Bosentan for Pulmonary arterial hypertension

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

WHO group 1 Pulmonary arterial hypertension in adults with WHO Functional class II, III, or IV symptoms to improve exercise ability and prevent further disability.
Treatment of WHO Group 1 Pulmonary arterial hypertension in children older than 3 years of age with idiopathic or congenital PAH to improve pulmonary vascular resistance and exercise ability.
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.

WHO Functional Classification for Pulmonary Hypertension
WHO Class 1	No limitation of activity
WHO Class 2	Slight limitation of activity. Ordinary activity may cause some symptoms
WHO Class 3	Marked limitation of activity. Less than ordinary activity causes symptoms
WHO Class 4	Severe limitation of physical activity. Any activity causes symptoms or patients with right heart failure.

Bosentan Dose in Adults

Bosentan dose in the treatment of Pulmonary artery hypertension:

Weight less than 40 kgs:
- 62.5 mg orally twice a day.
Weight more than 40 kgs:
- 62.5 mg orally twice a day for 4 weeks initially.
- The dose may be increased to a maintenance dose of 125 mg twice a day.
- Doses greater than 125 mg twice a day may increase the risks of hepatotoxicity without any additional benefits.
- Treatment may be tapered off over 3 - 7 days and not discontinued abruptly.

Co-administration with ritonavir:

Dosage adjustment for concurrent use with ritonavir:
- Patients receiving ritonavir for at least 10 days:
  - Initiate with bosentan 62.5 mg once a day or on alternate days based on tolerability.
- Patients on bosentan therapy:
  - Discontinue bosentan 36 hours before the initiation of ritonavir.
  - After at least 10 days of the initiation of ritonavir, resume bosentan 62.5 mg once a day or every other day based on tolerability.

Off label use in the treatment of Prevention of digital ulcers in systemic sclerosis:

62.5 mg orally twice a day for 4 weeks followed by an increase to a maintenance dose of 125 mg twice a day for up to 12 weeks.

Off label use in the treatment of Raynaud phenomenon in systemic sclerosis:

62.5 mg orally twice a day for 4 weeks followed by an increase to a maintenance dose of 125 mg twice a day.

Bosentan Dose in Childrens

Dose in the treatment of Pulmonary arterial hypertension:

Infants and Children younger than 12 years:
- 1 mg/kg/dose orally twice a day initially
- Increase the dose to a target dose of 2 mg/kg/dose twice a day to a maximum dose of 125 mg/dose.
Children older than 12 years and Adolescents:
- Weight 20 to 40 kgs:
  - 31.25 mg orally twice a day
  - Increase to a target dose of 62.5 mg twice a day.
- weight more than 40 kgs:
  - 62.5 mg orally twice day
  - Increase to a target dose of 125 mg twice a day.

Alternate dosing as per manufacturer's labeling:

Children older than 3 years:
- 4 - 8 kgs:
  - 16 mg orally twice a day.
- 8 - 16 kgs:
  - 32 mg orally twice a day.
- 16 - 24 kg:
  - 48 mg orally twice a day.
- 24 - 40 kg:
  - 64 mg orally twice a day.
Adolescents:
- less than 40 kgs:
  - 5 mg orally twice a day.
- more than 40 kgs:
  - 62.5 mg orally twice a day for 4 weeks
  - The dose may be increased to a target dose of 125 mg twice a day.

Pregnancy Risk Factor: X

[US Boxed Warning]
- A pregnancy test is required before starting therapy with bosentan for female patients of reproductive potential.
- Before starting therapy, pregnant women must be notified.
- Therapy and for up to one month following the last dose of therapy, at least two effective contraceptives must be used (except for patients who have received intrauterine devices or tubal ligation).
- Monthly pregnancy tests can be requested. Missed cycles must be reported.
- It can also decrease the sperm count in men.

Bosentan Use during breastfeeding:

It is not advised to breastfeed during this therapy.

Bosentan Dose in Renal Disease:

Dose adjustment in patients with renal impairment is not required and the drug is not removed from the body by dialysis.

Bosentan Dose in Liver Disease:

Liver dysfunction at treatment initiation:

Mild impairment (Child-Pugh class A):
- Adjustment in dosage is not necessary.
Moderate to severe impairment (Child-Pugh class B and C) and/or baseline transaminase more than 3 times the upper limits of normal:
- Avoid its use.

Hepatotoxicity during treatment:

Elevation Liver enzymes accompanied by clinical symptoms of hepatotoxicity like fatigue, nausea & vomiting, abdominal pain, fever, or jaundice or serum bilirubin more than 2 times the upper limits of normal:
- Discontinue treatment.
AST/ALT more than 3 times but less than 5 times the upper limits of normal in patients weighing more than 40 kgs:
- Reduce the dose to 62.5 mg twice a day or withhold treatment and monitor at least every two weeks.
- May reintroduce treatment if the levels return to baseline.
- After reintroducing treatment, recheck transaminases within three days and at least every two weeks thereafter.
AST/ALT more than 5 times but less than 8 times the upper limits of normal in patients weighing more than 40 kg:
- Stop treatment.
- Monitor Liver functions every 2 weeks.
- May reintroduce treatment if the levels return to baseline.
- After reintroducing treatment, recheck transaminases within three days and at least every two weeks thereafter.
AST/ALT more than 8 times the upper limits of normal:
- Stop therpy and do not reintroduce.

Common Side Effects of Bosentan Include:

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

Less Common Side Effects of Bosentan Include:

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

Contraindication to Bosentan include

Allergy to bosentan and any component of this formulation
Use of glyburide or cyclosporine simultaneously (Glibenclamide).
Pregnancy.
Moderate to severe liver impairment

Warnings and Precautions

Fluid retention and peripheral swelling:
- Patients may develop peripheral edema and fluid retention may occur requiring diuretics therapy.
- Patients with heart failure should use it with caution.
- The AHA in its scientific statement has labeled it as an agent that may exacerbate myocardial dysfunction.
Hematologic effects
- A reduction in hemoglobin or hematocrit can occur during the first weeks of therapy.
- Before starting therapy, it is important to monitor hemoglobin and hematocrit after 1 and 3 months, and every 3 months thereafter.
Hepatotoxicity: [US Boxed Warning]
- Bosentan is liver toxic and can cause elevations in transaminase and bilirubin.
- It is important to monitor the liver functions and adjust the dosage.
- Patients who are on long-term therapy for more than one year may develop liver fibrosis or cirrhosis.
- Patients with hepatic injury symptoms or bilirubin levels that exceed the normal upper limit should be stopped from receiving treatment.
- Patients with a baseline liver disease that is moderate or severe in severity and patients with transaminases greater then three times the normal upper limit should not be initiated therapy.
Hypersensitivity
- Allergy reactions may include DRESS (Drug Reaction With Eosinophilia Systemic Symptoms), anaphylaxis and rash.
Spermatogenesis:
- It can adversely impact sperm count.
Pulmonary venoocclusive disease
- If patients develop signs of pulmonary embolism after receiving bosentan therapy, it is important to consider the possibility that they have pulmonary vein-occlusive disease. Treatment may be stopped.

Bosentan: Drug Interaction

Risk Factor C (Monitor therapy)
Benzhydrocodone	CYP3A4 Inducers (Moderate) may decrease the serum concentration of Benzhydrocodone. Speciﬁcally, the serum concentrations of hydrocodone may be reduced.
CloZAPine	CYP3A4 Inducers (Moderate) may decrease the serum concentration of CloZAPine.
Codeine	CYP3A4 Inducers (Moderate) may decrease serum concentrations of the active metabolite(s) of Codeine.
CYP2C9 Inhibitors (Moderate)	May increase the serum concentration of Bosentan. Management: Concomitant use of both a CYP2C9 inhibitor and a CYP3A inhibitor or a single agent that inhibits both enzymes with bosentan is likely to cause a large increase in serum concentrations of bosentan and is not recommended. See monograph for details.
CYP3A4 Inhibitors (Moderate)	May increase the serum concentration of Bosentan. Management: Concomitant use of both a CYP2C9 inhibitor and a CYP3A inhibitor or a single agent that inhibits both enzymes with bosentan is likely to cause a large increase in serum concentrations of bosentan and is not recommended. See monograph for details.
CYP3A4 Inhibitors (Strong)	May increase the serum concentration of Bosentan. Management: Concomitant use of both a CYP2C9 inhibitor and a CYP3A inhibitor or a single agent that inhibits both enzymes with bosentan is likely to cause a large increase in serum concentrations of bosentan and is not recommended. See monograph for details.
CYP3A4 Substrates (High risk with Inducers)	Bosentan may decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Doravirine	CYP3A4 Inducers (Moderate) may decrease the serum concentration of Doravirine.
Eltrombopag	May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates.
Estriol (Systemic)	CYP3A4 Inducers (Moderate) may decrease the serum concentration of Estriol (Systemic).
Estriol (Topical)	CYP3A4 Inducers (Moderate) may decrease the serum concentration of Estriol (Topical).
FentaNYL	CYP3A4 Inducers (Moderate) may decrease the serum concentration of FentaNYL.
Gemﬁbrozil	May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates. See separate drug interaction monographs for agents listed as exceptions.
Glecaprevir and Pibrentasvir	CYP3A4 Inducers (Moderate) may decrease the serum concentration of Glecaprevir and Pibrentasvir.
HYDROcodone	CYP3A4 Inducers (Moderate) may decrease the serum concentration of HYDROcodone.
Ibrutinib	CYP3A4 Inducers (Moderate) may decrease the serum concentration of Ibrutinib.
Ifosfamide	CYP3A4 Inducers (Moderate) may decrease serum concentrations of the active metabolite(s) of Ifosfamide. CYP3A4 Inducers (Moderate) may increase serum concentrations of the active metabolite(s) of Ifosfamide.
Macimorelin	Bosentan may diminish the diagnostic effect of Macimorelin.
Mirodenaﬁl	CYP3A4 Inducers (Moderate) may decrease the serum concentration of Mirodenaﬁl.
Naldemedine	CYP3A4 Inducers (Moderate) may decrease the serum concentration of Naldemedine.
NiMODipine	CYP3A4 Inducers (Moderate) may decrease the serum concentration of NiMODipine.
Phosphodiesterase 5 Inhibitors	Bosentan may decrease the serum concentration of Phosphodiesterase 5 Inhibitors. Phosphodiesterase 5 Inhibitors may increase the serum concentration of Bosentan.
RifAMPin	May decrease the serum concentration of Bosentan. Following the initial several weeks of concurrent rifampin, this effect is most likely. RifAMPin may increase the serum concentration of Bosentan. This effect is most likely to be observed within the initial few weeks of concurrent therapy (and may be greatest immediately following initiation of the combination). Management: Weekly monitoring of liver function tests during the ﬁrst 4 weeks of concurrent therapy is recommended, with a return to normal recommended monitoring thereafter as appropriate.
Rolapitant	CYP3A4 Inducers (Moderate) may decrease the serum concentration of Rolapitant.
Simvastatin	Bosentan may decrease the serum concentration of Simvastatin.
Teriﬂunomide	May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates.
Vitamin K Antagonists (eg, warfarin)	Bosentan may increase the metabolism of Vitamin K Antagonists.
Zolpidem	CYP3A4 Inducers (Moderate) may decrease the serum concentration of Zolpidem.
Risk Factor D (Consider therapy modification)
Atazanavir	Bosentan may decrease the serum concentration of Atazanavir. Atazanavir may increase the serum concentration of Bosentan. Management: Concurrent use of atazanavir (without ritonavir) and bosentan is not recommended. Bosentan dose adjustments are required when used together with atazanavir/ritonavir.
Brigatinib	CYP3A4 Inducers (Moderate) may decrease the serum concentration of Brigatinib. Management: Avoid concurrent use of brigatinib with moderate CYP3A4 inducers when possible. If combined, increase the daily dose of brigatinib in 30 mg increments after 7 days of treatment with the current brigatinib dose, up to maximum of twice the dose.
Clarithromycin	Bosentan may increase serum concentrations of the active metabolite(s) of Clarithromycin. Speciﬁcally, bosentan may increase concentrations of 14-hydroxyclarithromycin. Bosentan may decrease the serum concentration of Clarithromycin. Clarithromycin may increase the serum concentration of Bosentan. Management: Consider alternative antimicrobial if possible. The clinical activity of clarithromycin may be altered, and increased bosentan toxicity may be expected.
Cobicistat	May increase the serum concentration of Bosentan. Management: See full drug interaction monograph for details.
Daclatasvir	CYP3A4 Inducers (Moderate) may decrease the serum concentration of Daclatasvir. Management: Increase the daclatasvir dose to 90 mg once daily if used with a moderate CYP3A4 inducer.
Darunavir	Bosentan may decrease the serum concentration of Darunavir. Darunavir may increase the serum concentration of Bosentan. Management: Use bosentan 62.5 mg/day or every other day in adults taking ritonavir- or cobicistat-boosted darunavir for at least 10 days. Stop bosentan for at least 36 hrs before starting boosted darunavir; wait at least 10 days before restarting bosentan.
Estrogen Derivatives (Contraceptive)	Bosentan may decrease the serum concentration of Estrogen Derivatives (Contraceptive). Management: Use an alternative (i.e., non-hormonal) means of contraception for all women of childbearing potential who are using bosentan, and do not rely on hormonal contraceptives alone.
Fosamprenavir	Bosentan may decrease the serum concentration of Fosamprenavir. Fosamprenavir may increase the serum concentration of Bosentan. Management: Use bosentan 62.5 mg/day or every other day in adult patients taking fosamprenavir for at least 10 days. Temporarily stop bosentan (for at least 36 hrs) before starting fosamprenavir; wait at least 10 days before restarting bosentan.
GuanFACINE	CYP3A4 Inducers (Moderate) may decrease the serum concentration of GuanFACINE. Management: Increase the guanfacine dose by up to double when initiating concomitant therapy with moderate CYP3A4 inducers. Increase guanfacine dose gradually over 1-2 weeks if moderate CYP3A4 inducer therapy is just beginning.
Indinavir	May increase the serum concentration of Bosentan. Bosentan may decrease the serum concentration of Indinavir. Management: Initiate bosentan at, or adjust bosentan to, 62.5 mg once daily or every other day (based on tolerability) in indinavir-treated patients (see ritonavir fordosing if that agent is used). Additionally, monitor for possible reduced response to indinavir.
Lopinavir	May increase the serum concentration of Bosentan. Bosentan may decrease the serum concentration of Lopinavir. Management: Use bosentan 62.5 mg/day or every other day in adult patients taking lopinavir/ritonavir for at least 10 days. Temporarily stop bosentan(for at least 36 hrs) before starting lopinavir/ritonavir; wait at least 10 days before restarting bosentan.
Lorlatinib	CYP3A4 Inducers (Moderate) may enhance the hepatotoxic effect of Lorlatinib. CYP3A4 Inducers (Moderate) may decrease the serum concentration of Lorlatinib. Management: Avoid use of lorlatinib with moderate CYP3A4 inducers. If such a combination must be used, monitor AST, ALT, and bilirubin within 48 hours of starting the combination and at least three times within the ﬁrst week of combined use.
Lurasidone	CYP3A4 Inducers (Moderate) may decrease the serum concentration of Lurasidone. Management: Monitor for decreased lurasidone effects if combined with moderate CYP3A4 inducers and consider increasing the lurasidone dose if coadministered with a moderate CYP3A4 inducer for 7 or more days.
Nelﬁnavir	May increase the serum concentration of Bosentan. Bosentan may decrease the serum concentration of Nelﬁnavir. Management: Initiate bosentan at, or adjust bosentan dose to, 62.5 mg once daily or every other day (based on tolerability) in patients who receive nelﬁnavir. Additionally, monitor for possible reduced clinical response to nelﬁnavir.
Palbociclib	CYP3A4 Inducers (Moderate) may decrease the serum concentration of Palbociclib. Management: The US label does not provide speciﬁc recommendations concerning use with moderate CYP3A4 inducers, but the Canadian label recommends avoiding use of moderate CYP3A4 inducers.
Perampanel	CYP3A4 Inducers (Moderate) may decrease the serum concentration of Perampanel. Management: Increase the perampanel starting dose to 4 mg/day when perampanel is used concurrently with moderate and strong CYP3A4 inducers.
Progestins (Contraceptive)	Bosentan may decrease the serum concentration of Progestins (Contraceptive). Management: Use an alternative (i.e., non-hormonal) means of contraception for all women of childbearing potential who are using bosentan, and do not rely on hormonal contraceptives alone.
Ritonavir	May increase the serum concentration of Bosentan. Management: Use bosentan 62.5 mg daily or every other day in adult patients who have been on ritonavir for at least 10 days. Temporarily stop bosentan (for at least 36 hrs) before starting ritonavir; wait until at least 10 days on ritonavir before restarting.
Saquinavir	Bosentan may decrease the serum concentration of Saquinavir. Saquinavir may increase the serum concentration of Bosentan. Management: Use bosentan 62.5 mg/day or every other day in adult patients taking saquinavir/ritonavir for at least 10 days. Temporarily stop bosentan (for at least 36 hrs) before starting saquinavir/ritonavir; wait at least 10 days before restarting bosentan.
Tipranavir	Bosentan may decrease the serum concentration of Tipranavir. Tipranavir may increase the serum concentration of Bosentan. Management: Use bosentan 62.5 mg/day or every other day in adult patients taking tipranavir/ritonavir for at least 10 days. Temporarily stop bosentan (for at least 36 hrs) before starting tipranavir/ritonavir; wait at least 10 days before restarting bosentan.
Tolvaptan	May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates.
Risk Factor X (Avoid combination)
Antihepaciviral Combination Products	CYP3A4 Inducers (Moderate) may decrease the serum concentration of Antihepaciviral Combination Products.
Asunaprevir	CYP3A4 Inducers (Moderate) may decrease the serum concentration of Asunaprevir.
Axitinib	CYP3A4 Inducers (Moderate) may decrease the serum concentration of Axitinib.
Bedaquiline	CYP3A4 Inducers (Moderate) may decrease the serum concentration of Bedaquiline.
Bosutinib	CYP3A4 Inducers (Moderate) may decrease the serum concentration of Bosutinib.
Cobimetinib	CYP3A4 Inducers (Moderate) may decrease the serum concentration of Cobimetinib.
CycloSPORINE (Systemic)	May increase the serum concentration of Bosentan. Bosentan may decrease the serum concentration of CycloSPORINE (Systemic).
Dasabuvir	CYP3A4 Inducers (Moderate) may decrease the serum concentration of Dasabuvir.
Deﬂazacort	CYP3A4 Inducers (Moderate) may decrease serum concentrations of the active metabolite(s) of Deﬂazacort.
Elbasvir	CYP3A4 Inducers (Moderate) may decrease the serum concentration of Elbasvir.
Encorafenib	CYP3A4 Inducers (Moderate) may decrease the serum concentration of Encorafenib.
Flibanserin	CYP3A4 Inducers (Moderate) may decrease the serum concentration of Flibanserin.
GlyBURIDE	May enhance the hepatotoxic effect of Bosentan. GlyBURIDE may decrease the serum concentration of Bosentan. Bosentan may decrease the serum concentration of GlyBURIDE.
Grazoprevir	CYP3A4 Inducers (Moderate) may decrease the serum concentration of Grazoprevir.
Neratinib	CYP3A4 Inducers (Moderate) may decrease the serum concentration of Neratinib.
Nisoldipine	CYP3A4 Inducers (Moderate) may decrease the serum concentration of Nisoldipine.
Olaparib	CYP3A4 Inducers (Moderate) may decrease the serum concentration of Olaparib.
Ranolazine	CYP3A4 Inducers (Moderate) may decrease the serum concentration of Ranolazine.
Simeprevir	CYP3A4 Inducers (Moderate) may decrease the serum concentration of Simeprevir.
Sonidegib	CYP3A4 Inducers (Moderate) may decrease the serum concentration of Sonidegib.
Ulipristal	Bosentan may decrease the serum concentration of Ulipristal.
Velpatasvir	CYP3A4 Inducers (Moderate) may decrease the serum concentration of Velpatasvir.
Venetoclax	CYP3A4 Inducers (Moderate) may decrease the serum concentration of Venetoclax.

How to take Bosentan?

It may be taken with or without regard to meals.
The dispersible tablets may be dispersed in a small amount of water immediately before administration.

Mechanism of action of Bosentan:

It acts as an antagonist to endothelin-receptors on the endothelium, vascular smooth muscles and other tissues.
Vasodilation is caused by the inhibition of endothelin receptors.

98% of the drug's ingredients areProtein-boundIt is.

It isMetabolizedvia CYP2C9 or 3A4. It has been abioavailabilityAbout 50% off and morehalf-life eliminationAbout 5 hours. TheTime to reach plasma peak concentrationIt takes between 3 and 5 hours, and is primarilyexcreted via feces.

International Brands of Bosentan: