DRUG INTERACTIONS-(summary)

 Strong CYP2C8 inhibitors: increased exposure to selexipag and its active metabolite. Avoid concomitant use. 

44/15 PRODUCT DETAILS 

Drug Name-               UPTRAVI 

Active Ingredient-      Selexipag

 Approved date         12/21/2015                                                                                       

FDA approved use-  To treat pulmonary arterial hyperstension     

HIGHLIGHTS OF PRESCRIBING INFORMATION -

These highlights do not include all the information needed to use UPTRAVI® safely and effectively. See full prescribing information for UPTRAVI® . UPTRAVI® (selexipag) tablets, for oral use

Initial U.S. Approval: 2015

INDICATIONS AND USAGE-

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.

ADVERSE REACTIONS-

 Adverse reactions occurring more frequently (>5%) on UPTRAVI compared to placebo are headache, diarrhea, jaw pain, nausea, myalgia, vomiting, pain in extremity, and flushing.

CONTRAINDICATIONS-

 None

WARNINGS AND PRECAUTIONS-

 Pulmonary edema in patients with pulmonary veno-occlusive disease. If confirmed, discontinue treatment. 

DOSAGE AND ADMINISTRATION-

 Starting dose: 200 mcg twice daily.

 Increase the dose by 200 mcg twice daily at weekly intervals to the highest tolerated dose up to 1600 mcg twice daily.

 Maintenance dose is determined by tolerability. (

 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.

DOSAGE FORMS AND STRENGTHS-

 Tablets: 200 mcg, 400 mcg, 600 mcg, 800 mcg, 1000 mcg, 1200 mcg, 1400 mcg, 1600 mcg.  

PATIENT COUNSELING INFORMATION -

Advise the patient to read the FDA-approved patient labeling (Patient Package Insert).

Inform patients: ? what to do if they miss a dose ? not to split, crush, or chew tablets.

Manufactured for: Actelion Pharmaceuticals US, Inc. 5000 Shoreline Court, Ste. 200 South San Francisco, CA 94080, USA ACT20151221 ? 2015 Actelion Pharmaceuticals US, Inc. All rights reserved.

CLINICAL PHARMACOLOGY

Mechanism of Action -                                                                                                    Selexipag is an oral prostacyclin receptor (IP receptor) agonist that is structurally distinct from prostacyclin.

2 Pharmacodynamics

Cardiac electrophysiology: At the maximum tolerated dose of 1600 mcg twice daily, selexipag does not prolong the QT interval to any clinically relevant extent.

3 Pharmacokinetics -                                                                                                    The pharmacokinetics of selexipag and its active metabolite have been studied primarily in healthy subjects.

Absorption-

 Upon oral administration, maximum observed plasma concentrations of selexipag and its active metabolite after oral administration are reached within about 1–3 hours and 3–4 hours, respectively.

Distribution-                                                                                                             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).

Metabolism -                                                                                                                   Selexipag undergoes enzymatic hydrolysis of the acylsulfonamide by hepatic carboxylesterase 1, to yield the active metabolite.

Elimination-                                                                                                                  Elimination of selexipag is predominately via metabolism with a mean terminal half-life of 0.8-2.5 hours. The active metabolite has a terminal half-life of 6.2-13.5 hours.

Specific Populations:                                                                                                       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.

Age: The 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 Impairment: 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. 

Drug Interaction Studies: In vitro studies Selexipag is hydrolyzed to its active metabolite by hepatic carboxylesterase

USE IN SPECIFIC POPULATIONS

Pregnancy Risk Summary

There are no adequate and well-controlled studies with UPTRAVI in pregnant women.

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.

2 Lactation                                                                                                                           It 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 Reference ID: 3864143 potential for serious adverse reactions in nursing infants, discontinue nursing or discontinue UPTRAVI.

3 Pediatric Use                                                                                                             Safety and effectiveness in pediatric patients have not been established.

4. Geriatric Use                                                                                                                     Of the 1368 subjects in clinical studies of UPTRAVI 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.

5. 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.

6. 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 

OVERDOSAGE -                                                                                                               Isolated cases of overdose 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.