Uptravi Generic Name: uptravi selexipag tablets Brand Name: Uptravi Drug Class: PAH, Prostacyclin Agonists side effects drug center uptravi (uptravi selexipag tablets) drug Related Drugs Adcirca Adempas Alyq Flolan Letairis Remodulin Revatio Tracleer Tyvaso Veletri Ventavis Viagra Health Resources Pulmonary Hypertension PROFESSIONAL CONSUMER SIDE EFFECTS Contents Drug Description Indications & Dosage Side Effects Drug Interactions Warnings & Precautions Overdosage & Contraindications Clinical Pharmacology Medication Guide Drug Description What is Uptravi and how is it used? Uptravi is a prescription medicine used to treat the symptoms of Pulmonary Arterial Hypertension (PAH) Disease Progression. Uptravi may be used alone or with other medications. Uptravi belongs to a class of drugs called PAH, Prostacyclin Agonists. It is not known if Uptravi is safe and effective in children. What are the possible side effects of Uptravi? Uptravi may cause serious side effects including: hives, difficulty breathing, swelling of your face, lips, tongue, or throat, pale skin, unusual tiredness, lightheadedness, shortness of breath, cold hands and feet, anxiety, sweating, pale skin, severe shortness of breath, grasping for breath, cough with foamy mucus, chest pain, and fast or uneven heart rate Get medical help right away, if you have any of the symptoms listed above. The most common side effects of Uptravi include: headache, jaw pain, muscle pain, pain in your arms or legs, nausea, vomit, diarrhea, and flushing (warmth, redness, or tingly feeling) Tell the doctor if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of Uptravi. For more information, ask your doctor or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. DESCRIPTION UPTRAVI (selexipag) is a selective non-prostanoid IP prostacyclin receptor agonist. The chemical name of selexipag is 2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N- (methylsulfonyl) acetamide. It has a molecular formula of C26H32N4O4S and a molecular weight of 496.62. Selexipag has the following structural formula: Selexipag is a pale yellow crystalline powder that is practically insoluble in water. In the solid state selexipag is very stable, is not hygroscopic, and is not light sensitive. Depending on the dose strength, each round film-coated tablet for oral administration contains 200, 400, 600, 800, 1000, 1200, 1400, or 1600 mcg of selexipag. The tablets include the following inactive ingredients: D-mannitol, corn starch, low substituted hydroxypropylcellulose, hydroxypropylcellulose, and magnesium stearate. The tablets are film coated with a coating material containing hypromellose, propylene glycol, titanium dioxide, carnauba wax along with mixtures of iron oxide red, iron oxide yellow or iron oxide black. Indications & Dosage INDICATIONS Pulmonary Arterial Hypertension UPTRAVI 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]. DOSAGE AND ADMINISTRATION Recommended Dosage UPTRAVI Film-Coated Tablets The recommended starting dosage of UPTRAVI tablets is 200 micrograms (mcg) given twice daily. Tolerability may be improved when taken with food [see CLINICAL PHARMACOLOGY]. 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 Injection Use 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. Preparation Instructions Reconstitute 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 a polypropylene syringe with 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. Dilution UPTRAVI for injection must be diluted in glass 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 1 for reconstituted transfer volume) from the UPTRAVI vial using a single, appropriately sized polypropylene syringe and 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°F77°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 TRADENAME intravenous based on current UPTRAVI tablets dose UPTRAVI tablets dose (mcg) fortwice 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 Administration Instructions 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 not use a filter for administration. 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. Interruptions And Discontinuations If a dose of UPTRAVI is missed, patients should take a missed dose as soon as possible unless the next dose is within the next 6 hours. If treatment is missed for 3 days or more, restart UPTRAVI at a lower dose and then retitrate. Dosage Adjustment In Patients With Hepatic Impairment No 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 mcg once daily at weekly intervals, as tolerated [see Use In Specific Populations, and CLINICAL PHARMACOLOGY]. Avoid use of UPTRAVI in patients with severe hepatic impairment (Child-Pugh class C). Dosage Adjustment With Co-Administration Of Moderate CYP2C8 Inhibitors When co-administered with moderate CYP2C8 inhibitors (e.g., clopidogrel, deferasirox and teriflunomide), reduce the dosing of UPTRAVI to once daily [see DRUG INTERACTIONS and CLINICAL PHARMACOLOGY]. HOW SUPPLIED Dosage Forms And Strengths UPTRAVI is available in the following presentations: Film-Coated Tablets 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] UPTRAVI For Injection 1800 mcg selexipag [Lyophilized powder white to almost white broken cake or powdered material, supplied in a 10 mL single-dose glass vial] Storage And Handling UPTRAVI® (selexipag) film-coated, round tablets are supplied in the following configurations: Strength (mcg) Color Debossing NDC-XXX Bottle of 60 NDC-XXX Bottle of 140 200 Light yellow 2 66215-602-06 66215-602-14 400 Red 4 66215-604-06 Not Available 600 Light violet 6 66215-606-06 Not Available 800 Green 8 66215-608-06 Not Available 1000 Orange 10 66215-610-06 Not Available 1200 Dark violet 12 66215-612-06 Not Available 1400 Dark yellow 14 66215-614-06 Not Available 1600 Brown 16 66215-616-06 Not Available UPTRAVI® (selexipag) tablets are also supplied in a Titration Pack [NDC 66215-628-20] that includes a 140-count bottle of 200-mcg tablets and a 60-count bottle of 800-mcg tablets. Store at 20°C to 25°C (68°F to 77°F). Excursions are permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature]. Keep out of reach of children. UPTRAVI® (selexipag) for injection, for intravenous use, is supplied in a 10 mL Type I glass vial closed by a stopper and sealed with an aluminum flip-off button, containing 1800 mcg of selexipag [NDC 66215-718-01]. UPTRAVI (selexipag) for injection is available in cartons containing 1 single-dose vial. Storage conditions for UPTRAVI for injection: Store the original carton containing glass vial in a refrigerator at 2°C to 8°C (36°F to 46°F) until use in order to protect from light. Manufactured for: Actelion Pharmaceuticals US, Inc. a Janssen Pharmaceutical Company South San Francisco, CA 94080. Revised: Jul 2021 Side Effects SIDE EFFECTS Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of UPTRAVI has been evaluated in a long-term, placebo-controlled study enrolling 1156 patients with symptomatic PAH (GRIPHON study) [see Clinical Studies]. The exposure to UPTRAVI in this trial was up to 4.2 years with median duration of exposure of 1.4 years. Table 1 presents adverse reactions more frequent on UPTRAVI than on placebo by ≥3%. Table 1 Adverse Reactions Adverse Reaction UPTRAVI Placebo N=575 N=577 Headache 65% 32% Diarrhea 42% 18% Jaw pain 26% 6% Nausea 33% 18% Myalgia 16% 6% Vomiting 18% 9% Pain in extremity 17% 8% Flushing 12% 5% Arthralgia 11% 8% Anemia 8% 5% Decreased appetite 6% 3% Rash 11% 8% These adverse reactions are more frequent during the dose titration phase. Hyperthyroidism was observed in 1% (n=8) of patients on UPTRAVI and in none of the patients on placebo. Laboratory Test Abnormalities Hemoglobin In a Phase 3 placebo-controlled study in patients with PAH, mean absolute changes in hemoglobin at regular visits compared to baseline ranged from −0.34 to −0.02 g/dL in the selexipag group compared to −0.05 to 0.25 g/dL in the placebo group. A decrease in hemoglobin concentration to below 10 g/dL was reported in 8.6% of patients treated with selexipag and 5.0% of placebo-treated patients. Thyroid Function Tests In a Phase 3 placebo-controlled study in patients with PAH, a reduction (up to −0.3 MU/L from a baseline median of 2.5 MU/L) in median thyroid-stimulating hormone (TSH) was observed at most visits in the selexipag group. In the placebo group, little change in median values was apparent. There were no mean changes in triiodothyronine or thyroxine in either group. Postmarketing Experience The following adverse reactions have been identified during postapproval use of Uptravi. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Symptomatic hypotension Drug Interactions DRUG INTERACTIONS CYP2C8 Inhibitors Concomitant administration with gemfibrozil, a strong inhibitor of CYP2C8, doubled 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 [see CONTRAINDICATIONS and CLINICAL PHARMACOLOGY]. Although not studied, use of UPTRAVI with moderate CYP2C8 inhibitors (e.g., teriflunomide and deferasirox) can be expected to increase exposure to the active metabolite of selexipag. Consider a less frequent dosing regimen, e.g., once-daily, when initiating UPTRAVI in patients on a moderate CYP2C8 inhibitor. Reduce UPTRAVI when a moderate CYP2C8 inhibitor is initiated. CYP2C8 Inducers Concomitant administration with an inducer of CYP2C8 and UGT 1A3 and 2B7 enzymes (rifampin) halved exposure to the active metabolite. Increase dose up to twice of UPTRAVI when co-administered with rifampin. Reduce UPTRAVI when rifampin is stopped [see CLINICAL PHARMACOLOGY]. Warnings & Precautions WARNINGS Included as part of the "PRECAUTIONS" Section PRECAUTIONS Pulmonary Edema With Pulmonary Veno-Occlusive Disease Should signs of pulmonary edema occur, consider the possibility of associated pulmonary venoocclusive disease. If confirmed, discontinue UPTRAVI. Patient Counseling Information Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION). Inform Patients To take a missed dose as soon as possible, unless the next dose is within the next 6 hours. Not to split, crush, or chew tablets. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility Carcinogenesis In the 2-year carcinogenicity studies, chronic oral administration of selexipag revealed no evidence of carcinogenic potential in rats at 100 mg/kg/day and mice at 500 mg/kg/day which resulted in the exposures to the active metabolite more than 25 times the human exposure at the maximum recommended human oral dose of 1600 mcg twice daily on an AUC basis. Mutagenesis Selexipag and the active metabolite are not genotoxic on the basis of the overall evidence of conducted genotoxicity studies. Fertility In rats administered with selexipag orally, the no effect dose for effects on fertility was 60 mg/kg/day which resulted in the exposure to the active metabolite approximately 175 times the human exposure at the maximum recommended human oral dose of 1600 mcg twice daily on an AUC basis. Use In Specific Populations Pregnancy Risk Summary There are no adequate and well-controlled studies with UPTRAVI in pregnant women. Animal reproduction studies performed with selexipag showed no clinically relevant effects on embryofetal development and survival. A slight reduction in maternal as well as in fetal body weight was observed when pregnant rats were administered selexipag during organogenesis at a dose producing an exposure to the active metabolite approximately 47 times that in humans at the maximum recommended human dose. No adverse developmental outcomes were observed with oral administration of selexipag to pregnant rabbits during organogenesis at exposures to the active metabolite up to 50 times the human exposure at the maximum recommended human dose. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data Pregnant rats were treated with selexipag using oral doses of 2, 6, and 20 mg/kg/day (up to 47 times the exposure to the active metabolite at the maximum recommended human oral dose of 1600 mcg twice daily on an area under the curve [AUC] basis) during the period of organogenesis (gestation days 7 to 17). Selexipag did not cause adverse developmental effects to the fetus in this study. A slight reduction in fetal body weight was observed in parallel with a slight reduction in maternal body weight at the high dose. Pregnant rabbits were treated with selexipag using oral doses of 3, 10, and 30 mg/kg (up to 50 times the exposure to the active metabolite at the maximum recommended human oral dose of 1600 mcg twice daily on an AUC basis) during the period of organogenesis (gestation days 6 to 18). Selexipag did not cause adverse developmental effects to the fetus in this study. In a pre-and post-natal development study, pregnant rats were treated with selexipag from gestation day 7 through lactation day 20 at oral doses of 2, 6, and 20 mg/kg/day (up to 35 times the exposure to the active metabolite at the maximum recommended human dose of 1600 mcg twice daily on an AUC basis). Treatment with selexipag did not cause adverse developmental effects in this study at any dose. Lactation It 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. Pediatric Use Safety and effectiveness in pediatric patients have not been established. Geriatric Use Of the 1,368 subjects in clinical studies of UPTRAVI tablets, 248 subjects were 65 years of age and older, while 19 were 75 and older. No overall differences were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity cannot be ruled out. Patients With Hepatic Impairment No 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 and CLINICAL PHARMACOLOGY]. Patients With Renal Impairment No adjustment to the dosing regimen is needed in patients with estimated glomerular filtration rate >15 mL/min/1.73 m2. There is no clinical experience with UPTRAVI in patients undergoing dialysis or in patients with glomerular filtration rates <15 mL/min/1.73 m2 [see CLINICAL PHARMACOLOGY]. Overdosage & Contraindications OVERDOSE Isolated cases of overdose with UPTRAVI tablets up to 3200 mcg were reported. Mild, transient nausea was the only reported consequence. In the event of overdose, supportive measures must be taken as required. Dialysis is unlikely to be effective because selexipag and its active metabolite are highly protein-bound. CONTRAINDICATIONS Concomitant use of strong inhibitors of CYP2C8 (e.g., gemfibrozil) [see DRUG INTERACTIONS and CLINICAL PHARMACOLOGY]. Clinical Pharmacology CLINICAL PHARMACOLOGYMechanism Of ActionSelexipag is an oral prostacyclin receptor (IP receptor) agonist that is structurally distinct from prostacyclin. Selexipag is hydrolyzed by carboxylesterase 1 to yield its active metabolite, which is approximately 37-fold as potent as selexipag. Selexipag and the active metabolite are selective for the IP receptor versus other prostanoid receptors (EP1-4, DP, FP, and TP).PharmacodynamicsCardiac ElectrophysiologyAt the maximum tolerated dose of 1600 mcg twice daily, selexipag does not prolong the QT interval to any clinically relevant extent.Platelet AggregationBoth selexipag and its active metabolite caused concentration-dependent inhibition of platelet aggregation in vitro with an IC50 of 5.5 μM and 0.21 μM, respectively. However, at clinically relevant concentrations, there was no effect on platelet aggregation test parameters as seen following multiple-dose administrations of selexipag in healthy subjects from 400 mcg up to 1800 mcg twice daily.Pulmonary HemodynamicsA Phase 2 clinical study assessed hemodynamic variables after 17 weeks of treatment in patients with PAH WHO Functional Class II–III and concomitantly receiving endothelin receptor antagonists (ERAs) and/or phosphodiesterase type 5 (PDE-5) inhibitors. Patients titrating selexipag to an individually tolerated dose (200 mcg twice daily increments up to 800 mcg twice daily) (N=33) achieved a statistically-significant mean reduction in pulmonary vascular resistance of 30.3% (95% confidence interval [CI] −44.7%, −12.2%) and an increase in cardiac index (median treatment effect) of 0.41 L/min/m2 (95% CI 0.10, 0.71) compared to placebo (N=10).Drug InteractionIn a study in healthy subjects, selexipag (400 mcg twice a day) did not influence the pharmacodynamic effect of warfarin on the international normalized ratio.PharmacokineticsThe 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 administration, were dose-proportional up to a single dose of 800 mcg and multiple doses of up to 1800 mcg twice daily.In healthy subjects, inter-subject variability in exposure (area under the curve over a dosing interval, AUC) at steady-state 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.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. Exposure to the active metabolite is approximately 30% higher after oral administration compared to the same intravenous dose in healthy subjects.AbsorptionThe absolute bioavailability of 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.DistributionThe 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).MetabolismSelexipag 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.EliminationElimination 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. 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.ExcretionIn 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.Specific PopulationsNo 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.AgeThe pharmacokinetic variables (Cmax and 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.Hepatic ImpairmentIn 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 [see Use In Specific Populations].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.Renal ImpairmentA 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 m2 and < 30 mL/min/1.73 m2) [see Use In Specific Populations].Drug Interaction StudiesIn Vitro StudiesSelexipag 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 on in vivo drug interaction studies are presented in Figures 1 and 2.Figure 1 Effect of Other Drugs on UPTRAVI and its Active Metabolite* ERA and PDE-5 inhibitor data from GRIPHON.Figure 2 Effect of UPTRAVI on Other Drugs Clinical StudiesPulmonary Arterial HypertensionThe effect of selexipag on progression of PAH was demonstrated in a multi-center, double-blind, placebo-controlled, parallel group, event-driven study (GRIPHON) in 1156 patients with symptomatic (WHO Functional Class I [0.8%], II [46%], III [53%], and IV [1%]) PAH. Patients were randomized to either placebo (N = 582), or UPTRAVI (N = 574). The dose was increased in weekly intervals by increments of 200 mcg twice a day to the highest tolerated dose up to 1600 mcg twice a day.The primary study endpoint was the time to first occurrence up to end-of-treatment of: a) death, b) hospitalization for PAH, c) PAH worsening resulting in need for lung transplantation, or balloon atrial septostomy, d) initiation of parenteral prostanoid therapy or chronic oxygen therapy, or e) other disease progression based on a 15% decrease from baseline in 6MWD plus worsening of Functional Class or need for additional PAH-specific therapy.The mean age was 48 years, the majority of patients were white (65%) and female (80%). Nearly all patients were in WHO Functional Class II and III at baseline.Idiopathic or heritable PAH was the most common etiology in the study population (58%) followed by PAH associated with connective tissue disease (29%), PAH associated with congenital heart disease with repaired shunts (10%), drugs and toxins (2%), and HIV (1%).At baseline, the majority of enrolled patients (80%) were being treated with a stable dose of an endothelin receptor antagonist (15%), a PDE-5 inhibitor (32%), or both (33%).Patients on selexipag achieved doses within the following groups: 200-400 mcg (23%), 600-1000 mcg (31%) and 1200-1600 mcg (43%).Treatment with UPTRAVI resulted in a 40% reduction (99% CI: 22 to 54%; two-sided log-rank p-value < 0.0001) of the occurrence of primary endpoint events compared to placebo (Table 2; Figure 3). The beneficial effect of UPTRAVI was primarily attributable to a reduction in hospitalization for PAH and a reduction in other disease progression events (Table 2). The observed benefit of UPTRAVI was similar regardless of the dose achieved when patients were titrated to their highest tolerated dose [see DOSAGE AND ADMINISTRATION].Figure 3 Kaplan-Meier Estimates of the First Morbidity-Mortality Event in GRIPHONTable 2 Primary Endpoints and Related Components in GRIPHONUPTRAVIN=574PlaceboN=582Hazard Ratio(99% CI)p-valuen%n%Primary endpoint events up to the end of treatmentAll primary endpoint events15527.024241.60.60[0.46,0.78]<0.0001As first event:Hospitalization for PAHOther disease Progression (Decrease in 6MWD plus worsening functional class or need for other therapy)DeathParenteral prostanoid or chronic oxygen therapyPAH worsening resulting in need for lung transplantation or balloon atrial septostomy7813.610918.7386.610017.2284.9183.1101.7132.210.220.3It is not known if the excess number of deaths in the selexipag group is drug-related because there were so few deaths and the imbalance was not observed until 18 months into GRIPHON.Figures 4A, B, and C show time to first event analyses for primary endpoint components of hospitalization for PAH (A), other disease progression (B), and death (C)—all censored 7 days after any primary end point event (because many patients on placebo transitioned to open-label UPTRAVI at this point).Figure 4A Hospitalization for PAH as the First Endpoint in GRIPHONFigure 4B Disease Progression as the First Endpoint in GRIPHONFigure 4C Death as the First Endpoint in GRIPHONThe treatment effect of UPTRAVI on time to first primary event was consistent irrespective of background PAH therapy (i.e., in combination with an ERA, PDE-5i, both, or without background therapy) (Figure 5).Figure 5 Subgroup Analyses of the Primary Endpoint in GRIPHONNote: Race group “Other” is not displayed in analysis, as the population is less than 30. EU = Number of UPTRAVI patients with events, NU = Number of patients randomized to UPTRAVI, EP = Number of Placebo patients with events, NP = Number of patients randomized to Placebo, HR = Hazard Ratio, CI = Confidence Interval, the size of the squares represent the number of patients in the subgroup.Note: The figure above presents effects in various subgroups all of which are baseline characteristics and all were prespecified. The 99% confidence limits that are shown do not take into account how many comparisons were made, nor do they reflect the effect of a particular factor after adjustment for all other factors. Apparent homogeneity or heterogeneity among groups should not be over-interpreted.6-Minute Walk Distance (6MWD)Exercise capacity was evaluated as a secondary endpoint. Median absolute change from baseline to week 26 in 6MWD measured at trough (i.e., at approximately 12 hours post-dose) was +4 meters with UPTRAVI and -9 meters in the placebo group. This resulted in a placebo-corrected median treatment effect of 12 meters (99% CI: 1, 24 meters; two-sided p = 0.005).Long-Term Treatment Of PAHIn long-term follow-up of patients who were treated with UPTRAVI in the pivotal study and the open-label extension (N=574), Kaplan-Meier estimates of survival of these patients across the GRIPHON study and the long-term extension study at 1, 2, 5 and 7 years were 92%, 85%, 71%, and 63%, respectively. The median exposure to UPTRAVI was 3 years. These uncontrolled observations do not allow comparison with a control group not given UPTRAVI and cannot be used to determine the long-term effect of UPTRAVI on mortality. Medication Guide PATIENT INFORMATION UPTRAVI® (up-TRA-vee) (selexipag) tablets UPTRAVI® (up-TRA-vee) (selexipag) for injection What is UPTRAVI? UPTRAVI is a prescription medicine used to treat pulmonary arterial hypertension (PAH) which is high blood pressure in the arteries of your lungs. UPTRAVI can help slow down the progression of your disease and lower your risk of being hospitalized for PAH. It is not known if UPTRAVI is safe and effective in children. Do not take UPTRAVI if you take gemfibrozil because this medicine may affect how UPTRAVI works and cause side effects. Before you take UPTRAVI, tell your healthcare provider about all of your medical conditions, including if you: have liver problems. have narrowing of the pulmonary veins, a condition called pulmonary veno-occlusive disease. are pregnant or plan to become pregnant. It is not known if UPTRAVI will harm your unborn baby. are breastfeeding or plan to breastfeed. It is not known if UPTRAVI passes into your breast milk. You and your healthcare provider should decide if you will take UPTRAVI or breastfeed. You should not do both. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. UPTRAVI and other medicines may affect each other causing side effects. Do not start any new medicine until you check with your healthcare provider. How should I take UPTRAVI? UPTRAVI tablets Take UPTRAVI exactly as your healthcare provider tells you to take it. Do not stop taking UPTRAVI unless your healthcare provider tells you to stop. Your healthcare provider will slowly increase your dose to find the dose of UPTRAVI that is right for you. If you have side effects, your healthcare provider may tell you to change your dose of UPTRAVI. UPTRAVI can be taken with or without food. Taking UPTRAVI with food may help you tolerate UPTRAVI better. UPTRAVI is usually taken 2 times each day. Swallow UPTRAVI tablets whole. Do not split, crush or chew UPTRAVI tablets. If you miss a dose of UPTRAVI, take it as soon as you remember. If your next scheduled dose is due within 6 hours, skip the missed dose. Take the next dose at your regular time. If you miss 3 or more days of UPTRAVI, call your healthcare provider to see if your dose needs to be changed. If you take too much UPTRAVI, call your healthcare provider or go to the nearest hospital emergency room right away. UPTRAVI given by intravenous (IV) injection Your healthcare provider will give you UPTRAVI into your vein through an intravenous (IV) line. Your healthcare provider will decide how much UPTRAVI for injection you will receive each day, based on your current dose of UPTRAVI tablets. What are the possible side effects of UPTRAVI? The most common side effects of UPTRAVI include: headache diarrhea jaw pain nausea muscle pain vomiting pain in arms or legs flushing pain in joints low red blood cell count decreased appetite rash pain, redness or swelling at the injection site for UPTRAVI for injection These are not all of the possible side effects of UPTRAVI. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store UPTRAVI tablets? Store UPTRAVI tablets at room temperature between 68°F and 77°F (20°C and 25°C). Keep UPTRAVI and all medicines out of the reach of children. General information about the safe and effective use of UPTRAVI Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use UPTRAVI for a condition for which it was not prescribed. Do not give UPTRAVI to other people, even if they have the same symptoms that you have. It may harm them. You can ask your healthcare provider or pharmacist for information about UPTRAVI that is written for health professionals. What are the ingredients in UPTRAVI? UPTRAVI tablets Active ingredient:selexipag Inactive ingredients:corn starch, D-mannitol, hydroxypropyl cellulose, low substituted hydroxypropyl cellulose, and magnesium stearate. The tablets are film coated with a coating material containing carnauba wax, hypromellose, propylene glycol, titanium dioxide, along with mixtures of iron oxide black, iron oxide red, or iron oxide yellow. UPTRAVI for injection Active ingredient:selexipag Inactive ingredients:glycine, phosphoric acid, polysorbate 20, and sodium hydroxide. This Patient Information has been approved by the U.S. Food and Drug Administration.
Drug Description What is Uptravi and how is it used? Uptravi is a prescription medicine used to treat the symptoms of Pulmonary Arterial Hypertension (PAH) Disease Progression. Uptravi may be used alone or with other medications. Uptravi belongs to a class of drugs called PAH, Prostacyclin Agonists. It is not known if Uptravi is safe and effective in children. What are the possible side effects of Uptravi? Uptravi may cause serious side effects including: hives, difficulty breathing, swelling of your face, lips, tongue, or throat, pale skin, unusual tiredness, lightheadedness, shortness of breath, cold hands and feet, anxiety, sweating, pale skin, severe shortness of breath, grasping for breath, cough with foamy mucus, chest pain, and fast or uneven heart rate Get medical help right away, if you have any of the symptoms listed above. The most common side effects of Uptravi include: headache, jaw pain, muscle pain, pain in your arms or legs, nausea, vomit, diarrhea, and flushing (warmth, redness, or tingly feeling) Tell the doctor if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of Uptravi. For more information, ask your doctor or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. DESCRIPTION UPTRAVI (selexipag) is a selective non-prostanoid IP prostacyclin receptor agonist. The chemical name of selexipag is 2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N- (methylsulfonyl) acetamide. It has a molecular formula of C26H32N4O4S and a molecular weight of 496.62. Selexipag has the following structural formula: Selexipag is a pale yellow crystalline powder that is practically insoluble in water. In the solid state selexipag is very stable, is not hygroscopic, and is not light sensitive. Depending on the dose strength, each round film-coated tablet for oral administration contains 200, 400, 600, 800, 1000, 1200, 1400, or 1600 mcg of selexipag. The tablets include the following inactive ingredients: D-mannitol, corn starch, low substituted hydroxypropylcellulose, hydroxypropylcellulose, and magnesium stearate. The tablets are film coated with a coating material containing hypromellose, propylene glycol, titanium dioxide, carnauba wax along with mixtures of iron oxide red, iron oxide yellow or iron oxide black. Indications & Dosage INDICATIONS Pulmonary Arterial Hypertension UPTRAVI 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]. DOSAGE AND ADMINISTRATION Recommended Dosage UPTRAVI Film-Coated Tablets The recommended starting dosage of UPTRAVI tablets is 200 micrograms (mcg) given twice daily. Tolerability may be improved when taken with food [see CLINICAL PHARMACOLOGY]. 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 Injection Use 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. Preparation Instructions Reconstitute 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 a polypropylene syringe with 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. Dilution UPTRAVI for injection must be diluted in glass 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 1 for reconstituted transfer volume) from the UPTRAVI vial using a single, appropriately sized polypropylene syringe and 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°F77°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 TRADENAME intravenous based on current UPTRAVI tablets dose UPTRAVI tablets dose (mcg) fortwice 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 Administration Instructions 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 not use a filter for administration. 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. Interruptions And Discontinuations If a dose of UPTRAVI is missed, patients should take a missed dose as soon as possible unless the next dose is within the next 6 hours. If treatment is missed for 3 days or more, restart UPTRAVI at a lower dose and then retitrate. Dosage Adjustment In Patients With Hepatic Impairment No 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 mcg once daily at weekly intervals, as tolerated [see Use In Specific Populations, and CLINICAL PHARMACOLOGY]. Avoid use of UPTRAVI in patients with severe hepatic impairment (Child-Pugh class C). Dosage Adjustment With Co-Administration Of Moderate CYP2C8 Inhibitors When co-administered with moderate CYP2C8 inhibitors (e.g., clopidogrel, deferasirox and teriflunomide), reduce the dosing of UPTRAVI to once daily [see DRUG INTERACTIONS and CLINICAL PHARMACOLOGY]. HOW SUPPLIED Dosage Forms And Strengths UPTRAVI is available in the following presentations: Film-Coated Tablets 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] UPTRAVI For Injection 1800 mcg selexipag [Lyophilized powder white to almost white broken cake or powdered material, supplied in a 10 mL single-dose glass vial] Storage And Handling UPTRAVI® (selexipag) film-coated, round tablets are supplied in the following configurations: Strength (mcg) Color Debossing NDC-XXX Bottle of 60 NDC-XXX Bottle of 140 200 Light yellow 2 66215-602-06 66215-602-14 400 Red 4 66215-604-06 Not Available 600 Light violet 6 66215-606-06 Not Available 800 Green 8 66215-608-06 Not Available 1000 Orange 10 66215-610-06 Not Available 1200 Dark violet 12 66215-612-06 Not Available 1400 Dark yellow 14 66215-614-06 Not Available 1600 Brown 16 66215-616-06 Not Available UPTRAVI® (selexipag) tablets are also supplied in a Titration Pack [NDC 66215-628-20] that includes a 140-count bottle of 200-mcg tablets and a 60-count bottle of 800-mcg tablets. Store at 20°C to 25°C (68°F to 77°F). Excursions are permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature]. Keep out of reach of children. UPTRAVI® (selexipag) for injection, for intravenous use, is supplied in a 10 mL Type I glass vial closed by a stopper and sealed with an aluminum flip-off button, containing 1800 mcg of selexipag [NDC 66215-718-01]. UPTRAVI (selexipag) for injection is available in cartons containing 1 single-dose vial. Storage conditions for UPTRAVI for injection: Store the original carton containing glass vial in a refrigerator at 2°C to 8°C (36°F to 46°F) until use in order to protect from light. Manufactured for: Actelion Pharmaceuticals US, Inc. a Janssen Pharmaceutical Company South San Francisco, CA 94080. Revised: Jul 2021 Side Effects SIDE EFFECTS Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of UPTRAVI has been evaluated in a long-term, placebo-controlled study enrolling 1156 patients with symptomatic PAH (GRIPHON study) [see Clinical Studies]. The exposure to UPTRAVI in this trial was up to 4.2 years with median duration of exposure of 1.4 years. Table 1 presents adverse reactions more frequent on UPTRAVI than on placebo by ≥3%. Table 1 Adverse Reactions Adverse Reaction UPTRAVI Placebo N=575 N=577 Headache 65% 32% Diarrhea 42% 18% Jaw pain 26% 6% Nausea 33% 18% Myalgia 16% 6% Vomiting 18% 9% Pain in extremity 17% 8% Flushing 12% 5% Arthralgia 11% 8% Anemia 8% 5% Decreased appetite 6% 3% Rash 11% 8% These adverse reactions are more frequent during the dose titration phase. Hyperthyroidism was observed in 1% (n=8) of patients on UPTRAVI and in none of the patients on placebo. Laboratory Test Abnormalities Hemoglobin In a Phase 3 placebo-controlled study in patients with PAH, mean absolute changes in hemoglobin at regular visits compared to baseline ranged from −0.34 to −0.02 g/dL in the selexipag group compared to −0.05 to 0.25 g/dL in the placebo group. A decrease in hemoglobin concentration to below 10 g/dL was reported in 8.6% of patients treated with selexipag and 5.0% of placebo-treated patients. Thyroid Function Tests In a Phase 3 placebo-controlled study in patients with PAH, a reduction (up to −0.3 MU/L from a baseline median of 2.5 MU/L) in median thyroid-stimulating hormone (TSH) was observed at most visits in the selexipag group. In the placebo group, little change in median values was apparent. There were no mean changes in triiodothyronine or thyroxine in either group. Postmarketing Experience The following adverse reactions have been identified during postapproval use of Uptravi. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Symptomatic hypotension Drug Interactions DRUG INTERACTIONS CYP2C8 Inhibitors Concomitant administration with gemfibrozil, a strong inhibitor of CYP2C8, doubled 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 [see CONTRAINDICATIONS and CLINICAL PHARMACOLOGY]. Although not studied, use of UPTRAVI with moderate CYP2C8 inhibitors (e.g., teriflunomide and deferasirox) can be expected to increase exposure to the active metabolite of selexipag. Consider a less frequent dosing regimen, e.g., once-daily, when initiating UPTRAVI in patients on a moderate CYP2C8 inhibitor. Reduce UPTRAVI when a moderate CYP2C8 inhibitor is initiated. CYP2C8 Inducers Concomitant administration with an inducer of CYP2C8 and UGT 1A3 and 2B7 enzymes (rifampin) halved exposure to the active metabolite. Increase dose up to twice of UPTRAVI when co-administered with rifampin. Reduce UPTRAVI when rifampin is stopped [see CLINICAL PHARMACOLOGY]. Warnings & Precautions WARNINGS Included as part of the "PRECAUTIONS" Section PRECAUTIONS Pulmonary Edema With Pulmonary Veno-Occlusive Disease Should signs of pulmonary edema occur, consider the possibility of associated pulmonary venoocclusive disease. If confirmed, discontinue UPTRAVI. Patient Counseling Information Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION). Inform Patients To take a missed dose as soon as possible, unless the next dose is within the next 6 hours. Not to split, crush, or chew tablets. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility Carcinogenesis In the 2-year carcinogenicity studies, chronic oral administration of selexipag revealed no evidence of carcinogenic potential in rats at 100 mg/kg/day and mice at 500 mg/kg/day which resulted in the exposures to the active metabolite more than 25 times the human exposure at the maximum recommended human oral dose of 1600 mcg twice daily on an AUC basis. Mutagenesis Selexipag and the active metabolite are not genotoxic on the basis of the overall evidence of conducted genotoxicity studies. Fertility In rats administered with selexipag orally, the no effect dose for effects on fertility was 60 mg/kg/day which resulted in the exposure to the active metabolite approximately 175 times the human exposure at the maximum recommended human oral dose of 1600 mcg twice daily on an AUC basis. Use In Specific Populations Pregnancy Risk Summary There are no adequate and well-controlled studies with UPTRAVI in pregnant women. Animal reproduction studies performed with selexipag showed no clinically relevant effects on embryofetal development and survival. A slight reduction in maternal as well as in fetal body weight was observed when pregnant rats were administered selexipag during organogenesis at a dose producing an exposure to the active metabolite approximately 47 times that in humans at the maximum recommended human dose. No adverse developmental outcomes were observed with oral administration of selexipag to pregnant rabbits during organogenesis at exposures to the active metabolite up to 50 times the human exposure at the maximum recommended human dose. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data Pregnant rats were treated with selexipag using oral doses of 2, 6, and 20 mg/kg/day (up to 47 times the exposure to the active metabolite at the maximum recommended human oral dose of 1600 mcg twice daily on an area under the curve [AUC] basis) during the period of organogenesis (gestation days 7 to 17). Selexipag did not cause adverse developmental effects to the fetus in this study. A slight reduction in fetal body weight was observed in parallel with a slight reduction in maternal body weight at the high dose. Pregnant rabbits were treated with selexipag using oral doses of 3, 10, and 30 mg/kg (up to 50 times the exposure to the active metabolite at the maximum recommended human oral dose of 1600 mcg twice daily on an AUC basis) during the period of organogenesis (gestation days 6 to 18). Selexipag did not cause adverse developmental effects to the fetus in this study. In a pre-and post-natal development study, pregnant rats were treated with selexipag from gestation day 7 through lactation day 20 at oral doses of 2, 6, and 20 mg/kg/day (up to 35 times the exposure to the active metabolite at the maximum recommended human dose of 1600 mcg twice daily on an AUC basis). Treatment with selexipag did not cause adverse developmental effects in this study at any dose. Lactation It 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. Pediatric Use Safety and effectiveness in pediatric patients have not been established. Geriatric Use Of the 1,368 subjects in clinical studies of UPTRAVI tablets, 248 subjects were 65 years of age and older, while 19 were 75 and older. No overall differences were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity cannot be ruled out. Patients With Hepatic Impairment No 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 and CLINICAL PHARMACOLOGY]. Patients With Renal Impairment No adjustment to the dosing regimen is needed in patients with estimated glomerular filtration rate >15 mL/min/1.73 m2. There is no clinical experience with UPTRAVI in patients undergoing dialysis or in patients with glomerular filtration rates <15 mL/min/1.73 m2 [see CLINICAL PHARMACOLOGY]. Overdosage & Contraindications OVERDOSE Isolated cases of overdose with UPTRAVI tablets up to 3200 mcg were reported. Mild, transient nausea was the only reported consequence. In the event of overdose, supportive measures must be taken as required. Dialysis is unlikely to be effective because selexipag and its active metabolite are highly protein-bound. CONTRAINDICATIONS Concomitant use of strong inhibitors of CYP2C8 (e.g., gemfibrozil) [see DRUG INTERACTIONS and CLINICAL PHARMACOLOGY]. Clinical Pharmacology CLINICAL PHARMACOLOGYMechanism Of ActionSelexipag is an oral prostacyclin receptor (IP receptor) agonist that is structurally distinct from prostacyclin. Selexipag is hydrolyzed by carboxylesterase 1 to yield its active metabolite, which is approximately 37-fold as potent as selexipag. Selexipag and the active metabolite are selective for the IP receptor versus other prostanoid receptors (EP1-4, DP, FP, and TP).PharmacodynamicsCardiac ElectrophysiologyAt the maximum tolerated dose of 1600 mcg twice daily, selexipag does not prolong the QT interval to any clinically relevant extent.Platelet AggregationBoth selexipag and its active metabolite caused concentration-dependent inhibition of platelet aggregation in vitro with an IC50 of 5.5 μM and 0.21 μM, respectively. However, at clinically relevant concentrations, there was no effect on platelet aggregation test parameters as seen following multiple-dose administrations of selexipag in healthy subjects from 400 mcg up to 1800 mcg twice daily.Pulmonary HemodynamicsA Phase 2 clinical study assessed hemodynamic variables after 17 weeks of treatment in patients with PAH WHO Functional Class II–III and concomitantly receiving endothelin receptor antagonists (ERAs) and/or phosphodiesterase type 5 (PDE-5) inhibitors. Patients titrating selexipag to an individually tolerated dose (200 mcg twice daily increments up to 800 mcg twice daily) (N=33) achieved a statistically-significant mean reduction in pulmonary vascular resistance of 30.3% (95% confidence interval [CI] −44.7%, −12.2%) and an increase in cardiac index (median treatment effect) of 0.41 L/min/m2 (95% CI 0.10, 0.71) compared to placebo (N=10).Drug InteractionIn a study in healthy subjects, selexipag (400 mcg twice a day) did not influence the pharmacodynamic effect of warfarin on the international normalized ratio.PharmacokineticsThe 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 administration, were dose-proportional up to a single dose of 800 mcg and multiple doses of up to 1800 mcg twice daily.In healthy subjects, inter-subject variability in exposure (area under the curve over a dosing interval, AUC) at steady-state 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.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. Exposure to the active metabolite is approximately 30% higher after oral administration compared to the same intravenous dose in healthy subjects.AbsorptionThe absolute bioavailability of 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.DistributionThe 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).MetabolismSelexipag 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.EliminationElimination 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. 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.ExcretionIn 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.Specific PopulationsNo 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.AgeThe pharmacokinetic variables (Cmax and 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.Hepatic ImpairmentIn 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 [see Use In Specific Populations].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.Renal ImpairmentA 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 m2 and < 30 mL/min/1.73 m2) [see Use In Specific Populations].Drug Interaction StudiesIn Vitro StudiesSelexipag 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 on in vivo drug interaction studies are presented in Figures 1 and 2.Figure 1 Effect of Other Drugs on UPTRAVI and its Active Metabolite* ERA and PDE-5 inhibitor data from GRIPHON.Figure 2 Effect of UPTRAVI on Other Drugs Clinical StudiesPulmonary Arterial HypertensionThe effect of selexipag on progression of PAH was demonstrated in a multi-center, double-blind, placebo-controlled, parallel group, event-driven study (GRIPHON) in 1156 patients with symptomatic (WHO Functional Class I [0.8%], II [46%], III [53%], and IV [1%]) PAH. Patients were randomized to either placebo (N = 582), or UPTRAVI (N = 574). The dose was increased in weekly intervals by increments of 200 mcg twice a day to the highest tolerated dose up to 1600 mcg twice a day.The primary study endpoint was the time to first occurrence up to end-of-treatment of: a) death, b) hospitalization for PAH, c) PAH worsening resulting in need for lung transplantation, or balloon atrial septostomy, d) initiation of parenteral prostanoid therapy or chronic oxygen therapy, or e) other disease progression based on a 15% decrease from baseline in 6MWD plus worsening of Functional Class or need for additional PAH-specific therapy.The mean age was 48 years, the majority of patients were white (65%) and female (80%). Nearly all patients were in WHO Functional Class II and III at baseline.Idiopathic or heritable PAH was the most common etiology in the study population (58%) followed by PAH associated with connective tissue disease (29%), PAH associated with congenital heart disease with repaired shunts (10%), drugs and toxins (2%), and HIV (1%).At baseline, the majority of enrolled patients (80%) were being treated with a stable dose of an endothelin receptor antagonist (15%), a PDE-5 inhibitor (32%), or both (33%).Patients on selexipag achieved doses within the following groups: 200-400 mcg (23%), 600-1000 mcg (31%) and 1200-1600 mcg (43%).Treatment with UPTRAVI resulted in a 40% reduction (99% CI: 22 to 54%; two-sided log-rank p-value < 0.0001) of the occurrence of primary endpoint events compared to placebo (Table 2; Figure 3). The beneficial effect of UPTRAVI was primarily attributable to a reduction in hospitalization for PAH and a reduction in other disease progression events (Table 2). The observed benefit of UPTRAVI was similar regardless of the dose achieved when patients were titrated to their highest tolerated dose [see DOSAGE AND ADMINISTRATION].Figure 3 Kaplan-Meier Estimates of the First Morbidity-Mortality Event in GRIPHONTable 2 Primary Endpoints and Related Components in GRIPHONUPTRAVIN=574PlaceboN=582Hazard Ratio(99% CI)p-valuen%n%Primary endpoint events up to the end of treatmentAll primary endpoint events15527.024241.60.60[0.46,0.78]<0.0001As first event:Hospitalization for PAHOther disease Progression (Decrease in 6MWD plus worsening functional class or need for other therapy)DeathParenteral prostanoid or chronic oxygen therapyPAH worsening resulting in need for lung transplantation or balloon atrial septostomy7813.610918.7386.610017.2284.9183.1101.7132.210.220.3It is not known if the excess number of deaths in the selexipag group is drug-related because there were so few deaths and the imbalance was not observed until 18 months into GRIPHON.Figures 4A, B, and C show time to first event analyses for primary endpoint components of hospitalization for PAH (A), other disease progression (B), and death (C)—all censored 7 days after any primary end point event (because many patients on placebo transitioned to open-label UPTRAVI at this point).Figure 4A Hospitalization for PAH as the First Endpoint in GRIPHONFigure 4B Disease Progression as the First Endpoint in GRIPHONFigure 4C Death as the First Endpoint in GRIPHONThe treatment effect of UPTRAVI on time to first primary event was consistent irrespective of background PAH therapy (i.e., in combination with an ERA, PDE-5i, both, or without background therapy) (Figure 5).Figure 5 Subgroup Analyses of the Primary Endpoint in GRIPHONNote: Race group “Other” is not displayed in analysis, as the population is less than 30. EU = Number of UPTRAVI patients with events, NU = Number of patients randomized to UPTRAVI, EP = Number of Placebo patients with events, NP = Number of patients randomized to Placebo, HR = Hazard Ratio, CI = Confidence Interval, the size of the squares represent the number of patients in the subgroup.Note: The figure above presents effects in various subgroups all of which are baseline characteristics and all were prespecified. The 99% confidence limits that are shown do not take into account how many comparisons were made, nor do they reflect the effect of a particular factor after adjustment for all other factors. Apparent homogeneity or heterogeneity among groups should not be over-interpreted.6-Minute Walk Distance (6MWD)Exercise capacity was evaluated as a secondary endpoint. Median absolute change from baseline to week 26 in 6MWD measured at trough (i.e., at approximately 12 hours post-dose) was +4 meters with UPTRAVI and -9 meters in the placebo group. This resulted in a placebo-corrected median treatment effect of 12 meters (99% CI: 1, 24 meters; two-sided p = 0.005).Long-Term Treatment Of PAHIn long-term follow-up of patients who were treated with UPTRAVI in the pivotal study and the open-label extension (N=574), Kaplan-Meier estimates of survival of these patients across the GRIPHON study and the long-term extension study at 1, 2, 5 and 7 years were 92%, 85%, 71%, and 63%, respectively. The median exposure to UPTRAVI was 3 years. These uncontrolled observations do not allow comparison with a control group not given UPTRAVI and cannot be used to determine the long-term effect of UPTRAVI on mortality. Medication Guide PATIENT INFORMATION UPTRAVI® (up-TRA-vee) (selexipag) tablets UPTRAVI® (up-TRA-vee) (selexipag) for injection What is UPTRAVI? UPTRAVI is a prescription medicine used to treat pulmonary arterial hypertension (PAH) which is high blood pressure in the arteries of your lungs. UPTRAVI can help slow down the progression of your disease and lower your risk of being hospitalized for PAH. It is not known if UPTRAVI is safe and effective in children. Do not take UPTRAVI if you take gemfibrozil because this medicine may affect how UPTRAVI works and cause side effects. Before you take UPTRAVI, tell your healthcare provider about all of your medical conditions, including if you: have liver problems. have narrowing of the pulmonary veins, a condition called pulmonary veno-occlusive disease. are pregnant or plan to become pregnant. It is not known if UPTRAVI will harm your unborn baby. are breastfeeding or plan to breastfeed. It is not known if UPTRAVI passes into your breast milk. You and your healthcare provider should decide if you will take UPTRAVI or breastfeed. You should not do both. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. UPTRAVI and other medicines may affect each other causing side effects. Do not start any new medicine until you check with your healthcare provider. How should I take UPTRAVI? UPTRAVI tablets Take UPTRAVI exactly as your healthcare provider tells you to take it. Do not stop taking UPTRAVI unless your healthcare provider tells you to stop. Your healthcare provider will slowly increase your dose to find the dose of UPTRAVI that is right for you. If you have side effects, your healthcare provider may tell you to change your dose of UPTRAVI. UPTRAVI can be taken with or without food. Taking UPTRAVI with food may help you tolerate UPTRAVI better. UPTRAVI is usually taken 2 times each day. Swallow UPTRAVI tablets whole. Do not split, crush or chew UPTRAVI tablets. If you miss a dose of UPTRAVI, take it as soon as you remember. If your next scheduled dose is due within 6 hours, skip the missed dose. Take the next dose at your regular time. If you miss 3 or more days of UPTRAVI, call your healthcare provider to see if your dose needs to be changed. If you take too much UPTRAVI, call your healthcare provider or go to the nearest hospital emergency room right away. UPTRAVI given by intravenous (IV) injection Your healthcare provider will give you UPTRAVI into your vein through an intravenous (IV) line. Your healthcare provider will decide how much UPTRAVI for injection you will receive each day, based on your current dose of UPTRAVI tablets. What are the possible side effects of UPTRAVI? The most common side effects of UPTRAVI include: headache diarrhea jaw pain nausea muscle pain vomiting pain in arms or legs flushing pain in joints low red blood cell count decreased appetite rash pain, redness or swelling at the injection site for UPTRAVI for injection These are not all of the possible side effects of UPTRAVI. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store UPTRAVI tablets? Store UPTRAVI tablets at room temperature between 68°F and 77°F (20°C and 25°C). Keep UPTRAVI and all medicines out of the reach of children. General information about the safe and effective use of UPTRAVI Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use UPTRAVI for a condition for which it was not prescribed. Do not give UPTRAVI to other people, even if they have the same symptoms that you have. It may harm them. You can ask your healthcare provider or pharmacist for information about UPTRAVI that is written for health professionals. What are the ingredients in UPTRAVI? UPTRAVI tablets Active ingredient:selexipag Inactive ingredients:corn starch, D-mannitol, hydroxypropyl cellulose, low substituted hydroxypropyl cellulose, and magnesium stearate. The tablets are film coated with a coating material containing carnauba wax, hypromellose, propylene glycol, titanium dioxide, along with mixtures of iron oxide black, iron oxide red, or iron oxide yellow. UPTRAVI for injection Active ingredient:selexipag Inactive ingredients:glycine, phosphoric acid, polysorbate 20, and sodium hydroxide. This Patient Information has been approved by the U.S. Food and Drug Administration.
