Treprostinil

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: 20 mg/20 mL (20 mL); 50 mg/20 mL (20 mL); 100 mg/20 mL (20 mL); 200 mg/20 mL (20 mL) [contains metacresol]

Generic: 20 mg/20 mL (20 mL); 50 mg/20 mL (20 mL); 100 mg/20 mL (20 mL); 200 mg/20 mL (20 mL)

Tablet Extended Release, Oral:

Orenitram: 0.125 mg, 0.25 mg, 1 mg, 2.5 mg, 5 mg [contains fd&c blue #2 (indigotine)]

Pharmacology

Mechanism of Action

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

Pharmacokinetics/Pharmacodynamics

Absorption

Oral: Affected by food; AUC_inf increased by 49% when administered following a high-fat, high-calorie meal compared to fasting conditions. Relative bioavailability following oral administration of 1 mg is not significantly altered by meals ranging from 250 to 500 calories.

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%

Use in Specific Populations

Special Populations: Hepatic Function Impairment

Cl reduced up to 80% in patients with hepatic impairment. C_max 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) (World Health Organization [WHO] Group I) in patients with New York Heart Association (NYHA) Class II to IV symptoms to decrease exercise-associated symptoms; to diminish clinical deterioration when transitioning from epoprostenol.

Inhalation: Treatment of PAH (WHO Group I) in patients with NYHA Class III symptoms to improve exercise ability.

Oral: Treatment of PAH (WHO Group 1) in patients with WHO Functional Class II to III symptoms to delay disease progression and to delay disease progression and to improve exercise capacity or PAH associated with connective tissue disease.

Contraindications

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

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

Canadian labeling: Additional contraindications (not in US labeling): Hypersensitivity to treprostinil or any component of the formulation.

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.

Dosage and Administration

Dosing: Adult

Pulmonary arterial hypertension (group 1):

Note: Prior to initiation, patients should be carefully evaluated at a pulmonary hypertension center (ideally prior to the start of therapy) for ability to administer treprostinil and care for the infusion system outside of inpatient setting or inhalation system and accessories required for administration. Immediate access to a back-up pump, infusion sets, or inhalation device, accessories, and medication is essential to prevent treatment interruptions (ACCP [Klinger 2019]; Hopkins 2019).

Inhalation: Note: Consider in patients as additional treatment in patients who remain symptomatic on stable doses of endothelin receptor antagonists (ERA) or phosphodiesterase type 5 inhibitors; may consider, in combination with oral agents, in World Health Organization (WHO) Functional Class IV treatment-naive patients who decline or cannot receive IV prostacyclin therapy; may initiate in WHO Functional Class III patients who have rapid disease progression or poor clinical prognosis. Not recommended as initial therapy or as second line agent for treatment of naive WHO Functional Class II patients (ACCP [Klinger 2019]; Hopkins 2019).

Initial: 18 mcg (3 inhalations) every 4 hours (4 times/day) while patient is awake; if 3 inhalations are not tolerated, reduce to 1 to 2 inhalations, then increase to 3 inhalations as tolerated (Fares 2012).

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

Oral: Initial: 0.125 to 0.25 mg every 8 to 12 hours; dosing every 8 hours is generally preferred to improve tolerance; increase dose in increments of 0.125 mg (preferred), or 0.25 mg, or 0.5 mg, no more frequently than every 3 to 4 days as tolerated to achieve optimal clinical response (Chakinala 2017; Rahaghi 2017). Initiate 0.125 mg every 8 hours in patients with hypotension, low tolerance for side effects, or <60 kg (Rahaghi 2017). If dose increments are not tolerated, consider slower titration. Maximum dose is determined by tolerability; some experts recommend a target dose of 4 mg three times daily at 3 months and 8 mg three times daily at 12 months (Rahaghi 2017). If intolerable effects occur, decrease dose in increments of 0.125 mg every 8 hours or 0.25 mg every 12 hours.

Discontinuation of therapy: Avoid abrupt discontinuation. Upon discontinuation, reduce the dose in increments of 0.5 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 every 8 hours as tolerated. Note: Consider transition to oral therapy in patients who are more stable and may be able to tolerate the transition (eg, WHO Functional Class I or II) patients.

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

Note: Some experts suggest ~1 mg oral treprostinil 3 times daily is similar to 6 ng/kg/minute of IV treprostinil infusion in a 70 kg person (Chakinala 2017).

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 re-titrate.

Dosage adjustment for concurrent use in patients receiving strong CYP2C8 inhibitors (eg, gemfibrozil): Initiate a starting dose of 0.125 mg every 12 hours; increase in increments of 0.125 mg every 12 hours no more frequently than 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, using the following equation:

Multiply the oral total daily dose (mg) by 139, then divide by patient's weight (kg) to calculate the total daily dose of parenteral treprostinil (ng/kg/minute).

SubQ or IV continuous infusion: Note: Recommended as treatment in WHO Functional Class III patients with evidence of rapid disease progression or poor clinical prognosis; in WHO Functional Class IV treatment-naive patients. Not recommended as initial therapy or as second line agent for treatment of naive WHO Functional Class II patients (ACCP [Klinger 2019]; Hopkins 2019).

New to prostacyclin therapy: Initial: 1.25 ng/kg/minute; if dose cannot be tolerated, 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; may increase dose more often if tolerated. Note: The optimal dose varies; target dose is generally 40 to 80 ng/kg/minute, but can be higher based on clinical response (Coons 2013).

Discontinuation of therapy: 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 re-titration.

Weight changes after initiation of therapy: Due to the narrow therapeutic range, patient weight changes can significantly affect the dosage adjustment of treprostinil. Some experts recommend using the patient's baseline weight for treprostinil dosing, and only adjust by the actual body weight when variation in weight is ≥10 kg (Raeisi-Giglou 2017).

Transitioning from epoprostenol (see table): Note: Transition should occur in a hospital setting to follow response (eg, walking distance, sign/symptoms of disease progression). Transition is accomplished by initiating the infusion of treprostinil, and increasing the treprostinil dose, 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.

In the following step-wise approach, the initial epoprostenol dose is defined as the dose the patient was receiving at the beginning of the conversion to treprostinil.

Dosing: Geriatric

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

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 similar approved high-pH glycine diluent (eg, 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: For inhalation only via the Tyvaso Inhalation System; do not mix with other medications; inhalation solution is not for oral ingestion. Prior to the first treatment session of each day, transfer the entire contents of one ampule (undiluted) into the medicine chamber; one ampule contains sufficient volume of medication for all 4 treatment sessions in a single day. Each treatment session will take 2 to 3 minutes; 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. Clean inhalation device chamber with a dry cloth once a week; clean device accessories daily (after last treatment session) with mild, soapy, warm water, rinse and air dry. Avoid skin or eye contact; 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. Administer by continuous infusion using a central indwelling catheter and an external infusion pump. The ambulatory infusion pump should 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. IV infusion sets with an in-line 0.22 or 0.2 micron filter should be used for central and peripheral administration. If transitioning from the use of an external infusion pump to an implantable IV infusion pump (eg, Implantable System for Remodulin), refer to the pump manufacturer's manual for instructions regarding preparation, programming, implantation, and refilling.

Oral: Administer with food (minimum of 250 calories containing 30% to 50% fat) (Lim 2013; Pugliese 2016); 3 times daily dosing is less dependent on food intake (Rahaghi 2017). Swallow tablets whole; do not crush, split or chew; use only intact tablets.

SubQ infusion: 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). Abdominal fat is the most common site used but other sites used include hips, thighs, and underarms (Bishop 2012).

Storage

Injection solution: Store vials at 25°C (77°F); excursions are permitted between 2°C and 30°C (36°F and 86°F). Contents of a vial should not be used past 30 days after initial needle access into the vial. IV solutions prepared with Remodulin sterile diluent or similar approved high-pH glycine diluent (eg, Flolan sterile diluent) may be stored for 14 days at room temperature; solutions prepared with SWFI or NS may be stored for 4 hours at room temperature or 24 hours refrigerated. See prescribing information for additional details.

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 20°C to 25°C (68°F to 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

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 Inhibitors (Moderate): May increase 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

Lumacaftor and Ivacaftor: May decrease the serum concentration of CYP2C8 Substrates (High Risk with Inhibitors or Inducers). Lumacaftor and Ivacaftor may increase the serum concentration of CYP2C8 Substrates (High Risk with Inhibitors or Inducers). 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 (oral: 15% to 45%; oral inhalation: 15%), vasodilation (SubQ: 11%)

Central nervous system: Infusion-site pain (SubQ: 85%, severe: 39%), headache (oral: 63% to 75%; oral inhalation: 41%; SubQ: 27%)

Dermatologic: Skin rash (SubQ: 14%)

Gastrointestinal: Diarrhea (oral: 30% to 69%; SubQ: 25%), nausea (19% to 40%), vomiting (oral: 17% to 36%), upper abdominal pain (oral: 5% to 12%)

Local: Infusion site reaction (SubQ: 83%, severe: 38%, including erythema, induration, skin rash)

Neuromuscular & skeletal: Limb pain (oral: 14% to 18%), jaw pain (11% to 18%)

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

1% to 10%:

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

Endocrine & metabolic: Hypokalemia (oral: 4% to 9%)

Gastrointestinal: Abdominal distress (oral: 6% to 8%)

Frequency not defined:

Central nervous system: Pain, paresthesia

Gastrointestinal: Sore throat

Hematologic & oncologic: Bleeding tendency disorder, decreased platelet aggregation, hematoma

Neuromuscular & skeletal: Swelling of extremities (arm)

Respiratory: Epistaxis (long-term therapy), hemoptysis (long-term therapy), nasal discomfort (long-term therapy), pneumonia (long-term therapy), wheezing (long-term therapy)

<1%, postmarketing, and/or case reports: Angioedema, arthralgia, catheter infection (central venous), cellulitis, dizziness, dyspepsia, maculopapular rash, muscle spasm, myalgia, ostealgia, papular rash, pruritus, 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.

• 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 using an external infusion pump 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. The use of an implantable IV infusion pump may have a lower risk of blood stream infections compared to the use of an external IV infusion pump.
• 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

Pregnancy Considerations

Information related to the use of treprostinil for the treatment of pulmonary arterial hypertension (PAH) in pregnant women is limited (Lim 2019; Rosengarten 2015; Smith 2012; Xiang 2018; Zhang 2018).

Untreated PAH in pregnancy increases the risk for maternal heart failure, stroke, preterm delivery, low birth weight, and maternal/fetal death. Women with PAH are encouraged to avoid pregnancy. When treatment is needed, agents with more information may be preferred for use in pregnant women (ESC [Regitz-Zagrosek 2018]).

Patient Education

What is this drug used for?

• It is used to treat high blood pressure in the lungs.

Frequently reported side effects of this drug

• Headache
• Flushing
• Jaw pain
• Diarrhea
• Nausea
• Vomiting
• Painful extremities
• Abdominal pain
• Tablet shell in stool
• Throat irritation
• Cough
• Muscle pain
• Bone pain

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Bleeding like 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 severe or persistent bleeding
• Low potassium like 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
• Trouble breathing
• Burning or numbness feeling
• Injection site irritation or pain
• Signs of a significant reaction like 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. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.