Bosentan - Dosage, Indication, Contraindication, and Adverse Effect

Overview

Bosentan is a medication used to treat the symptoms of pulmonary arterial hypertension (PAH) in adults and children aged three and older. It increases the patient's ability to exercise and reduces disease progression.

The elevated blood pressure that develops in the main artery of the lungs is referred to as pulmonary arterial hypertension. This artery is responsible for transporting blood to the lungs from the ventricle on the right side of the heart. The right ventricle must work harder to pump sufficient blood through the lungs when the smaller blood capillaries in the lungs become more resistant to the blood flow due to blockage. Bosentan effectively reduces the hormone levels often present in high quantities in the blood and lungs of persons with pulmonary arterial hypertension. Additionally, it is helpful because it increases the blood supply to the lungs and decreases the workload on the heart.

This medication is only available through the Tracleer REMS (risk evaluation and mitigation strategy) scheme, a restricted distribution program.

Drug Development and Approval-

Actelion pharmaceuticals limited. (Actelion) submitted NDA (new drug application) 209279 for Bosentan dispersible tablets on August 5, 2016, for treating pulmonary arterial hypertension in adults and children. The drug was approved and authorized in November 2001 for treating pulmonary arterial hypertension.

Indications-

Patients with WHO (World health organization) functional class III are treated for pulmonary arterial hypertension (PAH) to enhance their activity capacity and alleviate their symptoms.

Efficacy has also been shown in the following conditions:

• Primary (idiopathic and heritable) PAH.

• PAH due to scleroderma in the absence of severe interstitial pulmonary disease.

• PAH with congenital systemic-to-pulmonary shunts and Eisenmenger's physiology.

• Patients with PAH (pulmonary arterial hypertension) WHO functional class II have also demonstrated some improvement.

• Bosentan is also approved to prevent new digital ulcers in patients with systemic sclerosis and persistent digital ulcer disease.

Contraindications-

• Hypersensitivity to the active ingredient or any of the excipients.

• Moderate to severe hepatic impairment, corresponding to Child-Pugh classes B or C.

• Liver aminotransferases like aspartate aminotransferases (AST) and alanine aminotransferases (ALT), with baseline values larger than three times the standard upper limit.

• Co-administration of cyclosporin A.

• Pregnancy.

• Women of reproductive age and who are using contraceptives.

Composition-

• Each film-coated tablet contains 62.5 milligrams and 125 milligrams of Bosentan inside of it (as monohydrate).

• This medication has less than one mmol of sodium per tablet, equivalent to 23 mg. Hence, it is almost sodium-free.

Dosage Forms and Strengths-

• 62.5 mg tablets as bi-convex, orange-white, round tablets debossed with 62.5 mark as identification.

• 125 mg of oval, biconvex, and orange-white tablets, debossed with identification marking as 125.

• 32 mg tablets for oral suspension, which are clover-shaped, quadrisected, pale yellow to off-white, and debossed with 32 on the side opposite the quadrisection lines.

For Patients

What Is Bosentan?

Bosentan has been shown to reduce blood pressure in the lungs, making it easier for the heart to circulate blood throughout the body.

The medical condition known as pulmonary arterial hypertension (PAH) can be treated with Bosentan in patients of any age as long as they are at least three years old. This drug is known to improve the capacity for exercise and delay the progression of the disease.

Bosentan can only be obtained through a specific scheme and from licensed pharmacies. Individuals must be enrolled in the program to understand this medication's potential drawbacks and advantages.

Why Is Bosentan Prescribed?

Bosentan is used to treat high blood pressure in the blood vessels that carry blood to the lungs (pulmonary arterial hypertension, or PAH) in adults and children older than three years. In addition, Bosentan may make it easier for people with PAH to exercise and slow down how fast their symptoms get worse. Bosentan is an endothelin receptor antagonist, which is a type of medicine. It works by stopping endothelin from doing its job. Endothelin is a natural substance that narrows blood vessels and prevents blood from generally flowing in people with PAH.

How Should This Medicine Be Used?

• Bosentan can be taken by mouth as a tablet or as a dispersible tablet that can be dissolved and mixed with liquid. Most people take it in the morning and evening, with or without food.

• Take Bosentan around the same time every day to help you remember to take it and follow the instructions on the leaflet provided. In case of any confusion, ask the doctor or pharmacist to explain it.

• Please do not take it more or less or more often than prescribed by the doctor.

• To use a tablet that is in a dispersible form, put it in a small amount of liquid right before consuming. If the doctor prescribes to take half a tablet, carefully break the dispersible tablet on the line.

• Follow the directions for taking the half tablet, and put the other half back in the opened blister in the package. Use the rest of the pill within seven days. Do not break the tablet into quarters.

• Most likely, the doctor will start you on a low dose of Bosentan and then increase it after four weeks. Bosentan keeps the symptoms of PAH in check, but it does not cure the disease. Before the individual feels the full benefit of Bosentan, it may take one to two months or longer. Even if one feels like they are fine, continue taking Bosentan. Please do not stop Bosentan unless the doctor tells the patient to stop. Suddenly ceasing to take Bosentan may cause the symptoms to get worse. It is the doctor that decides the dosage and also when to stop taking this medicine.

What Is the Right Way to Store and Dispose of This Medicine?

• Keep this medicine in the container it came in, close it tightly, and keep it away from kids. Keep it at room temperature and out of places where it is excessively hot or humid.

• Medications that are no longer needed should be thrown away in a certain way so that pets, children, and other people cannot get to them. However, never flush this medicine down the toilet. Instead, a medicine take-back program is the best way to eliminate stacked-up old medication. Find out about take-back programs that run locally by talking to your pharmacist or calling the local garbage or recycling department.

• Keep all medicines out of sight and out of reach of children. Many containers, like those for weekly pill organizers, eye drops, creams, patches, and inhalers, are not made to be child-proof, so even young children can easily open them. To keep young children from poisoning themselves, always lock the safety caps and put the medicine in a safe place right away. This should be somewhere up and away, out of their sight and reach.

What Are the Possible Side Effects of Bosentan?

Bosentan has the potential to induce major adverse effects to call medical help if one has any of the following symptoms:

• Leg or ankle swelling, with or without weight gain.

• Light-headed sensation, as if a person might pass out.

• Symptoms of liver issues, which can be presented as pale skin, unusual weariness, feeling light-headed or short of breath, and icy hands and feet, are symptoms of low red blood cell count (anemia), nausea, vomiting, fever, upper stomach pain, weariness, dark urine, jaundice (yellowing of the skin or eyes).

• Lung problems with the presenting symptoms like anxiety, sweating, pale skin, severe shortness of breath, wheezing, gasping for breath, cough with frothy mucus, chest pain, and fast or irregular heart rate.

Some of Bosentan's most common side effects:

• Joint discomfort.

• Headache.

• Dizziness.

• Flushing (a warm, red, or tingling sensation).

• An irregular heartbeat.

• Symptoms of a cold include a stuffy nose, sinus pain, sneezing, and a sore throat.

What Precautions Should Be Followed Before Starting the Therapy With Bosentan?

Before using Bosentan, notify the doctor and pharmacist:

• Inform them about any allergies to the drug or its ingredients.

• Do not take Cyclosporine or Glyburide while taking Bosentan.

• Tell the doctor and pharmacist about all drugs, vitamins, supplements, and herbal products used.

Ensure to inform the physician if the patient uses any of the following drugs:

• Amiodarone.

• Cholesterol-lowering medications (statins) such as Atorvastatin.

• Lovastatin and Simvastatin.

• Diltiazem.

• Erythromycin.

• Fluconazole.

• Gemfibrozil.

• Itraconazole.

• Ketoconazole.

• Rifampin.

• Ritonavir.

• Voriconazole.

• Many other medications may interact with Bosentan, so inform the doctor about all the drugs you use. Your doctor may modify your drug doses or check for side effects.

• In case of a heart problem, inform the doctor and the medication used for the condition.

• It is not advisable to breastfeed while taking this medication. So it is important to inform the physician if one is breastfeeding or planning to breastfeed.

• The individuals under treatment should be aware that the dispersible pills are sweetened with aspartame, a source of phenylalanine if the patient has phenylketonuria (PKU). This genetic disorder requires adherence to a specific diet to prevent brain damage that can result in severe intellectual incapacity.

What Should Be Done in Case of a Missed Dose?

It can be taken immediately as soon as one remembers the missed dose. However, if the next dose is approaching, skip the missing dose and resume the regular dosing regimen. Do not duplicate the dose to make up for a missing one. In case of confusion, it is always best to inform the physician about the missed dose and follow their advice.

What Should Be Done in Case of Overdose or an Emergency?

In the event of an overdose and If the person has collapsed, had a seizure, is having difficulty breathing, or cannot be awakened, call the emergency immediately.

For Doctors

Pharmacologic Class of Drug: Endothelin antagonists.

Generic Name: Bosentan.

Formulation- The drug is available in tablet form and also as a dispersible tablet that is quadrisected on one side and debossed with the number of the dosage strength on the other. Each table contains Bosentan monohydrate as an active ingredient. Cellulose microcrystalline, calcium hydrogen phosphate anhydrous, croscarmellose sodium, silica colloidal anhydrous, tartaric acid, tutti frutti taste, aspartame (E951), acesulfame potassium, and magnesium stearate are among the inactive ingredients. In addition, each dispersible tablet contains a trace of phenylalanine (1.87 mg).

Drug Description- Bosentan has a molecular formula of C27H29N5O6S•H2O and a molecular weight of 569.64. Bosentan is a powder that is white to yellow. It does not dissolve well in water (1.0 mg/100 mL) or in aqueous solutions with a low pH (0.1 mg/100 mL at pH 1.1 and 4.0; 0.2 mg/100 mL at pH 5.0). As pH increases, solubility increases (43 mg/100 mL at pH 7.5). When it is solid, Bosentan is very stable, does not absorb water, and is not affected by light.

Drug Substance and Form- Bosentan is a white to yellowish powder insoluble in water and aqueous solutions at low pH. It is stable in the solid state and neither hygroscopic nor light sensitive. Bosentan is a highly substituted pyrimidine derivative with no chiral centers. It is chemically known as 4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxyphenoxy)-[2,2'] -bipyrimidin-4-yl] - monohydrate of benzenesulfonamide.

Expiration Date and Storage Requirements-

• According to the quality assessment, the available stability statistics justify the planned 60-month shelf-life in the suggested commercial packaging (blisters composed of a bottom aluminum foil and a child-resistant push-through aluminum foil.

• The product should be stored at 20ºC – 25ºC (68ºF – 77ºF).

• The divided dispersible tablet can be stored for up to 7 days.

Therapeutic Indications-

• Bosentan is recommended for treating pulmonary arterial hypertension (PAH) (WHO Group 1) in adults to enhance exercise capacity and reduce clinical deterioration.

• Patients with WHO Functional Class II-IV symptoms and etiologies of idiopathic or heritable PAH (60%), PAH associated with connective tissue diseases (21 %), and PAH associated with congenital heart disease with left-to-right shunts (18 %).

• In pediatric patients three years and older with idiopathic or congenital PAH to improve pulmonary vascular resistance (PVR), which is anticipated to increase exercise capacity.

Contraindications-

1. Pregnancy: Bosentan is contraindicated in pregnant or potentially pregnant females. Females of reproductive potential must take two effective forms of contraception during treatment and one month after quitting Bosentan to prevent conception.

2. Use in Conjunction With Cyclosporine A: Coadministration of Cyclosporine A and Bosentan enhanced plasma concentrations of Bosentan significantly. The use of Bosentan With Cyclosporin A together is therefore contraindicated.

3. Use in Conjunction With Glyburide: Patients receiving Glyburide concurrently with Bosentan were shown to have an elevated risk of liver enzyme increases. Therefore, it is contraindicated to combine Glyburide and Bosentan.

4. Hypersensitivity: Bosentan is contraindicated in people with hypersensitivity to the drug or its components. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), anaphylaxis, rash, and angioedema have been observed.

Route of Administration-

• Oral

Dosage and Administration-

FDA-Labeled Usual Dose for Adults with Pulmonary Hypertension:

Use: For treating pulmonary arterial hypertension (PAH) (WHO Group 1) to enhance exercise capacity and reduce clinical deterioration.

Initial Dose: 62.5 mg twice daily orally for four weeks.

Maintenance Dose: Increase to 125 mg twice daily orally after the initial dose.

Standard Pediatric Dosage for Pulmonary Hypertension: For pediatric patients three years or older with idiopathic or congenital PAH to lower pulmonary vascular resistance, which is anticipated to increase exercise capacity.

• 3 to 12 Years of Age:

  • 4 kg to 8 kg: 16 mg twice daily Orally Greater than 8 kg to 16 kg: 32 mg twice daily Orally

  • Between 16 kg and 24 kg: 48 mg orally twice daily

  • Between 24 kg and 40 kg: 64 mg orally twice daily

• More than Twelve Years:

  • Less than 40 kg: 62.5 mg twice daily orally

  • More than 40 kg: 62.5 mg twice daily orally for 4 weeks, then increase to 125 mg twice daily orally.

Observations: Doses greater than 125 mg twice daily did not appear to give extra benefits adequate to outweigh the higher risk of hepatotoxicity.

Drug Interactions-

Bosentan has severe adverse reactions to other drugs, some of which are as follows:

• Artemether or Lumefantrine.

• Cariprazine.

• Cobimetinib.

• Cyclosporine.

• Dienogest or estradiol valerate.

• Doravirine.

• Elvitegravir/cobicistat/emtricitabine/tenofovir DF.

• Fostemsavir.

• Glyburide.

• Lsavuconazonium sulfate.

• Lonafarnib.

• Lorlatinib.

• Lumacaftor/ivacaftor.

• Lumefantrine.

• Naloxegol.

• Ombitasvir/paritaprevir/ritonavir & dasabuvir (DSC).

• Panobinostat.

• Praziquantel.

• Regorafenib.

• Roflumilast.

• Vandetanib.

Warnings-

The Potential Risk for Hepatotoxicity and Embryo-fetal Toxicity:

Due to the dangers of hepatotoxicity and birth abnormalities, Bosentan is only offered through the Tracleer REMS Program, a restricted program. The Tracleer risk evaluation and mitigation strategy include the Tracleer REMS Program (REMS). Prescribers, patients, and pharmacies must enroll in the Tracleer REMS program.

Requirements of the Tracleer REMS are-

• Healthcare professionals who prescribe Bosentan must evaluate the prescriber's educational materials, join the Tracleer REMS Program, and comply with its criteria.

• Healthcare practitioners must examine serum aminotransferases (ALT/AST) and bilirubin and agree to order and monitor these tests regularly for females of reproductive potential, ensure that the patient is not pregnant, and decides to order monthly pregnancy tests.

• To receive Tracleer, all patients must comprehend the risks and advantages of the medication and sign an enrollment form.

• Pharmacies that dispense Tracleer must enroll in the Tracleer REMS program and agree to comply with its rules.

Hepatotoxicity-

• In clinical investigations, Bosentan induced an increase in liver aminotransferases (ALT and AST) of at least threefold the upper limit of normal (ULN) in around 11 % of patients, in some instances accompanied by an increase in bilirubin. Serum aminotransferase levels must be tested before treatment begins and afterward every month.

• In the postmarketing period, in close monitoring, rare incidences of unexplained hepatic cirrhosis were described in patients with numerous comorbidities and pharmacological treatments following extended greater than 12 months) treatment with Bosentan. In addition, there have been cases of liver failure. In these instances, Bosentan's involvement could not be ruled out.

• In at least one case, the first presentation (after 20 months of medication) comprised substantial elevations in aminotransferase and bilirubin levels along with non-specific symptoms, all of which reduced slowly over time once Bosentan was discontinued. This case highlights the significance of strict adherence to the monthly monitoring schedule for the duration of treatment and the treatment algorithm, which includes discontinuing Bosentan in the event of an aminotransferase elevation accompanied by signs or symptoms of liver dysfunction.

• Aminotransferase elevations necessitate close monitoring. Patients with high aminotransferases ( three times ULN) at baseline should generally avoid Bosentan since monitoring for hepatotoxicity may be more challenging. This Medication should be discontinued if liver aminotransferase elevations are accompanied by clinical signs of hepatotoxicity (such as nausea, vomiting, fever, abdominal pain, jaundice, or unusual lethargy), exhaustion) or increases in bilirubin. There is no prior experience with reintroducing this drug under these conditions.

Embryonic Toxicity-

• Based on animal studies, Bosentan is likely to cause significant birth abnormalities in pregnant females. Therefore, pregnancy must be ruled out before starting this medication.

• Females of reproductive potential must utilize two reliable methods of contraception during therapy for one month after stopping Bosentan unless the patient has an intrauterine device (IUD) or tubal sterilization, in which case no further contraception is required.

• Hormonal contraceptives, including oral, injectable, transdermal, and implanted contraceptives, should not be used as the sole method of contraception in patients receiving Bosentan, as they may not be the effective means of contraception.

• Perform monthly pregnancy testing.

Fluid Retention-

• Peripheral edema is a documented clinical outcome of PAH and deteriorating PAH, as well as Bosentan and other endothelin receptor antagonists. 1.7 % (placebo-corrected) of PAH patients taking Bosentan had fluid retention or edema.

• Patients with pulmonary hypertension have reported fluid retention weeks after initiating Bosentan. Decompensated heart failure requires diuretics, fluid control, or hospitalization.

• If clinically substantial fluid retention develops with or without weight gain, further assessment is needed to ascertain the reason, such as the necessity for treatment or Bosentan discontinuation.

Pulmonary Veno-Occlusive Disease-

• Consider the likelihood of concomitant pulmonary veno-occlusive illness, and Bosentan should be discontinued if signs of pulmonary edema appear.

Decreased Sperm Count-

• Bosentan patients' sperm levels are lower. Preclinical results suggest that Bosentan, like other endothelin receptor antagonists, may impair spermatogenesis.

Usage of Drugs in Specific Populations:

1. Pregnancy-

• According to evidence from animal reproduction studies, Bosentan may cause fetal injury, including birth abnormalities and fetal death, when administered to a pregnant female and is prohibited during pregnancy. There is little information available about Bosentan use in pregnant women. Oral treatment of Bosentan to pregnant rats at twice the maximum recommended human dose showed teratogenic consequences in rats, including abnormalities of the head, mouth, face, and prominent blood vessels. Inform pregnant women about the potential harm to the fetus.

• The estimated background risk of serious birth abnormalities and miscarriage is unknown. Every pregnancy carries the possibility of a birth deformity, miscarriage, or other catastrophic outcomes. The U.S. general population's estimated background risk of serious birth abnormalities and miscarriage in clinically diagnosed pregnancies is 2-4 % and 15-20 %, respectively.

2. Lactation-

• Bosentan's presence in human milk, its effects on breastfed babies, and milk production are unknown. Because Bosentan might cause fluid retention and hepatotoxicity in breastfed newborns, women should be advised not to breastfeed while taking it.

3. Females and Males of Reproductive Potential-

• Females of reproductive potential must utilize two reliable methods of contraception during therapy for one month after stopping Bosentan unless the patient has an intrauterine device (IUD) or tubal sterilization, in which case no further contraception is required.

• Hormonal contraceptives, including oral, injectable, transdermal, and implanted contraceptives, should not be used as the sole method of contraception in patients receiving Bosentan, as they may not be the effective means of contraception.

• Bosentan patients' sperm levels are lower. Preclinical results suggest that Bosentan, like other endothelin receptor antagonists, may impair spermatogenesis.

4. Geriatric Use-

• In the clinical studies of Bosentan, there was no significant number of participants aged 65 and older to evaluate whether or not their responses differed from those of younger participants.

5. Impaired Hepatic Function-

• Because there is evidence that Bosentan's main route of excretion is biliary, liver damage could be expected to increase bosentan exposure of Cmax(peak plasma concentration) and AUC(Area under the curve).

• Pharmacokinetics have not been studied in people with severe liver impairment. Systemic exposures to Bosentan and its active metabolite rose considerably in patients with moderate hepatic impairment.

• Bosentan should be generally avoided in patients with moderate to severe liver impairment.

• The pharmacokinetics of Bosentan was not affected in patients with mild hepatic impairment.

6. Impaired Renal Function-

The effect of renal impairment on bosentan pharmacokinetics is minor and does not necessitate dosage change.

Data on Animal Studies-

• Bosentan was found to be teratogenic in rats at oral dosages two times the MRHD (in mg/m2). Bosentan exhibited dose-dependent teratogenic effects in a rat embryo-fetal toxicity study, including abnormalities of the head, mouth, face, and big blood vessels. At oral doses of two and ten times the MRHD (in mg/m2), Bosentan increased stillbirths and mortality.

• Although no birth abnormalities were seen in rabbits given oral dosages of up to 10.5 g/day in a 70 kg individual, plasma concentrations of Bosentan in rabbits were lower than in rats. The similarities between the abnormalities caused by Bosentan and those shown in endothelin-1 knockout mice and animals treated with other endothelin receptor antagonists suggest that embryo-fetal damage is a class effect of these medicines.

Mechanism of Action-

Bosentan is an endothelin receptor type ETA and ETB selective and competitive antagonist. Bosentan shows a modest preference for ETA receptors over ETB receptors. The clinical consequences of dual endothelin blockage are unknown.Endothelin-1 (ET-1) is a neurohormone that exerts its effects by interacting with ETA and ETB receptors in the endothelium and vascular smooth muscle. ET-1 levels are higher in the plasma and lung tissue of PAH patients, indicating a pathogenic function for ET-1 in this condition.

Pharmacokinetics-

• In healthy adult subjects, maximum plasma concentrations of Bosentan are achieved within three to five hours of oral treatment, and the terminal elimination half-life is around five hours.

• Adult patients with PAH have around twice the exposure to Bosentan after intravenous and oral treatment as healthy adult counterparts.

• In a study evaluating relative bioavailability in healthy people, the peak plasma concentration and area under the plasma concentration-time curve for Bosentan were 14 % and 11 % lower, respectively, after administration of the oral dispersible tablet versus the film-coated tablet.

Absorption-

In healthy individuals, the absolute bioavailability of Bosentan is around 50 % and is unaffected by food. Bosentan is firmly bound (greater than 98 %) to plasma proteins, namely albumin. Therefore, Bosentan is incapable of penetrating erythrocytes. The distribution volume is approximately 18 L.

Metabolism-

One of Bosentan's three metabolites is pharmacologically active and may contribute 10 % to 20 % of the drug's impact. Bosentan is a potential inducer of CYP2C9, CYP3A, and mostly CYP19. Multiple oral dosages decrease plasma concentrations in healthy people to 50 to 65 % of levels reported following a single dose, perhaps due to the auto-induction of liver enzymes involved in metabolism. The steady-state condition is reached within three to five days.

Excretion-

Bosentan is removed via biliary excretion after liver metabolism. Therefore, less than three percent of an orally delivered dosage is absorbed in the urine. In patients with PAH, the total clearance following a single intravenous dose is around four L/h.

Clinical Toxicology-

Bosentan is well tolerated and poses a very minimal risk of toxicity when patients are monitored appropriately. Bosentan plasma levels increased 30-fold when combined with cyclosporin A, resulting in severe headaches, nausea, and vomiting.However, there were no significant side effects or toxicity in these patients. During one postmarketing period, a male patient overdosed on 10,000 mg of Bosentan and experienced nausea, vomiting, hypotension, impaired vision, and sweating. The patient was able to recover completely after receiving proper blood pressure support.

Patient Counseling Information-

• Recommend that the patient read the FDA (Food and Drug Administration) - approved patient medication guide.

• Inform the patient that this drug is only available through the Tracleer REMS Program, a restricted access program.

• Instruct patients about the complications and procedures to follow to avoid the complications.

• Discuss with the patient the need to measure serum aminotransferases monthly.

• Explain the toxicity to embryos and fetuses for female patients of reproductive age who are planning to conceive.

• Educate and counsel female patients of reproductive potential about the importance of using reliable contraceptive techniques during Bosentan treatment and for one month after medication discontinuation.

• Inform the patient that Brosentan is only available from specialized pharmacies that are part of the Tracleer REMS program.

• To certify that they understand the hazards of Tracleer, patients must sign the Tracleer patient enrollment and consent form.

• Advise the patient to avoid making the tablet into quarters.

Conclusion

The only available treatments for pulmonary arterial hypertension before the development of Bosentan were intravenous drugs like Epoprostenol. Since then, Bosentan has been the first-line treatment for people with pulmonary artery hypertension. Clinical trials have shown that Bosentan is effective as monotherapy or, more frequently, as a component of combination therapy.

Due to its minimal risk of toxicity, ease of administration, effectiveness, and disease-modifying qualities, Bosentan is one of the most often used medications for treating people with pulmonary artery hypertension. Whether the combination therapy yields the greatest outcomes with low to no toxicity will require further study. It is best to use an interprofessional team approach when using Bosentan for pulmonary arterial hypertension to guide cases to ideal outcomes with few side effects or drug interactions.