Bosentan is a medication primarily used in the treatment of pulmonary arterial hypertension (PAH) and idiopathic pulmonary fibrosis (IPF). It belongs to a class of drugs called endothelin receptor antagonists, which work by blocking the effects of endothelin, a substance in the body that causes blood vessels to narrow and become tight.

In PAH, the blood vessels in the lungs become narrow and constricted, leading to increased blood pressure in the pulmonary arteries. Bosentan helps to widen these blood vessels, reducing the blood pressure and improving blood flow through the lungs, which can alleviate symptoms and improve exercise capacity in patients with PAH.

Bosentan is an endothelin receptor antagonist. It binds to the endothelin receptors and inhibits them resulting in vasodilation. It is used to treat the following conditions [Ref]:

• It is indicated in the treatment of pulmonary arterial hypertension WHO class 1 to improve exercise tolerance and prevent further deterioration.
• Idiopathic or congenital pulmonary arterial hypertension in children who are 3 years of age or older to improve vascular resistance.

Off-label uses of Bosentan include:

• Prevention of digital ulcers in patients with scleroderma.
• Raynaud's phenomenon.

Note: In patients with Pulmonary arterial hypertension and WHO functional class IV symptoms, it may be used as second-line therapy.

Bosentan Dose in Adult

Bosentan dose in the treatment of Pulmonary artery hypertension:  

For people who weigh less than 40 kilograms:

• They typically start with a dose of 62.5 milligrams taken by mouth twice a day, and this dosage stays the same for maintenance.

For people who weigh 40 kilograms or more:

• Initially, they also start with 62.5 milligrams taken by mouth twice a day for 4 weeks.
• After 4 weeks, the dosage is increased to 125 milligrams taken by mouth twice a day for maintenance.
• It's usually not recommended to take more than 125 milligrams twice a day because higher doses don't seem to give extra benefits and may cause liver problems.

When stopping the medication, it's important to gradually reduce the dosage over 3 to 7 days to avoid worsening symptoms.

If someone is taking bosentan and also needs to take ritonavir, a different medication, there are some special instructions:

• If they're already taking ritonavir, they should start with a lower dose of bosentan, either 62.5 milligrams once daily or every other day, depending on how they tolerate it.
• If they're starting ritonavir while already on bosentan, they should stop taking bosentan 36 hours before starting ritonavir.
• After being on ritonavir for at least 10 days, they can start taking bosentan again at the lower dose of 62.5 milligrams once daily or every other day, depending on how they feel.

Bosentan off-label use in the therapy of Prevention of digital ulcers in systemic sclerosis:  

• Typically started with a lower dose of 62.5 milligrams taken by mouth twice a day for 4 weeks, and then increased to a higher dose of 125 milligrams twice a day for maintenance.
• These trials lasted for up to 12 weeks to see how well bosentan worked in preventing these sores.

Bosentan off-label use in the treatment of Raynaud phenomenon in systemic sclerosis:

• Started with 62.5 milligrams taken orally twice daily for 4 weeks, then increased to a maintenance dose of 125 milligrams twice daily.
• These studies, conducted over several weeks, aimed to assess the effectiveness of bosentan in managing Raynaud phenomenon associated with systemic sclerosis.

Bosentan Dose in Children

Bosentan Dose in the treatment of Pulmonary arterial hypertension:  

Infants and Children younger than 12 years:

• Start with 1 milligram per kilogram of body weight taken orally twice daily.
• Increase to a target dose of 2 milligrams per kilogram of body weight taken twice daily, up to a maximum of 125 milligrams per dose.

Children ≥12 years and Adolescents:

• For those weighing >20 to 40 kilograms: Begin with 31.25 milligrams orally twice daily, then increase to 62.5 milligrams twice daily.
• For those weighing >40 kilograms: Start with 62.5 milligrams orally twice daily, then increase to 125 milligrams twice daily.

Alternate dosing (per manufacturer's labeling):

• Children ≥3 years:
  • For weights:
    • 4 to 8 kilograms: 16 milligrams orally twice daily.
    • 8 to 16 kilograms: 32 milligrams orally twice daily.
    • 16 to 24 kilograms: 48 milligrams orally twice daily.
    • 24 to 40 kilograms: 64 milligrams orally twice daily.
• Adolescents:
  • For those weighing ≤40 kilograms: Take 62.5 milligrams orally twice daily.
  • For those weighing >40 kilograms: Initially, take 62.5 milligrams orally twice daily for 4 weeks, then increase to a target dose of 125 milligrams twice daily.

Dosage adjustment for concurrent use with ritonavir:

• When bosentan is taken with ritonavir:
  • There are no specific recommendations for children; dosage adjustment is suggested based on adult experience.
• When ritonavir is added to bosentan:
  • There are no specific recommendations for children; discontinue bosentan 36 hours before starting ritonavir. After at least 10 days on ritonavir, resume bosentan at an adjusted dose.

Pregnancy Risk Factor: X

[US Boxed Warning]

• Bosentan comes with a serious warning for pregnant women, as it can cause significant birth defects based on animal studies.
• Before starting treatment with bosentan, it's crucial to confirm that a woman isn't pregnant.
• Throughout treatment and for a month after stopping bosentan, women of childbearing age must use two reliable forms of birth control, unless they have an intrauterine device (IUD) or tubal sterilization.
• Hormonal contraceptives like pills or patches shouldn't be relied upon alone because they might not work effectively with bosentan.
• Monthly pregnancy tests are necessary during treatment.
• Even if a partner has had a vasectomy, an extra form of contraception is needed when using hormonal or barrier methods.
• When starting treatment, women should have a negative pregnancy test within the first 5 days of their menstrual cycle and at least 11 days after unprotected intercourse.
• Any missed periods or suspicion of pregnancy should be reported.

Bosentan Use during Breastfeeding:

• It's unclear if bosentan is present in breast milk, and because there's a risk of serious side effects in breastfed babies, the manufacturer advises against breastfeeding while taking bosentan.

Bosentan Dose in Renal Disease:

• No dosage adjustment is needed for people with kidney problems when taking bosentan, as the medication is unlikely to be removed effectively by dialysis.
• This is because bosentan has a high molecular weight and binds extensively to proteins in the blood.

Bosentan Dose in Liver Disease:

Liver dysfunction at treatment initiation:

• For mild impairment, no dosage adjustment is needed.
• But for moderate to severe impairment, or if baseline transaminase levels are over 3 times the upper limit of normal (ULN), bosentan should be avoided. In these cases, the drug's levels in the body can rise significantly.

If liver problems develop during treatment, changes are made based on transaminase levels (enzymes indicating liver function):

• If transaminase levels rise along with symptoms like fatigue, nausea, or jaundice, or if bilirubin levels rise to 2 times ULN, treatment should be stopped.
• If AST/ALT levels rise to 3-5 times ULN, in patients over 40 kilograms, additional tests should confirm the rise. If confirmed, the dose is reduced or treatment is paused and monitored closely.
• If AST/ALT levels rise to 5-8 times ULN, treatment is stopped, and liver enzyme levels are monitored regularly.
• If AST/ALT levels rise above 8 times ULN, treatment is stopped without the possibility of reintroduction.

Common Side Effects of Bosentan Include:

• Central Nervous System:
  • Headache
• Cardiovascular:
  • Edema
• Respiratory:
  • Respiratory Tract Infection
• Hepatic:
  • Increased Serum ALT
  • Increased Serum AST

Less Common Side Effects of Bosentan Include:

• Endocrine & Metabolic:
  • Fluid Retention
• Cardiovascular:
  • Flushing
  • Chest Pain
  • Syncope
  • Hypotension
  • Palpitations
• Respiratory:
  • Sinusitis
• Hematologic & Oncologic:
  • Anemia
• Neuromuscular & Skeletal:
  • Arthralgia

Contraindications to Bosentan 

Bosentan should not be used in individuals with:

• Known hypersensitivity to bosentan or any of its ingredients.
• Concurrent use of certain medications like cyclosporine or glyburide.
• Pregnancy, as it can cause serious birth defects and should be avoided by women who are or may become pregnant.

In Canada, additional contraindications include:

• Moderate to severe liver impairment, especially when liver enzyme levels (ALT or AST) are over 3 times the upper limit of normal (ULN), particularly if total bilirubin levels are over 2 times ULN.

Warnings and Precautions

Fluid retention and peripheral swelling:

• Bosentan treatment or the disease itself (pulmonary arterial hypertension) can lead to fluid buildup, causing swelling in the legs or other parts of the body.
• Some people may even require treatment for heart failure due to fluid retention.
• If significant swelling occurs, along with weight gain, it's important to get evaluated to find out the cause and decide on the right treatment, which might include stopping bosentan.
• Bosentan should be used cautiously in people with existing heart failure, as fluid retention can lead to complications.
• According to the American Heart Association, bosentan is recognized as a treatment that could worsen underlying heart muscle problems.

Hematologic effects

• When starting bosentan therapy, there might be a drop in hematocrit and hemoglobin levels, usually happening within the first few weeks.
• However, these levels typically stabilize within 4 to 12 weeks of treatment.
• It's important to check hemoglobin levels before starting treatment, then after 1 and 3 months, and every 3 months afterward.
• If there's a significant decrease in hemoglobin, it needs further evaluation to understand why and decide on the appropriate management.

Hepatotoxicity: [US Boxed Warning]

• Bosentan carries a serious warning for liver problems.
• Regular monitoring of liver enzymes (ALT or AST) is necessary, starting before treatment and continuing monthly thereafter.
• If liver enzyme levels rise without symptoms or elevated bilirubin, dosage adjustments may be made.
• Rare cases of unexplained liver cirrhosis and even liver failure have occurred after long-term use, especially in patients with multiple health issues and medications.
• Treatment should be stopped if liver enzymes rise significantly, with or without symptoms like fatigue or jaundice, or if bilirubin levels increase.
• It's not known if it's safe to restart treatment after stopping due to liver issues.
• Avoid using bosentan in patients with high baseline liver enzymes or severe liver problems.
• Elevated liver enzymes, usually without symptoms, can occur at any time during treatment but may reverse with dose changes or stopping treatment.
• When considering starting treatment in patients with less severe symptoms, weigh the benefits against the risk of liver problems.

Hypersensitivity

• Hypersensitivity reactions to bosentan are possible and can include severe conditions like Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), anaphylaxis, as well as rash and swelling (angioedema).

Spermatogenesis:

• Bosentan treatment can lead to reduced sperm counts in men and may affect sperm production negatively.

Pulmonary venoocclusive disease

• If signs of pulmonary edema develop, it's important to consider the possibility of pulmonary veno-occlusive disease, a rare condition where the veins in the lungs become blocked.
• This condition may require stopping bosentan treatment.

Bosentan: Drug Interaction

How to take Bosentan?

• With or Without Food: Bosentan can be taken with or without food.
• Tablets for Oral Suspension (Dispersible Tablets):
  • Before Taking: Disperse the tablet in a small amount of water right before taking it.
  • Dosage: The 32 mg dispersible tablet can be split into halves but should not be broken into quarters.

Mechanism of action of Bosentan:

• Bosentan is an endothelin receptor antagonist that works by blocking endothelin receptors found on both the endothelium (the inner lining of blood vessels) and vascular smooth muscle (the muscle in the walls of blood vessels).
• These receptors, when stimulated, typically cause blood vessels to constrict, leading to increased blood pressure.
• By blocking both types of endothelin receptors, Bosentan helps to prevent this vasoconstriction.
• It has a slightly stronger affinity for the A subtype of endothelin receptors.

Distribution:

• Volume of Distribution: Approximately 18 liters, but it doesn't distribute into red blood cells.

Protein Binding:

• Plasma Protein Binding: Over 98%, primarily to albumin.

Metabolism:

• Route: Metabolized in the liver via enzymes CYP2C9 and 3A4 to three metabolites, one of which is active and contributes to about 10% to 20% of its pharmacological activity.
• Autoinduction: Steady-state plasma concentrations are 50% to 65% of those reached after a single dose, likely due to the drug's ability to induce liver enzymes. Steady-state is typically reached within 3 to 5 days.

Bioavailability:

• Approximately 50%.

Half-life:

• Elimination: Around 5 hours, but it may be prolonged in conditions like heart failure, and possibly in pulmonary arterial hypertension (PAH).

Time to Peak:

• Plasma Concentration: It takes 3 to 5 hours to reach peak plasma concentration after administration.

Excretion:

• Feces: Excreted primarily in the feces as metabolites.
• Urine: Less than 3% is excreted unchanged in urine.

International Brands of Bosentan:

• ACT Bosentan
• APO-Bosentan
• BIO-Bosentan
• MYLAN-Bosentan
• PMS-Bosentan
• SANDOZ Bosentan
• TEVA-Bosentan
• Tracleer
• Bosencard
• Bosentadin
• Bosentadine
• Bosentas
• Boxtel
• Lupibose
• Pahsentan
• Pulmiprove
• Pulmofirst
• Pulmonat
• Pulmoten
• Stayveer
• Tracleer
• Trasentan
• Usenta
• Zuxtana

Bosentan Brands in Pakistan: