ulcers.
Liver function: Elevations in liver aminotransferases, i.e. aspartate and alanine aminotransferases (AST and/or ALT), associated with Bosentan are dose dependent. Liver enzyme changes typically occur within the first 26 weeks of treatment but may also occur late in treatment. These increases may be partly due to competitive inhibition of the elimination of bile salts from hepatocytes but other mechanisms, which have not been clearly established, are probably also involved in the occurrence of liver dysfunction. The accumulation of Bosentan in hepatocytes leading to cytolysis with potentially severe damage of the liver, or an immunological mechanism, are not excluded. Liver dysfunction risk may also be increased when medicinal products that are inhibitors of the bile salt export pump, e.g. Rifampicin, Glibenclamide and Cyclosporine A, are co-administered with Bosentan, but limited data are available. (See Table 2.)

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Hemoglobin concentration: Treatment with Bosentan has been associated with dose-related decreases in hemoglobin concentration. It is recommended that hemoglobin concentrations be checked prior to initiation of treatment, every month during the first 4 months, and quarterly thereafter. If a clinically relevant decrease in hemoglobin concentration occurs, further evaluation and investigation should be undertaken to determine the cause and need for specific treatment.
Pulmonary veno-occlusive disease: Cases of pulmonary edema have been reported with vasodilators (mainly prostacyclins) when used in patients with pulmonary veno-occlusive disease. Consequently, should signs of pulmonary edema occur when Bosentan is administered in patients with PAH, the possibility of associated veno-occlusive disease should be considered.
Pulmonary arterial hypertension patients with concomitant left ventricular failure: Treatment with diuretics should be considered in patients with evidence of fluid retention before the start of treatment with Bosentan.
Pulmonary arterial hypertension associated with HIV infection: An increased long-term risk of hepatic toxicity and hematological adverse events cannot be excluded when Bosentan is used in combination with antiretroviral medicinal products. Due to the potential for interactions related to the inducing effect of Bosentan on CYP450, which could affect the efficacy of antiretroviral therapy, these patients should also be monitored carefully regarding their HIV infection.
Pulmonary hypertension secondary to chronic obstructive pulmonary disease (COPD): An increase in minute ventilation and a decrease in oxygen saturation were observed, and the most frequent adverse event was dyspnea, which resolved with discontinuation of Bosentan.
Concomitant use with other medicinal products: Concomitant use of Bosentan and Cyclosporine A is contraindicated. Concomitant use of Bosentan with Glibenclamide, Fluconazole and Rifampicin is not recommended.
Concomitant administration of both a CYP3A4 inhibitor and a CYP2C9 inhibitor with Bosentan should be avoided.
Women of childbearing potential: As Bosentan may render hormonal contraceptives ineffective and taking into account the risk that pulmonary hypertension deteriorates with pregnancy: Bosentan treatment must not be initiated in women of childbearing potential unless they practice reliable contraception and the result of the pre-treatment pregnancy test is negative.
Hormonal contraceptives cannot be the sole method of contraception during treatment with Bosentan.
Monthly pregnancy tests are recommended during treatment to allow early detection of pregnancy.

Pregnancy: There are no reliable data on the use of Bosentan in pregnant women. The potential risk for humans is still unknown. Bosentan is contraindicated in pregnancy.
Women of childbearing potential: Before the initiation of Bosentan treatment in women of childbearing potential, the absence of pregnancy should be checked, appropriate advice on reliable methods of contraception provided, and reliable contraception initiated. Patients and prescribers must be aware that due to potential pharmacokinetic interactions, Bosentan may render hormonal contraceptives ineffective. Therefore, women of childbearing potential must not use hormonal contraceptives (including oral, injectable, transdermal or implantable forms) as the sole method of contraception but must use an additional or an alternative reliable method of contraception. If there is any doubt about what contraceptive advice should be given to the individual patient, consultation with a gynecologist is recommended. Because of possible hormonal contraception failure during Bosentan treatment, and also bearing in mind the risk that pulmonary hypertension severely deteriorates with pregnancy, monthly pregnancy tests during treatment with Bosentan are recommended to allow early detection of pregnancy.
Breastfeeding: It is not known whether Bosentan is excreted into human breast milk. Breastfeeding is not recommended during treatment with Bosentan.
Fertility: It cannot be excluded that Bosentan may have a detrimental effect on spermatogenesis in men. In male children, a long-term impact on fertility after treatment with Bosentan cannot be excluded.

Tabulated list of adverse reactions: (See Table 3.)

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Pediatric population: Liver test abnormalities and decrease hemoglobin concentration was reported.

Bosentan is an inducer of the cytochrome P450 (CYP) isoenzymes CYP2C9 and CYP3A4. Consequently, plasma concentrations of substances metabolized by these isoenzymes will be decreased when Bosentan is co-administered. The possibility of altered efficacy of medicinal products metabolized by these isoenzymes should be considered. The dosage of these products may need to be adjusted after initiation, dose change or discontinuation of concomitant Bosentan treatment.
Bosentan is metabolized by CYP2C9 and CYP3A4. Inhibition of these isoenzymes may increase the plasma concentration of Bosentan (see Ketoconazole). The influence of CYP2C9 inhibitors on Bosentan concentration has not been studied. The combination should be used with caution.
Fluconazole and other inhibitors of both CYP2C9 and CYP3A4: Co-administration with Fluconazole, which inhibits mainly CYP2C9, but to some extent also CYP3A4, could lead to large increases in plasma concentrations of Bosentan. The combination is not recommended. For the same reason, concomitant administration of both a potent CYP3A4 inhibitor (such as Ketoconazole, Itraconazole or Ritonavir) and a CYP2C9 inhibitor (such as Voriconazole) with Bosentan is not recommended.
Cyclosporine A: Co-administration of Bosentan and cyclosporine A (a calcineurin inhibitor) is contraindicated (see Contraindication). When co-administered, initial trough concentrations of Bosentan were approximately 30-fold higher than those measured after Bosentan alone. At steady state, Bosentan plasma concentrations were 3- to 4-fold higher than with Bosentan alone. The mechanism of this interaction is most likely inhibition of transport protein-mediated uptake of Bosentan into hepatocytes by cyclosporine. The blood concentrations of Cyclosporine A (a CYP3A4 substrate) decreased by approximately 50%. This is most likely due to induction of CYP3A4 by Bosentan.
Tacrolimus, Sirolimus: Co-administration of Tacrolimus or Sirolimus and Bosentan has not been studied in man but co-administration of Tacrolimus or Sirolimus and Bosentan may result in increased plasma concentrations of Bosentan in analogy to co-administration with cyclosporine A. Concomitant Bosentan may reduce the plasma concentrations of Tacrolimus and Sirolimus. Therefore, concomitant use of Bosentan and Tacrolimus or Sirolimus is not advisable. Patients in need of the combination should be closely monitored for adverse events related to Bosentan and for Tacrolimus and Sirolimus blood concentrations.
Glibenclamide: Co-administration of Bosentan 125 mg twice daily for 5 days decreased the plasma concentrations of Glibenclamide (a CYP3A4 substrate) by 40%, with potential significant decrease of the hypoglycemic effect. The plasma concentrations of Bosentan were also decreased by 29%. In addition, an increased incidence of elevated aminotransferase may be observed in patients receiving concomitant therapy. Both Glibenclamide and Bosentan inhibit the bile salt export pump, which could explain the elevated aminotransferases. This combination should not be used. No drug-drug interaction data are available with the other sulfonylureas.
Rifampicin: Co-administration of Bosentan 125 mg twice daily with Rifampicin, a potent inducer of CYP2C9 and CYP3A4 for 7 days, will decrease the plasma concentrations of Bosentan by 58%, and this decrease could achieve almost 90% in an individual case. As a result, a significantly reduced effect of Bosentan is expected when it is co-administered with Rifampicin. Concomitant use of Rifampicin and Bosentan is not recommended. Data on other CYP3A4 inducers, e.g. Carbamazepine, Phenobarbital, Phenytoin and St. John's Wort are lacking, but their concomitant administration is expected to lead to reduced systemic exposure to Bosentan. A clinically significant reduction of efficacy cannot be excluded.
Lopinavir + Ritonavir (and other Ritonavir-boosted protease inhibitors): Co-administration of Bosentan 125 mg twice daily and Lopinavir + Ritonavir 400 + 100 mg twice daily for 9.5 days will result in initial trough plasma concentrations of Bosentan that were approximately 48-fold higher than those measured after Bosentan administered alone. On day 9, plasma concentrations of Bosentan were approximately 5-fold higher than with Bosentan administered alone. Inhibition by Ritonavir of transport protein-mediated uptake into hepatocytes and of CYP3A4, thereby reducing the clearance of Bosentan, most likely causes this interaction. When administered concomitantly with Lopinavir + Ritonavir, or other Ritonavir-boosted protease inhibitors, the patient's tolerability of Bosentan should be monitored.
After co-administration of Bosentan for 9.5 days, the plasma exposures to Lopinavir and Ritonavir may be decreased to a clinically non-significant extent (by approximately 14% and 17%, respectively). However, full induction by Bosentan might not have been reached and a further decrease of protease inhibitors cannot be excluded. Appropriate monitoring of the HIV therapy is recommended. Similar effects would be expected with other Ritonavir-boosted protease inhibitors (see Precautions).
Other antiretroviral agents: No specific recommendation can be made with regard to other available antiretroviral agents due to the lack of data. Due to the marked hepatotoxicity of Nevirapine, which could add to Bosentan liver toxicity, this combination is not recommended.
Hormonal contraceptives: Co-administration of Bosentan 125 mg twice daily for 7 days with a single dose of oral contraceptive containing Norethisterone 1 mg + Ethinyl estradiol 35 mcg decreased the AUC of Norethisterone and Ethinyl estradiol by 14% and 31%, respectively. However, decreases in exposure were as much as 56% and 66%, respectively, in individual subjects. Therefore, hormone-based contraceptives alone, regardless of the route of administration (i.e. oral, injectable, transdermal or implantable forms), are not considered as reliable methods of contraception (see Precautions and Use in Pregnancy & lactation).
Warfarin: Co-administration of Bosentan 500 mg twice daily for 6 days may decrease the plasma concentrations of both S-Warfarin (a CYP2C9 substrate) and R-warfarin (a CYP3A4 substrate) by 29% and 38%, respectively. Concomitant administration of Bosentan with Warfarin in patients with PAH may not result in clinically relevant changes in International Normalized Ratio (INR) or Warfarin dose. No dose adjustment is needed for Warfarin and similar oral anticoagulant agents when Bosentan is initiated, but intensified monitoring of INR is recommended, especially during Bosentan initiation and the up-titration period.
Simvastatin: Co-administration of Bosentan 125 mg twice daily for 5 days decreased the plasma concentrations of Simvastatin (a CYP3A4 substrate) and its active β-hydroxy acid metabolite by 34% and 46%, respectively. The plasma concentrations of Bosentan were not affected by concomitant Simvastatin. Monitoring of cholesterol levels and subsequent dosage adjustment should be considered.
Ketoconazole: Co-administration for 6 days of Bosentan 62.5 mg twice daily with Ketoconazole, a potent CYP3A4 inhibitor, increased the plasma concentrations of Bosentan approximately 2-fold. No dose adjustment of Bosentan is considered necessary. Although not demonstrated through in vivo studies, similar increases in Bosentan plasma concentrations are expected with the other potent CYP3A4 inhibitors (such as Itraconazole or Ritonavir). However, when combined with a CYP3A4 inhibitor, patients who are poor metabolizers of CYP2C9 are at risk of increases in Bosentan plasma concentrations that may be of higher magnitude, thus leading to potential harmful adverse events.
Epoprostenol: Combination of Bosentan and Epoprostenol may indicate that after both single- and multiple-dose administration, the C_max and AUC values of Bosentan is similar in patients with or without continuous infusion of Epoprostenol (see Pharmacology under Actions).
Sildenafil: Co-administration of Bosentan 125 mg twice daily (steady state) with Sildenafil 80 mg three times a day (at steady state) concomitantly administered during 6 days may result in a 63% decrease in the Sildenafil AUC and a 50% increase in the Bosentan AUC. Caution is recommended in the case of co-administration.
Tadalafil: Bosentan (125 mg twice daily) reduced Tadanafil (40 mg once per day) systemic exposure by 42% and C_max by 27% following multiple dose co-administrations. Tadalafil did not affect the exposure (AUC and C_max) of Bosentan or its metabolites.
Digoxin: Co-administration for 7 days of Bosentan 500 mg twice daily with Digoxin decreased the AUC, C_max and C_min of Digoxin by 12%, 9% and 23%, respectively. The mechanism for this interaction may be induction of P-glycoprotein. This interaction is unlikely to be of clinical relevance.
Pediatric population: Interaction studies have only been performed in adults.

Store at temperature of not more than 30°C.

Other Antihypertensives

C02KX01 - bosentan ; Belongs to the class of other antihypertensives. Used in the treatment of pulmonary arterial hypertension.

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