Treprostinil Monograph for Professionals - Drugs.com (original) (raw)
Brand names: Orenitram, Remodulin, Tyvaso
Drug class: Prostacyclin and Prostacyclin Derivatives
Chemical name: [[(1R,2R,3aS,9aS)-2,3,3a,4,9,9a-Hexahydro-2-hydroxy-1-[(3S)-3-hydroxyoctyl]-1H-benz[f]inden-5-yl]oxy]-acetic acid
Molecular formula: C23H34O5C23H34O5•C4H11NO2
CAS number: 81846-19-7
Introduction
Vasodilator; a synthetic analog of prostacyclin.
Uses for Treprostinil
Pulmonary Arterial Hypertension
Treprostinil is used parenterally (as a continuous sub-Q or IV infusion) for treatment of pulmonary arterial hypertension (PAH; WHO group 1) to reduce symptoms associated with exercise; efficacy established in patients with NYHA functional class II–IV (predominantly class III) PAH (idiopathic, heritable, or associated with connective tissue disease or congenital systemic-to-pulmonary shunts). Also used parenterally to reduce rate of clinical deterioration in patients who require conversion from epoprostenol therapy; carefully consider risks and benefits of each drug prior to transition.
Treprostinil is used by oral inhalation to improve exercise ability in patients with PAH; efficacy established principally in patients with NYHA functional class III PAH (idiopathic, heritable, or associated with connective tissue disease). Clinical experience with orally inhaled treprostinil is based primarily on short-term trials in patients receiving the drug as add-on therapy to bosentan or sildenafil.
Treprostinil diolamine is used orally (as extended-release tablets) to delay disease progression and improve exercise capacity in patients with PAH; efficacy established principally in patients with WHO functional class II–III PAH (idiopathic, heritable, or associated with connective tissue disease). Oral treprostinil may be more convenient than inhaled or parenteral formulations; however, studies have shown only modest benefits of oral treprostinil on exercise capacity. When the drug is used as the sole vasodilator in patients with PAH, the effect on exercise capacity is approximately 10% of the deficit, and the effect, if any, in combination with other vasodilators is probably even less.
Treprostinil and treprostinil diolamine have been designated orphan drugs by FDA for treatment of PAH.
Expert consensus guidelines recommend that all adult patients with symptomatic PAH be treated with established PAH-specific medications. IV, sub-Q, inhaled, or oral treprostinil is recommended among several options for treatment of WHO/NYHA class III or IV PAH. Selection of drug therapy should be based on disease severity (WHO/NYHA class) in addition to comorbid conditions, concomitant medications, adverse effects, route of administration, costs, and patient preferences.
Pulmonary Hypertension Associated with Interstitial Lung Disease
Treprostinil is used by oral inhalation for the treatment of pulmonary hypertension associated with interstitial lung disease (PH-ILD; WHO Group 3) to improve exercise ability. Effectiveness established primarily in patients with idiopathic interstitial pneumonia inclusive of idiopathic pulmonary fibrosis, combined pulmonary fibrosis and emphysema, and WHO Group 3 connective tissue disease.
Treprostinil Dosage and Administration
Administration
Treprostinil is administered by continuous sub-Q or IV infusion, or by oral inhalation.
Treprostinil diolamine is administered orally (as extended-release tablets).
IV or Sub-Q Administration
Treprostinil injection is administered by continuous sub-Q or IV infusion; manufacturer states that sub-Q administration preferred, but the drug may be administered by IV infusion if sub-Q route is not tolerated because of severe site pain or reaction.
The commercially available injection can be administered with or without further dilution. (See Dilution under Dosage and Administration.)
Sub-Q administration: Administer by continuous sub-Q infusion through a sub-Q catheter using a controlled-infusion device (ambulatory infusion pump). Consult manufacturer's labeling for pump specifications. To avoid potential interruptions in drug delivery, patient must have immediate access to backup infusion pump and sub-Q infusion sets (since abrupt withdrawal or sudden, large dosage reductions may result in worsening of PAH symptoms).
IV administration: Administer by continuous IV infusion through a permanent indwelling central venous catheter using a controlled-infusion device (ambulatory infusion pump). Consult manufacturer's labeling for pump specifications. A peripheral IV catheter (preferably placed in a large vein) may be used temporarily until central venous access can be established. To avoid potential interruptions in drug delivery, patient must have immediate access to backup infusion pump and IV infusion sets (since abrupt withdrawal or sudden, large dosage reductions may result in worsening of PAH symptoms).
Dilution
If further dilution is desired, may dilute with one of the following diluents: sterile water for injection, 0.9% sodium chloride injection, sterile diluent for treprostinil or Remodulin, or other similar approved high-pH glycine diluent (e.g., sterile diluent for Flolan or epoprostenol). Storage requirements and administration time limits vary based on the specific diluent used. (See Storage under Stability.)
Rate of Administration
Administer by continuous sub-Q or IV infusion at a calculated rate based on patient's dose (ng/kg per minute), weight (kg), and treprostinil concentration (mg/mL).
For administration of undiluted treprostinil, calculate rate using the following formula:
undiluted infusion rate (mL/hr) = [dose (ng/kg per minute) × weight (kg) × 0.00006] ÷ treprostinil vial strength (mg/mL)
For administration of diluted treprostinil injection, calculate concentration and volume using the following formulas:
Step 1: Calculate the concentration of diluted treprostinil solution:
diluted treprostinil concentration (mg/mL) = [dose (ng/kg per minute) × weight (in kg) × 0.00006] ÷ infusion rate (mL/hr)
Step 2: Calculate the volume of treprostinil solution needed to make the required diluted concentration for the given reservoir size:
volume of treprostinil injection (mL) = [diluted treprostinil concentration (mg/mL) ÷ treprostinil vial strength (mg/mL)] × total volume of diluted treprostinil in reservoir (mL)
The calculated volume of treprostinil injection is then added to the reservoir along with the sufficient volume of diluent to achieve the desired total volume in the reservoir.
Oral Inhalation Solution
Treprostinil inhalation solution is for oral inhalation only; do not ingest.
Administer using only the Tyvaso Inhalation System (ultrasonic, pulsed delivery device and related accessories). Patients should have access to a back-up Tyvaso Inhalation System device in the event of equipment malfunction. Instruct patients on proper administration (including dosing frequency), use, and maintenance of the device.
Administer 4 times daily during waking hours at equally spaced intervals of approximately 4 hours.
Prior to first inhalation session, transfer entire contents of a single 2.9-mL ampul of drug into medicine cup supplied by the manufacturer. One ampul should contain enough drug for one day of treatment. After each inhalation session, cap inhalation device and store upright with remaining drug inside for ≤24 hours. Discard medicine cup and any unused solution at end of each day and clean Tyvaso Inhalation System device according to manufacturer's instructions.
Do not mix with other drugs.
Do not allow solution to come into contact with the eyes or skin.
Oral Inhalation Powder
Administer in 4 separate, equally spaced treatment sessions (approximately 4 hours apart) per day, during waking hours. If the prescribed dose is >64 mcg per treatment session, more than 1 cartridge will be needed per session.
Use treprostinil inhalation powder only with the Tyvaso DPI inhaler and administer using a single inhalation per cartridge.
If refrigerated, cartridges and inhaler should be at room temperature for 10 minutes before use.
Patients should follow the instructions for use for operation and care of the Tyvaso DPI Inhaler. Between each of the 4 daily treatment sessions, store the inhaler with the mouthpiece attached and empty. Wipe the outside of the inhaler with a clean, dry cloth only, if needed. Do not rinse or wash the inhaler; always keep the inhaler dry. After 7 days of use, throw away the used inhaler into regular household trash.
Do not use the Tyvaso DPI Inhaler with other medications.
Oral Administration
Administer treprostinil diolamine extended-release tablets orally 2 or 3 times daily (approximately every 12 or 8 hours, respectively) with food. A three-times daily dosing regimen may produce less variation in drug concentrations, reduce adverse effects, and improve tolerability.
Do not split, crush, or chew tablets.
If a dose is missed, take as soon as it is remembered; if a patient misses ≥2 doses, restart therapy at a lower dosage and retitrate.
Advise patients that the tablet shell in the extended-release tablets is designed to remain intact during passage through the GI tract and may be passed in the stool.
Dosage
Available as treprostinil (injection, oral inhalation) and treprostinil diolamine (extended-release tablets); dosage expressed in terms of treprostinil.
Adults
PAH
Continuous Sub-Q or IV Infusion
Initially, 1.25 ng/kg per minute. If initial dosage is not tolerated, reduce infusion rate to 0.625 ng/kg per minute.
Adjust dosage to achieve symptomatic improvement while minimizing adverse effects. Increase infusion rate based on clinical response in increments of 1.25 ng/kg per minute at weekly intervals for the first 4 weeks and then 2.5 ng/kg per minute at weekly intervals for the remaining duration of the infusion.
Several months may be required to identify optimal dosage.
For transition to an implantable IV infusion pump, the initial dose should be the same as the current dose the patient is receiving using the external infusion pump at the time of transition.
Oral Inhalation Solution
Initially, 18 mcg (3 breaths) per treatment session 4 times daily. If initial dosage not tolerated, reduce to 1 or 2 breaths per treatment session, then increase up to 3 breaths as tolerated. Continue to increase dose by 3 breaths per treatment session every 1–2 weeks until target maintenance dosage of 9–12 breaths per treatment session, 4 times daily is attained. If unable to titrate to target dosage, maintain patient on highest possible tolerated dosage.
If a treatment session is missed or interrupted, resume therapy as soon as possible at usual dosage.
Oral Inhalation Powder
Initially, one 16-mcg cartridge per treatment session, 4 times daily. Increase dosage by an additional 16 mcg per treatment session at intervals of approximately 1 to 2 weeks to reach maintenance dosage, Target maintenance dosage is usually 48 mcg to 64 mcg per session.
If titration is not tolerated, continue treatment at the highest tolerated dose.
If a scheduled treatment session is missed, resume therapy as soon as possible at the usual dosage.
Transition from treprostinil oral inhalation solution to the inhalation powder: For patients transitioning from orally inhaled treprostinil solution to orally inhaled treprostinil powder, the following dosage regimens provide similar exposure.
| Treprostinil Oral Inhalation Powder (Tyvaso DPI) Cartridge Strength | Treprostinil Oral Inhalation Solution (Tyvaso) Number of Breaths |
|---|---|
| 16 mcg | ≤5 (≤30 mcg) |
| 32 mcg | 6 to 7 (36 to 42 mcg) |
| 48 mcg | 8 to 10 (48 to 60 mcg) |
| 64 mcg | 11 to 12 (66 to 72 mcg) |
Oral
Initially, 0.25 mg twice daily (approximately every 12 hours) or 0.125 mg 3 times daily (approximately every 8 hours) as extended-release tablets. Increase dosage by 0.25 or 0.5 mg twice daily or 0.125 mg 3 times daily no more frequently than every 3–4 days. Appropriate maintenance dosage determined by tolerability. Consider slower titration for patients not tolerating such increases. Decrease dosage in increments of 0.125 mg 3 times daily or 0.25 mg twice daily if intolerable adverse effects occur. Avoid abrupt discontinuance.
Dosage reductions recommended when used concomitantly with potent CYP2C8 inhibitors.
Conversion from Epoprostenol to Sub-Q or IV Treprostinil Therapy
Continuous Sub-Q or IV Infusion
Perform transition in a hospital setting where patient can be closely monitored.
Initiate treprostinil at a dosage equivalent to 10% of the current epoprostenol dosage; gradually increase treprostinil dosage while simultaneously decreasing dosage of epoprostenol. Manufacturer recommends the following titration protocol:
| Step | Epoprostenol Dosage | Treprostinil Dosage |
|---|---|---|
| 1 | Unchanged | 10% of starting epoprostenol dosage |
| 2 | 80% of starting epoprostenol dosage | 30% of starting epoprostenol dosage |
| 3 | 60% of starting epoprostenol dosage | 50% of starting epoprostenol dosage |
| 4 | 40% of starting epoprostenol dosage | 70% of starting epoprostenol dosage |
| 5 | 20% of starting epoprostenol dosage | 90% of starting epoprostenol dosage |
| 6 | 5% of starting epoprostenol dosage | 110% of starting epoprostenol dosage |
| 7 | 0 | 110% of starting epoprostenol dosage + additional 5–10% increments as needed |
Individually titrate treprostinil dosage to allow transition from epoprostenol therapy while balancing symptoms of PAH and prostacyclin-related adverse effects. Manage any increase in PAH symptoms (e.g., shortness of breath) by initially increasing dosage of treprostinil; manage symptoms of excess prostacyclin (e.g., facial flushing, headache, jaw pain) by initially decreasing dosage of epoprostenol.
Other transition protocols have been used successfully. Limited data indicate that patients whose therapy is transitioned from epoprostenol to IV treprostinil appear to require higher average dosages of treprostinil to maintain the same clinical benefits.
Transitioning from Parenteral to Oral Treprostinil
Continuous Sub-Q or IV Infusion to Oral
Decrease dosage of sub-Q or IV treprostinil while simultaneously increasing dosage of oral treprostinil. May reduce dosage of parenteral treprostinil up to 30 ng/kg per minute per day and simultaneously increase dosage of oral treprostinil up to 6 mg per day (2 mg administered 3 times daily) if tolerated. The following equation can be used to estimate a comparable total daily dose of oral treprostinil using current parenteral treprostinil dose:
oral treprostinil total daily dose (mg)= 0.0072 × parenteral treprostinil dose (ng/kg per minute) × weight (kg)
Planned Short-term Interruption of Oral Therapy
Oral to Continuous Sub-Q or IV Infusion
In patients unable to take oral medications, consider temporary sub-Q or IV infusion of treprostinil. Use the following formula to calculate total daily dose of parenteral treprostinil using current oral dose:
parenteral treprostinil (ng/kg per minute)= [139 × oral treprostinil total daily dose (mg)] ÷ weight (kg)
Pulmonary Hypertension Associated with Interstitial Lung Disease
Oral Inhalation Solution
Initially, 18 mcg (3 breaths) per treatment session. If this initial dosage is not tolerated, reduce dosage to 1 or 2 breaths per treatment session, then subsequently increase to 3 breaths as tolerated. Increase dosage further by 3 breaths per treatment session every 1–2 weeks until the target maintenance dosage of 9–12 breaths per treatment session, 4 times daily, is achieved.
Patients who are unable to reach the target dosage due to adverse effects should be maintained on the highest possible tolerated dosage.
If a treatment session is missed or interrupted, resume therapy as soon as possible at the usual dosage.
Oral Inhalation Powder
The recommended initial dosage of orally inhaled treprostinil powder is one 16 mcg cartridge per treatment session, 4 times daily. To reach maintenance dosage, increase dosage of orally inhaled treprostinil powder by an additional 16 mcg per treatment session at intervals of approximately 1 to 2 weeks. The target maintenance dosage is usually 48 mcg to 64 mcg per session.
If titration is not tolerated, continue treatment at the highest tolerated dose.
If a scheduled treatment session is missed, resume therapy as soon as possible at the usual dosage.
Transition from treprostinil oral inhalation solution to the inhalation powder: For patients transitioning from orally inhaled treprostinil solution to orally inhaled treprostinil powder, the following dosage regimens provide similar exposure.
| Treprostinil Oral Inhalation Powder (Tyvaso DPI) Cartridge Strength | Treprostinil Oral Inhalation Solution (Tyvaso) Number of Breaths |
|---|---|
| 16 mcg | ≤5 (≤30 mcg) |
| 32 mcg | 6 to 7 (36 to 42 mcg) |
| 48 mcg | 8 to 10 (48 to 60 mcg) |
| 64 mcg | 11 to 12 (66 to 72 mcg) |
Special Populations
Hepatic Impairment
In patients with mild to moderate hepatic impairment, decrease initial dosage of sub-Q or IV treprostinil to 0.625 ng/kg per minute (based on ideal body weight).
Titrate orally inhaled treprostinil solution and powder slowly in patients with hepatic impairment because of the possibility of increased systemic exposure to the drug.
In patients with mild hepatic impairment (Child-Pugh class A), initiate oral treprostinil at a dosage of 0.125 mg twice daily and increase in increments of 0.125 mg twice daily every 3–4 days.
Renal Impairment
No dosage adjustments are required in patients with renal impairment; treprostinil is not cleared by dialysis.
Geriatric Patients
Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy.
Cautions for Treprostinil
Contraindications
- Parenteral or orally inhaled treprostinil: None known.
- Oral treprostinil: Severe hepatic impairment (Child-Pugh class C).
Warnings/Precautions
Risk of Infection with IV Administration
Risk of serious and potentially fatal blood stream infections and sepsis associated with drug delivery system (external infusion pump with a long-term indwelling central venous catheter). Patients must use strict aseptic technique in routine catheter care and in the preparation and administration of treprostinil. Sub-Q administration is preferred when the drug is given parenterally.
Use of a high-pH glycine diluent (e.g., Remodulin [treprostinil] sterile diluent for injection, Flolan [epoprostenol sodium] sterile diluent for injection, sterile diluent for generic epoprostenol sodium for injection) with IV treprostinil associated with a lower incidence of blood stream infections compared with neutral diluents (e.g., sterile water for injection, 0.9% sodium chloride injection).
Precautions Related to Orally Inhaled Treprostinil
Like other inhaled prostaglandins, may cause acute bronchospasm. Patients with asthma or COPD, or other bronchial hyperreactivity, are at increased risk. Ensure that such patients are treated optimally for reactive airway disease prior to and during treatment with treprostinil.
Precautions Related to Treprostinil Tablets
The extended-release tablet shell of oral treprostinil (Orenitram) does not dissolve and may become lodged in a diverticulum in patients with diverticulosis.
Adequate Patient Evaluation and Monitoring
Because of the complex nature of the disease and potential for treatment-related complications, experts recommend referral of PAH patients to specialized centers experienced in the management of pulmonary vascular diseases.
Withdrawal of Therapy
Avoid abrupt withdrawal or sudden, large dosage reductions; may result in worsening of PAH symptoms.
Risk of Bleeding
Possible increased risk of bleeding, particularly in patients receiving anticoagulant therapy.
Risk of Symptomatic Hypotension
Risk of symptomatic hypotension in patients with low systemic arterial pressure.
Specific Populations
Pregnancy
Limited data are available; insufficient to evaluate the risk associated with adverse developmental outcomes. Consideration also must be given to the risks to the mother and the fetus associated with PAH.
Lactation
Not known whether treprostinil is distributed into milk or whether the drug has any effects on the breastfed infant or on milk production.
Pediatric Use
Parenteral treprostinil: Safety and efficacy not established in children or adolescents ≤16 years of age. Clinical studies did not include sufficient numbers of patients ≤16 years of age to determine whether pediatric patients respond differently than adults. Titrate dosage carefully.
Oral or orally inhaled treprostinil: Safety and efficacy not established in patients <18 years of age.
Geriatric Use
Clinical studies of parenteral treprostinil did not include sufficient numbers of patients ≥65 years of age to determine whether geriatric patients respond differently than younger patients.
Clinical studies of orally inhaled treprostinil solution in patients with PAH and PH-ILD, noted that the treatment effects and safety profile observed in geriatric patients were similar to younger patients.
Clinical studies of treprostinil tablets in patients ≥65 years of age demonstrated slightly higher absolute and relative adverse event rates compared to younger patients.
Select dosage carefully in geriatric patients. Consider greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly.
Hepatic Impairment
Adjust dosage of sub-Q or IV treprostinil in patients with mild to moderate hepatic impairment.
Adjust dosage of oral treprostinil in patients with mild hepatic impairment. Avoid use of oral treprostinil in patients with moderate hepatic impairment; contraindicated in patients with severe hepatic impairment.
Parenteral and orally inhaled treprostinil not studied in patients with severe hepatic impairment.
Renal Impairment
Pharmacokinetics of oral treprostinil not substantially altered in patients with severe or end-stage renal disease; oral treprostinil not removed by dialysis.
Common Adverse Effects
Sub-Q therapy: Infusion site pain and reaction (e.g., erythema, induration, rash).
IV therapy: Arm swelling, paresthesias, hematoma, pain.
Sub-Q and IV treprostinil: Headache, diarrhea, nausea, jaw pain, vasodilation, dizziness, edema, pruritus, hypotension.
Orally inhaled solution: Cough and throat irritation; headache; GI effects; muscle, jaw, or bone pain; flushing; syncope.
Orally inhaled powder: Cough, headache, shortness of breath, and nausea.
Tablets: Headache, diarrhea, nausea, flushing, jaw pain, extremity pain, hypokalemia, abdominal discomfort.
Drug Interactions
Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes
Extensively metabolized, principally by CYP2C8. Does not inhibit CYP1A2, 2A6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A in vitro. Does not induce CYP1A2, 2B6, 2C9, 2C19, or 3A in vitro. Pharmacokinetic interactions with drugs metabolized by the CYP enzyme system are considered unlikely.
CYP2C8 inhibitors: May increase exposure to treprostinil. When used concomitantly with a potent CYP2C8 inhibitor, reduce initial oral treprostinil dosage to 0.125 mg twice daily; increase dosage by 0.125 mg twice daily not more frequently than every 3–4 days as tolerated. Not determined if the changes in exposure of treprostinil with inhibitors or inducers of CYP2C8 observed for the oral administration would be similar when administered via the inhalation or parenteral route.
CYP2C8 inducers: May decrease exposure to treprostinil.
Specific Drugs
| Drug | Interaction | Comments |
|---|---|---|
| Acetaminophen | Pharmacokinetics of oral or sub-Q treprostinil not substantially affected | |
| Anticoagulants | Potential for increased risk of bleeding Warfarin: No clinically important interaction observed | |
| Antihypertensive agents | Additive hypotensive effect possible | |
| Bosentan | Pharmacokinetic interaction not observed with oral treprostinil | Dosage adjustment of oral treprostinil not necessary |
| Diuretics | Additive hypotensive effect possible | |
| Esomeprazole | Pharmacokinetic interaction not observed with oral treprostinil | Dosage adjustment of oral treprostinil not necessary |
| Fluconazole | Pharmacokinetics of oral or sub-Q treprostinil not substantially affected | Dosage adjustment of oral treprostinil not necessary |
| Gemfibrozil | Increased systemic exposure to oral formulation of treprostinil; possible increased risk of adverse effects with treprostinil | Reduce initial oral treprostinil dosage to 0.125 mg twice daily; increase dosage by 0.125 mg twice daily every 3–4 days as tolerated |
| Rifampin | Decreased systemic exposure to oral formulation of treprostinil; possible reduced efficacy of treprostinil | Dosage adjustment of oral treprostinil not necessary |
| Sildenafil | Pharmacokinetic interaction not observed with oral treprostinil | Dosage adjustment of oral treprostinil not necessary |
| Vasodilating agents | Additive hypotensive effect possible |
Treprostinil Pharmacokinetics
Absorption
Bioavailability
Rapidly and completely absorbed after sub-Q infusion; absolute bioavailability is 100%.
Sub-Q and IV treprostinil are bioequivalent at steady-state dosage of 10 ng/kg per minute.
Mean absolute systemic bioavailability following oral inhalation solution is approximately 64 and 72% following doses of 18 and 36 mcg, respectively.
Systemic exposure of orally inhaled powder post-inhalation was approximately proportional to the doses administered (16 to 64 mcg).
Absolute oral bioavailability of treprostinil diolamine is approximately 17%. Bioavailability and peak plasma concentrations of oral treprostinil increased when administered following a high-fat, high-calorie meal.
Plasma Concentrations
Steady-state concentrations occur in approximately 10 hours following sub-Q administration.
Peak plasma concentrations of treprostinil achieved approximately 10–15 minutes after oral inhalation.
Peak plasma concentrations of treprostinil occur approximately 4–6 hours following oral administration. Steady-state concentrations of oral treprostinil occur approximately 1–2 days following twice- and thrice-daily dosing regimens.
Special Populations
Peak plasma concentrations of sub-Q treprostinil increased by twofold or fourfold in patients with portopulmonary hypertension and mild or moderate hepatic impairment, respectively, compared with healthy individuals.
In patients with mild, moderate, or severe hepatic impairment, peak plasma concentrations and systemic exposure of oral treprostinil increased by 1.6-, 4-, or 4.8-fold and 2.1-, 4.8-, or 7.6-fold, respectively, compared with individuals with normal hepatic function.
Distribution
Plasma Protein Binding
91–96%.
Elimination
Metabolism
Extensively metabolized in liver, principally by CYP2C8 and to a lesser extent by CYP2C9; 5 metabolites described thus far.
Elimination Route
Following oral administration, unchanged drug is excreted in urine (0.19%) and feces (1.13%); metabolites are excreted in urine (64%).
Following sub-Q administration, excreted in urine (79%) and feces (13%); only 4% is excreted unchanged in urine.
Half-life
Biphasic; terminal half-life of approximately 4 hours (following sub-Q administration).
Mean terminal half-life ranged from 27 to 50 minutes after a single dose of orally inhaled powder.
Special Populations
In patients with hepatic insufficiency, clearance was reduced by up to 80% compared with healthy adults.
In patients with renal impairment, clearance may be reduced since treprostinil and its metabolites are eliminated principally by the kidneys.
Stability
Storage
Parenteral
Injection
25°C (may be exposed to 2–30°C).
May use vial for ≤30 days after initial entry.
May store undiluted drug in a single reservoir (syringe) for ≤72 hours at 37°C.
Solutions of treprostinil diluted with high-pH glycine diluent (sterile diluent for treprostinil or Remodulin, sterile diluent for epoprostenol or Flolan): Stable at room temperature for ≤14 days at concentrations as low as 0.004 mg/mL (4 mcg/mL). May administer diluted drug for up to 48 hours at 40°C.
Solutions of treprostinil diluted with sterile water or 0.9% sodium chloride for injection: Stable at room temperature for ≤4 hours or under refrigeration for ≤24 hours. May administer diluted drug for up to 48 hours at 40°C.
Oral Inhalation
Inhalation Solution
25°C (may be exposed to 15–30°C) for unopened ampuls in unopened foil pouch.
Use ampuls within 7 days after opening foil pouch; store unopened ampuls in pouch until use because drug is light-sensitive.
Once drug solution is placed in medicine cup in inhalation device, use within 24 hours. Discard any unused solution at end of day.
Inhalation Powder
2–25°C (excursions permitted).
Oral
Extended-release Tablets
20–25°C (may be exposed to 15–30°C).
Actions
- Pharmacologic actions (e.g., vasodilation of pulmonary and systemic arterial vascular beds, inhibition of platelet aggregation) similar to those of epoprostenol.
- In animals, vasodilatory effects reduce right and left ventricular afterload and increase cardiac output and stroke volume.
- Causes dose-related negative inotropic and lusitropic effect.
- Orally inhaled treprostinil solution exhibits high pulmonary selectivity and produces sustained pulmonary vasodilation without substantial systemic effects.
- Modest and temporary effects on QTc interval prolongation observed following single oral inhalation solution doses; possibly an artifact of the rapidly changing heart rate produced by the drug. Effects of oral or parenteral treprostinil on QTc not studied.
Advice to Patients
- Instruct patients in the proper administration of orally inhaled treprostinil solution or powder, including dosing, setup, operation, cleaning, and maintenance of the Tyvaso Inhalation System or Tyvaso DPI Inhaler.
- Advise patients to have immediate access to a backup pump and infusion sets (when administered parenterally) or a backup Tyvaso Inhalation System device (when administered via oral inhalation) in order to avoid potential interruptions in drug therapy secondary to drug delivery device failure or equipment malfunction.
Advise patients to avoid skin or eye contact with treprostinil oral inhalation solution. If skin or eye contact occurs, instruct patients to immediately rinse affected area with water. - Advise patients to only use treprostinil powder cartridges with the Tyvaso DPI Inhaler; discard inhaler and replace with a new inhaler every 7 days.
- Inform patients to swallow treprostinil extended-release oral tablets whole with food. Do not split, chew, crush, or break; do not take a tablet that is damaged or broken.
- Inform patients that the biologically inert components of the extended-release tablets remain intact during GI transit and are eliminated in the feces as an insoluble shell.
- Advise patients and caregivers to seek medical attention if they experience signs or symptoms of abrupt withdrawal of therapy or suspect a pump malfunction during treatment with treprostinil injection.
- Inform patients that in the event that a scheduled treatment session with orally inhaled treprostinil is missed or interrupted, resume therapy as soon as possible.
- Inform patients taking treprostinil extended-release oral tablets that abrupt discontinuation of therapy could result in worsening of PAH symptoms.
- Advise patients and caregivers to seek medical attention if they experience signs or symptoms of an overdose of treprostinil.
- Advise females to inform their clinicians if they are or plan to become pregnant or plan to breast-feed.
- Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.
- Importance of informing patients of other important precautionary information. (See Cautions.)
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Preparations
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Treprostinil diolamine extended-release tablets (Orenitram), treprostinil injection (Remodulin), treprostinil inhalation solution (Tyvaso), and treprostinil inhalation powder (Tyvaso DPI) are available only through specialty pharmacies. For additional information, the manufacturer should be contacted at 877-864-8437.
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Treprostinil
| Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
| Oral Inhalation | Powder, for oral inhalation | 16 mcg per cartridge | Tyvaso DPI (available as single-dose cartridges for use with the Tyvaso DPI inhaler) | United Therapeutics |
| 32 mcg per cartridge | Tyvaso DPI (available as single-dose cartridges for use with the Tyvaso DPI inhaler) | United Therapeutics | ||
| 48 mcg per cartridge | Tyvaso DPI (available as single-dose cartridges for use with the Tyvaso DPI inhaler) | United Therapeutics | ||
| 64 mcg per cartridge | Tyvaso DPI (available as single-dose cartridges for use with the Tyvaso DPI inhaler) | United Therapeutics | ||
| Solution, for oral inhalation | 0.6 mg/mL (1.74 mg) | Tyvaso (available with Tyvaso Inhalation System) | United Therapeutics | |
| Parenteral | Injection, for continuous sub-Q or IV infusion via controlled-infusion device only | 1 mg/mL* | Remodulin | United Therapeutics |
| Treprostinil Injection | ||||
| 2.5 mg/mL* | Remodulin | United Therapeutics | ||
| Treprostinil Injection | ||||
| 5 mg/mL* | Remodulin | United Therapeutics | ||
| Treprostinil Injection | ||||
| 10 mg/mL* | Remodulin | United Therapeutics | ||
| Treprostinil Injection | ||||
| 20 mg/mL | Remodulin | United Therapeutics |
Treprostinil Diolamine
| Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
| Oral | Tablets, extended-release | 0.125 mg (of treprostinil) | Orenitram | United Therapeutics |
| 0.25 mg (of treprostinil) | Orenitram | United Therapeutics | ||
| 1 mg (of treprostinil) | Orenitram | United Therapeutics | ||
| 2.5 mg (of treprostinil) | Orenitram | United Therapeutics | ||
| 5 mg (of treprostinil) | Orenitram | United Therapeutics |
AHFS DI Essentials™. © Copyright 2024, Selected Revisions April 26, 2023. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.