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Treprostinil: Drug information

Treprostinil: Drug information
(For additional information see "Treprostinil: Patient drug information" and see "Treprostinil: Pediatric drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)
Brand Names: US
  • Orenitram;
  • Orenitram Month 1;
  • Orenitram Month 2;
  • Orenitram Month 3;
  • Remodulin;
  • Tyvaso;
  • Tyvaso DPI Maintenance Kit;
  • Tyvaso DPI Titration Kit;
  • Tyvaso Refill;
  • Tyvaso Starter
Brand Names: Canada
  • Remodulin
Pharmacologic Category
  • Prostacyclin;
  • Prostaglandin;
  • Vasodilator
Dosing: Adult
Pulmonary arterial hypertension

Pulmonary arterial hypertension:

Note: Consult a pulmonary arterial hypertension specialist for all management decisions; choice of therapy is dependent on etiology, risk stratification, cardiopulmonary comorbidities, and response to other agents. Parenteral prostacyclin analogues are generally reserved for initial therapy in high-risk patients or used as adjunctive therapy in patients who continue to deteriorate on oral agents (Ref).

Inhalation:

Dry powder inhaler:

Initial: 16 mcg per treatment session inhaled 4 times per day approximately every 4 hours while patient is awake.

Maintenance: If tolerated, increase each inhaled dose by an additional 16 mcg per treatment session at approximately 1- to 2-week intervals; target dose: 48 to 64 mcg inhaled per session; continue at highest dose tolerated if adverse effects preclude titration.

Solution for inhalation:

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

Maintenance: If tolerated, increase each dose by 3 inhalations at approximately 1- to 2-week intervals; studies establishing effectiveness used a target dose of 54 mcg (9 inhalations) 4 times per day.

The following regimens provide similar exposure:

Conversion from Treprostinil Solution for Inhalation to Dry Powder Inhaler

Treprostinil solution: Number of breaths (total dose)

Treprostinil dry powder inhaler (cartridge strength)

≤5 breaths (≤30 mcg)

16 mcg

6 to 7 breaths (36 to 42 mcg)

32 mcg

8 to 10 breaths (48 to 60 mcg)

48 mcg

11 to 12 breaths (66 to 72 mcg)

64 mcg

Oral:

Initial: 0.125 mg every 8 hours to 0.25 mg every 12 hours; dosing every 8 hours is generally preferred to improve tolerability (especially in patients with hypotension, low tolerance for side effects, or <60 kg) (Ref).

Titration and maintenance: Increase dose in increments of 0.125 mg every 8 hours, or by 0.25 mg or 0.5 mg every 12 hours, no more frequently than every 3 to 4 days as tolerated to achieve optimal clinical response (Ref). Maximum dose is determined by tolerability; some experts recommend a target dose of 4 mg 3 times daily at 3 months, 6 mg 3 times daily at 6 months, and 8 mg 3 times daily at 12 months (Ref). If intolerable adverse effects occur, decrease dose in increments of 0.125 mg every 8 hours or 0.25 mg every 12 hours.

Discontinuation of therapy: Reduce the total daily dose in increments of 0.5 to 1 mg per day until discontinued; avoid abrupt discontinuation.

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.

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 stable and more likely 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 of oral treprostinil administered every 8 hours is similar to 6 ng/kg/minute of IV treprostinil infusion in a 70 kg person (Ref).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult Drug Interactions database for more information.

Planned short-term interruption in oral treatment: If patients are unable to continue oral treatment, a temporary infusion of parenteral treprostinil may be considered, using the following equation:

Total daily dose of parenteral treprostinil (ng/kg/minute) = (Oral total daily dose [mg] x 139) / patient weight (kg)

SUBQ or IV continuous infusion:

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. The optimal dose varies; target dose is generally 40 to 80 ng/kg/minute, but can be higher based on clinical response (Ref).

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 (Ref).

Transitioning from epoprostenol to treprostinil (see table): Note: Transition should occur in a hospital setting to monitor response. 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 adverse effects should be treated by decreasing the dose of epoprostenol.

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

Transitioning from IV Epoprostenol to SUBQ or IV Treprostinil

Step

Epoprostenol Dose

Treprostinil Dose

1

Maintain current dose

Initiate at 10% current epoprostenol dose

2

Decrease to 80% of starting dose

Increase to 30% of starting epoprostenol dose

3

Decrease to 60% of starting dose

Increase to 50% of starting epoprostenol dose

4

Decrease to 40% of starting dose

Increase to 70% of starting epoprostenol dose

5

Decrease to 20% of starting dose

Increase to 90% of starting epoprostenol dose

6

Decrease to 5% of starting dose

Increase to 110% of starting epoprostenol dose

7

Discontinue epoprostenol

Maintain current dose and increase by 5% to 10% as needed

Pulmonary hypertension associated with interstitial lung disease

Pulmonary hypertension associated with interstitial lung disease: Inhalation:

Dry powder inhaler:

Initial: 16 mcg per treatment session inhaled 4 times per day approximately every 4 hours while patient is awake.

Maintenance: If tolerated, increase each inhaled dose by an additional 16 mcg per treatment session at approximately 1- to 2-week intervals; target dose: 48 to 64 mcg inhaled per session; continue at highest dose tolerated if adverse effects preclude titration.

Solution for inhalation:

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

Maintenance: If tolerated, increase each dose by 3 inhalations at ~1- to 2-week intervals; studies establishing effectiveness used a target dose of 72 mcg (12 inhalations) 4 times per day.

The following regimens provide similar exposure:

Conversion from Treprostinil Solution for Inhalation to Dry Powder Inhaler

Treprostinil solution: Number of breaths (total dose)

Treprostinil dry powder inhaler (cartridge strength)

≤5 breaths (≤30 mcg)

16 mcg

6 to 7 breaths (36 to 42 mcg)

32 mcg

8 to 10 breaths (48 to 60 mcg)

48 mcg

11 to 12 breaths (66 to 72 mcg)

64 mcg

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Adult

IV or SUBQ continuous infusion: No dosage adjustment necessary.

Inhalation, Oral: No dosage adjustment necessary.

Hemodialysis: Treprostinil is not removed by dialysis.

Dosing: Hepatic Impairment: Adult

Inhalation:

Mild to moderate impairment: 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.

Severe impairment: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

SUBQ or IV continuous infusion:

Mild to moderate impairment: Initial: 0.625 ng/kg/minute. Hepatic impairment increases systemic exposure to treprostinil; 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 no more frequently than every 3 to 4 days.

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

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

Dosing: Older Adult

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

Dosing: Pediatric

(For additional information see "Treprostinil: Pediatric drug information")

Note: Doses are expressed in units of nanograms/kg/minute. A clinician with expertise in pulmonary arterial hypertension should be consulted for all management decisions.

Pulmonary arterial hypertension

Pulmonary arterial hypertension:

Adolescents >16 years:

New to prostacyclin therapy: Continuous IV or SUBQ infusion: Initial: 1.25 nanogram/kg/minute; if dose cannot be tolerated, reduce to 0.625 nanogram/kg/minute. Increase dose in increments of 1.25 nanogram/kg/minute per week for first 4 weeks, followed by increments of 2.5 nanogram/kg/minute per week for remainder of therapy; may increase dose more often if tolerated.

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 retitration. All patients should have access to back-up medication and infusion pumps.

Weight changes after initiation of therapy: Due to the narrow therapeutic range, patient weight changes can significantly affect the dosage adjustment of treprostinil. Based on experience in adults, 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 (Ref).

Transitioning from epoprostenol to treprostinil (see table): Transition should occur in a hospital setting to monitor response. Transition is accomplished by initiating the infusion of treprostinil and increasing the treprostinil dose, while simultaneously reducing the dose of IV epoprostenol. During transition, increases in pulmonary arterial hypertension symptoms should be first treated with an increase in treprostinil dose. Occurrence of prostacyclin-associated adverse effects should be treated by decreasing the dose of epoprostenol.

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

Transitioning From IV Epoprostenol to SUBQ or IV Treprostinil (Continuous Infusion)

Step

Epoprostenol Dose

Treprostinil Dose

1

Maintain current dose

Initiate at 10% current epoprostenol dose

2

Decrease to 80% of starting dose

Increase to 30% of starting epoprostenol dose

3

Decrease to 60% of starting dose

Increase to 50% of starting epoprostenol dose

4

Decrease to 40% of starting dose

Increase to 70% of starting epoprostenol dose

5

Decrease to 20% of starting dose

Increase to 90% of starting epoprostenol dose

6

Decrease to 5% of starting dose

Increase to 110% of starting epoprostenol dose

7

Discontinue epoprostenol

Maintain current dose and increase by 5% to 10% as needed

Dosing: Kidney Impairment: Pediatric

Adolescents >16 years: Continuous IV or SUBQ infusion: No dosage adjustment necessary. Treprostinil is not cleared by dialysis.

Dosing: Hepatic Impairment: Pediatric

Adolescents >16 years: Continuous IV or SUBQ infusion:

Mild to moderate impairment: Initial: 0.625 nanogram/kg/minute (ideal body weight). Hepatic impairment increases systemic exposure to treprostinil; 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.

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions reported in adults.

>10%:

Cardiovascular: Flushing (oral, oral inhalation: 15% to 45%), vasodilation (SUBQ: 11%)

Dermatologic: Skin rash (SUBQ: 14%)

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

Hypersensitivity: Severe infusion-related reaction (SUBQ: 38%)

Local: Infusion-site pain (SUBQ: 85%; severe: 39%), infusion-site reaction (including erythema, induration, skin rash: SUBQ: 83%)

Nervous system: Headache (oral: 63% to 75%; oral inhalation: 41%; SUBQ: 27%)

Neuromuscular & skeletal: Jaw pain (oral, SUBQ: 11% to 18%), limb pain (oral: 14% to 18%)

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

1% to 10%:

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

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

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

Frequency not defined:

Hematologic & oncologic: Decreased platelet aggregation

Respiratory: Hemoptysis (oral inhalation), nasal discomfort (oral inhalation)

Postmarketing (any formulation):

Dermatologic: Cellulitis, maculopapular rash, papular rash, pruritus

Gastrointestinal: Dyspepsia

Hematologic & oncologic: Thrombocytopenia

Hypersensitivity: Angioedema

Nervous system: Dizziness

Neuromuscular & skeletal: Arthralgia, muscle spasm, myalgia, ostealgia

Contraindications

Injection/Inhalation: There are no contraindications listed in the US 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.

Warnings/Precautions

Concerns related to adverse effects:

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

• Bronchospasm: Acute bronchospasm may occur when administered via inhalation; use with caution in patients with bronchial hyperreactivity (eg, asthma, chronic obstructive pulmonary disease).

• 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.

Concurrent drug therapy issues:

• 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.

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Powder, Inhalation:

Tyvaso DPI Maintenance Kit: 16 mcg (112 ea); 32 mcg (112 ea); 48 mcg (112 ea); 64 mcg (112 ea); 112 x 32MCG & 112 x48MCG (224 ea [DSC])

Tyvaso DPI Titration Kit: 16 & 32 & 48 MCG (252 ea); 112 x 16MCG & 84 x 32MCG (196 ea)

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,indigo carmine)]

Tablet Extended Release Therapy Pack, Oral:

Orenitram Month 1: 0.125 mg (126s) and 0.25 mg (42s) (168 ea) [contains fd&c blue #2 (indigotine,indigo carmine)]

Orenitram Month 2: 0.125 (126s) and 0.25 mg (210s) (336 ea) [contains fd&c blue #2 (indigotine,indigo carmine)]

Orenitram Month 3: 0.125 mg (126s), 0.25 mg (42s), and 1 mg (84s) (252 ea) [contains fd&c blue #2 (indigotine,indigo carmine)]

Generic Equivalent Available: US

May be product dependent

Pricing: US

Powder (Tyvaso DPI Maintenance Kit Inhalation)

16 mcg (per each): $246.48

32 mcg (per each): $246.48

48 mcg (per each): $246.48

64 mcg (per each): $246.48

Powder (Tyvaso DPI Titration Kit Inhalation)

16 & 32 & 48 mcg (per each): $109.55

112 x 16MCG &84 x 32MCG (per each): $140.85

Solution (Remodulin Injection)

20 mg/20 mL (per mL): $76.40

50 mg/20 mL (per mL): $191.00

100 mg/20 mL (per mL): $382.00

200 mg/20 mL (per mL): $763.99

Solution (Treprostinil Injection)

20 mg/20 mL (per mL): $68.76 - $72.58

50 mg/20 mL (per mL): $171.90 - $181.45

100 mg/20 mL (per mL): $343.80 - $362.90

200 mg/20 mL (per mL): $687.59 - $725.79

Solution (Tyvaso Inhalation)

0.6 mg/mL (per mL): $308.96

Solution (Tyvaso Refill Inhalation)

0.6 mg/mL (per mL): $308.96

Solution (Tyvaso Starter Inhalation)

0.6 mg/mL (per mL): $344.66

Tablet Extended Release Therapy Pack (Orenitram Month 1 Oral)

0.125 & 0.25 mg (per each): $10.42

Tablet Extended Release Therapy Pack (Orenitram Month 2 Oral)

0.125 & 0.25 mg (per each): $13.54

Tablet Extended Release Therapy Pack (Orenitram Month 3 Oral)

0.125 & 0.25 &1 mg (per each): $29.17

Tablet, controlled release (Orenitram Oral)

0.125 mg (per each): $8.33

0.25 mg (per each): $16.66

1 mg (per each): $66.66

2.5 mg (per each): $166.65

5 mg (per each): $333.31

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Dosage Forms: Canada

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

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, sodium chloride, sodium citrate]

Administration: Adult

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.

Dry powder inhalation: For inhalation only with the Tyvaso DPI inhaler. Administer using a single inhalation per cartridge; if prescribed dose is >64 mcg per treatment session, more than one cartridge will be needed per session. If refrigerated, allow blister strips and inhaler to warm to room temperature for 10 minutes prior to use. In between use, store inhaler with the mouthpiece attached and empty. Wipe outside of inhaler with a clean, dry cloth only, if needed; do not rinse or wash inhaler (always keep inhaler dry). Discard inhaler after 7 days of use.

Solution for 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) (Ref); 3 times daily dosing is less dependent on food intake (Ref). Swallow tablets whole; do not crush, split or chew; use only intact tablets.

Bariatric surgery: Tablet, extended release: Some institutions may have specific protocols that conflict with these recommendations; refer to institutional protocols as appropriate. Inhaled and injectable formulations are available. If safety and efficacy can be effectively monitored, no change in formulation or administration is required after bariatric surgery; however, close clinical monitoring is advised in the immediate and long-term postoperative period for the theoretical circumstance of reduced absorption after bariatric surgery. Abrupt discontinuation (or loss of absorption) may lead to worsening of pulmonary hypertension symptoms.

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 (Ref)), 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 (Ref). Abdominal fat is the most common site used but other sites used include hips, thighs, and underarms (Ref).

Administration: Pediatric

Note: Avoid treatment interruptions or rapid large dosage reductions. Immediate access to medication, a back-up pump, and infusion sets are essential to prevent treatment interruptions.

Adolescents >16 years: Parenteral:

Continuous 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% or better 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.

Continuous 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% or better accuracy of the programmed rate; and be positive pressure driven. The reservoir should be made of polyvinyl chloride, polypropylene, or glass. Based on experience in adults, 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 (Ref)), 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 (Ref). Abdominal fat is the most common site used, but other sites used include hips, thighs, and underarms (Ref).

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 improve exercise capacity or PAH associated with connective tissue disease.

Pulmonary hypertension associated with interstitial lung disease (inhalation only): Treatment of pulmonary hypertension associated with interstitial lung disease (WHO Group 3) to improve exercise ability.

Metabolism/Transport Effects

Substrate of CYP2C8 (major), CYP2C9 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential

Drug Interactions

Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.

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

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

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

Pregnancy Considerations

Information related to the use of treprostinil for the treatment of pulmonary arterial hypertension (PAH) in pregnant patients is limited (Lim 2019; Luo 2020; 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. Patients with PAH are encouraged to avoid becoming pregnant. When treatment is needed, agents with more information may be preferred for use in pregnant patients (ESC [Regitz-Zagrosek 2018]).

Breastfeeding Considerations

It is not known if treprostinil is present in breast milk.

Monitoring Parameters

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

Mechanism of Action

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

Pharmacokinetics (Adult Data Unless Noted)

Absorption:

Oral: Affected by food; AUCinf 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.

Protein binding: 91% to 96%.

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

Bioavailability: Inhalation solution: 64% to 72% (dose-dependent); SUBQ: 100%; Oral: ~17%.

Half-life elimination: Terminal: Dry powder inhaler: 27 to 50 minutes; SUBQ: ~4 hours.

Time to peak: Dry powder inhaler: Median: ~10 minutes; Inhalation solution: ~7 to 15 minutes; Oral: 4 to 6 hours.

Excretion:

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

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

Pharmacokinetics: Additional Considerations (Adult Data Unless Noted)

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.

Brand Names: International
International Brand Names by Country
For country code abbreviations (show table)

  • (AE) United Arab Emirates: Remodulin;
  • (AR) Argentina: Remodulin | Treprostinil;
  • (AT) Austria: Remodulin | Trepulmix | Trisuva;
  • (AU) Australia: Remodulin;
  • (BE) Belgium: Remodulin;
  • (CH) Switzerland: Remodulin | Treprostinil orpha;
  • (CO) Colombia: Remodulin | Timeraxone | Tyvaso;
  • (CZ) Czech Republic: Remodulin | Trepulmix | Tresuvi;
  • (DE) Germany: Remodulin | Treprostinil beta | Treprostinil Tillomed | Trepulmix | Tresuvi;
  • (EE) Estonia: Remodulin;
  • (ES) Spain: Treprostinilo dr. reddys | Treprostinilo Ferrer | Trepulmix | Tresuvi;
  • (FI) Finland: Remodulin | Treposa | Treprostinil Tillomed;
  • (FR) France: Remodulin | Treprostinil Reddy | Treprostinil Tillomed;
  • (GB) United Kingdom: Treprostinil | Trepulmix;
  • (GR) Greece: Remodulin;
  • (HR) Croatia: Remodulin;
  • (HU) Hungary: Remodulin | Tresuvi;
  • (IE) Ireland: Treposuvi;
  • (IL) Israel: Remodulin;
  • (IT) Italy: Remodulin | Treprostinil dr reddys | Trepulmix | Tresuvi;
  • (JP) Japan: Treprost;
  • (LT) Lithuania: Remodulin | Treprostinil Tillomed;
  • (LU) Luxembourg: Trepulmix;
  • (LV) Latvia: Remodulin | Treposuvi | Trepulmix;
  • (MX) Mexico: Remodulin;
  • (NL) Netherlands: Remodulin;
  • (NO) Norway: Tresuvi;
  • (PL) Poland: Remodulin | Trepulmix | Tresuvi;
  • (PR) Puerto Rico: Remodulin | Treprostinil;
  • (PT) Portugal: Remodulin | Tresuvi;
  • (SE) Sweden: Remodulin | Treprostinil Tillomed | Tresuvi;
  • (SI) Slovenia: Remodulin | Treprostinil amomed;
  • (SK) Slovakia: Tresuvi;
  • (TW) Taiwan: Remodulin
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