Pulmoten62.50 mg

Pulmoten is a dual endothelin receptor antagonist (ERA) indicated in the management of pulmonary arterial hypertension (PAH, WHO Group 1).

Established / Approved Uses

• Treatment of pulmonary arterial hypertension (PAH) in patients with WHO Functional Class II–IV symptoms, to improve exercise ability and delay clinical worsening, in patients with idiopathic or heritable PAH, or PAH associated with connective tissue disease.
• Pediatric PAH (idiopathic or congenital) in patients 3 years of age and older, using weight-based dosing with a dispersible tablet formulation where available.

Guideline-Supported / Adjunct Uses

• PAH associated with congenital systemic-to-pulmonary shunts, including Eisenmenger syndrome, is supported by pulmonary hypertension treatment guidelines, generally as part of specialist-directed combination therapy with other PAH-specific agents (e.g. phosphodiesterase-5 inhibitors, prostacyclin analogues).

Pulmoten is not indicated for other forms of pulmonary hypertension (e.g. due to left heart disease or chronic lung disease) and must only be prescribed and monitored by a physician experienced in the management of PAH.

Each film-coated tablet contains Bosentan Monohydrate equivalent to bosentan 62.5 mg or 125 mg. A pediatric dispersible tablet strength (equivalent to bosentan 32 mg) containing Bosentan Monohydrate is also available in some markets for weight-based pediatric dosing.

Pulmoten is the monohydrate salt form of bosentan, the first orally active dual endothelin receptor antagonist developed for clinical use. It blocks both endothelin type A (ET-A) and type B (ET-B) receptors, counteracting the vasoconstrictive and proliferative effects of endothelin-1, a peptide implicated in the pathophysiology of pulmonary arterial hypertension.

Pulmoten is used as a specialist-prescribed, long-term oral therapy for PAH and requires structured safety monitoring, including regular liver function testing, throughout treatment.

Endothelin Receptor Antagonist (ERA); Pulmonary Antihypertensive Agent. Pulmoten is classified within this drug class.

Bosentan Monohydrate acts as a competitive antagonist at both endothelin-A (ET-A) and endothelin-B (ET-B) receptors, with slightly higher affinity for ET-A receptors.

Endothelin-1 (ET-1) is a potent endogenous vasoconstrictor and mitogen that is found at increased plasma and tissue concentrations in patients with pulmonary arterial hypertension. By blocking ET-1 binding at both receptor subtypes on vascular smooth muscle and endothelial cells, Bosentan Monohydrate reduces pulmonary vascular resistance, decreases pulmonary arterial pressure, and improves cardiac output, without a clinically significant reflex increase in heart rate.

Pharmacokinetics: Bosentan (from Bosentan Monohydrate) is well absorbed orally (absolute bioavailability ~50%), extensively bound to plasma proteins (>98%), and metabolized in the liver mainly via CYP2C9 and CYP3A4 to three metabolites (one of which is pharmacologically active). It is eliminated primarily via biliary excretion into feces, with an elimination half-life of approximately 5 hours at steady state. Bosentan Monohydrate also induces its own metabolism (autoinduction) and induces CYP3A4/CYP2C9, resulting in numerous drug interactions.

Pulmoten tablets should be taken by mouth in the morning and evening, with or without food. Tablets should be swallowed with water. Dispersible pediatric tablets may be dispersed in a spoonful of water before administration.

If a dose is missed, it should be taken as soon as remembered unless it is close to the next scheduled dose; do not double the dose. Pulmoten must not be stopped or the dose changed without consulting the prescribing physician, given the risk of rebound worsening of PAH.

Pulmoten is a substrate and inducer of CYP3A4 and CYP2C9; clinically significant interactions include:

• Cyclosporine A: Contraindicated. Co-administration substantially increases bosentan (from Pulmoten) plasma concentrations and markedly decreases cyclosporine concentrations.
• Glyburide (glibenclamide): Contraindicated with Pulmoten due to an increased risk of elevated liver aminotransferases; the combination may also reduce the hypoglycemic effect of glyburide.
• Strong CYP3A4/CYP2C9 inducers (e.g. rifampin, carbamazepine, phenytoin, St. John's Wort): May markedly reduce plasma concentrations of Pulmoten, risking loss of efficacy; avoid combination where possible.
• CYP3A4 inhibitors (e.g. ketoconazole and other azole antifungals): May increase exposure to Pulmoten; monitor for adverse effects.
• Hormonal contraceptives: Pulmoten may reduce the efficacy of hormonal contraceptives; an additional reliable (non-hormonal, barrier) method of contraception is required in females of reproductive potential (see Pregnancy and Lactation).
• Warfarin and other agents: Pulmoten does not require routine warfarin dose adjustment, but periodic INR monitoring is prudent whenever therapy is initiated or changed. Concomitant sildenafil may result in reduced sildenafil concentrations; clinical monitoring is advised.

A full medication review by the prescribing physician is recommended before starting Pulmoten.

The most commonly reported adverse effects of Pulmoten include:

• Headache
• Flushing
• Edema / fluid retention (see Precautions and Warnings)
• Hypotension and palpitations
• Elevated liver aminotransferases (see Precautions and Warnings)
• Nasopharyngitis and sinusitis
• Decreased hemoglobin / anemia
• Decreased sperm count (reported with the endothelin receptor antagonist class)

Serious effects requiring prompt medical attention include signs of liver injury (jaundice, dark urine, right upper abdominal pain, unusual fatigue) and significant fluid retention or shortness of breath. Patients should report any new or worsening symptoms while taking Pulmoten to their physician promptly.

Pregnancy: Pulmoten is contraindicated in pregnancy. Animal studies have shown clear evidence of embryo-fetal toxicity and teratogenicity. Females of reproductive potential must have a negative pregnancy test before starting Pulmoten, use two reliable methods of contraception (including a non-hormonal method, since Pulmoten may reduce hormonal contraceptive efficacy) throughout treatment and for one month after stopping, and undergo monthly pregnancy testing while on therapy. If pregnancy occurs during treatment, Pulmoten should be stopped immediately and the physician contacted without delay.

Lactation: It is not known whether bosentan (from Pulmoten) is excreted in human breast milk. Because of the potential for serious adverse effects in a nursing infant, a decision should be made, in consultation with a physician, whether to discontinue breastfeeding or discontinue Pulmoten, taking into account the importance of the drug to the mother.

Boxed Warnings

Hepatotoxicity: Pulmoten can cause hepatotoxicity, including cases of liver failure. Liver function tests (LFTs) must be obtained before starting treatment and monthly throughout treatment, with specific dose-reduction, interruption, or discontinuation rules depending on the degree of transaminase elevation. This monthly monitoring requirement is mandatory and non-negotiable for the duration of therapy.

Embryo-fetal toxicity: Pulmoten is contraindicated in pregnancy. Females of reproductive potential require monthly pregnancy testing, confirmed use of two reliable methods of contraception, and monthly prescription renewal tied to a negative pregnancy test result, administered through a restricted distribution (REMS-type) program (see Pregnancy and Lactation).

Other Precautions

• Fluid retention / edema: May occur, particularly during the first weeks of treatment; monitor closely in patients with pre-existing heart failure or fluid overload.
• Decreased hemoglobin / anemia: Monitor blood counts, particularly in the initial months of therapy.
• Decreased sperm count: Reported with endothelin receptor antagonists as a class; discuss fertility implications with the physician if relevant.
• Drug interactions: Significant CYP450-mediated interactions require careful medication review before and during treatment (see Interaction).
• Specialist management required: Pulmoten must only be prescribed and monitored under a restricted distribution/REMS-type program by physicians experienced in PAH management, given the boxed warnings and specialized monitoring needs.

Limited experience with overdose of Pulmoten is available. Reported effects at high doses have included headache, nausea, vomiting, hypotension, and flushing. In the event of a suspected overdose, seek immediate medical attention or contact a poison control center / emergency services; supportive measures should be provided under medical supervision. Because bosentan (from Pulmoten) is highly protein-bound, dialysis is not expected to be effective in enhancing its elimination. Do not attempt any specific home treatment for a suspected overdose.

Store at room temperature (below 30°C), away from light and moisture. Keep out of reach of children.

• Hepatic impairment: Contraindicated in moderate-to-severe hepatic impairment; use with monthly LFT monitoring in mild impairment (see Dosage and Precautions).
• Renal impairment: No routine dose adjustment of Pulmoten required; use with caution and clinical monitoring in severe renal impairment or dialysis.
• Elderly: Clinical experience has not identified a need for dose adjustment based on age alone; use with the same monitoring precautions as in younger adults.
• Pediatric patients: Approved for patients 3 years of age and older with idiopathic or congenital PAH using weight-based dosing (see Pediatric Uses); safety and efficacy below 3 years of age have not been established.
• Females of reproductive potential: Subject to mandatory pregnancy testing and contraception requirements (see Pregnancy and Lactation).

Pulmoten is generally used as a long-term, chronic therapy for pulmonary arterial hypertension, with treatment duration determined by the treating specialist based on clinical response, functional class, and tolerability. Response and liver function should be reassessed regularly. Pulmoten should not be stopped abruptly without medical supervision, as sudden discontinuation may lead to rebound worsening of PAH symptoms; if discontinuation is necessary, a physician-guided gradual dose reduction is generally recommended.

Endothelin Receptor Antagonist (dual ETA/ETB blocker); Pulmonary Arterial Hypertension (PAH)-specific therapy. Bosentan Monohydrate belongs to this class of medicines.

Bosentan Monohydrate works by blocking both endothelin-A (ET-A) and endothelin-B (ET-B) receptors on vascular smooth muscle and endothelial cells, preventing the binding of endothelin-1 (ET-1), a naturally occurring peptide that causes vasoconstriction and promotes smooth muscle cell proliferation in the pulmonary vasculature. By antagonizing these receptors, Bosentan Monohydrate lowers pulmonary vascular resistance and pulmonary arterial pressure, and improves cardiac index, thereby improving exercise capacity and slowing clinical progression of pulmonary arterial hypertension.

X – Contraindicated in pregnancy (legacy FDA pregnancy category, based on documented embryo-fetal toxicity in animal studies).

Pulmoten is approved for the treatment of idiopathic or congenital pulmonary arterial hypertension in pediatric patients 3 years of age and older, using a weight-based dosing schedule with a dispersible tablet formulation (see Dosage and Administration table). As in adults, monthly liver function monitoring and adherence to the restricted distribution program requirements are necessary throughout treatment.

Safety and efficacy of Pulmoten in children younger than 3 years of age have not been established, and its use in this age group is not recommended outside specialist clinical judgment.