. 2016 Dec;25(142):418–430. doi: 10.1183/16000617.0083-2016

TABLE 2.

Protocols for up-titration of therapies that target the prostacyclin pathway

PGI₂ therapy	Initiation protocol	Up-titration protocol	Target dose and dosing frequency	Dose adjustments	Additional comments
Epoprostenol
Flolan [18]	Short-term: 2 ng·kg⁻¹·min⁻¹; if this is not tolerated, a lower dose which is tolerated should be identified^# Long-term: 4 ng·kg⁻¹·min⁻¹ less than MTD identified during short-term dosing; if MTD ≤5 ng·kg⁻¹·min⁻¹, infusion should be started at 1 ng·kg⁻¹·min^{−1^¶}	Increased by increments of 2 ng·kg⁻¹·min⁻¹ every 15 min or longer^#	Until maximum haemodynamic benefit or dose-limiting pharmacological effects^# Administered as continuous infusion^#^{,^¶}	Increase: by 1–2 ng·kg⁻¹·min⁻¹ at intervals sufficient to allow assessment of clinical response; these intervals should be at least 15 min^¶ Decrease: gradually in 2 ng·kg⁻¹·min⁻¹ decrements every 15 min or longer until dose-limiting effects resolve^¶	Short-term dosing should be conducted in a hospital with adequate resuscitation equipment^# Abrupt withdrawal of Flolan or sudden large reductions in infusion rates should be avoided due to the risk of potential fatal rebound effects^¶ Except in life-threatening situations, infusion rates should be adjusted only under the direction of a physician^¶
Veletri [19]	Short-term: 2 ng·kg⁻¹·min⁻¹; if this is not tolerated, a lower dose which is tolerated should be identified^# Long-term: 4 ng·kg⁻¹·min⁻¹ less than MTD identified during short-term dosing; if MTD ≤5 ng·kg⁻¹·min⁻¹, infusion should be started at half the MTD^¶	Increased by increments of 2 ng·kg⁻¹·min⁻¹ every 15 min or longer^#	Until maximum haemodynamic benefit or dose-limiting pharmacological effects are elicited^# Administered as continuous infusion^#^{,^¶}	Increase: by 1–2 ng·kg⁻¹·min⁻¹ at intervals sufficient to allow assessment of clinical response; these intervals should be at least 15 min^¶ Decrease: gradually in 2 ng·kg⁻¹·min⁻¹ decrements every 15 min or longer until dose-limiting effects resolve^¶	Short-term dosing should be conducted in a hospital with adequate resuscitation equipment^# Abrupt withdrawal of Veletri or sudden large reductions in infusion rates should be avoided due to the risk of potential fatal rebound effects^¶ Except in life-threatening situations, infusion rates should be adjusted only under the direction of a physician^¶
Treprostinil
Remodulin i.v./s.c. [6]	1.25 ng·kg⁻¹·min⁻¹ for patients new to PGI₂ infusion therapy; reduce to 0.625 ng·kg⁻¹·min⁻¹ if 1.25 ng·kg⁻¹·min⁻¹ is not tolerated	The prescribing information suggests increments of 1.25 ng·kg⁻¹·min⁻¹ per week for the first 4 weeks of treatment and increments of 2.5 ng·kg⁻¹·min⁻¹ per week after 4 weeks of up-titration. In clinical practice, the dose is usually increased more quickly, aiming to reach 20 ng·kg⁻¹·min⁻¹ after 4 weeks [29]	Based on clinical response Administered as a continuous infusion	NA	Avoid abrupt cessation In the case of mild to moderate hepatic insufficiency, decrease initial dose to 0.625 ng·kg⁻¹·min⁻¹ If transitioning from i.v. epoprostenol, the dose should be increased while simultaneously reducing the dose of i.v. epoprostenol. The transition to Remodulin should take place in the hospital with constant observation of response
Tyvaso [8]	3 breaths (18 µg) per treatment session; if 3 breaths are not tolerated, reduce to 1 or 2 breaths and subsequently increase to 3 breaths as tolerated	Increase by an additional 3 breaths at 1–2-week intervals	9 breaths (54 µg) per treatment session, 4 times daily	NA	Titrate slowly in patients with hepatic or renal insufficiency
Orenitram [11]	0.25 mg twice or 0.125 mg three times daily	Increase by 0.25 or 0.5 mg twice daily or 0.125 mg three times daily, not more than every 3–4 days as tolerated	MTD is determined by tolerability; increase to highest MTD Administered twice or three times daily	If intolerable pharmacological effects occur, decrease the dose in increments of 0.25 mg	If transitioning from i.v./s.c. Remodulin, the dose should be increased while simultaneously decreasing the i.v./s.c. infusion rate In the case of mild hepatic impairment, initiate at 0.125 mg twice daily, increase at 0.125 mg twice daily every 3–4 days Avoid abrupt discontinuation
Iloprost
Ilomedin [7]	0.5 ng·kg⁻¹·min⁻¹ for 30 min	Increase by 0.5 ng·kg⁻¹·min⁻¹ in 30-min intervals up to 2.0 ng·kg⁻¹·min⁻¹	MTD within the range of 0.5–2.0 ng·kg⁻¹·min⁻¹ Administered as an i.v. infusion over 6 h daily	If undesirable side-effects occur, the infusion rate should be reduced until the tolerable dose is found	Should only be used under strict monitoring in hospitals or outpatient clinics with adequate facilities
Ventavis [9]	2.5 µg per treatment session	Increase to 5 µg if initial dose is well tolerated	Administered 6–9 times daily, depending on individual need and tolerability, up to 5 µg per treatment session	In cases of poor tolerability of the 5 µg dose, the dose should be reduced to 2.5 µg per treatment session	In patients with hepatic impairment, special caution should be exercised during initial dose titration
Beraprost
Dorner [15]	20 µg three times daily	The dosage may be increased gradually according to symptoms	Maximum daily dose should not exceed 9 tablets (180 µg) If the dose is increased, it may be taken 3–4 times daily	NA
Selexipag
Uptravi [12]	200 µg twice daily, 12 h apart	Increased in increments of 200 µg twice daily, at weekly intervals	MTD (can range from 200 to 1600 µg twice daily) Administered twice daily	If the patient reaches a dose that cannot be tolerated, the dose should be reduced to the previous dose level	At the beginning of treatment, and at each up-titration step, it is recommended to take the first dose in the evening If treatment is missed for 3 days or more, Uptravi should be re-started at a lower dose and then up-titrated Withdrawal of Uptravi should be done gradually, while an alternative therapy is introduced

PGI₂: prostaglandin I₂ (prostacyclin); MTD: maximum tolerated dose; NA: not available. ^#: short term; ^¶: long term.