Selexipag

The dosing of Selexipag is highly individualized and follows a strict titration (gradual increase) schedule to ensure the patient reaches the highest dose they can tolerate without excessive side effects.

Starting Dose

According to the FDA-approved labeling, the recommended starting dose is 200 mcg taken twice daily (BID). This initial phase allows the body to adjust to the medication's vasodilatory effects.

Titration Phase

Healthcare providers typically instruct patients to increase the dose in increments of 200 mcg BID, usually at weekly intervals. For example, after one week at 200 mcg BID, the dose may be increased to 400 mcg BID, then 600 mcg BID the following week, and so on. This continues until the patient reaches their 'highest tolerated dose' or the maximum dose of 1600 mcg twice daily. If a patient experiences intolerable side effects (such as severe headache or jaw pain) at a certain level, the dose is usually decreased to the previous tolerated level.

Maintenance Dose

The maintenance dose is the highest dose the patient tolerated during the titration phase. Patients should continue this dose consistently to maintain the therapeutic effect on the pulmonary vasculature.

As of 2026, the safety and effectiveness of Selexipag in pediatric patients (under the age of 18) have not been established. Clinical trials in children are ongoing, but currently, Selexipag is not FDA-approved for use in the pediatric population. Healthcare providers may occasionally use it off-label in specialized pediatric centers, but this is not standard practice and requires extreme caution.

Renal Impairment

For patients with mild or moderate renal impairment (kidney dysfunction), no adjustment to the starting dose is generally required. However, there is limited clinical data regarding the use of Selexipag in patients with severe renal impairment (estimated glomerular filtration rate < 30 mL/min/1.73 m²). In these cases, titration should be performed with extra caution.

Hepatic Impairment

• Mild Hepatic Impairment (Child-Pugh Class A): No dose adjustment is required.
• Moderate Hepatic Impairment (Child-Pugh Class B): The starting dose is 200 mcg once daily, and the dose should be increased only once weekly. This is because the liver's ability to metabolize the drug is reduced, leading to higher drug levels in the blood.
• Severe Hepatic Impairment (Child-Pugh Class C): Selexipag has not been studied in this population and its use should be avoided.

Elderly Patients

Clinical studies did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function.

Selexipag should be taken twice daily, ideally in the morning and evening.

• With or Without Food: Selexipag can be taken with or without food. However, taking the tablets with food may help improve the tolerability of common side effects like nausea or diarrhea.
• Swallow Whole: Tablets should be swallowed whole with water. They should not be crushed, chewed, or split, as this can affect the controlled release and absorption of the medication.
• Storage: Store the tablets at room temperature, between 20°C to 25°C (68°F to 77°F). Keep them in the original packaging to protect them from moisture.

If a dose of Selexipag is missed, it should be taken as soon as possible unless the next scheduled dose is within the next 6 hours. If it is within 6 hours of the next dose, the missed dose should be skipped, and the regular schedule should be resumed. Patients should never take two doses at once to make up for a missed one. If treatment is missed for 3 days or more, patients should contact their doctor, as the dose may need to be restarted at a lower level and re-titrated.

Signs of a Selexipag overdose are typically exaggerations of its known side effects, including severe headache, nausea, vomiting, diarrhea, and a significant drop in blood pressure (hypotension). If an overdose is suspected, seek emergency medical attention immediately. There is no specific antidote for Selexipag; treatment is supportive and focused on maintaining blood pressure and hydration.

> Important: Follow your healthcare provider's dosing instructions exactly. Do not adjust your dose or stop taking Selexipag without medical guidance, as sudden discontinuation can lead to a worsening of PAH symptoms.

Because Selexipag works by dilating blood vessels throughout the body, not just in the lungs, it commonly causes 'prostacyclin-type' side effects. These are most frequent during the titration phase as the body adjusts to the medication. According to data from the GRIPHON trial (2015), the most common adverse reactions include:

• Headache: This is the most frequently reported side effect, occurring in approximately 65% of patients. It is usually described as a dull or throbbing sensation and often improves over time or with the use of over-the-counter analgesics like acetaminophen (Tylenol).
• Diarrhea: Reported by about 42% of patients. This is due to the activation of IP receptors in the gastrointestinal tract. It is typically mild to moderate but can lead to dehydration if not managed.
• Jaw Pain: A unique side effect of prostacyclin therapies, jaw pain (occurring in 25% of patients) often occurs with the first bite of food. It is thought to be related to vasodilation of the salivary glands or blood vessels in the jaw.
• Nausea and Vomiting: These gastrointestinal symptoms affect about 33% and 18% of patients, respectively. Taking the medication with food often mitigates these effects.
• Myalgia (Muscle Pain) and Arthralgia (Joint Pain): Generalized aches in the muscles and joints are common (16-11%) and can usually be managed with standard pain relief measures.
• Flushing: A sudden feeling of warmth and redness in the face and neck, occurring in about 12% of patients due to peripheral vasodilation.

• Anemia: A decrease in red blood cell count or hemoglobin levels. This may cause fatigue or shortness of breath. Healthcare providers typically monitor blood counts periodically.
• Decreased Appetite: Some patients may experience a loss of interest in food, which can lead to unintended weight loss.
• Rash: Skin eruptions or hives may occur in some individuals.
• Tachycardia: An abnormally fast heart rate, which may feel like palpitations or a racing heart.

• Hypotension: While Selexipag is intended to lower pulmonary blood pressure, it can occasionally cause systemic blood pressure to drop too low, leading to dizziness or fainting.
• Hyperthyroidism: There have been rare reports of changes in thyroid function, specifically an overactive thyroid, in patients taking Selexipag. Symptoms may include weight loss, anxiety, and heat intolerance.

While most side effects of Selexipag are manageable, some require urgent medical evaluation.

> Warning: Stop taking Selexipag and call your doctor immediately if you experience any of these:

• Pulmonary Edema (Fluid in the Lungs): If you develop sudden, severe shortness of breath, a cough that produces frothy sputum, or difficulty breathing when lying flat, this may be a sign of Pulmonary Veno-Occlusive Disease (PVOD). If PVOD is confirmed, Selexipag must be discontinued permanently.
• Severe Allergic Reaction (Anaphylaxis): Symptoms include swelling of the face, lips, or tongue; difficulty swallowing or breathing; and severe skin rash or hives.
• Significant Anemia: Extreme paleness, severe exhaustion, or fainting should be reported immediately.
• Worsening Heart Failure: Signs include rapid weight gain, swelling in the legs or abdomen (edema), and increased difficulty breathing during normal activities.

Long-term use of Selexipag is generally well-tolerated once the maintenance dose is established. However, chronic prostacyclin stimulation can lead to persistent mild GI issues or a slight, stable reduction in hemoglobin levels. There is no evidence currently suggesting that Selexipag causes long-term organ damage to the liver or kidneys, provided it is used as directed and monitored by a specialist.

As of the current 2026 clinical guidelines, there are no FDA black box warnings for Selexipag. Unlike some other PAH medications (like ERAs), Selexipag does not have a REMS (Risk Evaluation and Mitigation Strategy) program for hepatotoxicity or teratogenicity, though precautions regarding pregnancy still apply.

Report any unusual symptoms to your healthcare provider. Many side effects can be managed by adjusting the titration schedule or using supportive medications, rather than stopping the drug entirely.

Selexipag is a potent vasodilator and must be used with caution, particularly during the initiation and titration phases. Patients should be aware that while the drug is effective at delaying disease progression, it is not a cure for PAH. It requires strict adherence to the twice-daily schedule and regular follow-up appointments with a pulmonary hypertension specialist. Patients should also be warned about the risk of Pulmonary Veno-Occlusive Disease (PVOD), a rare but serious condition where the small veins in the lungs become blocked. If signs of pulmonary edema occur, the drug must be stopped immediately.

No FDA black box warnings for Selexipag. However, this does not mean the drug is without risk; it simply means the FDA has not identified a single catastrophic risk that requires the highest level of boxed warning. Standard precautions and monitoring remain mandatory.

• Pulmonary Veno-Occlusive Disease (PVOD): If signs of pulmonary edema (fluid in the lungs) occur when starting Selexipag, the possibility of associated PVOD should be considered. Since Selexipag dilates the pulmonary arteries but cannot fix the blocked veins in PVOD, it can cause fluid to back up into the lungs. If PVOD is confirmed, the patient should not continue Selexipag.
• Anemia: Decreases in hemoglobin concentration and red blood cell count have been observed in clinical trials. This typically occurs early in treatment and stabilizes over time. Patients with pre-existing anemia should be treated before starting Selexipag.
• Hypotension: Selexipag can lower systemic blood pressure. Caution should be used in patients with pre-existing low blood pressure or those taking other antihypertensive medications.
• Hyperthyroidism: Changes in thyroid function have been reported. Patients should be monitored for signs of an overactive thyroid, such as rapid heart rate or unexplained weight loss.
• Bleeding Risk: While Selexipag does not directly cause bleeding, prostacyclin agonists inhibit platelet aggregation. This could theoretically increase the risk of bleeding, especially in patients taking anticoagulants (blood thinners).

To ensure the safe use of Selexipag, healthcare providers typically require the following monitoring:

• Hemoglobin/Hematocrit: Blood tests should be performed before starting treatment and periodically thereafter (e.g., at 3 months and 6 months) to check for anemia.
• Blood Pressure and Heart Rate: These should be checked regularly, especially during the dose titration phase.
• Thyroid Function Tests: If symptoms of hyperthyroidism develop, a TSH (Thyroid Stimulating Hormone) test should be ordered.
• Clinical Assessment: Regular evaluation of WHO Functional Class and exercise capacity (like the 6-minute walk test) to ensure the drug is working.

Selexipag may cause dizziness or headaches, particularly during the titration phase. Patients should determine how they react to the medication before driving or operating heavy machinery. If you feel lightheaded or have a severe headache, avoid these activities until the symptoms resolve.

There is no direct chemical interaction between Selexipag and alcohol. However, alcohol is a vasodilator and can lower blood pressure. Combining alcohol with Selexipag may increase the risk of dizziness, fainting, or flushing. It is generally recommended to limit alcohol consumption while taking this medication.

Abruptly stopping Selexipag can lead to a 'rebound' effect, where pulmonary blood pressure rises rapidly, potentially leading to a life-threatening crisis. If the drug must be stopped, it should ideally be tapered down under strict medical supervision. If you run out of medication, contact your specialty pharmacy or doctor immediately to ensure you do not miss doses.

> Important: Discuss all your medical conditions, including any history of liver disease, thyroid problems, or anemia, with your healthcare provider before starting Selexipag.

• Strong CYP2C8 Inhibitors (e.g., Gemfibrozil): This is the most critical interaction. Gemfibrozil (a medication used to lower cholesterol) significantly increases the exposure to both Selexipag and its active metabolite (by approximately 2-fold and 11-fold, respectively). This massive increase in drug levels significantly raises the risk of severe toxicity and overdose. Therefore, the concomitant use of Selexipag with strong CYP2C8 inhibitors is strictly contraindicated.

• Moderate CYP2C8 Inhibitors (e.g., Clopidogrel, Deferasirox, Teriflunomide): These medications can increase the levels of the active metabolite of Selexipag. While not strictly contraindicated, the dose of Selexipag may need to be adjusted (often limited to once-daily dosing), and patients must be monitored very closely for side effects.
• CYP2C8 Inducers (e.g., Rifampin): Rifampin can significantly decrease the exposure to the active metabolite of Selexipag, potentially making the treatment less effective. Healthcare providers may need to increase the Selexipag dose during co-administration.
• Other PAH Therapies: While Selexipag is often used with ERAs (like Bosentan) or PDE-5 inhibitors (like Sildenafil), Bosentan is a moderate inducer of CYP3A4 and CYP2C9. Studies show that Bosentan slightly decreases the exposure to Selexipag, but no dose adjustment is usually required when these are used together.

• Antihypertensives: Since Selexipag lowers blood pressure, taking it with other blood pressure-lowering drugs (beta-blockers, ACE inhibitors, diuretics) may lead to additive effects, increasing the risk of hypotension (low blood pressure).
• Anticoagulants and Antiplatelets: Because Selexipag inhibits platelet aggregation, there is a theoretical risk of increased bleeding when taken with drugs like warfarin, apixaban, or aspirin. Patients should be monitored for signs of bruising or bleeding.

• High-Fat Meals: Taking Selexipag with a high-fat meal delays absorption but does not significantly change the total amount of drug absorbed. However, food is generally recommended to help the stomach tolerate the medication.
• Grapefruit Juice: Grapefruit is a known inhibitor of CYP3A4. While CYP3A4 is a minor pathway for Selexipag metabolism, it is generally wise to avoid large amounts of grapefruit juice to prevent unpredictable changes in drug levels.

• St. John’s Wort: This herbal supplement is a potent inducer of many metabolic enzymes, including CYP3A4. It may reduce the effectiveness of Selexipag. Use should be avoided.
• Garlic, Ginkgo, and Ginseng: These supplements may have mild antiplatelet effects. Combining them with Selexipag could theoretically increase bleeding risk, though clinical data is limited.

Selexipag is not known to interfere with common laboratory tests, such as glucose, electrolytes, or basic metabolic panels. However, it does cause a physiological decrease in hemoglobin, which will be reflected in a Complete Blood Count (CBC). It may also affect thyroid function tests (TSH, T3, T4).

For each major interaction, the mechanism usually involves the CYP2C8 enzyme system. Inhibition of this enzyme leads to toxic accumulation, while induction leads to therapeutic failure. Management strategies always involve either avoiding the combination or performing more frequent clinical monitoring and dose adjustments.

> Important: Tell your doctor about ALL medications, supplements, and herbal products you are taking, including over-the-counter pain relievers and vitamins.

There are specific circumstances where the risks of Selexipag clearly outweigh any potential benefits. In these cases, the drug must never be used:

1. 1Hypersensitivity: Patients with a known allergy to Selexipag or any of the inactive ingredients in the tablet (such as D-mannitol, corn starch, or magnesium stearate) must not take the medication. An allergic reaction could manifest as skin rash, swelling, or anaphylaxis.
2. 2Coadministration with Strong CYP2C8 Inhibitors: As mentioned in the interactions section, drugs like Gemfibrozil are absolutely contraindicated. The mechanism is the inhibition of the primary metabolic pathway of the active metabolite ACT-333679, leading to an 11-fold increase in exposure, which is clinically dangerous.

Relative contraindications are conditions where the drug should be used with extreme caution and only if the potential benefit justifies the potential risk:

• Severe Hepatic Impairment (Child-Pugh Class C): Due to the lack of safety data and the critical role of the liver in metabolizing the drug, use is generally avoided.
• Pulmonary Veno-Occlusive Disease (PVOD): If a patient is suspected of having PVOD, Selexipag is contraindicated because vasodilators can cause life-threatening pulmonary edema in these individuals.
• Severe Renal Impairment: Patients with an eGFR < 30 mL/min require very careful titration due to limited data.
• Active Gastric Ulcers: Because prostacyclin agonists can affect the GI lining and platelet function, they may worsen active bleeding or ulcers.

There is no known cross-sensitivity between Selexipag and other classes of PAH medications, such as endothelin receptor antagonists or PDE-5 inhibitors. However, patients who have had severe adverse reactions to other prostacyclin analogs (like Epoprostenol or Treprostinil) should be monitored closely, as they may be more sensitive to the systemic vasodilatory effects of Selexipag.

> Important: Your healthcare provider will evaluate your complete medical history, including liver function and current medications, before prescribing Selexipag.

Selexipag is classified as having limited data regarding its use in pregnant women. Animal studies (in rats and rabbits) using doses much higher than the human therapeutic dose did not show evidence of fetal harm or teratogenicity (birth defects). However, because animal studies are not always predictive of human response, Selexipag should only be used during pregnancy if the potential benefit to the mother outweighs the potential risk to the fetus. It is important to note that untreated PAH poses a significant risk of maternal and fetal mortality. There is no specific data regarding its use in fertility treatments.

It is not known whether Selexipag or its metabolites are excreted in human milk. In animal studies, the drug was found to be present in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants (such as hypotension or GI distress), a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Selexipag is not approved for use in children under 18 years of age. The safety and efficacy in this population have not been established. Growth effects have not been specifically studied, but the drug's mechanism does not suggest a direct impact on bone growth. Pediatric PAH is a complex condition, and treatment usually involves other approved therapies like Sildenafil or Bosentan.

In the GRIPHON clinical trial, 19% of patients were 65 years of age or older. No overall differences in safety or effectiveness were observed between these patients and younger patients. However, geriatric patients are more likely to have decreased hepatic or renal function and may be taking multiple other medications (polypharmacy). This increases the risk of drug interactions and side effects like dizziness, which could lead to falls. Dose titration in the elderly should be slow and cautious.

• Mild to Moderate (eGFR > 30 mL/min): No adjustment to the starting dose is necessary. The kidneys play a minor role in the elimination of Selexipag (12%).
• Severe (eGFR < 30 mL/min): Use with caution. There is no data for patients on peritoneal dialysis or hemodialysis, and the drug's protein-bound nature suggests it is unlikely to be removed by dialysis.

• Mild (Child-Pugh A): No adjustment needed.
• Moderate (Child-Pugh B): The starting dose must be adjusted to 200 mcg once daily (instead of twice daily). This is because the exposure (AUC) to the drug is approximately 2-fold higher in these patients. Titration should remain at weekly intervals.
• Severe (Child-Pugh C): Avoid use entirely.

> Important: Special populations require individualized medical assessment and more frequent monitoring by a healthcare team.

Selexipag is a selective, non-prostanoid agonist of the prostacyclin (IP) receptor. Unlike prostacyclin analogs which can bind to multiple prostanoid receptors (EP1-4, DP, TP, and FP), Selexipag is highly specific for the IP receptor.

1. 1Activation: The active metabolite ACT-333679 binds to the IP receptor on the surface of vascular smooth muscle cells.
2. 2Signal Transduction: This binding activates the enzyme adenylate cyclase.
3. 3cAMP Production: Adenylate cyclase converts ATP to cyclic adenosine monophosphate (cAMP).
4. 4Vasodilation: Increased intracellular cAMP levels lead to the activation of protein kinase A (PKA), which causes the relaxation of the smooth muscle cells in the pulmonary arteries.
5. 5Anti-proliferation: cAMP also inhibits the signaling pathways that lead to the thickening of the vessel walls (remodeling).

Selexipag produces a dose-dependent increase in cardiac index and a decrease in pulmonary vascular resistance (PVR). The onset of effect is gradual, with significant improvements in hemodynamics typically observed after the maintenance dose is reached (usually 4-12 weeks). Unlike some other vasodilators, Selexipag does not typically cause significant 'rebound' hypertension if a single dose is missed, but chronic tolerance (loss of effect) has not been a major issue in long-term clinical trials.

| Parameter | Value |

|---|---|

| Bioavailability | ~49% |

| Protein Binding | ~99% (Albumin and AAG) |

| Half-life | 0.8–2.5h (Parent), 6.2–13.5h (Metabolite) |

| Tmax | 1–3h (Parent), 3–4h (Metabolite) |

| Metabolism | Hepatic (CE1, CYP2C8, CYP3A4) |

| Excretion | Fecal (93%), Renal (12%) |

• Molecular Formula: C26H33N4O4S
• Molecular Weight: 496.62 g/mol
• Solubility: Practically insoluble in water; soluble in organic solvents like methanol.
• Structure: It is a 2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl)acetamide. It is a non-prostanoid, meaning it does not have the classic cyclopentane ring structure of natural prostacyclins.

Selexipag is classified as a Prostacyclin Receptor Agonist [EPC]. It is the first and currently only drug in the non-prostanoid IP receptor agonist class. It is grouped therapeutically with other PAH treatments like Endothelin Receptor Antagonists (e.g., Macitentan) and Soluble Guanylate Cyclase Stimulators (e.g., Riociguat).