Drug Facts
Composition & Profile
Identifiers & Packaging
16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Orenitram is an 8-mm round biconvex tablet with strength identified by color and print and supplied as follows: Strength Color Printing on Tablets NDC # 100-Count Bottle NDC # 10-Count Bottle NDC # 10-Count Carton (Unit-Dose Blister) 0.125 mg White UT 0.125 66302-300-01 66302-300-10 66302-300-02 0.25 mg Green UT 0.25 66302-302-01 66302-302-10 66302-302-02 1 mg Yellow UT 1 66302-310-01 66302-310-10 66302-310-02 2.5 mg Pink UT 2.5 66302-325-01 66302-325-10 66302-325-02 5 mg Red UT 5 66302-350-01 66302-350-10 66302-350-02 Titration Kits for Orenitram are supplied in the following configurations: Titration Kit Blister Configurations NDC # Month 1 containing four weekly cartons Seven daily wallet blister packs in each weekly carton containing the following total number of tablets: Week 1 (twenty-one × 0.125 mg tablets) Week 2 (forty-two × 0.125 mg tablets) Week 3 (twenty-one × 0.125 mg tablets and twenty-one × 0.25 mg tablets) Week 4 (forty-two × 0.125 mg tablets and twenty-one × 0.25 mg tablets) 66302-361-28 Month 2 containing four weekly cartons Seven daily wallet blister packs in each weekly carton containing the following total number of tablets: Week 5 (twenty-one × 0.125 mg tablets and forty-two × 0.25 mg tablets) Week 6 (forty-two × 0.125 mg tablets and forty-two × 0.25 mg tablets) Week 7 (twenty-one × 0.125 mg tablets and sixty-three × 0.25 mg tablets) Week 8 (forty-two × 0.125 mg tablets and sixty-three × 0.25 mg tablets) 66302-362-56 Month 3 containing four weekly cartons Seven daily wallet blister packs in each weekly carton containing the following total number of tablets: Week 9 (twenty-one × 0.125 mg tablets and twenty-one × 1 mg tablets) Week 10 (forty-two × 0.125 mg tablets and twenty-one × 1 mg tablets) Week 11 (twenty-one × 0.125 mg tablets, twenty-one × 0.25 mg tablets, and twenty-one × 1 mg tablets) Week 12 (forty-two × 0.125 mg tablets, twenty-one × 0.25 mg tablets, and twenty-one × 1 mg tablets) 66302-363-84 16.2 Storage Store at 20°C to 25°C (68°F to 77°F) with excursions permitted to 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature]. Keep out of reach of children.; PRINCIPAL DISPLAY PANEL - 0.125 mg Tablet Bottle Label NDC 66302-300-01 100 Tablets Orenitram ® (treprostinil) Extended-Release Tablets 0.125 mg Swallow whole. Do not split, chew, crush, or break tablets. PRINCIPAL DISPLAY PANEL - 0.125 mg Tablet Bottle Label; PRINCIPAL DISPLAY PANEL - 0.125 mg Tablet Blister Pack Carton Orenitram ® (treprostinil) EXTENDED-RELEASE TABLETS 0.125 mg per tablet Swallow whole. Do not split, chew, crush, or break tablets. 10 Tablets (1 x 10 tablet blister pack) Pharmacist: Dispense the accompanying Patient Information Leaflet to each patient. Rx Only NDC 66302-300-02 PRINCIPAL DISPLAY PANEL - 0.125 mg Tablet Blister Pack Carton; PRINCIPAL DISPLAY PANEL - 0.25 mg Tablet Bottle Label NDC 66302-302-01 100 Tablets Orenitram ® (treprostinil) Extended-Release Tablets 0.25 mg Swallow whole. Do not split, chew, crush, or break tablets. PRINCIPAL DISPLAY PANEL - 0.25 mg Tablet Bottle Label; PRINCIPAL DISPLAY PANEL - 0.25 mg Tablet Blister Pack Carton Orenitram ® (treprostinil) EXTENDED-RELEASE TABLETS 0.25 mg per tablet Swallow whole. Do not split, chew, crush, or break tablets. 10 Tablets (1 x 10 tablet blister pack) Pharmacist: Dispense the accompanying Patient Information Leaflet to each patient. Rx Only NDC 66302-302-02 PRINCIPAL DISPLAY PANEL - 0.25 mg Tablet Blister Pack Carton; PRINCIPAL DISPLAY PANEL - 1 mg Tablet Bottle Label NDC 66302-310-01 100 Tablets Orenitram ® (treprostinil) Extended-Release Tablets 1 mg Swallow whole. Do not split, chew, crush, or break tablets. PRINCIPAL DISPLAY PANEL - 1 mg Tablet Bottle Label; PRINCIPAL DISPLAY PANEL - 1 mg Tablet Blister Pack Carton Orenitram ® (treprostinil) EXTENDED-RELEASE TABLETS 1 mg per tablet Swallow whole. Do not split, chew, crush, or break tablets. 10 Tablets (1 x 10 tablet blister pack) Pharmacist: Dispense the accompanying Patient Information Leaflet to each patient. Rx Only NDC 66302-310-02 PRINCIPAL DISPLAY PANEL - 1 mg Tablet Blister Pack Carton; PRINCIPAL DISPLAY PANEL - 2.5 mg Tablet Bottle Label NDC 66302-325-01 100 Tablets Orenitram ® (treprostinil) Extended-Release Tablets 2.5 mg Swallow whole. Do not split, chew, crush, or break tablets. PRINCIPAL DISPLAY PANEL - 2.5 mg Tablet Bottle Label; PRINCIPAL DISPLAY PANEL - 2.5 mg Tablet Blister Pack Carton Orenitram ® (treprostinil) EXTENDED-RELEASE TABLETS 2.5 mg per tablet Swallow whole. Do not split, chew, crush, or break tablets. 10 Tablets (1 x 10 tablet blister pack) Pharmacist: Dispense the accompanying Patient Information Leaflet to each patient. Rx Only NDC 66302-325-02 PRINCIPAL DISPLAY PANEL - 2.5 mg Tablet Blister Pack Carton; PRINCIPAL DISPLAY PANEL - 5 mg Tablet Bottle Label NDC 66302-350-01 100 Tablets Orenitram ® (treprostinil) Extended-Release Tablets 5 mg Swallow whole. Do not split, chew, crush, or break tablets. PRINCIPAL DISPLAY PANEL - 5 mg Tablet Bottle Label; PRINCIPAL DISPLAY PANEL - 5 mg Tablet Blister Pack Carton Orenitram ® (treprostinil) EXTENDED-RELEASE TABLETS 5 mg per tablet Swallow whole. Do not split, chew, crush, or break tablets. 10 Tablets (1 x 10 tablet blister pack) Pharmacist: Dispense the accompanying Patient Information Leaflet to each patient. Rx Only NDC 66302-350-02 PRINCIPAL DISPLAY PANEL - 5 mg Tablet Blister Pack Carton; PRINCIPAL DISPLAY PANEL - 0.125 mg 0.25 mg Titration Kit Carton - Month 1 Rx Only NDC 66302-361-28 Orenitram ® (treprostinil) EXTENDED-RELEASE TABLETS Titration Kit Month 1 0.125 mg per tablet 0.25 mg per tablet Swallow whole. Do not split, chew, crush, or break tablets. Kit Contains: 168 tablets (126 x 0.125 mg per tablet and 42 x 0.25 mg per tablet). Monthly carton contains 4 individual weekly cartons each with 7 daily wallet blister packs. PRINCIPAL DISPLAY PANEL - 0.125 mg 0.25 mg Titration Kit Carton - Month 1; PRINCIPAL DISPLAY PANEL - 0.125 mg 0.25 mg Titration Kit Carton - Month 2 Rx Only NDC 66302-362-56 Orenitram ® (treprostinil) EXTENDED-RELEASE TABLETS Titration Kit Month 2 0.125 mg per tablet 0.25 mg per tablet Swallow whole. Do not split, chew, crush, or break tablets. Kit Contains: 336 tablets (126 x 0.125 mg per tablet and 210 x 0.25 mg per tablet). Monthly carton contains 4 individual weekly cartons each with 7 daily wallet blister packs. PRINCIPAL DISPLAY PANEL - 0.125 mg 0.25 mg Titration Kit Carton - Month 2; PRINCIPAL DISPLAY PANEL - 0.125 mg 0.25 mg 1 mg Titration Kit Carton - Month 3 Rx Only NDC 66302-363-84 Orenitram ® (treprostinil) EXTENDED-RELEASE TABLETS Titration Kit Month 3 0.125 mg per tablet 0.25 mg per tablet 1 mg per tablet Swallow whole. Do not split, chew, crush, or break tablets. Kit Contains: 252 tablets (126 x 0.125 mg per tablet, 42 x 0.25 mg per tablet, and 84 × 1 mg per tablet). Monthly carton contains 4 individual weekly cartons each with 7 daily wallet blister packs. PRINCIPAL DISPLAY PANEL - 0.125 mg 0.25 mg 1 mg Titration Kit Carton - Month 3
- 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Orenitram is an 8-mm round biconvex tablet with strength identified by color and print and supplied as follows: Strength Color Printing on Tablets NDC # 100-Count Bottle NDC # 10-Count Bottle NDC # 10-Count Carton (Unit-Dose Blister) 0.125 mg White UT 0.125 66302-300-01 66302-300-10 66302-300-02 0.25 mg Green UT 0.25 66302-302-01 66302-302-10 66302-302-02 1 mg Yellow UT 1 66302-310-01 66302-310-10 66302-310-02 2.5 mg Pink UT 2.5 66302-325-01 66302-325-10 66302-325-02 5 mg Red UT 5 66302-350-01 66302-350-10 66302-350-02 Titration Kits for Orenitram are supplied in the following configurations: Titration Kit Blister Configurations NDC # Month 1 containing four weekly cartons Seven daily wallet blister packs in each weekly carton containing the following total number of tablets: Week 1 (twenty-one × 0.125 mg tablets) Week 2 (forty-two × 0.125 mg tablets) Week 3 (twenty-one × 0.125 mg tablets and twenty-one × 0.25 mg tablets) Week 4 (forty-two × 0.125 mg tablets and twenty-one × 0.25 mg tablets) 66302-361-28 Month 2 containing four weekly cartons Seven daily wallet blister packs in each weekly carton containing the following total number of tablets: Week 5 (twenty-one × 0.125 mg tablets and forty-two × 0.25 mg tablets) Week 6 (forty-two × 0.125 mg tablets and forty-two × 0.25 mg tablets) Week 7 (twenty-one × 0.125 mg tablets and sixty-three × 0.25 mg tablets) Week 8 (forty-two × 0.125 mg tablets and sixty-three × 0.25 mg tablets) 66302-362-56 Month 3 containing four weekly cartons Seven daily wallet blister packs in each weekly carton containing the following total number of tablets: Week 9 (twenty-one × 0.125 mg tablets and twenty-one × 1 mg tablets) Week 10 (forty-two × 0.125 mg tablets and twenty-one × 1 mg tablets) Week 11 (twenty-one × 0.125 mg tablets, twenty-one × 0.25 mg tablets, and twenty-one × 1 mg tablets) Week 12 (forty-two × 0.125 mg tablets, twenty-one × 0.25 mg tablets, and twenty-one × 1 mg tablets) 66302-363-84 16.2 Storage Store at 20°C to 25°C (68°F to 77°F) with excursions permitted to 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature]. Keep out of reach of children.
- PRINCIPAL DISPLAY PANEL - 0.125 mg Tablet Bottle Label NDC 66302-300-01 100 Tablets Orenitram ® (treprostinil) Extended-Release Tablets 0.125 mg Swallow whole. Do not split, chew, crush, or break tablets. PRINCIPAL DISPLAY PANEL - 0.125 mg Tablet Bottle Label
- PRINCIPAL DISPLAY PANEL - 0.125 mg Tablet Blister Pack Carton Orenitram ® (treprostinil) EXTENDED-RELEASE TABLETS 0.125 mg per tablet Swallow whole. Do not split, chew, crush, or break tablets. 10 Tablets (1 x 10 tablet blister pack) Pharmacist: Dispense the accompanying Patient Information Leaflet to each patient. Rx Only NDC 66302-300-02 PRINCIPAL DISPLAY PANEL - 0.125 mg Tablet Blister Pack Carton
- PRINCIPAL DISPLAY PANEL - 0.25 mg Tablet Bottle Label NDC 66302-302-01 100 Tablets Orenitram ® (treprostinil) Extended-Release Tablets 0.25 mg Swallow whole. Do not split, chew, crush, or break tablets. PRINCIPAL DISPLAY PANEL - 0.25 mg Tablet Bottle Label
- PRINCIPAL DISPLAY PANEL - 0.25 mg Tablet Blister Pack Carton Orenitram ® (treprostinil) EXTENDED-RELEASE TABLETS 0.25 mg per tablet Swallow whole. Do not split, chew, crush, or break tablets. 10 Tablets (1 x 10 tablet blister pack) Pharmacist: Dispense the accompanying Patient Information Leaflet to each patient. Rx Only NDC 66302-302-02 PRINCIPAL DISPLAY PANEL - 0.25 mg Tablet Blister Pack Carton
- PRINCIPAL DISPLAY PANEL - 1 mg Tablet Bottle Label NDC 66302-310-01 100 Tablets Orenitram ® (treprostinil) Extended-Release Tablets 1 mg Swallow whole. Do not split, chew, crush, or break tablets. PRINCIPAL DISPLAY PANEL - 1 mg Tablet Bottle Label
- PRINCIPAL DISPLAY PANEL - 1 mg Tablet Blister Pack Carton Orenitram ® (treprostinil) EXTENDED-RELEASE TABLETS 1 mg per tablet Swallow whole. Do not split, chew, crush, or break tablets. 10 Tablets (1 x 10 tablet blister pack) Pharmacist: Dispense the accompanying Patient Information Leaflet to each patient. Rx Only NDC 66302-310-02 PRINCIPAL DISPLAY PANEL - 1 mg Tablet Blister Pack Carton
- PRINCIPAL DISPLAY PANEL - 2.5 mg Tablet Bottle Label NDC 66302-325-01 100 Tablets Orenitram ® (treprostinil) Extended-Release Tablets 2.5 mg Swallow whole. Do not split, chew, crush, or break tablets. PRINCIPAL DISPLAY PANEL - 2.5 mg Tablet Bottle Label
- PRINCIPAL DISPLAY PANEL - 2.5 mg Tablet Blister Pack Carton Orenitram ® (treprostinil) EXTENDED-RELEASE TABLETS 2.5 mg per tablet Swallow whole. Do not split, chew, crush, or break tablets. 10 Tablets (1 x 10 tablet blister pack) Pharmacist: Dispense the accompanying Patient Information Leaflet to each patient. Rx Only NDC 66302-325-02 PRINCIPAL DISPLAY PANEL - 2.5 mg Tablet Blister Pack Carton
- PRINCIPAL DISPLAY PANEL - 5 mg Tablet Bottle Label NDC 66302-350-01 100 Tablets Orenitram ® (treprostinil) Extended-Release Tablets 5 mg Swallow whole. Do not split, chew, crush, or break tablets. PRINCIPAL DISPLAY PANEL - 5 mg Tablet Bottle Label
- PRINCIPAL DISPLAY PANEL - 5 mg Tablet Blister Pack Carton Orenitram ® (treprostinil) EXTENDED-RELEASE TABLETS 5 mg per tablet Swallow whole. Do not split, chew, crush, or break tablets. 10 Tablets (1 x 10 tablet blister pack) Pharmacist: Dispense the accompanying Patient Information Leaflet to each patient. Rx Only NDC 66302-350-02 PRINCIPAL DISPLAY PANEL - 5 mg Tablet Blister Pack Carton
- PRINCIPAL DISPLAY PANEL - 0.125 mg 0.25 mg Titration Kit Carton - Month 1 Rx Only NDC 66302-361-28 Orenitram ® (treprostinil) EXTENDED-RELEASE TABLETS Titration Kit Month 1 0.125 mg per tablet 0.25 mg per tablet Swallow whole. Do not split, chew, crush, or break tablets. Kit Contains: 168 tablets (126 x 0.125 mg per tablet and 42 x 0.25 mg per tablet). Monthly carton contains 4 individual weekly cartons each with 7 daily wallet blister packs. PRINCIPAL DISPLAY PANEL - 0.125 mg 0.25 mg Titration Kit Carton - Month 1
- PRINCIPAL DISPLAY PANEL - 0.125 mg 0.25 mg Titration Kit Carton - Month 2 Rx Only NDC 66302-362-56 Orenitram ® (treprostinil) EXTENDED-RELEASE TABLETS Titration Kit Month 2 0.125 mg per tablet 0.25 mg per tablet Swallow whole. Do not split, chew, crush, or break tablets. Kit Contains: 336 tablets (126 x 0.125 mg per tablet and 210 x 0.25 mg per tablet). Monthly carton contains 4 individual weekly cartons each with 7 daily wallet blister packs. PRINCIPAL DISPLAY PANEL - 0.125 mg 0.25 mg Titration Kit Carton - Month 2
- PRINCIPAL DISPLAY PANEL - 0.125 mg 0.25 mg 1 mg Titration Kit Carton - Month 3 Rx Only NDC 66302-363-84 Orenitram ® (treprostinil) EXTENDED-RELEASE TABLETS Titration Kit Month 3 0.125 mg per tablet 0.25 mg per tablet 1 mg per tablet Swallow whole. Do not split, chew, crush, or break tablets. Kit Contains: 252 tablets (126 x 0.125 mg per tablet, 42 x 0.25 mg per tablet, and 84 × 1 mg per tablet). Monthly carton contains 4 individual weekly cartons each with 7 daily wallet blister packs. PRINCIPAL DISPLAY PANEL - 0.125 mg 0.25 mg 1 mg Titration Kit Carton - Month 3
Overview
Orenitram is an extended-release osmotic tablet for oral administration. Orenitram is formulated as the diolamine salt of treprostinil, a tricyclic benzindene analogue of prostacyclin. The chemical name is Acetic acid, 2-[[(1 R ,2 R ,3a S ,9a S )-2,3,3a,4,9,9a-hexahydro-2-hydroxy-1-[(3 S )-3-hydroxyoctyl]-1 H -benz[f]inden-5-yl]oxy]-, complexed with 2,2'-iminobis[ethanol] (1:1). The molecular formula is C 23 H 34 O 5 ∙C 4 H 11 NO 2 , the molecular weight is 495.65, and it has the following structural formula: Orenitram tablets are formulated in five strengths, which contain 0.125 mg of treprostinil (equivalent to 0.159 mg treprostinil diolamine), 0.25 mg of treprostinil (equivalent to 0.317 mg treprostinil diolamine), 1 mg of treprostinil (equivalent to 1.27 mg treprostinil diolamine), 2.5 mg of treprostinil (equivalent to 3.17 mg treprostinil diolamine), or 5 mg of treprostinil (equivalent to 6.35 mg treprostinil diolamine). The formulations also contain xylitol, maltodextrin, sodium lauryl sulfate, magnesium stearate, cellulose acetate, triethyl citrate, polyvinyl alcohol, titanium dioxide, polyethylene glycol, and talc. In addition, tablets may contain colorants FD&C Blue #2, iron oxide yellow, and iron oxide red. The imprint ink contains shellac glaze, ethanol, isopropyl alcohol USP, iron oxide black, n-butyl alcohol, and propylene glycol. Orenitram is designed to release treprostinil at a near zero-order rate using an osmotic tablet technology. The tablet core is coated with a semi-permeable membrane and has a laser-drilled aperture through the membrane. Upon contact with water (e.g., after ingestion), the core tablet absorbs water through the semi-permeable membrane. The water dissolves the water-soluble treprostinil diolamine and the water-soluble osmotic excipients, which creates hydrostatic pressure within the membrane, eventually forcing the drug across the membrane at a controlled rate. Chemical Structure
Indications & Usage
Orenitram is a prostacyclin mimetic indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1): To delay disease progression and to improve exercise capacity. The studies that established effectiveness included predominately patients with WHO functional class II-III symptoms and etiologies of idiopathic or heritable PAH (66%) or PAH associated with connective tissue disease (26%). ( 1.1 ) 1.1 Pulmonary Arterial Hypertension Orenitram is indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) to delay disease progression and to improve exercise capacity. The studies that established effectiveness included predominately patients with WHO functional class II-III symptoms and etiologies of idiopathic or heritable PAH (66%) or PAH associated with connective tissue disease (26%).
Dosage & Administration
Give with food. Swallow tablets whole; use only intact tablets. ( 2.1 ) Starting dose: 0.125 mg TID or 0.25 mg BID. ( 2.1 ) Titrate by 0.125 mg TID or by 0.25 mg or 0.5 mg BID, not more frequently than every 3 to 4 days as tolerated. The maximum daily dose is 120 mg. ( 2.1 ) If transitioning from intravenous (IV) or subcutaneous (SC) Remodulin ® , the Orenitram dose should be increased while simultaneously decreasing the IV/SC infusion rate. ( 2.2 ) Mild hepatic impairment (Child Pugh Class A): Initiate at 0.125 mg BID. Increment at 0.125 mg BID not more frequently than every 3 to 4 days. ( 2.3 ) Avoid use in patients with moderate hepatic impairment. ( 2.3 ) 2.1 Recommended Dosing Take Orenitram with food. Swallow Orenitram tablets whole; do not crush, split, or chew. The recommended starting dose of Orenitram is 0.125 mg three times daily (TID) with food, taken approximately 8 hours apart or 0.25 mg twice daily (BID) with food, taken approximately 12 hours apart. Titrate by 0.125 mg TID or 0.25 or 0.5 mg BID not more frequently than every 3 to 4 days. Increase the dose to the highest tolerated dose. The recommended maximum daily dose is 120 mg. If dose increments are not tolerated, consider titrating slower. If intolerable pharmacologic effects occur, decrease the dose in increments of 0.125 mg TID or 0.25 mg BID. Avoid abrupt discontinuation [see Warnings and Precautions (5.1) ] . 2.2 Transitioning from Subcutaneous or Intravenous Routes of Administration of Treprostinil Decrease the dose of Remodulin while simultaneously increasing the dose of Orenitram. The dose of Remodulin can be reduced up to 30 ng/kg/min per day and the dose of Orenitram simultaneously increased up to 6 mg per day (2 mg TID) if tolerated. The following equation can be used to estimate a target total daily dose of Orenitram in mg using a patient's dose of intravenous (IV)/subcutaneous (SC) treprostinil (in ng/kg/min) and weight (in kg). Orenitram total daily dose (mg) = 0.0072 × Remodulin dose (ng/kg/min) × weight (kg) 2.3 Dose Adjustment in Patients with Hepatic Impairment In patients with mild hepatic impairment (Child Pugh Class A) start at 0.125 mg BID with 0.125 mg BID dose increments not more frequently than every 3 to 4 days. Avoid use of Orenitram in patients with moderate hepatic impairment (Child Pugh Class B). Orenitram is contraindicated in patients with severe hepatic impairment (Child Pugh Class C) due to increases in systemic exposure [see Contraindications (4) , Use in Specific Populations (8.6) , and Clinical Pharmacology (12.3) ] . 2.4 Dose Adjustment for Use with CYP2C8 Inhibitors When co-administered with strong CYP2C8 inhibitors (e.g., gemfibrozil) the initial dose is 0.125 mg BID with 0.125 mg BID dose increments not more frequently than every 3 to 4 days. 2.5 Interruptions and Discontinuation If a dose of medication is missed, the patient should take the missed dose as soon as possible, with food. If a patient misses two or more doses, restart at a lower dose and re-titrate. In the event of a planned short-term treatment interruption for patients unable to take oral medications, consider a temporary infusion of subcutaneous or intravenous treprostinil. To calculate the total daily dose (mg) of treprostinil for the parenteral route use the following equation: Remodulin (ng/kg/min) = 139 × Orenitram total daily dose (mg) weight (kg) When discontinuing Orenitram, reduce the dose in steps of 0.5 to 1 mg per day [see Warnings and Precautions (5.1) ] .
Warnings & Precautions
Do not abruptly discontinue dosing. ( 2.5 , 5.1 ) In patients with diverticulosis, Orenitram tablets can become lodged in a diverticulum. ( 5.2 ) 5.1 Worsening PAH Symptoms upon Abrupt Withdrawal Abrupt discontinuation or sudden large reductions in dosage of Orenitram may result in worsening of PAH symptoms. 5.2 Use in Patients with Blind-end Pouches The tablet shell does not dissolve. In patients with diverticulosis, Orenitram tablets can lodge in a diverticulum.
Contraindications
Severe hepatic impairment (Child Pugh Class C) [see Use In Specific Populations (8.6) and Clinical Pharmacology (12.3) ] . Severe hepatic impairment (Child Pugh Class C). ( 4 )
Adverse Reactions
Most common adverse reactions (incidence >10%) reported in clinical studies in patients treated with Orenitram compared with placebo are headache, diarrhea, nausea, vomiting, jaw pain, and flushing. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact United Therapeutics Corp. at 1-866-458-6479 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials 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 clinical practice. In a 12-week, placebo-controlled, monotherapy study (Study 1; WHO Group 1; functional class II-III), and an event-driven, placebo-controlled, combination therapy study (Study 4; WHO Group 1; functional class I-III), the most commonly reported adverse reactions that occurred in patients receiving Orenitram included: headache, diarrhea, nausea, and flushing. Orenitram patients in Study 1 (N=151) had access to 0.25 mg tablets at randomization. Approximately 91% of such patients in Study 1 experienced an adverse reaction, but only 4% discontinued therapy for an adverse reaction (compared to 3% receiving placebo). Study 4 enrolled a total of 690 patients, 346 received Orenitram and 344 received placebo. Overall, 19% of patients treated with Orenitram discontinued treatment in Study 4 due to an adverse event (compared to 4% of patients receiving placebo). The exposure to Orenitram in Study 4 was up to 5.1 years with a median duration of exposure of 1.2 years. Table 1 summarizes adverse events with rates at least 5% higher on Orenitram therapy than on placebo that were reported in either Study 1 or 4. Table 1: Adverse Events with Rates at Least 5% Higher on Orenitram Therapy than on Placebo in Either Study 1 or Study 4 Reaction Study 1 N=228 Includes all subjects in the Primary Analysis Population Study 4 N=690 Orenitram n=151 Placebo n=77 Orenitram n=346 Placebo n=344 Headache 63% 19% 75% 35% Diarrhea 30% 16% 69% 29% Nausea 30% 18% 40% 23% Vomiting 17% 16% 36% 10% Flushing 15% 6% 45% 8% Pain in jaw 11% 4% 18% 3% Pain in extremity 14% 8% 18% 9% Hypokalemia 9% 3% 4% 3% Abdominal discomfort 6% 0% 8% 4% Upper abdominal pain 5% 3% 12% 5% Orenitram was studied in a long-term, open-label, extension study in which 824 patients were dosed for a mean duration of approximately 2 years. About 70% of patients continued treatment with Orenitram for at least a year. The mean dose was 4.2 mg BID at one year. The adverse reactions were similar to those observed in the placebo-controlled trials. The safety of Orenitram was also evaluated in an open-label study transitioning patients from Remodulin. The safety profile during this study was similar to that observed in the three pivotal studies. 6.2 Post-Marketing Experience The following adverse reactions have been identified during postapproval use of Orenitram: dizziness, dyspepsia, vomiting, myalgia, and arthralgia. 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.
Drug Interactions
When co-administered with strong CYP2C8 inhibitors the initial dose is 0.125 mg BID with 0.125 mg BID dose increments not more frequently than every 3 to 4 days. ( 2.4 , 7.1 ) 7.1 Effect of CYP2C8 Inhibitors on Treprostinil Co-administration of Orenitram and the CYP2C8 enzyme inhibitor gemfibrozil in healthy adult volunteers increases exposure to treprostinil. Reduce the starting dose of Orenitram to 0.125 mg BID and use 0.125 mg BID increments not more frequently than every 3 to 4 days [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3) ] .
Storage & Handling
16.2 Storage Store at 20°C to 25°C (68°F to 77°F) with excursions permitted to 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature]. Keep out of reach of children.
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