Uptravi - Drug Monograph

Introduction

Uptravi (selexipag) is an oral prostacyclin receptor agonist developed by Actelion Pharmaceuticals (now part of Johnson & Johnson). It represents a significant advancement in the treatment of pulmonary arterial hypertension (PAH), a progressive and life-threatening condition characterized by elevated pulmonary arterial pressure leading to right heart failure. Uptravi was approved by the FDA in December 2015 and offers a novel mechanism of action distinct from other PAH therapies.

Mechanism of Action

Selexipag is a selective prostacyclin receptor (IP receptor) agonist. Unlike traditional prostacyclin analogs, selexipag is structurally distinct and undergoes hydrolysis to its active metabolite, ACT-333679. Both the parent compound and active metabolite selectively activate IP receptors, which are expressed on pulmonary arterial smooth muscle cells and endothelial cells.

Activation of IP receptors stimulates adenylate cyclase, increasing intracellular cyclic AMP (cAMP) levels. This results in:

• Vasodilation of pulmonary arterial beds
• Inhibition of vascular smooth muscle cell proliferation
• Antiplatelet effects
• Potential anti-inflammatory effects

The selective action on IP receptors may offer advantages over non-selective prostacyclin analogs by potentially reducing side effects associated with activation of other prostanoid receptors.

Indications

Uptravi is indicated for the treatment of pulmonary arterial hypertension (PAH, WHO Group 1) to delay disease progression and reduce the risk of hospitalization. It is approved for use in:

• Patients with WHO Functional Class II-III symptoms
• As monotherapy or in combination with other PAH therapies (endothelin receptor antagonists, phosphodiesterase-5 inhibitors)
• Both treatment-naïve patients and those already on background PAH therapy

Clinical benefits were demonstrated in the pivotal GRIPHON trial, which showed significant reduction in morbidity/mortality events.

Dosage and Administration

• Starting dose: 200 mcg twice daily
• Titration: Increase by 200 mcg twice daily at weekly intervals
• Target maintenance dose: 1600 mcg twice daily (based on tolerability)

• Oral administration with food
• Tablets should be swallowed whole with water
• Do not crush, split, or chew tablets

• Hepatic impairment: Use with caution in mild impairment; contraindicated in moderate-severe impairment
• Renal impairment: No dosage adjustment needed in mild-moderate impairment; use with caution in severe impairment
• Elderly: No specific dosage adjustment required
• Pediatrics: Safety and effectiveness not established

Pharmacokinetics

• Time to peak concentration (Tmax): 1.5-4 hours for selexipag; 2-4 hours for active metabolite
• Food increases exposure by approximately 30%
• Absolute bioavailability: Approximately 49%

• Protein binding: >99% for both selexipag and active metabolite
• Volume of distribution: Approximately 15.6 L for selexipag

• Primarily hydrolyzed by carboxylesterase 1 to active metabolite ACT-333679
• Further metabolism via CYP2C8 and CYP3A4 (minor pathways)
• Active metabolite is 37 times more potent than parent compound

• Half-life: Selexipag: 0.8-2.5 hours; Active metabolite: 6.2-13.5 hours
• Excretion: Primarily fecal (70%), with renal elimination accounting for <1%

Contraindications

• Hypersensitivity to selexipag or any component of the formulation
• Moderate or severe hepatic impairment (Child-Pugh B or C)
• Concomitant use with strong CYP2C8 inhibitors (e.g., gemfibrozil)

Warnings and Precautions

• Contraindicated in moderate to severe impairment
• Monitor closely in mild impairment

• Based on animal data, may cause fetal harm
• Use only if potential benefit justifies potential risk

• Not recommended during breastfeeding

• Avoid abrupt discontinuation (risk of PAH symptom worsening)
• Gradually reduce dose when discontinuing

Drug Interactions

• Gemfibrozil: Contraindicated (increases selexipag exposure 3.4-fold)
• Clopidogrel: Increases exposure to active metabolite (monitor closely)

• Trimethoprim: May increase selexipag exposure (use with caution)

• Rifampin: May decrease efficacy (monitor response)

• Moderate effect expected (monitor therapy)

Adverse Effects

• Headache (65%)
• Diarrhea (42%)
• Jaw pain (25%)
• Nausea (22%)
• Myalgia (16%)
• Flushing (14%)
• Anemia (13%)
• Decreased appetite (12%)
• Vomiting (12%)

• Pulmonary edema (potential indicator of PVOD)
• Hepatotoxicity
• Anemia (may require transfusion)

Monitoring Parameters

• Complete hepatic function panel
• Complete blood count with differential
• Renal function assessment
• Pregnancy test in women of childbearing potential

• Hepatic function (periodically)
• Hemoglobin/hematocrit (periodically)
• Signs/symptoms of adverse effects
• PAH symptom assessment (6-minute walk test, functional class)
• Signs of pulmonary edema

• Exercise capacity
• Symptom improvement
• Time to clinical worsening

Patient Education

• Take exactly as prescribed with food
• Do not stop abruptly without medical supervision
• If a dose is missed, take as soon as remembered unless close to next dose

• Common side effects include headache, diarrhea, and jaw pain
• Report any signs of liver problems (nausea, vomiting, abdominal pain, jaundice)
• Report any signs of anemia (fatigue, weakness, pale skin)

• Avoid pregnancy during treatment
• Inform all healthcare providers about Uptravi use
• Keep all follow-up appointments

• Seek immediate medical attention for signs of pulmonary edema (sudden weight gain, worsening shortness of breath, edema)

References

1. Sitbon O, et al. Selexipag for the Treatment of Pulmonary Arterial Hypertension. N Engl J Med. 2015;373(26):2522-2533. 2. Uptravi [package insert]. South San Francisco, CA: Actelion Pharmaceuticals US, Inc.; 2021. 3. Simonneau G, et al. Long-term outcomes of selexipag in pulmonary arterial hypertension: GRIPHON and its open-label extension. Eur Respir J. 2020;56(4):2001053. 4. Kuwano K, et al. Selexipag: A selective prostacyclin receptor agonist for the treatment of pulmonary arterial hypertension. Eur J Pharmacol. 2017;81:1-7. 5. FDA Approval Letter: NDA 207947. December 21, 2015. 6. Galie N, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J. 2016;37(1):67-119.