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Treprostinil Sodium

Class: Vasodilating Agents
VA Class: CV900
Chemical Name: [[(1R,2R,3aS,9aS)-2,3,3a,4,9,9a-Hexahydro-2-hydroxy-1-[(3S)-3-hydroxyoctyl]-1H-benz[f]inden-5-yl]oxy]-acetic acid
Molecular Formula: C23H34O5C23H34O5•C4H11NO2
CAS Number: 81846-19-7

Medically reviewed on March 12, 2018

Introduction

Vasodilator; a synthetic analog of prostacyclin.1 2 3 15 50

Uses for Treprostinil Sodium

Pulmonary Arterial Hypertension

Treprostinil is used parenterally (as a continuous sub-Q or IV infusion) for treatment of pulmonary arterial hypertension (PAH; WHO group 1) to reduce symptoms associated with exercise; efficacy established in patients with NYHA functional class II–IV (predominantly class III) PAH (idiopathic, heritable, or associated with connective tissue disease or congenital systemic-to-pulmonary shunts).1 2 3 Also used parenterally to reduce rate of clinical deterioration in patients who require conversion from epoprostenol therapy; carefully consider risks and benefits of each drug prior to transition.1 4 9 24 25

Treprostinil is used by oral inhalation to improve exercise ability in patients with PAH; efficacy established principally in patients with NYHA functional class III PAH (idiopathic, heritable, or associated with connective tissue disease).15 16 17 Controlled clinical experience with orally inhaled treprostinil is based primarily on short-term trials in patients receiving the drug as add-on therapy to bosentan or sildenafil.13 15 16 17

Treprostinil diolamine is used orally (as extended-release tablets) to improve exercise capacity in patients with PAH; efficacy established principally in patients with WHO functional class II–III PAH (idiopathic, heritable, or associated with connective tissue disease).50 52 Oral treprostinil may be more convenient than inhaled or parenteral formulations; however, studies have shown only modest benefits of oral treprostinil on exercise capacity.50 51 58 When the drug is used as the sole vasodilator in patients with PAH, the effect on exercise capacity is approximately 10% of the deficit, and the effect, if any, in combination with other vasodilators is probably even less.50

Parenteral or inhaled treprostinil is recommended as one of several treatment options for initial management of PAH in patients with NYHA/WHO functional class III or IV symptoms who are not candidates for calcium-channel blocker therapy or in whom such therapy failed.13 40 While oral treprostinil may be a potential initial treatment option for patients with less severe PAH, additional studies are needed.51 52

Individualize choice of therapy; consider factors such as disease severity, route of administration, potential adverse effects and costs of treatment, clinician experience, and patient preference.13 38 40

Combination therapy with drugs that target different pathophysiologic pathways of the disease should be considered since such therapy may provide additive and/or synergistic benefits.40 41 42 43 Results of studies evaluating combination therapy with treprostinil have been variable; some studies (inhaled treprostinil in combination with an endothelin-receptor antagonist or a PDE type 5 inhibitor) demonstrated improvements in 6-minute walking distance, while other studies (oral treprostinil with an endothelin-receptor antagonist and/or a PDE type 5 inhibitor) have not shown benefit.15 16 40 50 53 54

Treprostinil and treprostinil diolamine have been designated orphan drugs by FDA for treatment of PAH.31 57

Treprostinil Sodium Dosage and Administration

General

Restricted Distribution

  • All commercially available preparations of treprostinil are available only through specialty pharmacies.44 45 59

  • For additional information, contact the manufacturer at 1-877-864-8437.44 59

Administration

Treprostinil is administered by continuous sub-Q or IV infusion, or by oral inhalation.1

Treprostinil diolamine is administered orally (as extended-release tablets).50

When administered parenterally, sub-Q route generally preferred because of the risks associated with continuous IV administration (e.g., catheter-related infections); reserve IV use for patients who cannot tolerate sub-Q therapy (e.g., due to infusion-site pain or reaction) or in whom risks of IV therapy are considered warranted.1

Sub-Q Administration

For sub-Q use, administer as supplied without further dilution.1

Administer undiluted drug solution by continuous sub-Q infusion through a self-inserted sub-Q catheter using a controlled-infusion device (ambulatory infusion pump).1 Consult manufacturer's labeling for pump specifications.1

To avoid potential interruptions in drug delivery, patient must have immediate access to backup infusion pump and sub-Q infusion sets (since abrupt withdrawal or sudden, large dosage reductions may result in worsening of PAH symptoms).1

A single reservoir (syringe) of undiluted treprostinil may be administered for up to 72 hours at 37°C.1

Rate of Administration

Calculate sub-Q infusion rates using the following formula:1

sub-Q infusion rate (mL/hr) = [dose (ng/kg per minute) × weight (kg) × 0.00006] ÷ treprostinil dosage strength concentration (mg/mL)

IV Administration

For solution compatibility information, see Compatibility under Stability.

Must be diluted prior to IV administration.1 14 (See Dilution under Dosage and Administration.)

Administer diluted drug solution by continuous IV infusion through a permanent indwelling central venous catheter using a controlled-infusion device (ambulatory infusion pump).1 Consult manufacturer's labeling for pump specifications.1

A peripheral IV catheter (preferably placed in a large vein) may be used temporarily until central venous access can be established.1

To avoid potential interruptions in drug delivery, patient must have immediate access to backup infusion pump and IV infusion sets (since abrupt withdrawal or sudden, large dosage reductions may result in worsening of PAH symptoms).1

Consult manufacturer's labeling for additional information on preparation and administration of IV treprostinil.1 14

Dilution

Must be diluted with one of the following diluents prior to IV administration: sterile water for injection, 0.9% sodium chloride injection, Remodulin (treprostinil) sterile diluent for injection, Flolan (epoprostenol sodium) sterile diluent for injection, or sterile diluent for generic epoprostenol sodium.1 (See Storage under Stability.)

May administer diluted solutions for up to 48 hours at 40°C.1

Add appropriate amount of drug to a sufficient volume of diluent to fill pump reservoir (typical IV infusion system reservoirs have a total capacity of 50 or 100 mL).1 Select an infusion rate that will allow for an infusion period of ≤48 hours, and calculate concentration and amount of treprostinil required for the dilution according to the following formulas:1

diluted IV treprostinil concentration (mg/mL) = [dose (ng/kg per minute) × weight (kg) × 0.00006] ÷ IV infusion rate (mL/hr)

amount of treprostinil injection (mL) = [diluted IV treprostinil concentration (mg/mL) ÷ treprostinil vial strength (mg/mL)] × total reservoir volume (mL)

Oral Inhalation

Treprostinil inhalation solution is for oral inhalation only; do not ingest.15

Administer using only the Tyvaso Inhalation System (ultrasonic, pulsed delivery device and related accessories).15 Patients should have access to a back-up Tyvaso Inhalation System device in the event of equipment malfunction.15 Instruct patients on proper administration (including dosing frequency), use, and maintenance of the device.15

Administer 4 times daily during waking hours at equally spaced intervals of approximately 4 hours.15

Prior to first inhalation session, transfer entire contents of a single 2.9-mL ampul of drug into medicine cup supplied by the manufacturer.15 One ampul should contain enough drug for one day of treatment.15 19 After each inhalation session, cap inhalation device and store upright with remaining drug inside for ≤24 hours.15 Discard medicine cup and any unused solution at end of each day and clean Tyvaso Inhalation System device according to manufacturer's instructions.15

Do not mix with other drugs.15

Do not allow solution to come into contact with the eyes or skin.15

Oral Administration

Administer treprostinil diolamine extended-release tablets orally 2 or 3 times daily (approximately every 12 or 8 hours, respectively) with food.50 A three-times daily dosing regimen may produce less variation in drug concentrations, reduce adverse effects, and improve tolerability.51 55

Do not split, crush, or chew tablets.50

If a dose is missed, take as soon as it is remembered; if a patient misses ≥2 doses, restart therapy at a lower dosage and retitrate.50

Advise patients that the tablet shell in the extended-release tablets is designed to remain intact during passage through the GI tract and may be passed in the stool.50

Dosage

Available as treprostinil (injection, oral inhalation) and treprostinil diolamine (extended-release tablets); dosage expressed in terms of treprostinil.1 15 50

Adults

PAH
Continuous Sub-Q or IV Infusion

Initially, 1.25 ng/kg per minute.1 If initial dosage is not tolerated, reduce infusion rate to 0.625 ng/kg per minute.1

Adjust dosage to achieve symptomatic improvement while minimizing adverse effects.1 Increase infusion rate based on clinical response in increments of 1.25 ng/kg per minute at weekly intervals for the first 4 weeks and then 2.5 ng/kg per minute at weekly intervals for the remaining duration of the infusion.1

Several months may be required to identify optimal dosage.2 8 14

Oral Inhalation

Initially, 18 mcg (3 inhalations) per treatment session 4 times daily.15 If initial dosage not tolerated, reduce to 1 or 2 inhalations per treatment session, then increase up to 3 inhalations as tolerated.15 Continue to increase dose by 3 inhalations every 1–2 weeks until target maintenance dosage of 54 mcg (9 inhalations) per treatment session attained.15 If unable to titrate to target dosage, maintain patient on highest possible tolerated dosage.15

If a treatment session is missed or interrupted, resume therapy as soon as possible at usual dosage.15

Oral

Initially, 0.25 mg twice daily (approximately every 12 hours) or 0.125 mg 3 times daily (approximately every 8 hours) as extended-release tablets.50 Increase dosage every 3–4 days in increments of 0.25 or 0.5 mg twice daily or 0.125 mg 3 times daily until highest tolerated dosage achieved.50 Appropriate maintenance dosage determined by tolerability.50 Consider slower titration for patients not tolerating such increases.50 Decrease dosage in decrements of 0.25 mg if intolerable adverse effects occur.50

Avoid abrupt discontinuance; when discontinuing therapy, reduce dosage by 0.5–1 mg per day.50 (See Withdrawal of Therapy under Cautions.)

Dosage reductions recommended when used concomitantly with potent CYP2C8 inhibitors.50 (See Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes under Interactions.)

Conversion from Epoprostenol to Sub-Q or IV Treprostinil Therapy
Continuous Sub-Q or IV Infusion

Perform transition in a hospital setting where patient can be closely monitored.1

Initiate treprostinil at a dosage equivalent to 10% of the current epoprostenol dosage; gradually increase treprostinil dosage while simultaneously decreasing dosage of epoprostenol.1 Manufacturer recommends the following titration protocol:1

Step

Epoprostenol Dosage

Treprostinil Dosage

1

Unchanged

10% of starting epoprostenol dosage

2

80% of starting epoprostenol dosage

30% of starting epoprostenol dosage

3

60% of starting epoprostenol dosage

50% of starting epoprostenol dosage

4

40% of starting epoprostenol dosage

70% of starting epoprostenol dosage

5

20% of starting epoprostenol dosage

90% of starting epoprostenol dosage

6

5% of starting epoprostenol dosage

110% of starting epoprostenol dosage

7

0

110% of starting epoprostenol dosage + additional 5–10% increments as needed

Individually titrate treprostinil dosage to allow transition from epoprostenol therapy while balancing symptoms of PAH and prostacyclin-related adverse effects.1 Manage any increase in PAH symptoms (e.g., shortness of breath) by initially increasing dosage of treprostinil; manage symptoms of excess prostacyclin (e.g., facial flushing, headache, jaw pain) by initially decreasing dosage of epoprostenol.1

Other transition protocols have been used successfully.9 21 22 25 Limited data indicate that patients whose therapy is transitioned from epoprostenol to IV treprostinil appear to require higher average dosages of treprostinil to maintain the same clinical benefits.11 14 21 22 24 25

Transitioning from Parenteral to Oral Treprostinil
Continuous Sub-Q or IV Infusion to Oral

Decrease dosage of sub-Q or IV treprostinil while simultaneously increasing dosage of oral treprostinil.50 May reduce dosage of parenteral treprostinil up to 30 ng/kg per minute per day and simultaneously increase dosage of oral treprostinil up to 6 mg per day (2 mg administered 3 times daily) if tolerated.50 The following equation can be used to estimate a comparable total daily dose of oral treprostinil using current parenteral treprostinil dose:50

oral treprostinil total daily dose (mg)= 0.0072 × parenteral treprostinil dose (ng/kg per minute) × weight (kg)

Planned Short-term Interruption of Oral Therapy
Oral to Continuous Sub-Q or IV Infusion

In patients unable to take oral medications, consider temporary sub-Q or IV infusion of treprostinil.50 Use the following formula to calculate total daily dose of parenteral treprostinil using current oral dose:50

parenteral treprostinil (ng/kg per minute)= [139 × oral treprostinil total daily dose (mg)] ÷ weight (kg)

Special Populations

Hepatic Impairment

In patients with mild to moderate hepatic impairment, decrease initial dosage of sub-Q or IV treprostinil to 0.625 ng/kg per minute (based on ideal body weight).1

Titrate orally inhaled treprostinil slowly in patients with hepatic impairment because of the possibility of increased systemic exposure to the drug.15

In patients with mild hepatic impairment (Child-Pugh class A), initiate oral treprostinil at a dosage of 0.125 mg twice daily and increase in increments of 0.125 mg twice daily every 3–4 days.50 (See Hepatic Impairment under Cautions.)

Renal Impairment

Manufacturer makes no specific dosage recommendations for parenteral or orally inhaled treprostinil in patients with renal impairment;1 titrate dosage slowly because of the possibility of increased systemic exposure to the drug.1 15

Dosage adjustments of oral treprostinil not needed in patients with renal impairment.50 60 Oral treprostinil not removed by dialysis.50 60

Geriatric Patients

Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy.1 15 50

Cautions for Treprostinil Sodium

Contraindications

  • Parenteral or orally inhaled treprostinil: None known.1 15

  • Oral treprostinil: Severe hepatic impairment (Child-Pugh class C).50

Warnings/Precautions

Risk of Infection with IV Administration

Risk of serious and potentially fatal blood stream infections and sepsis associated with drug delivery system (long-term indwelling central venous catheter).1 14 25 28 Patients must use strict aseptic technique in routine catheter care and in the preparation and administration of treprostinil.1 Sub-Q administration is preferred when the drug is given parenterally.1

Use of a high-pH glycine diluent (e.g., Remodulin [treprostinil] sterile diluent for injection, Flolan [epoprostenol sodium] sterile diluent for injection, sterile diluent for generic epoprostenol sodium for injection) with IV treprostinil associated with a lower incidence of blood stream infections compared with neutral diluents (e.g., sterile water for injection, 0.9% sodium chloride injection).1

Precautions Related to Inhaled Treprostinil

Safety and efficacy of orally inhaled treprostinil not established in patients with lung disease (i.e., asthma, COPD).15 Monitor patients who develop acute pulmonary infections for any worsening of lung disease and loss of drug effect.15

Precautions Related to Oral Treprostinil

The extended-release tablet shell of oral treprostinil (Orenitram) does not dissolve and may become lodged in a diverticulum in patients with diverticulosis.50 (See Advice to Patients.)

Withdrawal of Therapy

Avoid abrupt withdrawal or sudden, large dosage reductions; may result in worsening of PAH symptoms.1 50

Hematologic Effects

Possible increased risk of bleeding, particularly in patients receiving anticoagulant therapy.1 15 (See Specific Drugs under Interactions.)

Hypotensive Effects

Risk of symptomatic hypotension.1 15

Specific Populations

Pregnancy

Parenteral and orally inhaled treprostinil: Category B.1 15 No adequate and well-controlled studies in pregnant women.1 15 In animal studies using sub-Q treprostinil, increased incidence of fetal skeletal variations associated with maternal toxicity observed.1

Oral treprostinil: Category C.50 No adequate and well-controlled studies in pregnant women.50 Animal studies have shown some evidence of harm (e.g., postimplantation loss, decreased fetal viability, external fetal and soft tissue malformations, fetal skeletal malformations).50

Lactation

Not known whether treprostinil is distributed into milk;1 15 50 discontinue nursing or the drug.50

Pediatric Use

Parenteral treprostinil: Safety and efficacy not established in children or adolescents <16 years of age.1 8 Clinical studies did not include sufficient numbers of patients ≤16 years of age to determine whether pediatric patients respond differently than adults.1 Titrate dosage carefully.8

Oral or orally inhaled treprostinil: Safety and efficacy not established in patients <18 years of age.15 50

Geriatric Use

Clinical studies did not include sufficient numbers of patients ≥65 years of age to determine whether geriatric patients respond differently than younger patients.1 15 50

Hepatic Impairment

Adjust dosage of sub-Q or IV treprostinil in patients with mild to moderate hepatic impairment.1 (See Hepatic Impairment under Dosage and Administration.)

Adjust dosage of oral treprostinil in patients with mild hepatic impairment.50 (See Hepatic Impairment under Dosage and Administration.) Avoid use of oral treprostinil in patients with moderate hepatic impairment; contraindicated in patients with severe hepatic impairment.50

Parenteral and orally inhaled treprostinil not studied in patients with severe hepatic impairment.1 15

Renal Impairment

Parenteral and orally inhaled treprostinil not studied in patients with renal impairment.1 15 However, possibility of reduced renal clearance of the drug in such patients.15

Pharmacokinetics of oral treprostinil not substantially altered in patients with severe or end-stage renal disease; oral treprostinil not removed by dialysis.50 60

Common Adverse Effects

Sub-Q therapy: Infusion site pain and reaction (e.g., erythema, induration, rash).1

IV therapy: Arm swelling, paresthesias, hematoma, pain.1

Sub-Q and IV therapy: Headache, diarrhea, nausea, jaw pain, vasodilation, dizziness, edema, pruritus, hypotension.1

Orally inhaled therapy: Cough and throat irritation; headache; GI effects; muscle, jaw, or bone pain; flushing; syncope.15 16

Oral therapy: Headache, diarrhea, nausea, flushing, jaw pain, extremity pain, hypokalemia, abdominal discomfort.50

Interactions for Treprostinil Sodium

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Extensively metabolized, principally by CYP2C8.1 29 Does not inhibit CYP1A2, 2A6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A in vitro.1 15 Does not induce CYP1A2, 2B6, 2C9, 2C19, or 3A in vitro.1 15 Pharmacokinetic interactions with drugs metabolized by the CYP enzyme system are considered unlikely.1

CYP2C8 inhibitors: May increase exposure to treprostinil.1 15 50 When used concomitantly with a potent CYP2C8 inhibitor, reduce initial oral treprostinil dosage to 0.125 mg twice daily; increase dosage by 0.125 mg twice daily every 3–4 days as tolerated.50

CYP2C8 inducers: May decrease exposure to treprostinil.1 15 50

Specific Drugs

Drug

Interaction

Comments

Acetaminophen

Pharmacokinetics of oral or sub-Q treprostinil not substantially affected1 15 55

Anticoagulants

Potential for increased risk of bleeding1 15 50 55

Warfarin: No clinically important interaction observed1 15 50

Antihypertensive agents

Additive hypotensive effect possible1 15 50 55

Bosentan

Pharmacokinetic interaction not observed with oral treprostinil1 15 29 50 56

Dosage adjustment of oral treprostinil not necessary50

Diuretics

Additive hypotensive effect possible1 15 50 55

Esomeprazole

Pharmacokinetic interaction not observed with oral treprostinil50 55

Dosage adjustment of oral treprostinil not necessary50

Fluconazole

Pharmacokinetics of oral or sub-Q treprostinil not substantially affected1 15 50 55

Dosage adjustment of oral treprostinil not necessary50

Gemfibrozil

Increased systemic exposure to oral formulation of treprostinil; possible increased risk of adverse effects with treprostinil1 15 50 56

Reduce initial oral treprostinil dosage to 0.125 mg twice daily; increase dosage by 0.125 mg twice daily every 3–4 days as tolerated50

Rifampin

Decreased systemic exposure to oral formulation of treprostinil; possible reduced efficacy of treprostinil1 15 50 56

Dosage adjustment of oral treprostinil not necessary50

Sildenafil

Pharmacokinetic interaction not observed with oral treprostinil1 15 50 56

Dosage adjustment of oral treprostinil not necessary50

Vasodilating agents

Additive hypotensive effect possible1 15 50

Treprostinil Sodium Pharmacokinetics

Absorption

Bioavailability

Rapidly and completely absorbed after sub-Q infusion; absolute bioavailability is 100%.1

Sub-Q and IV treprostinil are bioequivalent at steady-state dosage of 10 ng/kg per minute.1 9 30

Mean absolute systemic bioavailability following oral inhalation is approximately 64 and 72% following doses of 18 and 36 mcg, respectively.15

Absolute oral bioavailability of treprostinil diolamine is approximately 17%.50 Bioavailability and peak plasma concentrations of oral treprostinil increased when administered following a high-fat, high-calorie meal.50

Plasma Concentrations

Steady-state concentrations occur in approximately 10 hours following sub-Q administration.1

Peak plasma concentrations of treprostinil achieved approximately 10–15 minutes after oral inhalation.18

Peak plasma concentrations of treprostinil occur approximately 4–6 hours following oral administration.50 Steady-state concentrations of oral treprostinil occur approximately 1–2 days following twice- and thrice-daily dosing regimens.50

Special Populations

Peak plasma concentrations of sub-Q treprostinil increased by twofold or fourfold in patients with portopulmonary hypertension and mild or moderate hepatic impairment, respectively, compared with healthy individuals.1

In patients with mild, moderate, or severe hepatic impairment, peak plasma concentrations and systemic exposure of oral treprostinil increased by 1.6-, 4-, or 4.8-fold and 2.1-, 4.8-, or 7.6-fold, respectively, compared with individuals with normal hepatic function.50

Distribution

Plasma Protein Binding

91–96%.1 15 50

Elimination

Metabolism

Extensively metabolized in liver, principally by CYP2C8 and to a lesser extent by CYP2C9;1 15 50 5 metabolites described thus far.1 15

Elimination Route

Following oral administration, unchanged drug is excreted in urine (0.19%) and feces (1.13%); metabolites are excreted in urine (64%).50 63

Following sub-Q administration, excreted in urine (79%) and feces (13%).1 15

Half-life

Biphasic; terminal half-life of approximately 4 hours (following sub-Q administration).1 15

Special Populations

In patients with hepatic insufficiency, clearance was reduced by up to 80% compared with healthy adults.1 15

In patients with renal impairment, clearance may be reduced since treprostinil and its metabolites are eliminated principally by the kidneys.15

Stability

Storage

Parenteral

Injection

25°C (may be exposed to 15–30°C).1

May use vial for ≤30 days after initial entry.1

May store undiluted drug in a single reservoir (syringe) for ≤72 hours at 37°C.1

Solutions of treprostinil diluted with high-pH glycine diluent (Remodulin [treprostinil] sterile diluent for injection, Flolan [epoprostenol sodium] sterile diluent for injection, or sterile diluent for generic epoprostenol sodium): Stable at room temperature for ≤14 days at concentrations as low as 0.004 mg/mL (4 mcg/mL).1 Once dilution is in use, stable at 40°C for ≤48 hours.1

Solutions of treprostinil diluted with sterile water or 0.9% sodium chloride for injection: Stable at room temperature for ≤4 hours or under refrigeration for ≤24 hours.1 Once dilution is in use, stable at 40°C for ≤48 hours.1

Oral Inhalation

Inhalation Solution

25°C (may be exposed to 15–30°C) for unopened ampuls in unopened foil pouch.15

Use ampuls within 7 days after opening foil pouch; store unopened ampuls in pouch until use because drug is light-sensitive.15

Once drug solution is placed in medicine cup in inhalation device, use within 24 hours.15 Discard any unused solution at end of day.15

Oral

Extended-release Tablets

25°C (may be exposed to 15–30°C).50

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution Compatibility

Compatible1 HID

Sodium chloride 0.9%

VariableHID

Dextrose 5%

Actions

  • Pharmacologic actions (e.g., vasodilation of pulmonary and systemic arterial vascular beds, inhibition of platelet aggregation) similar to those of epoprostenol.2 3 62

  • In animals, vasodilatory effects reduce right and left ventricular afterload and increase cardiac output and stroke volume.1

  • Causes dose-related negative inotropic and lusitropic effect.1

  • Orally inhaled treprostinil exhibits high pulmonary selectivity and produces sustained pulmonary vasodilation without substantial systemic effects.18

  • Modest and temporary effects on QTc interval observed following single oral inhalation doses; possibly an artifact of the rapidly changing heart rate produced by the drug.1 15 Effects of oral or parenteral treprostinil on QTc not studied.1 50

Advice to Patients

  • Importance of informing patients that abrupt discontinuance of treprostinil therapy could result in worsening of PAH symptoms.50

  • Importance of advising patient that treprostinil is infused continuously through a self-inserted sub-Q or surgically placed indwelling central venous catheter, via an infusion pump, which will require a long-term commitment on the part of the patient.1

  • Importance of instructing patients regarding proper administration of extended-release tablets.50 Necessity of swallowing the tablets without splitting, chewing, crushing, or breaking.50 Importance of administering oral treprostinil with food.50

  • Importance of advising patient to use sterile technique when preparing and administering parenteral treprostinil.1

  • Importance of advising patients that subsequent management of PAH may require therapy with an alternate IV prostacyclin therapy (e.g., epoprostenol).1

  • Importance of understanding potential risks associated with therapy.1

  • Importance of patients receiving adequate training in the proper administration and dosing of orally inhaled treprostinil, and on set-up, operation, and maintenance of the Tyvaso Inhalation System device.15

  • Importance of having immediate access to a back-up pump and infusion sets (when administered parenterally) or a back-up Tyvaso Inhalation System device (when administered via oral inhalation) in order to avoid potential interruptions in drug therapy secondary to drug delivery device failure or equipment malfunction.1 15

  • Importance of advising patients that if a scheduled treatment session of orally inhaled treprostinil is missed, treatment should be resumed as soon as possible.15

  • Importance of informing patients that the biologically inert components of the extended-release tablets remain intact during GI transit and are eliminated in the feces as an insoluble shell.50

  • Importance of advising patients to avoid skin or eye contact with treprostinil oral inhalation solution.15 If skin or eye contact occurs, instruct patient to immediately rinse the affected area with water.15

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Available only through specialty pharmacies.44 45 59 (See Restricted Distribution under Dosage and Administration.)

Treprostinil

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral Inhalation

Solution, for nebulization

0.6 mg/mL (1.74 mg)

Tyvaso (available with Tyvaso Inhalation System)

United Therapeutics

Parenteral

Injection, for continuous sub-Q or IV infusion via controlled-infusion device only

1 mg/mL

Remodulin

United Therapeutics

2.5 mg/mL

Remodulin

United Therapeutics

5 mg/mL

Remodulin

United Therapeutics

10 mg/mL

Remodulin

United Therapeutics

Treprostinil Diolamine

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, extended-release

0.125 mg (of treprostinil)

Orenitram

United Therapeutics

0.25 mg (of treprostinil)

Orenitram

United Therapeutics

1 mg (of treprostinil)

Orenitram

United Therapeutics

2.5 mg (of treprostinil)

Orenitram

United Therapeutics

5 mg (of treprostinil)

Orenitram

United Therapeutics

AHFS DI Essentials. © Copyright 2018, Selected Revisions March 12, 2018. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. United Therapeutics Corp. Remodulin (treprostinil sodium) injection prescribing information. Research Triangle Park, NC; 2014 Dec.

2. Simonneau G, Barst RJ, Galie N et al. Continuous subcutaneous infusion of treprostinil, a prostacyclin analogue, in patients with pulmonary arterial hypertension: a double-blind, randomized, placebo-controlled trial. Am J Respir Crit Care Med. 2002; 165:800-4. http://www.ncbi.nlm.nih.gov/pubmed/11897647?dopt=AbstractPlus

3. Fleming T, Lindenfeld J, Lipicky R et al. Report from the 93rd Cardiovascular and renal drugs advisory committee meeting, August 9-10, 2001. Circulation. 2001; 104:1742. http://www.ncbi.nlm.nih.gov/pubmed/11591605?dopt=AbstractPlus

4. Vachiery JL, Hill N, Zwicke D et al. Transitioning from i.v. epoprostenol to subcutaneous treprostinil in pulmonary arterial hypertension. Chest. 2002; 121:1561-5. http://www.ncbi.nlm.nih.gov/pubmed/12006444?dopt=AbstractPlus

5. United Therapeutics Corporation. Cardiovascular and Renal drugs Advisory Committee presentation. NDA 21-272 Remodulin (treprostinil sodium) injection. Research Triangle Park, NC: 2001 Aug 21.

6. Newman JH. Treatment of primary pulmonary hypertension the next generation. N Engl J Med. 2002; 346:933-5. http://www.ncbi.nlm.nih.gov/pubmed/11907295?dopt=AbstractPlus

7. Food and Drug Administration. Cardiovascular and Renal Drugs Advisory Committee meeting. Rockville, MD; Aug 2001. From FDA web site. http://www.fda.gov/ohrms/dockets/ac/01/transcripts/3/3775tl_02.pdf

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