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Treprostinil

Pronunciation

(tre PROST in il)

Index Terms

  • Treprostinil Sodium

Dosage Forms

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

Solution, Inhalation:

Tyvaso: 0.6 mg/mL (2.9 mL)

Tyvaso Refill: 0.6 mg/mL (2.9 mL)

Tyvaso Starter: 0.6 mg/mL (2.9 mL)

Solution, Injection:

Remodulin: 1 mg/mL (20 mL); 2.5 mg/mL (20 mL); 5 mg/mL (20 mL); 10 mg/mL (20 mL) [contains metacresol]

Tablet Extended Release, Oral:

Orenitram: 0.125 mg, 0.25 mg, 1 mg, 2.5 mg [contains fd&c blue #2 (indigotine)]

Brand Names: U.S.

  • Orenitram
  • Remodulin
  • Tyvaso
  • Tyvaso Refill
  • Tyvaso Starter

Pharmacologic Category

  • Prostacyclin
  • Prostaglandin
  • Vasodilator

Pharmacology

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

Absorption

SubQ: Rapidly and completely

Distribution

14 L/70 kg ideal body weight

Metabolism

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

Excretion

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

Oral: Urine (0.19% as unchanged drug); feces (1.13% as unchanged drug)

Time to Peak

Oral: 4 to 6 hours

Half-Life Elimination

Terminal: ~4 hours

Protein Binding

91% to 96%

Special Populations: Hepatic Function Impairment

Cl reduced up to 80% in patients with hepatic impairment. Cmax increased 2-fold in patients with mild impairment; 4-fold in patients with moderate impairment; and 5-fold in patients with severe impairment.

Use: Labeled Indications

Pulmonary arterial hypertension:

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 (IV)

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.

Oral: Treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) in patients with WHO functional class II-III symptoms to improve exercise capacity.

Contraindications

Injection/inhalation: There are no contraindications listed in the manufacturer’s labeling.

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

Documentation of allergenic cross-reactivity for prostaglandins is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.

Dosing: Adult

Pulmonary arterial hypertension (PAH):

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 to 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

Oral: Initial: 0.25 mg every 12 hours or 0.125 mg every 8 hours; may increase dose in increments of 0.25 mg or 0.5 mg every 12 hours or 0.125 mg every 8 hours every 3 to 4 days as tolerated to achieve optimal clinical response. If dose increments are not tolerated, consider slower titration. Maximum dose is determined by tolerability. If intolerable effects occur, decrease dose in increments of 0.25 mg; avoid abrupt discontinuation. Upon discontinuation, reduce the dose in increments of 0.5 mg to 1 mg daily.

Conversion from injection to oral dosing: Decrease the dose of parenteral treprostinil up to 30 ng/kg/minute per day while simultaneously increasing the dose of oral treprostinil up to 2 mg 3 times daily as tolerated. To estimate a comparable total daily dose of oral treprostinil, use the following equation:

Treprostinil oral total daily dose (mg) = Parenteral treprostinil dose (ng/kg/minute) x weight (kg) x 0.0072

Missed doses: If a dose is missed, take the missed dose as soon as possible. If ≥2 doses are missed, restart at a lower dose and retitrate.

Dosage adjustment for concurrent use in patients receiving strong CYP2C8 inhibitors (gemfibrozil): Initiate a starting dose of 0.125 mg every 12 hours; increase in increments of 0.125 mg every 12 hours every 3 to 4 days.

Planned short-term treatment interruption: If patients are unable to continue oral treatment, a temporary infusion of parenteral treprostinil may be considered. Multiply the oral total daily dose (mg) by 139 and divide by patient’s weight (kg) to calculate the total daily dose of parenteral treprostinil (ng/kg/minute).

SubQ (preferred) or IV 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 to 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.

Transitioning From IV Epoprostenol to SubQ (Preferred) or IV Treprostinil

Step

Epoprostenol Dose

Treprostinil Dose

1

Maintain current dose

Initiate at 10% initial epoprostenol dose

2

Decrease to 80% initial dose

Increase to 30% initial epoprostenol dose

3

Decrease to 60% initial dose

Increase to 50% initial epoprostenol dose

4

Decrease to 40% initial dose

Increase to 70% initial epoprostenol dose

5

Decrease to 20% initial dose

Increase to 90% initial epoprostenol dose

6

Decrease to 5% initial dose

Increase to 110% initial epoprostenol dose

7

Discontinue epoprostenol

Maintain current dose plus additional 5% to 10% as needed

Table has been converted to the following text.

Transitioning From IV epoprostenol to SubQ (Preferred) or IV treprostinil

Step 1:

Epoprostenol: Maintain current dose

Treprostinil: Initiate at 10% initial epoprostenol dose

Step 2:

Epoprostenol: Decrease dose to 80% of starting dose

Treprostinil: Increase to 30% initial epoprostenol dose

Step 3:

Epoprostenol: Decrease dose to 60% of starting dose

Treprostinil: Increase to 50% initial epoprostenol dose

Step 4:

Epoprostenol: Decrease dose to 40% of starting dose

Treprostinil: Increase to 70% initial epoprostenol dose

Step 5:

Epoprostenol: Decrease dose to 20% of starting dose

Treprostinil: Increase to 90% initial epoprostenol dose

Step 6:

Epoprostenol: Decrease dose to 5% of starting dose

Treprostinil: Increase to 110% initial epoprostenol dose

Step 7:

Epoprostenol: Discontinue

Treprostinil: Maintain current dose plus additional 5% to 10% as needed

Dosing: Geriatric

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

Dosing: Pediatric

SubQ; IV infusion: Limited experience in patients ≤16 years of age.

Dosing: Renal Impairment

Inhalation, SubQ infusion, IV infusion: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied). Use with caution and titrate slowly.

Oral: No dosage adjustment necessary.

Hemodialysis: Treprostinil is not removed by dialysis.

Dosing: Hepatic Impairment

Inhalation: There are no dosage adjustments provided in the manufacturer’s labeling. However, hepatic impairment increases systemic exposure to treprostinil. Use with caution and titrate slowly.

Mild to moderate impairment: Initial: 0.625 ng/kg/minute (ideal body weight). Use with caution and titrate slowly.

Severe impairment: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied). Use with caution and titrate slowly.

Oral:

Mild impairment (Child-Pugh class A): Initial: 0.125 mg every 12 hours; increase in increments of 0.125 mg every 12 hours every 3 to 4 days.

Moderate impairment (Child-Pugh class B): Avoid use.

Severe impairment (Child-Pugh class C): Use is contraindicated by the manufacturer.

Reconstitution

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

Administration

Avoid treatment interruptions or rapid large dosage reductions with use of inhalation, IV, or SubQ formulations. 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. 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.

IV infusion: IV 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, Remodulin sterile diluent, 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. Infusion sets with an in-line 0.22 or 0.2 micron filter should be used for central and peripheral administration.

Oral: Administer with food. Swallow tablets whole; do not crush, split or chew; use only intact tablets.

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. Proactively manage infusion-site reactions based on individual patient needs and by combining multiple strategies, including improved dosing strategies (eg, more rapid dose escalation), appropriate site selection, less frequent infusion site changes (eg, every 2 to 5 weeks [Skoro-Sajer 2007]), and analgesic care (pharmacologic and nonpharmacologic) when pain occurs. Rotate infusion site when patient experiences continued site pain, itching, erythema, drainage, or bleeding; decreased site pain and need for site changes or discontinuation due to site pain may be reduced in patients who are managed proactively in this manner (Mathier 2010; Skoro-Sajer 2008; White 2013).

Compatibility

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

Storage

Injection solution: Store vials at 25°C (77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F). Contents of a vial should not be used past 30 days after initial needle access into the vial. Stability for up to 14 days at 37°C has been shown for IV infusion concentrations as low as 4,000 ng/mL.

Solution for inhalation: Store ampuls in foil packs at 25°C (77°F); excursions are permitted between 15°C and 30°C (59°F and 86°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.

Tablets: Store at 25°C (77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F).

Drug Interactions

Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.): Prostacyclin Analogues may enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Alcohol (Ethyl): May increase the absorption of Treprostinil. Specifically, a more rapid and/or complete absorption of Treprostinil from extended-release tablets is possible. Management: Avoid administration of treprostinil extended release tablets with alcohol, and advise patients to avoid this combination. No such interaction is expected with other treprostinil formulations. Consider therapy modification

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. Monitor therapy

Blood Pressure Lowering Agents: Prostacyclin Analogues may enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

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

CYP2C8 Inhibitors (Strong): May increase the serum concentration of Treprostinil. Management: Reduce the initial treprostinil extended release tablet dose to 0.125 mg twice daily, titrating by 0.125 mg twice daily every 3 to 4 days. No preemptive dose adjustment is recommended for other treprostinil products. Consider therapy modification

Highest Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification

MiFEPRIStone: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying). Management: Though the drugs listed here have uncertain QT-prolonging effects, they all have some possible association with QT prolongation and should generally be avoided when possible. Consider therapy modification

Moderate Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Monitor therapy

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

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

Thrombolytic Agents: May enhance the adverse/toxic effect of Prostacyclin Analogues. Specifically, the antiplatelet effects of prostacyclin analogues may lead to an increased risk of bleeding when combined with thrombolytic agents. Monitor therapy

Adverse Reactions

>10%:

Cardiovascular: Flushing (11% to 15%)

Central nervous system: Headache (27% to 63%)

Dermatologic: Skin rash (14%)

Gastrointestinal: Diarrhea (25% to 30%), nausea (19% to 30%)

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

Neuromuscular & skeletal: Limb pain (Oral: 14%), jaw pain (11% to 13%)

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

1% to 10%:

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

Central nervous system: Dizziness (9%)

Dermatologic: Pruritus (8%)

Endocrine & metabolic: Hypokalemia (Oral: 9%)

Gastrointestinal: Abdominal distress (Oral: 6%)

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

<1% (Limited to important or life-threatening): Angioedema, catheter infection (central venous), catheter sepsis (central venous), cellulitis, decreased platelet aggregation, hematoma, ostealgia, pain, paresthesia, swelling of extremities, thrombocytopenia, thrombophlebitis

Warnings/Precautions

Concerns related to adverse effects:

• Bleeding: May inhibit platelet aggregation and increases the risk of bleeding.

• 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 IV 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, IV, oral, 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.

- IV/SubQ: Dose reduction is recommended for the initial dose in patients with mild to moderate hepatic insufficiency; titrate dose slowly in patients with hepatic insufficiency; has not been studied in severe hepatic impairment.

- Oral: Dose reduction is recommended for patients with mild hepatic impairment. Avoid use in patients with moderate impairment; use is contraindicated in patients with severe impairment.

• Renal impairment: Inhalation, IV, SubQ: 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.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

• Ethanol use: Tablets should not be administered with ethanol because the release of treprostinil from the tablet may occur at a faster rate than intended.

Dosage form related issues:

• Tablet: Tablet shell does not dissolve and is eliminated in the feces as an insoluble shell; in patients with diverticulosis, tablet can lodge in a diverticulum.

Other warnings/precautions:

• Infection: Chronic continuous IV 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 injection 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 IV/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.

Monitoring Parameters

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

Pregnancy Risk Factor

B/C (product specific)

Pregnancy Considerations

Adverse events have been observed in some animal reproduction studies. Women with pulmonary arterial hypertension (PAH) are encouraged to avoid pregnancy (McLaughlin, 2009).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience headache, flushing, jaw pain, diarrhea, nausea, painful extremities, abdominal pain, tablet shell in stool, pharyngitis, muscle pain, or bone pain. Have patient report immediately to prescriber signs of bleeding (vomiting blood or vomit that looks like coffee grounds, coughing up blood, blood in the urine, black, red, or tarry stools, bleeding from the gums, abnormal vaginal bleeding, bruises without a reason or that get bigger, or any bleeding that is very bad or that will not stop), signs of low potassium (muscle pain or weakness, muscle cramps, or an abnormal heartbeat), severe dizziness, passing out, shortness of breath, excessive weight gain, swelling of arms or legs, burning or numbness feeling, persistent cough, or injection site irritation or pain (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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