Uptravi
(Selexipag)Dosage & Administration
See Full Prescribing Information for instructions on preparation and administration. (
Administer by intravenous infusion over 80 minutes using an infusion set made of DEHP-free polyvinyl chloride (PVC), natural latex rubber-free microbore tubing protected from light.
Do
Once the solution for infusion glass container is empty, continue the infusion at the same rate with 0.9% saline to empty the remaining solution for infusion in the IV line, to ensure that the entire solution for infusion has been administered.
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Uptravi Prescribing Information
Contraindications (Hypersensitivity to the active substance or to any of the excipients. Concomitant use of strong inhibitors of CYP2C8 (e.g., gemfibrozil) [see Drug Interactions (7.1)and Clinical Pharmacology (12.3)] .Concomitant use with strong CYP2C8 inhibitors. Hypersensitivity to the active substance or to any of the excipients. | 10/2021 |
- UPTRAVI is a prostacyclin receptor agonist indicated for the treatment of pulmonary arterial hypertension (PAH, WHO Group I) to delay disease progression and reduce the risk of hospitalization for PAH. ()
1.1 Pulmonary Arterial HypertensionUPTRAVI is indicated for the treatment of pulmonary arterial hypertension (PAH, WHO Group I) to delay disease progression and reduce the risk of hospitalization for PAH.
Effectiveness of UPTRAVI tablets was established in a long-term study in PAH patients with WHO Functional Class II–III symptoms.
Patients had idiopathic and heritable PAH (58%), PAH associated with connective tissue disease (29%), PAH associated with congenital heart disease with repaired shunts (10%)
[see Clinical Studies (14.1)].
- UPTRAVI tablets starting dose: 200 mcg twice daily. ()
2.1 Recommended DosageUPTRAVI Film-coated TabletsThe recommended starting dosage of UPTRAVI tablets is 200 micrograms (mcg) given twice daily. Tolerability may be improved when taken with food
[see Clinical Pharmacology (12.3)].Increase the dose in increments of 200 mcg twice daily, usually at weekly intervals, to the highest tolerated dose up to
1600 mcg twice daily. If a patient reaches a dose that cannot be tolerated, the dose should be reduced to the previous tolerated dose.
Do not split, crush, or chew tablets.
UPTRAVI for InjectionUse UPTRAVI for injection in patients who are temporarily unable to take oral therapy.
Administer UPTRAVI for injection twice daily by intravenous infusion at a dose that corresponds to the patient's current dose of UPTRAVI tablets (see Table 1). Administer UPTRAVI for injection as an 80-minute intravenous infusion.
- Increase the dose by 200 mcg twice daily at weekly intervals to the highest tolerated dose up to 1600 mcg twice daily. ()
2.1 Recommended DosageUPTRAVI Film-coated TabletsThe recommended starting dosage of UPTRAVI tablets is 200 micrograms (mcg) given twice daily. Tolerability may be improved when taken with food
[see Clinical Pharmacology (12.3)].Increase the dose in increments of 200 mcg twice daily, usually at weekly intervals, to the highest tolerated dose up to
1600 mcg twice daily. If a patient reaches a dose that cannot be tolerated, the dose should be reduced to the previous tolerated dose.
Do not split, crush, or chew tablets.
UPTRAVI for InjectionUse UPTRAVI for injection in patients who are temporarily unable to take oral therapy.
Administer UPTRAVI for injection twice daily by intravenous infusion at a dose that corresponds to the patient's current dose of UPTRAVI tablets (see Table 1). Administer UPTRAVI for injection as an 80-minute intravenous infusion.
- Maintenance dose is determined by tolerability. ()
2.1 Recommended DosageUPTRAVI Film-coated TabletsThe recommended starting dosage of UPTRAVI tablets is 200 micrograms (mcg) given twice daily. Tolerability may be improved when taken with food
[see Clinical Pharmacology (12.3)].Increase the dose in increments of 200 mcg twice daily, usually at weekly intervals, to the highest tolerated dose up to
1600 mcg twice daily. If a patient reaches a dose that cannot be tolerated, the dose should be reduced to the previous tolerated dose.
Do not split, crush, or chew tablets.
UPTRAVI for InjectionUse UPTRAVI for injection in patients who are temporarily unable to take oral therapy.
Administer UPTRAVI for injection twice daily by intravenous infusion at a dose that corresponds to the patient's current dose of UPTRAVI tablets (see Table 1). Administer UPTRAVI for injection as an 80-minute intravenous infusion.
- Moderate hepatic impairment: Starting dose 200 mcg once daily, increase the dose by 200 mcg once daily at weekly intervals to the highest tolerated dose up to 1600 mcg. ()
2.5 Dosage Adjustment in Patients with Hepatic ImpairmentNo dose adjustment of UPTRAVI is necessary for patients with mild hepatic impairment (Child-Pugh class A).
For patients with moderate hepatic impairment (Child-Pugh class B), the starting dose of UPTRAVI tablets is 200 mcg
once daily. Increase in increments of 200 mcgonce dailyat weekly intervals, as tolerated[see Use in Specific Populations (8.6)and Clinical Pharmacology (12.3)].Avoid use of UPTRAVI in patients with severe hepatic impairment (Child-Pugh class C).
- UPTRAVI for injection dose is determined by the patient's current dose of UPTRAVI tablets. Administer UPTRAVI for injection by intravenous infusion, twice daily. ()
2.2 Preparation InstructionsReconstitute and further dilute UPTRAVI for injection prior to intravenous infusion following aseptic procedures.
Determine the dose and total volume of reconstituted UPTRAVI solution required (see Table 1).
Reconstitution- Remove the carton of UPTRAVI for injection from the refrigerator and allow to stand for approximately 30 to 60 minutes to reach room temperature (20°C to 25°C [68°F to 77°F]).
- The vial needs to be protected from light at all times. Ensure the protective wrap around label is covering the entire vial.
- Peel back light protective wrap on vial to inspect the contents in the vial. It should appear white to almost white broken cake or powdered material. Immediately close the light protective wrap on the vial.
- Reconstitute UPTRAVI for injection using apolypropylene syringewith 8.6 mL of 0.9% Sodium Chloride Injection, USP and slowly inject into the UPTRAVI vial with the stream directed toward the inside wall of the vial to obtain a concentration of 225 mcg/mL of selexipag.
- Document date and time of first puncture. Complete infusion within 4 hours of first puncture.
- Gently invert the vial and repeat until powder is completely dissolved.Do not shake.
- Inspect the vial by peeling back the light protective wrap around label for discoloration. The reconstituted solution should appear clear, colorless and free from foreign material. Do not use if the reconstituted solution is discolored, cloudy, or contains visible particles.
ImageImageDilution- UPTRAVI for injection must be diluted inglass containers only.
- Withdraw 100 mL of 0.9% Sodium Chloride Injection, USP and transfer into an empty sterile glass container.
- Withdraw the required volume of reconstituted solution (see Table 1for reconstituted transfer volume) from the UPTRAVI vial using a single, appropriately sizedpolypropylene syringeand dilute into the glass container containing 100 mL 0.9% Sodium Chloride Injection, USP to obtain the desired final dose.
- Mix the diluted UPTRAVI infusion solution by gentle inversion of the glass container 5 times.Do not shake.
- Protect diluted UPTRAVI infusion solution from light at all times. Assign a 4-hour expiry from the time of first vial puncture and wrap the glass container completely with light protective cover.
- The UPTRAVI infusion solution should be kept at room temperature (20°C–25°C [68°F–77°F]) and must be infused within 4 hours from the first puncture of the vial stopper (including infusion time).
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. The diluted UPTRAVI infusion solution should be clear and colorless. Discard if particulate matter is observed.
UPTRAVI for injection vials are single-dose, for single administration. All remaining reconstituted product must be discarded.
Table 1 Dosing Table for UPTRAVI intravenous based on current UPTRAVI tablets dose UPTRAVI tablets dose (mcg) for twice daily dosing Corresponding IV UPTRAVI Dose (mcg) for twice daily dosing Reconstituted transfer volume (mL) for dilution 200 225 1.0 400 450 2.0 600 675 3.0 800 900 4.0 1000 1125 5.0 1200 1350 6.0 1400 1575 7.0 1600 1800 8.0
See Full Prescribing Information for instructions on preparation and administration. (
Administer by intravenous infusion over 80 minutes using an infusion set made of DEHP-free polyvinyl chloride (PVC), natural latex rubber-free microbore tubing protected from light.
Do
Once the solution for infusion glass container is empty, continue the infusion at the same rate with 0.9% saline to empty the remaining solution for infusion in the IV line, to ensure that the entire solution for infusion has been administered.
UPTRAVI is available in the following presentations:
- 200 mcg selexipag [Light yellow tablet debossed with 2]
- 400 mcg selexipag [Red tablet debossed with 4]
- 600 mcg selexipag [Light violet tablet debossed with 6]
- 800 mcg selexipag [Green tablet debossed with 8]
- 1000 mcg selexipag [Orange tablet debossed with 10]
- 1200 mcg selexipag [Dark violet tablet debossed with 12]
- 1400 mcg selexipag [Dark yellow tablet debossed with 14]
- 1600 mcg selexipag [Brown tablet debossed with 16]
- 1800 mcg selexipag [Lyophilized powder white to almost white broken cake or powdered material, supplied in a 10 mL single-dose glass vial]
- Nursing mothers: Discontinue UPTRAVI or breastfeeding. ()
8.2 LactationIt is not known if UPTRAVI is present in human milk. Selexipag or its metabolites were present in the milk of rats. Because many drugs are present in the human milk and because of the potential for serious adverse reactions in nursing infants, discontinue nursing or discontinue UPTRAVI.
- Severe hepatic impairment: Avoid use. ()
8.6 Patients with Hepatic ImpairmentNo adjustment to the dosing regimen is needed in patients with mild hepatic impairment (Child-Pugh class A).
A once-daily regimen is recommended in patients with moderate hepatic impairment (Child-Pugh class B) due to the increased exposure to selexipag and its active metabolite. There is no experience with UPTRAVI in patients with severe hepatic impairment (Child-Pugh class C). Avoid use of UPTRAVI in patients with severe hepatic impairment
[see Dosage and Administration (2.5)and Clinical Pharmacology (12.3)].
Concomitant use of strong inhibitors of CYP2C8 (e.g., gemfibrozil)
Concomitant administration with gemfibrozil, a strong inhibitor of CYP2C8, doubled the exposure to selexipag and increased exposure to the active metabolite by approximately 11-fold. Concomitant administration of UPTRAVI with strong inhibitors of CYP2C8 (e.g., gemfibrozil) is contraindicated
Concomitant administration of UPTRAVI tablets with clopidogrel, a moderate inhibitor of CYP2C8, had no relevant effect on the exposure to selexipag and increased the exposure to the active metabolite by approximately 2.7-fold
The pharmacokinetics of selexipag and its active metabolite have been studied primarily in healthy subjects. The pharmacokinetics of selexipag and the active metabolite, after both single- and multiple-dose oral administration, were dose-proportional up to a single dose of 800 mcg and multiple doses of up to 1800 mcg twice daily. The pharmacokinetics of selexipag and the active metabolite, after multiple-dose intravenous administration, were dose-proportional in the tested dose range from 450 to 1800 mcg twice a day.
In healthy subjects, inter-subject variability in exposure (area under the curve over a dosing interval, AUC) at steady-state following oral administration was 43% and 39% for selexipag and the active metabolite, respectively. Intra-subject variability in exposure was 24% and 19% for selexipag and the active metabolite, respectively.
Exposures to selexipag and the active metabolite at steady-state in PAH patients and healthy subjects were similar. The pharmacokinetics of selexipag and the active metabolite in PAH patients were not influenced by the severity of the disease and did not change with time.
The corresponding UPTRAVI tablets and UPTRAVI for injection doses (Table 1) provide similar exposure to the active metabolite in PAH patients at steady-state, whereas the exposure to selexipag is approximately twice as high after intravenous administration compared to oral administration.
Both in healthy subjects and PAH patients, after oral administration, exposure at steady-state to the active metabolite is approximately 3- to 4-fold that of selexipag.
The absolute bioavailability of orally administered selexipag is approximately 49%. Upon oral administration, maximum observed plasma concentrations of selexipag and its active metabolite are reached within about 1–3 hours and 3–4 hours, respectively.
In the presence of food, the absorption of selexipag was prolonged resulting in a delayed time to peak concentration (Tmax) and ~30% lower peak plasma concentration (Cmax). The exposure to selexipag and the active metabolite (AUC) did not significantly change in the presence of food.
The volume of distribution of selexipag at steady-state is 11.7 L.
Selexipag and its active metabolite are highly bound to plasma proteins (approximately 99% in total and to the same extent to albumin and alpha1-acid glycoprotein).
Selexipag is hydrolyzed to its active metabolite, (free carboxylic acid) in the liver and intestine by carboxylesterases. Oxidative metabolism, catalyzed mainly by CYP2C8 and to a smaller extent by CYP3A4, leads to the formation of hydroxylated and dealkylated products. UGT1A3 and UGT2B7 are involved in the glucuronidation of the active metabolite. Except for the active metabolite, none of the circulating metabolites in human plasma exceeds 3% of the total drug-related material.
Elimination of selexipag is predominately via metabolism with a mean terminal half-life of 0.8–2.5 hours. The terminal half-life of the active metabolite is 6.2–13.5 hours. Selexipag does not accumulate following twice daily repeat administration. There is minimal accumulation of the active metabolite upon twice daily repeat administration suggesting that the effective half-life is in the range of 3–4 hours. The total body clearance of selexipag is 17.9 L/hour.
In a study in healthy subjects with radiolabeled selexipag, approximately 93% of radioactive drug material was eliminated in feces and only 12% in urine. Neither selexipag nor its active metabolite were found in urine.
No clinically relevant effects of sex, race, age or body weight on the pharmacokinetics of selexipag and its active metabolite have been observed in healthy subjects or PAH patients.
The pharmacokinetic variables (Cmaxand AUC) were similar in adult and elderly subjects up to 75 years of age. There was no effect of age on the pharmacokinetics of selexipag and the active metabolite in PAH patients.
In subjects with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, exposure to selexipag was 2- and 4-fold that seen in healthy subjects. Exposure to the active metabolite of selexipag remained almost unchanged in subjects with mild hepatic impairment and was doubled in subjects with moderate hepatic impairment
Based on pharmacokinetic modeling of data from a study in subjects with hepatic impairment, the exposure to the active metabolite at steady-state in subjects with moderate hepatic impairment (Child-Pugh class B) after a once daily regimen is expected to be similar to that in healthy subjects receiving a twice daily regimen. The exposure to selexipag at steady-state in these patients during a once daily regimen is predicted to be approximately 2-fold that seen in healthy subjects receiving a twice-daily regimen.
A 40–70% increase in exposure (maximum plasma concentration and area under the plasma concentration-time curve) to selexipag and its active metabolite was observed in subjects with severe renal impairment (estimated glomerular filtration rate ≥15 mL/min/1.73 m2and <30 mL/min/1.73 m2)
Drug interaction studies have been performed in adult subjects using UPTRAVI tablets.
Selexipag is hydrolyzed to its active metabolite by carboxylesterases. Selexipag and its active metabolite both undergo oxidative metabolism mainly by CYP2C8 and to a smaller extent by CYP3A4. The glucuronidation of the active metabolite is catalyzed by UGT1A3 and UGT2B7. Selexipag and its active metabolite are substrates of OATP1B1 and OATP1B3. Selexipag is a substrate of P-gp, and the active metabolite is a substrate of the transporter of breast cancer resistance protein (BCRP).
Selexipag and its active metabolite do not inhibit or induce cytochrome P450 enzymes and transport proteins at clinically relevant concentrations.
The results of
* ERA and PDE-5 inhibitor data from GRIPHON.
