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Pronunciation

(tre PROST in il)

Generic Available (U.S.)

No

Index Terms

• Treprostinil Sodium

Brand Names: U.S.

• Remodulin®
• Tyvaso™

Brand Names: Canada

• Remodulin®

Pharmacologic Category

• Prostacyclin
• Prostaglandin
• Vasodilator

Use: Labeled Indications

Injection: Treatment of pulmonary arterial hypertension (PAH) (WHO Group I) in patients with NYHA Class II-IV symptoms to decrease exercise-associated symptoms; to diminish clinical deterioration when transitioning from epoprostenol (I.V.)

Inhalation: Treatment of pulmonary arterial hypertension (PAH) (WHO Group I) in patients with NYHA Class III symptoms to improve exercise ability. Note: Nearly all controlled clinical trial experience has been with concomitant bosentan or sildenafil.

Pregnancy Risk Factor

B

Pregnancy Considerations

Some skeletal malformations and maternal toxicity noted in animal studies. There are no adequate and well-controlled studies in pregnant women. Use with caution and only if clearly needed.

Lactation

Excretion in breast milk unknown/use caution

Contraindications

There are no contraindications listed in the FDA-approved labeling.

Warnings/Precautions

Concerns related to adverse effects:

• Hypotension: May produce symptomatic hypotension; use with caution in patients with low systemic arterial blood pressure.

• Rebound pulmonary hypertension: Abrupt withdrawal/large dosage reductions may worsen symptoms of PAH. If a SubQ or I.V. infusion is restarted within a few hours of discontinuation, the same dose rate may be used. Interruptions for longer periods may require retitration. Regardless of administration route (inhalation, I.V., SubQ), treatment interruptions should be avoided. Immediate access to medication, back-up inhalation device, or pump and infusion sets is essential to prevent treatment interruptions.

Disease-related concerns:

• Hepatic impairment: Use with caution in patients with hepatic impairment. Dose reduction is recommended for the initial dose (I.V., SubQ) in patients with mild-to-moderate hepatic insufficiency; titrate dose slowly in patients with hepatic insufficiency; has not been studied in severe hepatic impairment

• Renal impairment: Has not been studied in renal impairment; use with caution in patients with renal impairment. Titrate dose slowly in patients with renal insufficiency.

• Respiratory disease: Inhalation: Safety and efficacy have not been established in patients with underlying pulmonary disease (eg, asthma, COPD). Patients with acute pulmonary infections should be monitored closely for exacerbation or reduced efficacy.

Special populations:

• Elderly: Use with caution in patients ≥65 years of age; clinical trial experience in this population is limited.

Concurrent drug therapy issues:

• Anticoagulants/antiplatelet therapy: Treprostinil inhibits platelet aggregation, increasing the risk of bleeding; use with caution in patients receiving concurrent anticoagulant/antiplatelet therapy.

Other warnings/precautions:

• Infection: Chronic continuous I.V. infusion of treprostinil via a chronic indwelling central venous catheter has been associated with serious blood stream infections. This method of administration should be reserved for patients who are intolerant of the SubQ route or in whom the benefit outweighs the potential risks. Clinicians should routinely review with patient the importance of infection control practices for the management of a central venous catheter.

• Appropriate use: Treprostinil should only be used by clinicians experienced in the treatment of PAH. Prior to initiation, patients should be carefully evaluated for ability to administer treprostinil, either as an I.V./SubQ infusion or inhalation, and care for the infusion system/inhalation device. Initiation of infusion must occur in a setting where adequate personnel and equipment necessary for hemodynamic monitoring and emergency treatment are available.

Adverse Reactions

>10%:

Cardiovascular: Flushing (11%; inhalation: 15%)

Central nervous system: Headache (27% to 41%)

Dermatologic: Rash (14%)

Gastrointestinal: Diarrhea (25%), nausea (19% to 22%)

Local: Infusion site pain (SubQ: 85%; may improve after several months of therapy), infusion site reaction (SubQ: 83%)

Neuromuscular & skeletal: Jaw pain (13%)

Respiratory: Cough (inhalation: 54%), throat irritation/pharyngolaryngeal pain (inhalation: 25%)

1% to 10%:

Cardiovascular: Edema (9%), syncope (inhalation: 6%), hypotension (4%)

Central nervous system: Dizziness (9%)

Dermatologic: Pruritus (8%)

Respiratory: Epistaxis (inhalation), hemoptysis, pneumonia, wheezing (inhalation)

<1%, postmarketing, and/or case reports: Anxiety, arm swelling, bone pain, cellulitis, central venous catheter-related line infections, central venous catheter-related sepsis, hematoma, pain, paresthesia, restlessness, thrombocytopenia, thrombophlebitis

Metabolism/Transport Effects

Substrate of CYP2C8 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential

Drug Interactions

Anticoagulants: Prostacyclin Analogues may enhance the adverse/toxic effect of Anticoagulants. Specifically, the antiplatelet effects of these agents may lead to an increased risk of bleeding with the combination. Risk C: Monitor therapy

Antihypertensives: Prostacyclin Analogues may enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy

Antiplatelet Agents: Prostacyclin Analogues may enhance the antiplatelet effect of Antiplatelet Agents. Risk C: Monitor therapy

CYP2C8 Inducers (Strong): May decrease the serum concentration of Treprostinil. Risk C: Monitor therapy

CYP2C8 Inhibitors (Strong): May increase the serum concentration of Treprostinil. Risk C: Monitor therapy

Nonsteroidal Anti-Inflammatory Agents: Treprostinil may enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Bleeding may occur. Risk C: Monitor therapy

Salicylates: Treprostinil may enhance the adverse/toxic effect of Salicylates. Bleeding may occur. Risk C: Monitor therapy

Storage

Injection solution: Store vials at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Contents of a vial should not be used past 30 days after initial needle access into the vial. Stability for up to 48 hours at 37°C has been shown for I.V. infusion concentrations as low as 4000 ng/mL.

Solution for inhalation: Store ampules in foil packs at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 89°F). Protect from light. Once foil pack is opened, ampules should be used within 7 days. Following transfer of solution to inhalation device, solution should remain in device for no more than 24 hours; discard unused portion.

Reconstitution

Injection solution: For SubQ infusion, product should not be diluted prior to use. For I.V. infusion, dilute in SWFI, NS, or Flolan® sterile diluent to a final volume of either 50 mL or 100 mL (dependent on system reservoir and calculated dose).

Compatibility

Stable in SWFI, NS, or Flolan® sterile diluent; variable stability (consult detailed reference) in D₅W.

Mechanism of Action

Treprostinil is a direct vasodilator of both pulmonary and systemic arterial vascular beds; also inhibits platelet aggregation.

Pharmacodynamics/Kinetics

Absorption: SubQ: Rapidly and completely

Distribution: 14 L/70 kg ideal body weight

Protein binding: 91%

Metabolism: Hepatic (primarily by CYP2C8); forms 5 inactive metabolites (HU1-HU5)

Bioavailability: Inhalation: 64% to 72% (dose-dependent); SubQ: 100%

Half-life elimination: Terminal: ~4 hours

Excretion: Urine (79%; 4% as unchanged drug, 64% as metabolites); feces (13%)

Dosage

Pulmonary arterial hypertension (PAH):

Children: SubQ; I.V. infusion: Limited experience in patients ≤16 years of age.

Adults:

Inhalation: Note: Prior to initiation, patients should be carefully evaluated for ability to administer treprostinil and care for the inhalation system and accessories required for administration. Immediate access to a back-up inhalation device, accessories, and medication is essential to prevent treatment interruptions.

Initial: 18 mcg (or 3 inhalations) every 4 hours 4 times/day; if 3 inhalations are not tolerated, reduce to 1-2 inhalations, then increase to 3 inhalations as tolerated

Maintenance: If tolerated, increase dose by an additional 3 inhalations at approximately 1- to 2-week intervals; target dose and maximum dose: 54 mcg (or 9 inhalations) 4 times/day

SubQ (preferred) or I.V. infusion: Note: Prior to initiation, patients should be carefully evaluated for ability to administer treprostinil and care for the infusion system outside of inpatient setting. Immediate access to a back-up pump, infusion sets, and medication is essential to prevent treatment interruptions.

New to prostacyclin therapy: Initial: 1.25 ng/kg/minute; if dose cannot be tolerated due to systemic effects, reduce to 0.625 ng/kg/minute. Increase dose in increments of 1.25 ng/kg/minute per week for first 4 weeks, followed by increments of 2.5 ng/kg/minute per week for remainder of therapy. Limited experience with doses >40 ng/kg/minute. Note: Dose must be carefully and individually titrated (symptom improvement with minimal adverse effects). Avoid abrupt withdrawal. If infusion is restarted within a few hours of discontinuation, the same dose rate may be used. Interruptions for longer periods may require retitration.

Transitioning from epoprostenol (see table): Note: Transition should occur in a hospital setting to follow response (eg, walking distance, sign/symptoms of disease progression). May take 24-48 hours to transition. Transition is accomplished by initiating the infusion of treprostinil, and increasing it while simultaneously reducing the dose of intravenous epoprostenol. During transition, increases in PAH symptoms should be first treated with an increase in treprostinil dose. Occurrence of prostacyclin associated side effects should be treated by decreasing the dose of epoprostenol.

Elderly: Refer to adult dosing. Limited experience in patients ≥65 years; use caution.

Dosage adjustment in renal impairment: Titrate slowly in patients with renal impairment

Dosage adjustment in hepatic impairment:

Mild-to-moderate: Use with caution and titrate slowly in patients with hepatic impairment

SubQ; I.V. infusion: Initial: 0.625 ng/kg/minute (ideal body weight)

Severe: Has not been studied in patients with severe hepatic impairment

Administration: I.V.

Avoid abrupt withdrawal (including interruptions in delivery) or rapid large dosage reductions. Immediate access to a back-up pump, infusion sets, and medication is essential to prevent treatment interruptions.

I.V. infusion: I.V. use is recommended when SubQ infusion is not tolerated or when the benefit outweighs the potential risks of an indwelling central venous catheter. Solution must be diluted in SWFI, NS, or Flolan® sterile diluent prior to use and administered by continuous infusion using a central indwelling catheter and infusion pump. The ambulatory infusion pump should be small and lightweight; have occlusion/no delivery, low battery, programming error, and motor malfunction alarms; have ± 6% accuracy of the programmed rate; and be positive pressure driven. The reservoir should be made of polyvinyl chloride, polypropylene, or glass. Peripheral infusion may be used temporarily until central line is established.

Administration: Other

Avoid abrupt withdrawal (including interruptions in delivery) or rapid large dosage reductions. Immediate access to medication, a back-up inhalation device, or pump and infusion sets is essential to prevent treatment interruptions.

Inhalation: Do not mix with other medications. For inhalation only via the Tyvaso™ Inhalation System; consists of the Optineb-ir Model ON-100/7 (an ultrasonic, pulsed-delivery device) and accessories. Prior to the first treatment session of each day, transfer the entire contents of one ampule into the medicine chamber; one ampule contains sufficient volume of medication for all 4 treatment sessions in a single day. Between each session, the device should be capped and stored upright with the remaining medication inside. At the end of each day, the medicine chamber and any remaining medication must be discarded. Avoid contact of solution with eyes or skin; wash hands after handling.

SubQ infusion (preferred): Administer undiluted via continuous SubQ infusion using an appropriately-designed infusion pump. The ambulatory infusion pump should be small and lightweight; be able to adjust infusion rates in ~0.002 mL/hour increments; have occlusion/no delivery, low battery, programming error, and motor malfunction alarms; have ± 6% accuracy of the programmed rate; and be positive pressure driven. The reservoir should be made of polyvinyl chloride, polypropylene, or glass. Infusion site reactions may be helped by moving the infusion site every 3 days, local application of topical hot and cold packs, topical or oral analgesics. Injection site pain and erythema may improve after several months of treprostinil therapy.

Administration: I.V. Detail

pH 6-7.2

Monitoring Parameters

BP, dyspnea, fatigue, activity tolerance, symptoms of excessive dose (eg, headache, nausea, vomiting)

Patient Education

Therapy will probably be long-term. You will be taught how to store and prepare medication and how to care for and monitor the equipment; follow these directions completely. Notify contact person immediately with any problems or questions with equipment. You will be required to monitor your blood pressure and heart rate at regular intervals. You may experience mild headache, nervousness, dizziness, nausea, vomiting, diarrhea, or muscular pain. Report immediately any signs or symptoms of increased dizziness, acute or severe headache, increased difficulty breathing, fever or chills, unusual bleeding or bruising, or chest pain or palpitations. If administering through an I.V., notify healthcare provider if site is increasingly painful, red, or has pus forming.

Dental Health: Effects on Dental Treatment

No significant effects or complications reported. Treprostinil may enhance the risk of bleeding associated with other antiplatelet agents (aspirin or NSAIDs).

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions

Mental Health: Effects on Mental Status

May cause headache

Mental Health: Effects on Psychiatric Treatment

Nausea and diarrhea are common, these effects may be additive with concurrent use of SSRIs, lithium, or valproate. Treprostinil inhibits platelet aggregation. Concomitant use with SSRIs which possess some antiplatelet activity may increase the risk of bleeding.

Nursing: Physical Assessment/Monitoring

Initiation of therapy must be performed in a setting with necessary continuous pulmonary and hemodynamic arterial monitoring and emergency care. Chronic therapy may be needed; patient's ability to prepare and administer the medication should be carefully assessed. Evaluate effectiveness of therapy (improved pulmonary function and quality of life). Instruct patient/caregiver to monitor vital signs on regular basis.

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Injection, solution:

Remodulin®: 1 mg/mL (20 mL); 2.5 mg/mL (20 mL); 5 mg/mL (20 mL) [contains sodium chloride 5.3 mg/mL]

Remodulin®: 10 mg/mL (20 mL) [contains sodium chloride 4 mg/mL]

Solution, for oral inhalation:

Tyvaso™: 0.6 mg/mL (2.9 mL) [delivers ~6 mcg/inhalation]

References

Badesch DB, Abman SH, Simonneau G, et al, “Medical Therapy for Pulmonary Arterial Hypertension: Updated ACCP Evidence-Based Clinical Practice Guidelines,” Chest, 2007, 131(6):1917-28.

Centers for Disease Control and Prevention (CDC), “Bloodstream Infections Among Patients Treated With Intravenous Epoprostenol or Intravenous Treprostinil for Pulmonary Arterial Hypertension - Seven Sites, United States, 2003-2006,” MMWR Morb Mortal Wkly Rep, 2007, 56(8):170-2.

Gildea TR, Arroliga AC, and Minai OA, “Treatments and Strategies to Optimize the Comprehensive Management of Patients With Pulmonary Arterial Hypertension,” Cleve Clin J Med, 2003, 70(Suppl 1):18-27.

Gomberg-Maitland M, Tapson VF, Benza RL, et al, “Transition from Intravenous Epoprostenol to Intravenous Treprostinil in Pulmonary Hypertension,” Am J Respir Crit Care Med, 2005, 172(12):1586-9.

Lang I, Gomez-Sanchez M, Kneussl M, et al, “Efficacy of Long-term Subcutaneous Treprostinil Sodium Therapy in Pulmonary Hypertension,” Chest, 2006, 129(6):1636-43.

McLaughlin VV, Archer SL, Badesch DB, et al, “ACCF/AHA 2009 Expert Consensus Document on Pulmonary Hypertension: A Report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association Developed in collaboration with the American College of Chest Physicians; American Thoracic Society, Inc.; and the Pulmonary Hypertension Association,” J Am Coll Cardiol, 2009, 53(17):1573–619.

McLaughlin VV, Gaine SP, Barst RJ, et al, “Efficacy and Safety of Treprostinil: An Epoprostenol Analog for Primary Pulmonary Hypertension,” J Cardiovasc Pharmacol, 2003, 41(2):293-9.

Rubenfire M, McLaughlin VV, Allen RP, et al, “Transition From IV Epoprostenol to Subcutaneous Treprostinil in Pulmonary Arterial Hypertension,” Chest, 2007,132(3):757-63.

International Brand Names

• Remodulin (AR, AT, AU, BE, CH, CN, CZ, DE, DK, EE, FI, FR, GR, IL, IT, NL, NO, PT, SE, TW)

Lexi-Comp.com

Last full review/revision January 2012

Content last modified January 2012