Ravenell-62.5 Davipharm medicine for Tien Phat pulmonary hypertension (4 blisters x 14 tablets)

Bosentan is also indicated to reduce the number of new finger/feet sores in patients with stiffness and ulcerative finger/leg ulcers.

Pharmacological

Pharmacological Group: other anti -hypertension drugs

ATC code: C02K x01

Bosentan is a double -led reservo that the reservo is affinity on both the endothelin A and B (ETA and ETB) receptors. Bosentan reduces the resistance of pulmonary blood vessels and the whole body leads to an increase in heart rate without increasing heart rate.

Endothelin-1 neuroscience (ET-1) is one of the strong vascular contraction substances that can promote atherosclerosis, cell proliferation, hypertrophy and heart restructuring, and inflammation. Intermediate effects by Endothelin bonds ETA and ETB receptors located in the endothelium and blood vessel muscle cells. ET-1 concentration in tissue and plasma increases in some cardiovascular diseases and connective tissue diseases, including pulmonary hypertension, sclerosis, acute and chronic heart failure, myocardial ischemia, systemic hypertension and atherosclerosis, showing the pathological role of ET-1 in these diseases.

In pulmonary hypertension and heart failure, when there is no antagonistic resettlin endothelin, ET-1 concentration increases closely with the severity and prognosis of these diseases.

Bosentan competes with ET-1 and other ET peptides in connecting with ETA and ETB receptors. Agency for ETA receptors (k = 4.1 - 43 nanomol) is slightly higher than the ETB receptors (k = 38 - 730 nanomol). Bosentan is specialized with ET receptors and does not bind to other receptors.

Dynamic pharmacokinetics

Bosentan pharmacokinetics are mainly researched on healthy people. Clinical data is limited showing that Bosentan concentration in adult patients with pulmonary artery pressure is about 2 times higher than healthy people.

In healthy people, Bosentan's pharmacokinetics depends on the dose and time.

Semi -selling time and distribution volume decrease when increasing intravenous dose and increasing over time. After oral, the body exposure is proportional to the dose of up to 500 mg. At higher doses, CMAX and AUC are less proportional to the dose.

Absorb

In healthy people, absolutely bioavailable about 50% and not affected by food. The maximum plasma concentration is achieved after about 3-5 hours.

Distribution

Bosentan binds a lot (> 98%) with plasma proteins, mainly albumin. Bosentan does not penetrate the red blood cells. The distribution volume (VSS) is about 18 liters after an intravenous injection of a dose of 250 mg.

Metabolism and elimination

After an intravenous injection of a dose of 250 mg, the clearance is 8.2 l/h. The first -end sale time is 5.4 hours.

After using multi -dose, Bosentan's plasma concentration gradually decreases to 50-65% compared to single -dose use. This reduction may be due to the automatic touch of the metabolic enzyme in the liver. Stable state achieved after 3-5 days.

Bosentan is eliminated through bile after being metabolized in the liver by isenzyme CYP450, CYP2C9 and CYP3A4. Less than 3% of the dosage dosage except for urine.

Bosentan has 3 metabolites and only one of which has pharmacological activity. This metabolite is eliminated mainly without conversation. In adult patients, the amount of metabolites is more active than healthy people. In patients with evidence and the presence of cholestasis, the amount of metabolites with activity may increase.

Bosentan is the induction of CYP2CH and CYP3A4 and also the forms of CYP2C19 and P-Glycoprotein. In vitro, bosentan inhibit honey secretion in liver cells.

In vitro data shows that Bosentan has no inhibitory effect with testing isoenzymes (CYP1A2, 246, 2B6, 2C8, 2C9, 2D6, 2E1, 3A4). Therefore, Bosentan does not increase the plasma concentration of metabolic drugs by these isenzymes.

pharmacokinetics on special subjects

Patients with liver failure

In patients with mild liver failure (Child-Pugh a), there is no pharmacokinetic change. AUC
in a stable state of Bosentan is 9% higher, and the AUC of metabolites is active
higher than 33% in patients with mild liver failure compared to healthy patients.

There is no pharmacokinetic study in patients with severe liver failure (Child-Pugh C). Bosentan is contraindicated for patients with medium and severe liver failure (Child-Pugh B/C).

Patients with renal failure

In patients with severe renal failure (Creatinine clearance 15 - 30 ml/ min),
Bosentan concentration decreased by about 10%. Bosentan's metabolic plasma concentration increases about 2 times in patients with renal impairment compared to normal renal function.

No dose adjustment in patients with renal impairment. There is no specialized clinical experience in patients with hemolysis. Based on the physical and chemical properties and high protein cohesion, Bosentan cannot be removed from the dialysis method.

Caution when used

has not established Bosentan's effectiveness in patients with severe pulmonary hypertension. It is recommended to change through other treatments when the disease is severe (eg Epoprostenol) if the clinical condition worsens.

Assessing the benefits/risks of Bosentan is incomplete with patients ID according to the WHO classification table assessing the lung function in increased pulmonary artery pressure.

Should only be treated with bosentan if the systolic blood pressure is higher than 85 mmHg.

Bosentan has not shown the effect in healing existing fingers.

Liver function

Increased liver aminotransferase, for example AST, ALT due to Bosentan depends on the dose. The liver enzyme changes within the first 26 weeks of treatment but may also be later. Increasing liver enzymes may be due to competition inhibitors to eliminate bile salts from liver cells, but it can also be due to other unknown mechanisms, and can lead to liver failure. Bosentan accumulation in liver cells leads to serious liver necrosis, or cannot rule out the possibility of other physiological immunity. The risk of liver failure can be increased when using bile salt inhibitors, for example, Rifampicin, Glibenclamid and Cyclosporin A are simultaneously used with Bosentan, but the data is limited.

Testing for liver's aminotransferase level before starting treatment and monthly during treatment with Bosentan. In addition, the concentration of aminotransferase must be checked for 2 weeks after increasing the dose.

recommendations in the case of AST/ALT

AST/ALT increases from 3-5 times the normal limit on treatment recommendations and monitoring.

To be sure, the second liver test should be tested; If it is firm, based on the response to each fish that decides the use of Bosentan, can reduce the dose or stop bosentan.

Continue to monitor the concentration of aminotransferase at least every 2 weeks. If the concentration of aminotransferase returns to the level before treatment, consider continuing or reuse Bosentan.

AST/ALT increases from 5 to 8 times the normal limit on

To be sure, the second liver test should be tested; If it is sure, it is advisable to stop treating and monitoring the concentration of aminotransferase at least every 2 weeks. If the concentration of aminotransferase returns to the level before treatment, consider continuing or reuse Bosentan.

AST/ ALT increases over 8 normal limits on

Should stop treatment and do not consider using Bosentan again.

In case of clinical symptoms of liver damage, such as nausea, vomiting, fever, abdominal pain, jaundice, coma or abnormal fatigue, symptoms such as flu (joint pain, muscle pain, fever), must stop treatment and do not consider using Bosentan again.

Treatment with Bosentan

Bosentan treatment is only considered if the benefits of treatment with Bosentan are superior to the risk and when the liver's aminotransferase concentration is in the price range of
before treatment. It is necessary to consult the liver specialist. Using Bosentan re -uses should follow the recommended dose in the dosage and usage.

HAIMOGLOBIN concentration

The treatment with Bosentan is associated with reducing the concentration of auxiliary haemoglobin
. In the reference Placebo study, reducing the concentration of haemoglobin due to
bosentan does not progress and stable after 4-12 weeks after treatment. HAIMOGLOBIN levels should be checked before the beginning of treatment, each month in the first 4 months of treatment,
and every 3 months later. If there is a significant reduction in haemoglobin levels, evaluate and check more carefully to find out the causes and the need for specialized treatment. The case of anemia must be infused.

Pulmonary veins

The case of lungs has been reported to vasodilators (mainly prostacyclin) when used in patients with pulmonary veins. Therefore, if signs of pulmonary edema appear when treated with Bosentan in PAH patients, considering the possibility of being associated with pulmonary veins. There have been reports on the case of lungs in patients treated with Bosentan when the patient is diagnosed with suspected pulmonary embolism.

Patients with lung pressure hypertension and left ventricular failure

There is no specialized research in patients with lung pressure increased and at the same time suffer from left ventricular failure. It is recommended that patients monitor the signs of epidemic retention (for example, weight gain), especially if the ring is suffering from a serious impairment. If this case is encountered, it is recommended to use diuretics or increase diuretic dose in use. Consider using diuretics in patients with evidence that being kept before starting treatment with Bosentan.

Patients with pulmonary hypertension and HIV infection

Clinical research experience is limited when using Bosentan for patients with PAH in combination with HIV infection, being treated with Retrovirus anti -Retrovirus drugs. Researching the drug interaction between Bosentan and Lopinavir + Ritonavir in a healthy group shows that plasma bosentane concentration increases, the peak concentration reaches after the first 4 days of treatment. At the beginning of Bosentan treatment in patients, the protease inhibitors must closely monitor the patient's tolerance with Bosentan from the beginning of treatment, the risk of hypotension and liver function tests.

It is not possible to rule out the risk of long -term liver toxicity and increase hematological adverse events when Bosentan is used with antacids. Due to the ability to interact related to Bosentan's CYP450 touch effect, it may affect the effectiveness of Retrovirus anti -Retrovirus drugs, so closely monitoring in HIV -infected patients.

Secondary lung pressure caused by chronic obstructive pulmonary disease (COPD)

Condemory warnings

Ravenell-62.5 contains castor oil that can cause abdominal pain, diarrhea, nausea, vomiting.

To be out of reach of children.

The effect of drugs on driving and operating machinery

There is no specialized research on the impact of Bosentan on driving and operating machinery. However, Bosentan can lower blood pressure, with dizziness or fainting symptoms, which can affect the ability to drive and operate machinery.

Use drugs for women during pregnancy and lactation

Pregnancy

Animal research shows that toxicity on reproduction (teratogenic, embryo poison). There is no reliable data on the use of Bosentan for pregnant women. The risk on people is still unknown. Contraindicated Bosentan for pregnant women.

Women are likely to be pregnant

Bosentan may lose the contraceptive effect of hormonal contraceptives, and thereby can lead to the risk of lung pressure heavier during pregnancy as well as teratogenicity (observed in animals).

Do not start Bosentan treatment in women who are likely to get pregnant unless they use safe contraception and test results show that they are not pregnant before treatment.

Hormonal contraceptives cannot be the only contraceptive method during treatment with Bosentan.

Monthly pregnancy tests should be tested during treatment for early pregnancy.

Breastfeeding period

It is unclear whether Bosentan will be in breast milk or not. Do not recommend used for breastfeeding women.

reproduction

Animal research shows that the drug has an impact on the testes. When studying Bosentan effects on testicular function in PAH patients, 8 out of 24 patients shows a 42% reduction in sperm concentration from the basic level after 3 or 6 months of using Bosentan. Based on preclinical studies and data, Bosentan may not affect sperm amounts in men. In male patients, may have a longer effect on fertility after treatment with Bosentan.

Drug interaction

bosentan is the Cytochrom P450 (CYP), isoenzyme CYP3A4 and CYP2C9. In vitro data also shows the ability to touch CYP2C19. Therefore, plasma concentrations of metabolites by these isenzymes will decrease when used with bosentan. Consider the ability to change the effectiveness of metabolic drugs by these isenzymes. The willow should be adjusted at the beginning of treatment, change the dose or stop using Bosentan.

Bosentan is metabolized by CYP2C9 and CYP3A4. Inhibiting these isenzymes can increase the concentration of Bosentan. The impact of CYP2C9 inhibitors on Bosentan concentration is studied. Should be careful when coordinating.

fluconazole and inhibitors of both isenzyme CYP2C9 and CYP3A4

Used with fluconazole, the main inhibitor CYP2C9, but a certain extent also inhibits CYP3A4, which can lead to a significant increase in Bosentan concentration. Do not recommend common use. For this reason, the sharing of CYP3A4 inhibitors (e.g. ketoconazole, otraconazole or ritonavir) and CYP2C9 (e.g. Voriconazol) with Bosentan is not recommended.

cyclosporin a

Contraindicated to use bosentan with cyclosporin A (Calcineurin inhibitor).

When used in common, the initial bottom concentration of Bosentan increased by 30 times compared to the use of single bosentan. In a stable state, plasma bosentane concentration increased by 3-4 times compared to the single bosentan use. The interaction mechanism may be due to the inhibition of the absorption through the intermediary of bosentan's transport protein into liver cells by cyclosporin.

tacrolimus, syrolimus

Shared use of Tacrolimus or Sirolimus with Bosentan has not been studied, but used with Bosentan may increase the plasma concentration of Bosentan when extracted from cyclosporin A. Used with Bosentan can reduce the concentration of Tacrolimus and Sirolimus. Therefore, bosentan should not be used with syrolimus and tacrolimus. Patients need to coordinate these drugs should closely monitor adverse events related to blood concentration of Bosentan and Tacrolimus, Sirolimus.

glibenclamide

Shared use of bosentan 125 mg x 2 times/ day for 5 days reduces plasma concentrations of glibenclamid (substrate of CYP3A4) by 40%, which can significantly reduce hypoglycemic effects. Bosentan's plasma concentration also decreased by 29%. In addition, increasing the frequency of increased aminotransferase enzyme has been observed in patients using the combination of these two drugs. Both glibenclamid and bosentan inhibit the bile salt pump out, which can explain the mechanism that increases aminotransferase. Do not use this combination. There is no drug interactive data - drugs with other sulfonylure drugs.

rifampicin

Research in 9 healthy people using Bosentan 7 days at a dose of 125 mg twice a day with rifampicin, the substance has the ability to touch CYP2C9 and CYP3A4, the plasma concentration of Bosentan decreases 58%, and in some cases can be reduced to nearly 90%. Therefore, the effect of Bosentan is significantly reduced when used with rifampicin.

There is no recommendation to use rifampicin with bosentan. Lack of data on other CYP3A4 induction substances, such as carbamazepin, phenobarbital, phenytoin and st. John, but the common use can reduce Bosentan's concentration and can lead to clinical effect reduction.

lopinavir + ritonavir (and other protease inhibitors increase the effect of ritonavir)

Use with Bosentan 125 mg 2 times/day and Lopinavir + Ritonavir 400 + 100 mg x 2 times/day for 9.5 days in a healthy volunteer for the first bottom concentration of Bosentan 48 times higher than using Bosentan alone. On 9, the plasma bosentan concentration is about 5 times higher than using Bosentan alone. The inhibition of Ritonavir absorption through the channel of protein transporting into liver cells and CYP3A4 reduces Bosentan's clearance, almost all interact. When used with Lopinavir + Ritonavir, or other protease inhibitors that increase the effect of ritonavir, monitor the patient's bosentan tolerance.

After use with Bosentan for 9.5 days, Lopinavir concentration decreased by 14% and Ritonavir decreased by 17%. However, it may have not reached the level of touch completely by Bosentan and therefore the concentration of protease inhibitors can continue to decrease. Recommended monitoring of HIV treatment. The same effect may occur when using other protease inhibitors.

Other anti -Retrovirus drugs

Lack of data is therefore no recommendation for other anti -Retrovirus drugs. Due to Nevirapin's liver toxicity, plus Bosentan's liver poisoning, it is not recommended to use this combination.

Hormone contraceptives

Shared use of 125 mg bosentan x 2 times/day for 7 days with 1 dose of oral contraceptives containing 1 mg + Ethinyl estradiol 35 mcg reduces the AUC of Norethisteron 14% and Ethinyl estradiol 31%. Depending on the individual, the concentration may decrease by 56% and 66%. Therefore, the methods of contraception hormone with all lines used (oral, injection, subcutaneous or transplant), are not considered safe contraception.

warfarin

Use with Bosentan 500 mg twice a day for 6 days reduces the plasma concentration of S-warfarin (the substrate of CYP2C9) 29% and R-Warfarin (the substrate of CYP3A4) 38%. The common use of bosentan and warfarin clinically in patients with pulmonary hypertension does not show changes in international normalization index (INR) or Warfarin dose. In addition, the frequency of changing the doses of warfarin depends on the Inr or the same side effects between the group using bosentan-warfarin and the warfarin-placeboo. There is no need to adjust the dose of Warfarin and oral anticoagulants when using Bosentan, but recommends closely monitoring Inr, especially when starting to treat or increase the dose of Bosentan.

Simvastatin

Used with Bosentan 125 mg 2 times/day for 5 days to make Simvastatin concentration (substrate of CYP3A4) decreased by 34% and its active B-Hydroxy metabolites decreased by 46%. Bosentan's plasma concentrations are not reduced when used with simvastatin. Monitor cholesterol levels and consider adjusting the dose.

ketoconazole

Use Bosentan 62.5 mg 2 times/ day for 6 days with ketoconazole, CYP3A4 inhibitor, increasing the concentration of bosentane to about 2 times. No need to adjust the dose of Bosentan. Although not shown in Vivo research, the concentration of Bosentan may increase the same when used with other CYP3A4 inhibitors (for example: Itraconazole, Ritonavir). However, when combined with CYP3A4 inhibitors, patients with less CYP2C9 enzyme are at higher risk of increasing Bosentan concentration and the risk of side effects is also higher.

EPPROSTENOL

When combining EPPROSTENOL with single or multi -dose bosentan, Bosentan's CMAX and AUC are similar in patients with continuous or non -transmission of EproStenol.

Sildenafil

Use with Bosentan 125 mg 2 times/ day (stable state) with Sildenafil 80 mg x 3 times/ day (stable state) within 6 days in healthy volunteers showing reducing AUC Sildenafil 63% and reducing AUC Bosentan by 50%. Precautions when used together.

digoxin

Used with Bosentan 500 mg twice a day with digoxin in 7 days reducing AUC Digoxin by 12%, CMAX decreased by 9%and CMIN decreased by 23%. The interaction mechanism may be due to P-Glycoprotein sensor. This interaction may not mean clinically.