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Tyvaso Drug Information /
treprostinil - Drug Summary
Prostacyclin Analogs/Receptor Agonists for PAH
Analog of epoprostenol (prostacyclin) for treatment of pulmonary hypertension and pulmonary hypertension associated with interstitial lung disease
Given by oral inhalation, continuous subcutaneous or IV infusion, and oral extended-release tablet
Major advantage over IV epoprostenol is ease of use and less potential for serious infections when used subcutaneously
Orenitram, Remodulin, Tyvaso, Tyvaso Refill Kit, Tyvaso Starter Kit
Orenitram Oral Tab ER: 0.125mg, 0.25mg, 1mg, 2.5mg, 5mg
Remodulin/Treprostinil/Treprostinil Sodium Intravenous Inj Sol: 1mg, 1mL, 2.5mg, 5mg, 10mg
Remodulin/Treprostinil/Treprostinil Sodium Subcutaneous Inj Sol: 1mg, 1mL, 2.5mg, 5mg, 10mg
Tyvaso/Tyvaso Refill Kit/Tyvaso Starter Kit Respiratory (Inhalation) Sol: 0.6mg, 1mL
For the treatment of pulmonary hypertension and pulmonary hypertension associated interstitial lung disease.
For the treatment of pulmonary arterial hypertension (WHO Group 1) to diminish symptoms associated with exercise.
Intravenous or Subcutaneous infusion dosage
NOTE: Studies establishing effectiveness of treprostinil injection included patients with NYHA Functional Class II to IV symptoms and etiologies of idiopathic or heritable pulmonary arterial hypertension (PAH) (58%), PAH associated with congenital systemic-to-pulmonary shunts (23%), or PAH associated with connective tissue diseases (19%).
NOTE: Treprostinil injection is administered via continuous subcutaneous or IV infusion. Due to the risks associated with chronic central venous catheters, the subcutaneous route is preferred, but IV infusion is possible if the subcutaneous route is not tolerated because of severe injection site pain or reaction.
1.25 ng/kg/minute subcutaneous or IV continuous infusion initially. If dose not tolerated, reduce to 0.625 ng/kg/minute. Increase dose by increments no greater than 1.25 ng/kg/minute per week for first 4 weeks, then no greater than 2.5 ng/kg/minute per week for the remaining duration of infusion, depending upon clinical response; if tolerated, the dose may be adjusted more frequently. Avoid abrupt discontinuation of the infusion; however, if the infusion is temporarily stopped (i.e., for a few hours), it may be restarted at the previously used dose and rate. If the infusion is stopped for a longer period, it may need to be re-titrated when restarting treprostinil. In a 12-week pivotal trial, the mean infusion rate at the end of the study was 9.3 ng/kg/minute subcutaneously. In an open-label extension trial, with a mean duration of 1.6 years (Max exposure: 4.6 years), 29% of patients (n = 860) achieved a dose of at least 40 ng/kg/minute (Max: 290 ng/kg/minute) with a similar safety profile to the 12-week study. In an unpublished study, treprostinil was administered safely for an average of 422 days. Dosage selection and titration should be cautious in the elderly, considering the greater risk for decreased renal, hepatic, or cardiac function.
Adolescents 17 years
1.25 ng/kg/minute subcutaneous or IV continuous infusion initially. If dose not tolerated, reduce to 0.625 ng/kg/minute. Increase dose by increments no greater than 1.25 ng/kg/minute per week for first 4 weeks, then no greater than 2.5 ng/kg/minute per week for the remaining duration of infusion, depending upon clinical response; if tolerated, the dose may be adjusted more frequently. Avoid abrupt discontinuation of the infusion; however, if the infusion is temporarily stopped (i.e., for a few hours), it may be restarted at the previously used dose and rate. If the infusion is stopped for a longer period, it may need to be re-titrated when restarting treprostinil. In a 12-week pivotal trial, the mean infusion rate at the end of the study was 9.3 ng/kg/minute subcutaneously. In an open-label extension trial, with a mean duration of 1.6 years (Max exposure: 4.6 years), 29% of patients (n = 860) achieved a dose of at least 40 ng/kg/minute (Max: 290 ng/kg/minute) with a similar safety profile to the 12-week study. In an unpublished study, treprostinil was administered safely for an average of 422 days.
Children and Adolescents 16 years and younger†
2 ng/kg/minute subcutaneous or IV continuous infusion, initially. A stable dose is usually between 50 to 80 ng/kg/minute; maximum dose is not known. There is limited experience with treprostinil in pediatric patients. One small retrospective analysis describes the use of IV treprostinil in 13 patients 3 years of age and older who were transitioned from a stable dose of IV epoprostenol. In this report, IV treprostinil was initiated at the patients' original epoprostenol dose and titrated to a goal of 1.25 to 1.75 times the epoprostenol dose (see dosage for patients transitioning from epoprostenol to treprostinil below for transition methods). The mean treprostinil doses immediately after transition from epoprostenol, 6 months after the transition, and 12 months after the transition were 51.4 +/- 20 ng/kg/minute, 79 +/- 35 ng/kg/minute, and 86 +/- 40 ng/kg/minute respectively. In addition to this retrospective report, a limited number of patients 8 years of age and older were included in some pivotal trials. In these trials, pediatric data were not analyzed separately from adult data. The initial dose was 1.25 ng/kg/minute via continuous subcutaneous infusion and was increased based on clinical symptoms and adverse effects. The earliest study reported a mean dose of 9.3 ng/kg/minute subcutaneously at 12 weeks ; however, a long-term study reported mean subcutaneous infusion rates of 26, 36, 42, and 42 ng/kg/minute at 1, 2, 3, and 4 years respectively.
Oral inhalation dosage
NOTE: Studies establishing effectiveness of inhaled treprostinil included predominately patients with NYHA Functional Class III symptoms and etiologies of idiopathic or heritable pulmonary arterial hypertension (PAH) (56%) or PAH associated with connective tissue diseases (33%).
NOTE: While there are long-term data on use of parenteral treprostinil, nearly all controlled clinical experience with inhaled treprostinil has been in addition to a background of bosentan or sildenafil. The controlled clinical experience was limited to 12 weeks in duration.
Initially, 3 breaths (18 mcg) inhaled via the Tyvaso Inhalation System 4 times daily approximately 4 hours apart during waking hours; the patient should take 3 breaths during each treatment session. Each treatment session will take 2 to 3 minutes. If 3 breaths are not tolerated, reduce to 1 or 2 breaths and subsequently increase to 3 breaths, as tolerated. Increase dose by an additional 3 breaths per treatment session at approximately 1 to 2 week intervals, if tolerated, until the target dose of 9 to 12 breaths (54 to 72 mcg) per treatment session is reached. If target dose cannot be reached due to adverse effects, continue at the highest tolerated dose. The maximum recommended dosage is 12 breaths per treatment session administered 4 times daily. In general, dosage selection and titration should be cautious in the elderly, considering the greater risk for decreased renal, hepatic, or cardiac function. NOTE: The effects of the drug diminish over the minimum recommended dosing interval of 4 hours; treatment timing can be adjusted for planned activities.
For patients transitioning from epoprostenol to intravenous or subcutaneous treprostinil.
NOTE: The transition from epoprostenol to treprostinil should take place in a hospital with continuous observation to response (e.g., walking distance and signs and symptoms of disease progression).
Transition from epoprostenol to treprostinil is accomplished by initiating the infusion of treprostinil and increasing it, while simultaneously reducing the dose of intravenous 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. Step 1: Initiate an infusion of treprostinil that is 10% of the current epoprostenol dose; continue with the same epoprostenol dose; Step 2: Increase the treprostinil dose to 30% of the initial epoprostenol dose; reduce the epoprostenol dose to 80% of the initial dose; Step 3: Increase the treprostinil dose to 50% of the initial epoprostenol dose; reduce the epoprostenol dose to 60% of the initial dose; Step 4: Increase the treprostinil dose to 70% of the initial epoprostenol dose; reduce the epoprostenol dose to 40% of the initial dose; Step 5: Increase the treprostinil dose to 90% of the initial epoprostenol dose; reduce the epoprostenol dose to 20% of the initial dose; Step 6: Increase the treprostinil dose to 110% of the initial epoprostenol dose; reduce the epoprostenol dose to 5% of the initial dose; Step 7: Increase the treprostinil dose by 5 to 10% increments as needed; discontinue epoprostenol. Individually titrate the dose of treprostinil in a manner that balances prostacyclin-limiting adverse events. During the transition, increases in PAH symptoms (e.g., fatigue, dyspnea, chest pain, and pallor) should first be managed by increasing the dose of treprostinil; symptoms associated with prostacyclin and prostacyclin analogs (e.g., facial flush, headache, jaw pain, abdominal cramping, diarrhea, and hypotension) should first be managed by decreasing the dose of epoprostenol. Specific recommendations for amount of time that should be allowed for each step are not available from the manufacturer; however, one study suggests 6 hours should lapse before each increase in treprostinil dose (authors used subcutaneous treprostinil), while another suggests the entire transition should occur over a 24 to 48 hour period (authors used IV treprostinil). Alternatively, while receiving IV epoprostenol, one study suggests initiating a subcutaneous infusion of treprostinil at no more than 50% of the initial epoprostenol infusion (5 ng/kg/minute or less). Further dose increases of no more than 50% of the current treprostinil dose can occur after a minimum of 6 hours. Epoprostenol infusion is simultaneously, but slowly decreased by increments of no more than 2 ng/kg/minute. Decreases in epoprostenol dose are based on adverse symptoms of prostacyclin. In this study, 21 to 96 hours were necessary for successful transition to treprostinil. At completion of transition, doses of treprostinil range from 3 to 65 ng/kg/minute (mean = 22 ng/kg/minute).
Children† and Adolescents†
NOTE: Both transition methods described here are significantly more rapid than FDA-approved for adult patients. Based on the half-life of treprostinil, rapid titrations may not allow time for steady state concentrations to be reached. Use caution and carefully monitor patient's clinical status during entire transition period. Very limited data are available. One retrospective analysis describes 2 methods of transitioning pediatric patients receiving stable doses of IV epoprostenol to IV treprostinil. During the slow transition method (n = 7), IV treprostinil was initiated at the original epoprostenol dose, and the epoprostenol dose was decreased by half. Every 1 to 2 hours, the epoprostenol dose was decreased by 10 ng/kg/minute and the treprostinil dose was increased by 5 to 10 ng/kg/minute. The target treprostinil dose was 1.25 to 1.75 times the epoprostenol dose that the patient was receiving prior to the transition. During the rapid transition method (n = 6), the epoprostenol infusion was discontinued and the treprostinil infusion was initiated at the previous epoprostenol dose. The treprostinil dose was increased by 5 to 10 ng/kg/minute every 20 to 60 minutes, depending on clinical symptoms and adverse effects. The target treprostinil dose was 1.25 to 1.75 times the epoprostenol dose that the patient was receiving prior to the transition. At the time of transition, the mean epoprostenol dose was 36 +/- 13 ng/kg/minute IV, and 12 to 24 hours after transition, the mean treprostinil dose was 51.4 +/- 20 ng/kg/minute. Although both methods were reported to be well tolerated, the authors warn that the slower transition may be safer for patients with severe disease. A stable dose is usually between 50 to 80 ng/kg/minute; maximum dose is unknown.
For patients transitioning from intravenous or subcutaneous treprostinil to oral treprostinil.
For patients already receiving intravenous or subcutaneous treprostinil, use the following equation to estimate a comparable total daily dose of oral treprostinil: Total Daily Oral Treprostinil Dose = 0.0072 x Intravenous or Subcutaneous Treprostinil Dose (ng/kg/minute) x Weight (kg). Reduce the dose of intravenous or subcutaneous treprostinil by up to 30 ng/kg/minute per day while simultaneously increasing the dose of oral treprostinil up to 6 mg per day (2 mg PO 3 times daily), if tolerated.
For temporary subcutaneous or intravenous treprostinil infusion in patients unable to take oral treprostinil due to a planned, short-term treatment interruption.
Intravenous or Subcutaneous dosage
For patients already receiving oral treprostinil, use the following equation to calculate the parenteral dose: Intravenous/Subcutaneous Treprostinil Dose (ng/kg/minute) = 139 x Total Daily Oral Treprostinil Dose (mg)/Weight (kg).
For patients transitioning from an external infusion pump to an implantable intravenous infusion pump.
Intravenous infusion dosage
For patients already receiving IV or subcutaneous treprostinil by an external infusion pump, start at the current dose the patient is receiving using the external infusion pump at the time of transition to the implantable IV infusion pump.
For the treatment of pulmonary arterial hypertension (WHO Group 1) to delay disease progression and to improve exercise capacity.
Studies that established effectiveness included predominately patients with WHO functional class II to III symptoms and etiologies of idiopathic or heritable PAH (66%) or PAH associated with connective tissue disease (26%).
0.125 mg PO 3 times daily, approximately every 8 hours or 0.25 mg PO twice daily, approximately every 12 hours. Doses should be taken with food. Increase the dose by 0.125 mg 3 times daily or 0.25 or 0.5 mg twice daily not more frequently than every 3 to 4 days as tolerated to achieve optimal response. If dose increments are not tolerated, consider titrating slower. If intolerable pharmacologic effects occur, decrease the dose by increments of 0.125 mg 3 times daily or 0.25 mg twice daily. The appropriate maintenance dose is determined by tolerability. Coadministration of certain drugs may been to be avoided or dosage adjustments may be necessary; review drug interactions. In a controlled clinical trial, at 12 weeks, the mean dose was 3.4 mg twice daily, and at 2 years in a long-term, open-label extension study, the mean dose was 5 mg twice daily. Avoid abrupt discontinuation of therapy. When discontinuing oral therapy, reduce the dose in steps of 0.5 to 1 mg/day.
For the treatment of pulmonary hypertension associated with interstitial lung disease (WHO Group 3) to improve exercise ability.
Initially, 3 breaths (18 mcg) inhaled via the Tyvaso Inhalation System 4 times daily approximately 4 hours apart during waking hours; the patient should take 3 breaths during each treatment session. Each treatment session will take 2 to 3 minutes. If 3 breaths are not tolerated, reduce to 1 or 2 breaths and subsequently increase to 3 breaths, as tolerated. Increase dose by an additional 3 breaths per treatment session at approximately 1 to 2-week intervals, if tolerated, until the target dose of 9 to 12 breaths (54 to 72 mcg) per treatment session is reached. If target dose cannot be reached due to adverse effects, continue at the highest tolerated dose. The maximum recommended dosage is 12 breaths per treatment session administered 4 times daily. In general, dosage selection and titration should be cautious in the elderly, considering the greater risk for decreased renal, hepatic, or cardiac function. NOTE: The effects of the drug diminish over the minimum recommended dosing interval of 4 hours; treatment timing can be adjusted for planned activities.
Titrate parenteral dose to patient response, doses up to 290 ng/kg/min have been studied; 12 breaths via oral inhalation/treatment session, given 4 times daily; titrate oral tablets to clinical response and tolerability, doses up to 21 mg twice daily have been studied.
17 years and older: Titrate parenteral dose to patient response, doses up to 290 ng/kg/min have been studied; safe and effective use of the oral inhalation and tablets have not been established.
16 years and younger: Safe and effective use has not been not been established; however, mean doses of injectable treprostinil up to 86 ng/kg/min for chronic patients have been reported.
Safety and efficacy have not been established; however, mean doses of injectable treprostinil up to 86 ng/kg/min for chronic patients have been reported.
In patients with mild to moderate hepatic insufficiency, reduce the initial dose of treprostinil injection to 0.625 ng/kg/min (using ideal body weight) SC or IV and cautiously titrate upward. Follow the usual titration guidelines for indication. Specific guidelines for dosage adjustments of treprostinil for oral inhalation in hepatic impairment are not available; the plasma clearance of treprostinil is reduced in patients with hepatic insufficiency and these patients may therefore be at increased risk of dose-dependent adverse reactions. Cautiously titrate up the oral inhalation dose. Treprostinil for injection or inhalation has not been studied in severe hepatic impairment. In patients with mild hepatic insufficiency (Child-Pugh Class A), reduce the initial dose of oral treprostinil to 0.125 mg by mouth twice daily and increase by 0.125 mg increments twice daily not more frequently than every 3 to 4 days. Avoid use of treprostinil oral tablet in patients with moderate hepatic insufficiency (Child-Pugh Class B). Treprostinil oral tablet is contraindicated in patients with severe hepatic impairment (Child-Pugh Class C).
No dosage adjustments are required in patients with renal impairment; however, slow upward titration of the treprostinil for injection dose is recommended in this patient population. Considering that roughly 80% of the dose is excreted in the urine, with most as metabolites of unknown biological activity, caution and close monitoring for treprostinil toxicity is warranted.
Treprostinil is not removed by dialysis.
Administer with food. Swallow tablets whole and use only intact tablets.
Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Parenteral treprostinil is preferably administered subcutaneously but can be administered by a central intravenous line if the subcutaneous route is not tolerated because of severe site pain or reaction.
To avoid interruptions in drug delivery, the patient must have immediate access to a backup infusion pump and infusion sets. Avoid abrupt discontinuation of the infusion. If temporary cessation is necessary for less than a few hours, the infusion can be restarted at the previously used dose and rate; however, if the infusion is stopped for longer than a few hours, re-titration may be necessary.
To use a subcutaneous or external intravenous infusion pump designed for drug delivery, the infusion pump should: (1) have alarms for occlusion or no delivery, low battery, programming error and motor malfunctions; (2) have delivery accuracy to +/- 6% or better of the hourly dose; (3) be positive-pressure driven; and (4) have a reservoir made of polyvinyl chloride, polypropylene, or glass. The subcutaneous infusion pump should be adjustable to approximately 0.002 mL/hour. Alternatively, use an infusion pump cleared for use with treprostinil.
For use of an implantable intravenous infusion pump cleared for use with treprostinil, refer to the pump manufacturer's manual for specific instructions regarding preparation, programming, implantation, and refilling.
Storage: A single vial should be used no more than 30 days after the initial aseptic entry into the vial.
Treprostinil is administered by continuous IV infusion by a surgically placed central venous catheter using an ambulatory infusion pump or by an implantable IV infusion pump approved for use with treprostinil, such as the Implantable System for Remodulin (ISR). A peripheral IV cannula, placed preferably into a large vein, may be used temporarily to administer treprostinil when clinically indicated. However, use of a peripheral vein for more than a few hours may increase the risk of thrombophlebitis.
Infusion sets with an in-line 0.22 or 0.2 micron pore size filter should be used with the external intravenous infusion pump.
Intravenous infusion preparation for external infusion pump:
For administration of undiluted treprostinil
Calculate the infusion rate using the following formula: undiluted intravenous infusion rate (mL/hour) = [dose (ng/kg/minute) x weight (kg) x 0.00006] / treprostinil vial strength (mg/mL)
Undiluted treprostinil may be administered for 16 weeks at 40 degrees C.
For administration of diluted treprostinil
Treprostinil can be diluted with Remodulin sterile diluent for injection or similar approved high-pH glycine diluents (e.g., sterile diluent for Flolan or sterile diluent for epoprostenol sodium), Sterile Water for Injection, or 0.9% Sodium Chloride for Injection.
Calculate the concentration of diluted treprostinil using the following formula: diluted concentration (mg/mL) = [dose (ng/kg/minute) X weight (kg) X 0.00006] / intravenous infusion rate (mL/hour)
Typical ambulatory infusion pumps reservoirs have volumes of 50 or 100 mL. The IV infusion rate is predetermined based on the volume of the reservoir with a desired infusion length of 48 hours (i.e., for a 50 mL reservoir, the infusion rate would be 1 mL/hour; for a 100 mL reservoir, the infusion rate would be 2 mL/hour).
The volume of treprostinil needed to make the required concentration for the given reservoir can be calculated using the following formula: mL of treprostinil injection = [diluted concentration (mg/mL) / treprostinil vial strength (mg/mL)] X total volume of diluted treprostinil solution in reservoir (mL)
The reservoir should be filled with the calculated treprostinil volume and a sufficient amount of diluent to achieve the total volume of the reservoir.
Once diluted with any high-pH glycine diluent (sterile diluent for Remodulin, Flolan, or epoprostenol sodium), Sterile Water for Injection, or 0.9% Sodium Chloride for Injection, treprostinil may be administered for 48 hours at 40 degrees C.
Storage: If treprostinil is diluted with Sterile Water for Injection or 0.9% Sodium Chloride for Injection, it may be stored for 4 hours at room temperature or 24 hours if refrigerated. If treprostinil is diluted with an approved high-pH glycine diluent (sterile diluent for Remodulin, Flolan, or epoprostenol sodium), it may be stored for 14 days at room temperature at concentrations as low as 0.004 mg/mL.
Administer by continuous subcutaneous infusion via a self-inserted subcutaneous catheter using an ambulatory infusion pump designed for subcutaneous drug delivery.
Subcutaneous infusion preparation:
Further dilution is NOT required prior to continuous subcutaneous administration.
Do not mix or co-infuse with other medications.
Calculate the subcutaneous infusion rate using the following formula:
subcutaneous infusion rate = [dose (ng/kg/minute) X weight (kg) X 0.00006] / treprostinil vial strength (mg/mL)
During subcutaneous use, a single reservoir (syringe) of treprostinil can be administered up to 72 hours at a maximum temperature of 37 degrees C (98.6 degrees F).
Inhalation Administration
Oral Inhalation Administration
NOTE: Treprostinil solution for oral inhalation must be used only with the Tyvaso Inhalation System.
Avoid skin or eye contact with treprostinil solution. Do not orally ingest the treprostinil solution.
Patients should have access to a backup Tyvaso Inhalation System to avoid interruptions in therapy. Patients should follow the instructions for use for operation of the Tyvaso Inhalation System and for daily cleaning of the device components after the last treatment session of the day.
Do not mix treprostinil with other medications in the Tyvaso Inhalation System. Compatibility of treprostinil with other medications has not been studied.
One ampule of treprostinil contains a sufficient volume of medication for all 4 treatment sessions in a single day. Prior to the first treatment session, the patient should twist the top off a single treprostinil ampule and squeeze the entire contents into the medicine cup. Between each of the 4 daily treatment sessions, the device should be capped and stored upright with the remaining medication inside. At the end of each day, the medicine cup and any remaining medication must be discarded. The device must be cleaned each day according to the instructions for use.
Each treatment session will take 2 to 3 minutes.
Generic:
Orenitram:
Remodulin:
- Store at 77 degrees F
Tyvaso :
- After removing from pouch, protect from light and use product within one week
- Discard unused portion. Do not store for later use.
- Store unopened product at 77 degrees F; excursions permitted to 59-86 degrees F
- Store unused product in foil pouch
Tyvaso Refill Kit:
Tyvaso Starter Kit:
Treprostinil is contraindicated in any patient with a known hypersensitivity to the drug or to structurally related compounds.
Chronic intravenous administration of treprostinil delivered via external infusion pump with an indwelling central venous catheter is associated with a risk of blood stream infections (BSIs) and sepsis, which may be fatal. Parenteral treprostinil is preferably administered subcutaneously but can be administered by a central intravenous line if the subcutaneous route is not tolerated because of severe site pain or reaction. Administration of IV treprostinil with a high pH glycine diluent such as Sterile Diluent for Flolan or Sterile Diluent for Epoprostenol Sodium has been associated with a lower incidence of BSI compared to neutral diluents (Sterile Water for Injection, 0.9% Sodium Chloride Injection) when used along with catheter care guidelines.
Abrupt discontinuation
Abrupt discontinuation or sudden large reductions in dosage of treprostinil should be avoided. Treprostinil is a potent pulmonary and systemic vasodilator. Initiation of treprostinil injection should be performed in an adequate setting for monitoring physiologic response and emergency care. Only clinicians experienced in the diagnosis, treatment, and follow-up of primary arterial hypertension (PAH) should use treprostinil. Abrupt discontinuation of treprostinil therapy, including sudden reductions in dosage and interruptions in drug delivery, may result in worsening symptoms of PAH, and should be avoided. Symptoms can include dyspnea, dizziness, and asthenia. If temporary cessation of the infusion is necessary for less than a few hours, the infusion can be restarted at the previously used dose and rate; however, if the infusion is stopped for longer than a few hours, re-titration of the dose may be necessary. Patients using the inhalation delivery device should be advised to have access to a back-up device to avoid potential interruptions in therapy. Consider a temporary infusion of subcutaneous or intravenous treprostinil for patients on oral therapy who must undergo a planned short-term interruption of therapy.
Treprostinil is a pulmonary and systemic vasodilator. In patients with low systemic arterial pressure, treprostinil therapy may result in symptomatic hypotension.
Treprostinil inhibits platelet aggregation and increases the risk of bleeding, especially in patients receiving anticoagulants.
Oral treprostinil tablets are contraindicated in patients with severe hepatic impairment (Child-Pugh Class C). Use of oral treprostinil in patients with moderate hepatic impairment (Child-Pugh Class B) is to be avoided. A marked increase in the systemic exposure of treprostinil is seen in patients with hepatic impairment. In general, dosage adjustments of oral treprostinil and treprostinil for injection are required in patients with hepatic insufficiency, which may include hepatic disease or hepatitis. Upward titration of treprostinil injection and treprostinil oral inhalation should be slow and cautious. Studies with treprostinil for injection or inhalation have not been performed in patients with severe hepatic impairment.
Geriatric patients often have decreased renal, hepatic or cardiac function. In general, dose selection of treprostinil for elderly patients should be cautious, given the greater frequency of decreased organ function or concomitant disease and drug therapy in geriatric patients versus younger adults. Cautious titration and observation for toxicity is recommended as specific dosage adjustment recommendations based on age alone are not available. Sufficient numbers of patients 65 years of age or older were not included in clinical trials to determine if they respond differently than younger patients.
Use treprostinil tablets with caution in patients with diverticulitis. The tablet shell does not dissolve and can lodge in the diverticulum.
Avoid the use of treprostinil tablets in patients with alcoholism or ethanol use. With concomitant alcohol, release of treprostinil from the tablet may occur at a faster rate.
Limited case reports of treprostinil use during human pregnancy are insufficient to inform a drug-associated risk of adverse developmental outcomes. No adverse reproductive or developmental effects were seen when pregnant rats were exposed to subcutaneous infusions of treprostinil at doses as high as 900 ng/kg/minute (about 117 times the starting human subcutaneous infusion rate on a ng/m2 basis) or oral treprostinil at 20 mg/kg/day (about 48 times the human exposure based on AUC of the average subcutaneous infusion rate achieved in clinical trials). In rabbits, external and fetal soft tissue malformations and skeletal malformations were observed with subcutaneous infusion of treprostinil at 5 times the average rate used in clinical trials. No treprostinil treatment-related effects on labor and delivery were observed in animal studies. Pulmonary arterial hypertension is associated with increased risk of maternal and fetal mortality.
There are no data on the presence of treprostinil in human milk, the effects on the breast-fed infant, or the effects on milk production. Because many drugs are excreted in human milk, choose oral treprostinil or breast-feeding. Specific recommendations are not available for treprostinil for injection or inhalation.
injection site reaction / Rapid / 38.0-38.0
GI bleeding / Delayed / 1.3-1.3
edema / Delayed / 9.0-9.0
hypotension / Rapid / 4.0-4.0
hemoptysis / Delayed / 1.5-1.5
hematoma / Early / Incidence not known
erythema / Early / Incidence not known
chest pain (unspecified) / Early / Incidence not known
phlebitis / Rapid / Incidence not known
wheezing / Rapid / Incidence not known
bone pain / Delayed / Incidence not known
cough / Delayed / 54.0-54.0
flushing / Rapid / 11.0-45.0
throat irritation / Early / 25.0-25.0
rash / Early / 14.0-14.0
syncope / Early / 6.0-6.0
asthenia / Delayed / 3.0
dizziness / Early / 9.0
anorexia / Delayed / 3.0
paresthesias / Delayed / Incidence not known
infection / Delayed / Incidence not known
nasal irritation / Early / Incidence not known
epistaxis / Delayed / Incidence not known
Abciximab: (Moderate) Monitor patients for signs and symptoms of bleeding if treprostinil is administered with abciximab. Treprostinil inhibits platelet aggregation; abciximab is a platelet inhibitor. Coadministration increases the risk of bleeding.
Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) When used concurrently with anticoagulants or platelet inhibitors, treprostinil may increase the risk of bleeding.
Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (Moderate) When used concurrently with anticoagulants or platelet inhibitors, treprostinil may increase the risk of bleeding.
Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: (Moderate) When used concurrently with anticoagulants or platelet inhibitors, treprostinil may increase the risk of bleeding.
Alemtuzumab: (Moderate) Alemtuzumab may cause hypotension. Careful monitoring of blood pressure and hypotensive symptoms is recommended especially in patients with ischemic heart disease and in patients on antihypertensive agents.
Aliskiren; Amlodipine: (Moderate) Calcium-channel blockers can have additive hypotensive effects with other antihypertensive agents. This additive effect can be desirable, but the patient should be monitored carefully and the dosage should be adjusted based on clinical response.
Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Calcium-channel blockers can have additive hypotensive effects with other antihypertensive agents. This additive effect can be desirable, but the patient should be monitored carefully and the dosage should be adjusted based on clinical response. (Moderate) Thiazide diuretics can enhance the hypotensive effects of antihypertensive agents or diuretics if given concomitantly. This additive effect may be desirable, but dosages must be adjusted accordingly.
Aliskiren; Hydrochlorothiazide, HCTZ: (Moderate) Thiazide diuretics can enhance the hypotensive effects of antihypertensive agents or diuretics if given concomitantly. This additive effect may be desirable, but dosages must be adjusted accordingly.
Alprostadil: (Minor) Systemic alprostadil and treprostinil are both prostaglandins that reduce blood pressure, and would not be commonly prescribed together at the same time. The concomitant use of systemic alprostadil injection and treprostinil would be expected to cause additive hypotension. Systemic drug interactions with the urethral suppository (MUSE) or alprostadil intracavernous injection are unlikely in most patients because low or undetectable amounts of the drug are found in the peripheral venous circulation following administration. In those men with significant corpora cavernosa venous leakage, hypotension might be more likely. Use caution with in-clinic dosing for erectile dysfunction (ED) and monitor for the effects on blood pressure. However, in clinical trials with alprostadil intracavernous injection, anti-hypertensive agents had no apparent effect on the safety and efficacy of alprostadil.
Amifostine: (Major) Patients receiving antihypertensive agents should be closely monitored during amifostine infusions due to additive effects. If possible, patients should not take their antihypertensive medication 24 hours before receiving amifostine. Patients who can not stop their antihypertensive agents should not receive amifostine or be closely monitored during the infusion and, possibly, given lower doses.
Amiloride; Hydrochlorothiazide, HCTZ: (Moderate) Thiazide diuretics can enhance the hypotensive effects of antihypertensive agents or diuretics if given concomitantly. This additive effect may be desirable, but dosages must be adjusted accordingly.
Aminosalicylate sodium, Aminosalicylic acid: (Moderate) When used concurrently with anticoagulants or platelet inhibitors, treprostinil may increase the risk of bleeding.
Amlodipine: (Moderate) Calcium-channel blockers can have additive hypotensive effects with other antihypertensive agents. This additive effect can be desirable, but the patient should be monitored carefully and the dosage should be adjusted based on clinical response.
Amlodipine; Atorvastatin: (Moderate) Calcium-channel blockers can have additive hypotensive effects with other antihypertensive agents. This additive effect can be desirable, but the patient should be monitored carefully and the dosage should be adjusted based on clinical response.
Amlodipine; Benazepril: (Moderate) Calcium-channel blockers can have additive hypotensive effects with other antihypertensive agents. This additive effect can be desirable, but the patient should be monitored carefully and the dosage should be adjusted based on clinical response.
Amlodipine; Celecoxib: (Moderate) Calcium-channel blockers can have additive hypotensive effects with other antihypertensive agents. This additive effect can be desirable, but the patient should be monitored carefully and the dosage should be adjusted based on clinical response. (Moderate) NSAIDs may decrease the effect of antihypertensive agents through various mechanisms, including renal and peripheral vasoactive pathways.
Amlodipine; Olmesartan: (Moderate) Calcium-channel blockers can have additive hypotensive effects with other antihypertensive agents. This additive effect can be desirable, but the patient should be monitored carefully and the dosage should be adjusted based on clinical response.
Amlodipine; Valsartan: (Moderate) Calcium-channel blockers can have additive hypotensive effects with other antihypertensive agents. This additive effect can be desirable, but the patient should be monitored carefully and the dosage should be adjusted based on clinical response.
Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Calcium-channel blockers can have additive hypotensive effects with other antihypertensive agents. This additive effect can be desirable, but the patient should be monitored carefully and the dosage should be adjusted based on clinical response. (Moderate) Thiazide diuretics can enhance the hypotensive effects of antihypertensive agents or diuretics if given concomitantly. This additive effect may be desirable, but dosages must be adjusted accordingly.
Amobarbital: (Moderate) Concurrent use of amobarbital with antihypertensive agents may lead to hypotension. Monitor for decreases in blood pressure during times of coadministration.
Amyl Nitrite: (Moderate) Concomitant use of nitrates with other antihypertensive agents can cause additive hypotensive effects. Dosage adjustments may be necessary.
Anagrelide: (Moderate) Monitor patients for signs and symptoms of bleeding if treprostinil is administered with anagrelide. Treprostinil inhibits platelet aggregation; anagrelide is a platelet inhibitor. Coadministration increases the risk of bleeding.
Anticoagulants: (Moderate) When used concurrently with anticoagulants, treprostinil may increase the risk of bleeding.
Antithrombin III: (Moderate) When used concurrently with anticoagulants, treprostinil may increase the risk of bleeding.
Apixaban: (Moderate) When used concurrently with anticoagulants, treprostinil may increase the risk of bleeding.
Apraclonidine: (Minor) Alpha blockers as a class may reduce heart rate and blood pressure. While no specific drug interactions have been identified with systemic agents and apraclonidine during clinical trials, it is theoretically possible that additive blood pressure reductions could occur when apraclonidine is combined with the use of antihypertensive agents. Patients using cardiovascular drugs concomitantly with apraclonidine should have their pulse and blood pressure monitored periodically.
Argatroban: (Moderate) When used concurrently with anticoagulants, treprostinil may increase the risk of bleeding.
Aripiprazole: (Minor) Aripiprazole may enhance the hypotensive effects of antihypertensive agents.
Asenapine: (Moderate) Secondary to alpha-blockade, asenapine can produce vasodilation that may result in additive effects during concurrent use of antihypertensive agents. The potential reduction in blood pressure can precipitate orthostatic hypotension and associated dizziness, tachycardia, and syncope. If concurrent use of asenapine and antihypertensive agents is necessary, patients should be counseled on measures to prevent orthostatic hypotension, such as sitting on the edge of the bed for several minutes prior to standing in the morning and rising slowly from a seated position. Close monitoring of blood pressure is recommended until the full effects of the combination therapy are known.
Aspirin, ASA: (Moderate) When used concurrently with anticoagulants or platelet inhibitors, treprostinil may increase the risk of bleeding.
Aspirin, ASA; Butalbital; Caffeine: (Moderate) When used concurrently with anticoagulants or platelet inhibitors, treprostinil may increase the risk of bleeding.
Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) When used concurrently with anticoagulants or platelet inhibitors, treprostinil may increase the risk of bleeding.
Aspirin, ASA; Caffeine: (Moderate) When used concurrently with anticoagulants or platelet inhibitors, treprostinil may increase the risk of bleeding.
Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) When used concurrently with anticoagulants or platelet inhibitors, treprostinil may increase the risk of bleeding.
Aspirin, ASA; Caffeine; Orphenadrine: (Moderate) When used concurrently with anticoagulants or platelet inhibitors, treprostinil may increase the risk of bleeding.
Aspirin, ASA; Carisoprodol: (Moderate) When used concurrently with anticoagulants or platelet inhibitors, treprostinil may increase the risk of bleeding.
Aspirin, ASA; Carisoprodol; Codeine: (Moderate) When used concurrently with anticoagulants or platelet inhibitors, treprostinil may increase the risk of bleeding.
Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Moderate) When used concurrently with anticoagulants or platelet inhibitors, treprostinil may increase the risk of bleeding.
Aspirin, ASA; Dipyridamole: (Moderate) Monitor patients for signs and symptoms of bleeding if treprostinil is administered with dipyridamole. Treprostinil inhibits platelet aggregation; dipyridamole is a platelet inhibitor. Coadministration increases the risk of bleeding. (Moderate) When used concurrently with anticoagulants or platelet inhibitors, treprostinil may increase the risk of bleeding.
Aspirin, ASA; Omeprazole: (Moderate) When used concurrently with anticoagulants or platelet inhibitors, treprostinil may increase the risk of bleeding.
Aspirin, ASA; Oxycodone: (Moderate) When used concurrently with anticoagulants or platelet inhibitors, treprostinil may increase the risk of bleeding.
Aspirin, ASA; Pravastatin: (Moderate) When used concurrently with anticoagulants or platelet inhibitors, treprostinil may increase the risk of bleeding.
Atenolol; Chlorthalidone: (Moderate) Thiazide diuretics can enhance the hypotensive effects of antihypertensive agents or diuretics if given concomitantly. This additive effect may be desirable, but dosages must be adjusted accordingly.
Atropine; Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Moderate) When used concurrently with anticoagulants or platelet inhibitors, treprostinil may increase the risk of bleeding.
Azilsartan; Chlorthalidone: (Moderate) Thiazide diuretics can enhance the hypotensive effects of antihypertensive agents or diuretics if given concomitantly. This additive effect may be desirable, but dosages must be adjusted accordingly.
Baclofen: (Moderate) Baclofen has been associated with hypotension. Concurrent use with baclofen and antihypertensive agents may result in additive hypotension. Dosage adjustments of the antihypertensive medication may be required.
Benazepril; Hydrochlorothiazide, HCTZ: (Moderate) Thiazide diuretics can enhance the hypotensive effects of antihypertensive agents or diuretics if given concomitantly. This additive effect may be desirable, but dosages must be adjusted accordingly.
Bendroflumethiazide; Nadolol: (Moderate) Thiazide diuretics can enhance the hypotensive effects of antihypertensive agents or diuretics if given concomitantly. This additive effect may be desirable, but dosages must be adjusted accordingly.
Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Moderate) When used concurrently with anticoagulants or platelet inhibitors, treprostinil may increase the risk of bleeding.
Betrixaban: (Moderate) When used concurrently with anticoagulants, treprostinil may increase the risk of bleeding.
Bismuth Subsalicylate: (Moderate) When used concurrently with anticoagulants or platelet inhibitors, treprostinil may increase the risk of bleeding.
Bismuth Subsalicylate; Metronidazole; Tetracycline: (Moderate) When used concurrently with anticoagulants or platelet inhibitors, treprostinil may increase the risk of bleeding.
Bisoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Thiazide diuretics can enhance the hypotensive effects of antihypertensive agents or diuretics if given concomitantly. This additive effect may be desirable, but dosages must be adjusted accordingly.
Bivalirudin: (Moderate) When used concurrently with anticoagulants, treprostinil may increase the risk of bleeding.
Bortezomib: (Moderate) Patients on antihypertensive agents receiving bortezomib treatment may require close monitoring of their blood pressure and dosage adjustment of their medication. During clinical trials of bortezomib, hypotension was reported in roughly 12 percent of patients.
Bosentan: (Moderate) Bosentan has vasodilatory effects and may contribute additive hypotensive effects when given with other vasodilators. Combined use of iloprost with bosentan has been evaluated in patients with pulmonary hypertension. In a randomized, double-blind, placebo-controlled study (the STEP trial), 34 patients treated with bosentan 125 mg twice daily for at least 16 weeks tolerated the addition of inhaled iloprost. In this study, iloprost was dosed up to 5 mcg administered 6 to 9 times per day during waking hours. The mean daily inhaled iloprost dose was 27 mcg and the mean number of inhalations per day was 5.6. Although no specific interactions have been documented, patients should be monitored for increased additive hypotension.
Bupivacaine; Meloxicam: (Moderate) NSAIDs may decrease the effect of antihypertensive agents through various mechanisms, including renal and peripheral vasoactive pathways.
Candesartan; Hydrochlorothiazide, HCTZ: (Moderate) Thiazide diuretics can enhance the hypotensive effects of antihypertensive agents or diuretics if given concomitantly. This additive effect may be desirable, but dosages must be adjusted accordingly.
Cannabidiol: (Moderate) Consider a dose reduction of treprostinil as clinically appropriate, if adverse reactions occur when administered with cannabidiol. Increased treprostinil exposure is possible. Treprostinil is a CYP2C8 substrate. In vitro data predicts inhibition of CYP2C8 by cannabidiol potentially resulting in clinically significant interactions.
Captopril; Hydrochlorothiazide, HCTZ: (Moderate) Thiazide diuretics can enhance the hypotensive effects of antihypertensive agents or diuretics if given concomitantly. This additive effect may be desirable, but dosages must be adjusted accordingly.
Carbidopa; Levodopa: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
Carbidopa; Levodopa; Entacapone: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
Cariprazine: (Moderate) Orthostatic vital signs should be monitored in patients who are at risk for hypotension, such as those receiving cariprazine in combination with antihypertensive agents. Atypical antipsychotics may cause orthostatic hypotension and syncope, most commonly during treatment initiation and dosage increases. Patients should be informed about measures to prevent orthostatic hypotension, such as sitting on the edge of the bed for several minutes prior to standing in the morning, or rising slowly from a seated position. Consider a cariprazine dose reduction if hypotension occurs.
Celecoxib: (Moderate) NSAIDs may decrease the effect of antihypertensive agents through various mechanisms, including renal and peripheral vasoactive pathways.
Chloroprocaine: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
Chlorothiazide: (Moderate) Thiazide diuretics can enhance the hypotensive effects of antihypertensive agents or diuretics if given concomitantly. This additive effect may be desirable, but dosages must be adjusted accordingly.
Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Moderate) NSAIDs may decrease the effect of antihypertensive agents through various mechanisms, including renal and peripheral vasoactive pathways.
Chlorthalidone: (Moderate) Thiazide diuretics can enhance the hypotensive effects of antihypertensive agents or diuretics if given concomitantly. This additive effect may be desirable, but dosages must be adjusted accordingly.
Chlorthalidone; Clonidine: (Moderate) Thiazide diuretics can enhance the hypotensive effects of antihypertensive agents or diuretics if given concomitantly. This additive effect may be desirable, but dosages must be adjusted accordingly.
Choline Salicylate; Magnesium Salicylate: (Moderate) When used concurrently with anticoagulants or platelet inhibitors, treprostinil may increase the risk of bleeding.
Cilostazol: (Moderate) Monitor patients for signs and symptoms of bleeding if treprostinil is administered with cilostazol. Treprostinil inhibits platelet aggregation; cilostazol is a platelet inhibitor. Coadministration increases the risk of bleeding.
Clopidogrel: (Moderate) Reduce the starting dose of oral treprostinil to 0.125 mg twice daily when coadministered with clopidogrel; dose adjustments should be made in 0.125 mg twice daily increments every 3 to 4 days. Human pharmacokinetic studies of oral treprostinil indicate that coadministration of another potent CYP2C8 enzyme inhibitor results in a 2-fold increase in exposure to treprostinil, a CYP2C8 substrate. The clinical significance of this interaction with orally inhaled or parenteral treprostinil or with other CYP2C8 inhibitors is unknown; treprostinil dose adjustments may be necessary. Additionally, monitor patients for signs and symptoms of bleeding if treprostinil is administered with clopidogrel. Treprostinil inhibits platelet aggregation; clopidogrel is a platelet inhibitor. Coadministration increases the risk of bleeding.
Clozapine: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
Cocaine: (Major) Use of cocaine with antihypertensive agents may increase the antihypertensive effects of the antihypertensive medications or may potentiate cocaine-induced sympathetic stimulation.
Co-Enzyme Q10, Ubiquinone: (Moderate) Co-enzyme Q10, ubiquinone (CoQ10) may lower blood pressure. CoQ10 use in combination with antihypertensive agents may lead to additional reductions in blood pressure in some individuals. Patients who choose to take CoQ10 concurrently with antihypertensive medications should receive periodic blood pressure monitoring. Patients should be advised to inform their prescriber of their use of CoQ10.
Dabigatran: (Moderate) When used concurrently with anticoagulants, treprostinil may increase the risk of bleeding.
Dalteparin: (Moderate) When used concurrently with anticoagulants, treprostinil may increase the risk of bleeding.
Danaparoid: (Moderate) When used concurrently with anticoagulants, treprostinil may increase the risk of bleeding.
Desirudin: (Moderate) When used concurrently with anticoagulants, treprostinil may increase the risk of bleeding.
Dexmedetomidine: (Moderate) Concomitant administration of dexmedetomidine and treprostinil could lead to additive hypotension; use together with caution. Both agents are associated with a risk for hypotension. In clinical trials where other vasodilators were coadministered with dexmedetomidine injection an additive pharmacodynamic effect was not observed. Nonetheless, caution should be used when such agents are administered concomitantly with dexmedetomidine.
Dextromethorphan; Quinidine: (Moderate) Quinidine can decrease blood pressure and should be used cautiously in patients receiving antihypertensive agents due to the potential for additive hypotension.
Diclofenac: (Moderate) NSAIDs may decrease the effect of antihypertensive agents through various mechanisms, including renal and peripheral vasoactive pathways.
Diclofenac; Misoprostol: (Moderate) NSAIDs may decrease the effect of antihypertensive agents through various mechanisms, including renal and peripheral vasoactive pathways.
Diflunisal: (Moderate) NSAIDs may decrease the effect of antihypertensive agents through various mechanisms, including renal and peripheral vasoactive pathways.
Dihydroergotamine: (Minor) The combined use of vasodilators and the ergot alkaloids will likely result in antagonism of the vasoconstrictive effects of the ergot derivative. Clinically, for example, vasodilators may be used for supportive care of ergot alkaloid toxicity; with precautions to avoid hypotension.
Diltiazem: (Moderate) Calcium-channel blockers can have additive hypotensive effects with other antihypertensive agents. This additive effect can be desirable, but the patient should be monitored carefully and the dosage should be adjusted based on clinical response.
Diphenhydramine; Ibuprofen: (Moderate) NSAIDs may decrease the effect of antihypertensive agents through various mechanisms, including renal and peripheral vasoactive pathways.
Diphenhydramine; Naproxen: (Moderate) NSAIDs may decrease the effect of antihypertensive agents through various mechanisms, including renal and peripheral vasoactive pathways.
Dipyridamole: (Moderate) Monitor patients for signs and symptoms of bleeding if treprostinil is administered with dipyridamole. Treprostinil inhibits platelet aggregation; dipyridamole is a platelet inhibitor. Coadministration increases the risk of bleeding.
Duloxetine: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. Monitor blood pressure if the combination is necessary.
Edoxaban: (Moderate) When used concurrently with anticoagulants, treprostinil may increase the risk of bleeding.
Enalapril; Hydrochlorothiazide, HCTZ: (Moderate) Thiazide diuretics can enhance the hypotensive effects of antihypertensive agents or diuretics if given concomitantly. This additive effect may be desirable, but dosages must be adjusted accordingly.
Enflurane: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents.
Enoxaparin: (Moderate) When used concurrently with anticoagulants, treprostinil may increase the risk of bleeding.
Epoprostenol: (Moderate) Treprostinil can enhance the hypotensive effects of antihypertensive agents or diuretics if given concomitantly. This additive effect may be desirable, but dosages must be adjusted accordingly.
Eprosartan; Hydrochlorothiazide, HCTZ: (Moderate) Thiazide diuretics can enhance the hypotensive effects of antihypertensive agents or diuretics if given concomitantly. This additive effect may be desirable, but dosages must be adjusted accordingly.
Eptifibatide: (Moderate) Monitor patients for signs and symptoms of bleeding if treprostinil is administered with eptifibatide. Treprostinil inhibits platelet aggregation; eptifibatide is a platelet inhibitor. Coadministration increases the risk of bleeding.
Etodolac: (Moderate) NSAIDs may decrease the effect of antihypertensive agents through various mechanisms, including renal and peripheral vasoactive pathways.
Etomidate: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents.
Famotidine; Ibuprofen: (Moderate) NSAIDs may decrease the effect of antihypertensive agents through various mechanisms, including renal and peripheral vasoactive pathways.
Fenoprofen: (Moderate) NSAIDs may decrease the effect of antihypertensive agents through various mechanisms, including renal and peripheral vasoactive pathways.
Flurbiprofen: (Moderate) NSAIDs may decrease the effect of antihypertensive agents through various mechanisms, including renal and peripheral vasoactive pathways.
Fondaparinux: (Moderate) When used concurrently with anticoagulants, treprostinil may increase the risk of bleeding.
Fosinopril; Hydrochlorothiazide, HCTZ: (Moderate) Thiazide diuretics can enhance the hypotensive effects of antihypertensive agents or diuretics if given concomitantly. This additive effect may be desirable, but dosages must be adjusted accordingly.
Fospropofol: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents.
Gemfibrozil: (Moderate) Reduce the starting dose of oral treprostinil to 0.125 mg twice daily when coadministered with gemfibrozil; dose adjustments should be made in 0.125 mg twice daily increments every 3 to 4 days. Human pharmacokinetic studies of oral treprostinil indicate that coadministration of gemfibrozil, a cytochrome CYP2C8 enzyme inhibitor, results in a 2-fold increase in exposure to treprostinil, a CYP2C8 substrate. The clinical significance of this interaction with orally inhaled or parenteral treprostinil or with other CYP2C8 inhibitors is unknown; treprostinil dose adjustments may be necessary.
General anesthetics: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents.
Haloperidol: (Moderate) In general, haloperidol should be used cautiously with antihypertensive agents due to the possibility of additive hypotension.
Halothane: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents.
Heparin: (Moderate) When used concurrently with anticoagulants, treprostinil may increase the risk of bleeding.
Hydralazine; Hydrochlorothiazide, HCTZ: (Moderate) Thiazide diuretics can enhance the hypotensive effects of antihypertensive agents or diuretics if given concomitantly. This additive effect may be desirable, but dosages must be adjusted accordingly.
Hydralazine; Isosorbide Dinitrate, ISDN: (Moderate) Concomitant use of nitrates with other antihypertensive agents can cause additive hypotensive effects. Dosage adjustments may be necessary.
Hydrochlorothiazide, HCTZ: (Moderate) Thiazide diuretics can enhance the hypotensive effects of antihypertensive agents or diuretics if given concomitantly. This additive effect may be desirable, but dosages must be adjusted accordingly.
Hydrochlorothiazide, HCTZ; Methyldopa: (Moderate) Thiazide diuretics can enhance the hypotensive effects of antihypertensive agents or diuretics if given concomitantly. This additive effect may be desirable, but dosages must be adjusted accordingly.
Hydrochlorothiazide, HCTZ; Moexipril: (Moderate) Thiazide diuretics can enhance the hypotensive effects of antihypertensive agents or diuretics if given concomitantly. This additive effect may be desirable, but dosages must be adjusted accordingly.
Hydrocodone; Ibuprofen: (Moderate) NSAIDs may decrease the effect of antihypertensive agents through various mechanisms, including renal and peripheral vasoactive pathways.
Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Moderate) When used concurrently with anticoagulants or platelet inhibitors, treprostinil may increase the risk of bleeding.
Ibuprofen: (Moderate) NSAIDs may decrease the effect of antihypertensive agents through various mechanisms, including renal and peripheral vasoactive pathways.
Ibuprofen; Oxycodone: (Moderate) NSAIDs may decrease the effect of antihypertensive agents through various mechanisms, including renal and peripheral vasoactive pathways.
Ibuprofen; Pseudoephedrine: (Moderate) NSAIDs may decrease the effect of antihypertensive agents through various mechanisms, including renal and peripheral vasoactive pathways.
Iloperidone: (Moderate) Secondary to alpha-blockade, iloperidone can produce vasodilation that may result in additive effects during concurrent use with antihypertensive agents. The potential reduction in blood pressure can precipitate orthostatic hypotension and associated dizziness, tachycardia, and syncope. If concurrent use of iloperidone and antihypertensive agents is necessary, patients should be counseled on measures to prevent orthostatic hypotension, such as sitting on the edge of the bed for several minutes prior to standing in the morning and rising slowly from a seated position. Close monitoring of blood pressure is recommended until the full effects of the combination therapy are known.
Iloprost: (Moderate) Further reductions in blood pressure may occur when inhaled iloprost is administered to patients receiving other antihypertensive agents.
Indomethacin: (Moderate) NSAIDs may decrease the effect of antihypertensive agents through various mechanisms, including renal and peripheral vasoactive pathways.
Irbesartan; Hydrochlorothiazide, HCTZ: (Moderate) Thiazide diuretics can enhance the hypotensive effects of antihypertensive agents or diuretics if given concomitantly. This additive effect may be desirable, but dosages must be adjusted accordingly.
Isoflurane: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Minor) Human pharmacokinetic studies with an oral formulation of treprostinil (treprostinil diethanolamine) indicated that coadministration of rifampin, a cytochrome P450 (CYP) 2C8 enzyme inducer, decreased exposure to treprostinil. The clinical significance of this interaction with orally inhaled treprostinil and other CYP2C8 inducers is unknown.
Isoniazid, INH; Rifampin: (Minor) Human pharmacokinetic studies with an oral formulation of treprostinil (treprostinil diethanolamine) indicated that coadministration of rifampin, a cytochrome P450 (CYP) 2C8 enzyme inducer, decreased exposure to treprostinil. The clinical significance of this interaction with orally inhaled treprostinil and other CYP2C8 inducers is unknown.
Isosorbide Dinitrate, ISDN: (Moderate) Concomitant use of nitrates with other antihypertensive agents can cause additive hypotensive effects. Dosage adjustments may be necessary.
Isosorbide Mononitrate: (Moderate) Concomitant use of nitrates with other antihypertensive agents can cause additive hypotensive effects. Dosage adjustments may be necessary.
Ketamine: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents.
Ketoprofen: (Moderate) NSAIDs may decrease the effect of antihypertensive agents through various mechanisms, including renal and peripheral vasoactive pathways.
Ketorolac: (Moderate) NSAIDs may decrease the effect of antihypertensive agents through various mechanisms, including renal and peripheral vasoactive pathways.
Lansoprazole; Naproxen: (Moderate) NSAIDs may decrease the effect of antihypertensive agents through various mechanisms, including renal and peripheral vasoactive pathways.
Lepirudin: (Moderate) When used concurrently with anticoagulants, treprostinil may increase the risk of bleeding.
Levamlodipine: (Moderate) Calcium-channel blockers can have additive hypotensive effects with other antihypertensive agents. This additive effect can be desirable, but the patient should be monitored carefully and the dosage should be adjusted based on clinical response.
Levodopa: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
Lisinopril; Hydrochlorothiazide, HCTZ: (Moderate) Thiazide diuretics can enhance the hypotensive effects of antihypertensive agents or diuretics if given concomitantly. This additive effect may be desirable, but dosages must be adjusted accordingly.
Losartan; Hydrochlorothiazide, HCTZ: (Moderate) Thiazide diuretics can enhance the hypotensive effects of antihypertensive agents or diuretics if given concomitantly. This additive effect may be desirable, but dosages must be adjusted accordingly.
Lovastatin; Niacin: (Moderate) Cutaneous vasodilation induced by niacin may become problematic if high-dose niacin is used concomitantly with other antihypertensive agents. This effect is of particular concern in the setting of acute myocardial infarction, unstable angina, or other acute hemodynamic compromise.
Lurasidone: (Moderate) Due to the antagonism of lurasidone at alpha-1 adrenergic receptors, the drug may enhance the hypotensive effects of alpha-blockers and other antihypertensive agents. If concurrent use of lurasidone and antihypertensive agents is necessary, patients should be counseled on measures to prevent orthostatic hypotension, such as sitting on the edge of the bed for several minutes prior to standing in the morning and rising slowly from a seated position. Close monitoring of blood pressure is recommended until the full effects of the combination therapy are known.
Magnesium Salicylate: (Moderate) When used concurrently with anticoagulants or platelet inhibitors, treprostinil may increase the risk of bleeding.
Meclofenamate Sodium: (Moderate) NSAIDs may decrease the effect of antihypertensive agents through various mechanisms, including renal and peripheral vasoactive pathways.
Mefenamic Acid: (Moderate) NSAIDs may decrease the effect of antihypertensive agents through various mechanisms, including renal and peripheral vasoactive pathways.
Meloxicam: (Moderate) NSAIDs may decrease the effect of antihypertensive agents through various mechanisms, including renal and peripheral vasoactive pathways.
Methohexital: (Moderate) Concurrent use of methohexital and antihypertensive agents increases the risk of developing hypotension.
Methyclothiazide: (Moderate) Thiazide diuretics can enhance the hypotensive effects of antihypertensive agents or diuretics if given concomitantly. This additive effect may be desirable, but dosages must be adjusted accordingly.
Metolazone: (Moderate) Thiazide diuretics can enhance the hypotensive effects of antihypertensive agents or diuretics if given concomitantly. This additive effect may be desirable, but dosages must be adjusted accordingly.
Metoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Thiazide diuretics can enhance the hypotensive effects of antihypertensive agents or diuretics if given concomitantly. This additive effect may be desirable, but dosages must be adjusted accordingly.
Milrinone: (Moderate) Concurrent administration of antihypertensive agents could lead to additive hypotension when administered with milrinone. Titrate milrinone dosage according to hemodynamic response.
Monoamine oxidase inhibitors: (Moderate) Additive hypotensive effects may be seen when MAOIs are combined with antihypertensives or medications with hypotensive properties. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with treprostinil.
Nabumetone: (Moderate) NSAIDs may decrease the effect of antihypertensive agents through various mechanisms, including renal and peripheral vasoactive pathways.
Naproxen: (Moderate) NSAIDs may decrease the effect of antihypertensive agents through various mechanisms, including renal and peripheral vasoactive pathways.
Naproxen; Esomeprazole: (Moderate) NSAIDs may decrease the effect of antihypertensive agents through various mechanisms, including renal and peripheral vasoactive pathways.
Naproxen; Pseudoephedrine: (Moderate) NSAIDs may decrease the effect of antihypertensive agents through various mechanisms, including renal and peripheral vasoactive pathways.
Nesiritide, BNP: (Major) The potential for hypotension may be increased when coadministering nesiritide with antihypertensive agents.
Niacin, Niacinamide: (Moderate) Cutaneous vasodilation induced by niacin may become problematic if high-dose niacin is used concomitantly with other antihypertensive agents. This effect is of particular concern in the setting of acute myocardial infarction, unstable angina, or other acute hemodynamic compromise.
Niacin; Simvastatin: (Moderate) Cutaneous vasodilation induced by niacin may become problematic if high-dose niacin is used concomitantly with other antihypertensive agents. This effect is of particular concern in the setting of acute myocardial infarction, unstable angina, or other acute hemodynamic compromise.
Nimodipine: (Moderate) Calcium-channel blockers can have additive hypotensive effects with other antihypertensive agents. This additive effect can be desirable, but the patient should be monitored carefully and the dosage should be adjusted based on clinical response.
Nitrates: (Moderate) Concomitant use of nitrates with other antihypertensive agents can cause additive hypotensive effects. Dosage adjustments may be necessary.
Nitroglycerin: (Moderate) Concomitant use of nitrates with other antihypertensive agents can cause additive hypotensive effects. Dosage adjustments may be necessary.
Nitroprusside: (Moderate) Additive hypotensive effects may occur when nitroprusside is used concomitantly with other antihypertensive agents. Dosages should be adjusted carefully, according to blood pressure.
Nonsteroidal antiinflammatory drugs: (Moderate) NSAIDs may decrease the effect of antihypertensive agents through various mechanisms, including renal and peripheral vasoactive pathways.
Olanzapine: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Olanzapine; Fluoxetine: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Olanzapine; Samidorphan: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Calcium-channel blockers can have additive hypotensive effects with other antihypertensive agents. This additive effect can be desirable, but the patient should be monitored carefully and the dosage should be adjusted based on clinical response. (Moderate) Thiazide diuretics can enhance the hypotensive effects of antihypertensive agents or diuretics if given concomitantly. This additive effect may be desirable, but dosages must be adjusted accordingly.
Olmesartan; Hydrochlorothiazide, HCTZ: (Moderate) Thiazide diuretics can enhance the hypotensive effects of antihypertensive agents or diuretics if given concomitantly. This additive effect may be desirable, but dosages must be adjusted accordingly.
Oxaprozin: (Moderate) NSAIDs may decrease the effect of antihypertensive agents through various mechanisms, including renal and peripheral vasoactive pathways.
Oxymetazoline: (Major) The vasoconstricting actions of oxymetazoline, an alpha adrenergic agonist, may reduce the antihypertensive effects produced by treprostinil. If these drugs are used together, closely monitor for changes in blood pressure.
Pentosan: (Moderate) When used concurrently with anticoagulants, treprostinil may increase the risk of bleeding.
Pentoxifylline: (Moderate) Pentoxifylline has been used concurrently with antihypertensive drugs (beta blockers, diuretics) without observed problems. Small decreases in blood pressure have been observed in some patients treated with pentoxifylline; periodic systemic blood pressure monitoring is recommended for patients receiving concomitant antihypertensives. If indicated, dosage of the antihypertensive agents should be reduced.
Perindopril; Amlodipine: (Moderate) Calcium-channel blockers can have additive hypotensive effects with other antihypertensive agents. This additive effect can be desirable, but the patient should be monitored carefully and the dosage should be adjusted based on clinical response.
Piroxicam: (Moderate) NSAIDs may decrease the effect of antihypertensive agents through various mechanisms, including renal and peripheral vasoactive pathways.
Prasugrel: (Moderate) Monitor patients for signs and symptoms of bleeding if treprostinil is administered with prasugrel. Treprostinil inhibits platelet aggregation; prasugrel is a platelet inhibitor. Coadministration increases the risk of bleeding.
Prazosin: (Moderate) Prazosin is well-known to produce a 'first-dose' phenomenon. Some patients develop significant hypotension shortly after administration of the first dose. The first dose response (acute postural hypotension) of prazosin may be exaggerated in patients who are receiving beta-adrenergic blockers, diuretics, or other antihypertensive agents. Concomitant administration of prazosin with other antihypertensive agents is not prohibited, however. This can be therapeutically advantageous, but lower dosages of each agent should be used.
Procainamide: (Moderate) Procainamide can decrease blood pressure and should be used cautiously in patients receiving antihypertensive agents. Intravenous administration of procainamide is more likely to cause hypotensive effects.
Procaine: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
Propofol: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents.
Propranolol; Hydrochlorothiazide, HCTZ: (Moderate) Thiazide diuretics can enhance the hypotensive effects of antihypertensive agents or diuretics if given concomitantly. This additive effect may be desirable, but dosages must be adjusted accordingly.
Quinapril; Hydrochlorothiazide, HCTZ: (Moderate) Thiazide diuretics can enhance the hypotensive effects of antihypertensive agents or diuretics if given concomitantly. This additive effect may be desirable, but dosages must be adjusted accordingly.
Quinidine: (Moderate) Quinidine can decrease blood pressure and should be used cautiously in patients receiving antihypertensive agents due to the potential for additive hypotension.
Rasagiline: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives or medications with hypotensive properties. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with vasodilators. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
Rifampin: (Minor) Human pharmacokinetic studies with an oral formulation of treprostinil (treprostinil diethanolamine) indicated that coadministration of rifampin, a cytochrome P450 (CYP) 2C8 enzyme inducer, decreased exposure to treprostinil. The clinical significance of this interaction with orally inhaled treprostinil and other CYP2C8 inducers is unknown.
Risperidone: (Moderate) Risperidone may induce orthostatic hypotension and thus enhance the hypotensive effects of antihypertensive agents. Lower initial doses or slower dose titration of risperidone may be necessary in patients receiving antihypertensive agents concomitantly.
Rivaroxaban: (Moderate) When used concurrently with anticoagulants, treprostinil may increase the risk of bleeding.
Rofecoxib: (Moderate) NSAIDs may decrease the effect of antihypertensive agents through various mechanisms, including renal and peripheral vasoactive pathways.
Salicylates: (Moderate) When used concurrently with anticoagulants or platelet inhibitors, treprostinil may increase the risk of bleeding.
Salsalate: (Moderate) When used concurrently with anticoagulants or platelet inhibitors, treprostinil may increase the risk of bleeding.
Sevoflurane: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents.
Silodosin: (Moderate) During clinical trials with silodosin, the incidence of dizziness and orthostatic hypotension was higher in patients receiving concomitant antihypertensive treatment. Thus, caution is advisable when silodosin is administered with antihypertensive agents.
Spironolactone; Hydrochlorothiazide, HCTZ: (Moderate) Thiazide diuretics can enhance the hypotensive effects of antihypertensive agents or diuretics if given concomitantly. This additive effect may be desirable, but dosages must be adjusted accordingly.
Sulindac: (Moderate) NSAIDs may decrease the effect of antihypertensive agents through various mechanisms, including renal and peripheral vasoactive pathways.
Sumatriptan; Naproxen: (Moderate) NSAIDs may decrease the effect of antihypertensive agents through various mechanisms, including renal and peripheral vasoactive pathways.
Sympathomimetics: (Major) Avoid use of sympathomimetic agents with treprostinil. Sympathomimetics counteract the medications used to stabilize pulmonary hypertension, including treprostinil. Sympathomimetics can increase blood pressure, increase heart rate, and may cause vasoconstriction resulting in chest pain and shortness of breath in these patients. Patients should be advised to avoid amphetamine drugs, decongestants (including nasal decongestants) and sympathomimetic anorexiants for weight loss, including dietary supplements. Intravenous vasopressors may be used in the emergency management of pulmonary hypertension patients when needed, but hemodynamic monitoring and careful monitoring of cardiac status are needed to avoid ischemia and other complications.
Telmisartan; Amlodipine: (Moderate) Calcium-channel blockers can have additive hypotensive effects with other antihypertensive agents. This additive effect can be desirable, but the patient should be monitored carefully and the dosage should be adjusted based on clinical response.
Telmisartan; Hydrochlorothiazide, HCTZ: (Moderate) Thiazide diuretics can enhance the hypotensive effects of antihypertensive agents or diuretics if given concomitantly. This additive effect may be desirable, but dosages must be adjusted accordingly.
Tetrabenazine: (Moderate) Tetrabenazine may induce orthostatic hypotension and thus enhance the hypotensive effects of antihypertensive agents. Lower initial doses or slower dose titration of tetrabenazine may be necessary in patients receiving antihypertensive agents concomitantly.
Tetracaine: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents. Use extreme caution with the concomitant use of tetracaine and antihypertensive agents.
Thiazide diuretics: (Moderate) Thiazide diuretics can enhance the hypotensive effects of antihypertensive agents or diuretics if given concomitantly. This additive effect may be desirable, but dosages must be adjusted accordingly.
Thiopental: (Moderate) Concurrent use of thiopental and alpha-blockers or antihypertensive agents increases the risk of developing hypotension.
Thiothixene: (Moderate) Thiothixene should be used cautiously in patients receiving antihypertensive agents. Additive hypotensive effects are possible.
Ticagrelor: (Moderate) Monitor patients for signs and symptoms of bleeding if treprostinil is administered with ticagrelor. Treprostinil inhibits platelet aggregation; ticagrelor is a platelet inhibitor. Coadministration increases the risk of bleeding.
Ticlopidine: (Moderate) Monitor patients for signs and symptoms of bleeding if treprostinil is administered with ticlopidine. Treprostinil inhibits platelet aggregation; ticlopidine is a platelet inhibitor. Coadministration increases the risk of bleeding.
Tinzaparin: (Moderate) When used concurrently with anticoagulants, treprostinil may increase the risk of bleeding.
Tirofiban: (Moderate) Monitor patients for signs and symptoms of bleeding if treprostinil is administered with tirofiban. Treprostinil inhibits platelet aggregation; tirofiban is a platelet inhibitor. Coadministration increases the risk of bleeding.
Tizanidine: (Moderate) Concurrent use of tizanidine with antihypertensive agents can result in significant hypotension. Caution is advised when tizanidine is to be used in patients receiving concurrent antihypertensive therapy.
Tolmetin: (Moderate) NSAIDs may decrease the effect of antihypertensive agents through various mechanisms, including renal and peripheral vasoactive pathways.
Trandolapril; Verapamil: (Moderate) Calcium-channel blockers can have additive hypotensive effects with other antihypertensive agents. This additive effect can be desirable, but the patient should be monitored carefully and the dosage should be adjusted based on clinical response.
Trazodone: (Minor) Due to additive hypotensive effects, patients receiving antihypertensive agents concurrently with trazodone may have excessive hypotension. Decreased dosage of the antihypertensive agent may be required when given with trazodone.
Triamterene; Hydrochlorothiazide, HCTZ: (Moderate) Thiazide diuretics can enhance the hypotensive effects of antihypertensive agents or diuretics if given concomitantly. This additive effect may be desirable, but dosages must be adjusted accordingly.
Valdecoxib: (Moderate) NSAIDs may decrease the effect of antihypertensive agents through various mechanisms, including renal and peripheral vasoactive pathways.
Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Thiazide diuretics can enhance the hypotensive effects of antihypertensive agents or diuretics if given concomitantly. This additive effect may be desirable, but dosages must be adjusted accordingly.
Verapamil: (Moderate) Calcium-channel blockers can have additive hypotensive effects with other antihypertensive agents. This additive effect can be desirable, but the patient should be monitored carefully and the dosage should be adjusted based on clinical response.
Vorapaxar: (Moderate) Monitor patients for signs and symptoms of bleeding if treprostinil is administered with vorapaxar. Treprostinil inhibits platelet aggregation; vorapaxar is a platelet inhibitor. Coadministration increases the risk of bleeding.
Warfarin: (Moderate) When used concurrently with anticoagulants, treprostinil may increase the risk of bleeding.
Yohimbine: (Moderate) Yohimbine can increase blood pressure and therefore can antagonize the therapeutic action of antihypertensive agents. Use with particular caution in hypertensive patients with high or uncontrolled BP.
Ziprasidone: (Minor) Ziprasidone is a moderate antagonist of alpha-1 receptors and may cause orthostatic hypotension with or without tachycardia, dizziness, or syncope. Additive hypotensive effects are possible if ziprasidone is used concurrently with antihypertensive agents.
The major actions of treprostinil, a stable prostacyclin analog, are direct and potent vasodilation of pulmonary and systemic arterial beds, inhibition of platelet aggregation, and inhibition of smooth muscle cell proliferation. The vasodilatory effect results in reduced right and left ventricular afterload, increased cardiac output, and increased stroke volume. Clinically, dyspnea, fatigue and exercise capacities are improved.
Additionally, data indicate that inflammatory mechanisms may be important in the pathogenesis of primary pulmonary hypertension. Treprostinil has been shown to dose-dependently inhibit inflammatory cytokine (TNF-alpha, IL-1, IL-6, and GM-CSF) secretion and gene expression by human alveolar macrophages. Cytokine antagonism by blocking NF-kB nuclear translocation may also contribute to the efficacy of treprostinil therapy in pulmonary hypertension. Prostaglandins have been shown to inhibit this proliferation, theoretically by inducing elevations in cAMP. Treprostinil produced a significantly larger and more sustained increase in cAMP compared with beraprost, cicaprost or iloprost.
Treprostinil is administered as a continuous subcutaneous infusion via an ambulatory infusion pump, as a continuous intravenous (IV) infusion via a surgically placed central venous catheter, using an infusion pump designed for intravenous drug delivery, as an oral inhalation, using an ultrasonic, pulsed-delivery device, or as extended release oral tablets. The volume of distribution can be described by a two-compartment model with the volume in the central compartment roughly 14 L. Treprostinil is highly bound to human plasma protein (91 to 96%).
Extensive metabolism of treprostinil occurs in the liver, primarily by CYP2C8 and to a lesser extent by CYP2C9. Glucuronidation, oxidation, and dehydration appear to be involved in metabolite formation. Based on in vitro data, treprostinil does not inhibit or induce major CYP enzymes. The elimination of treprostinil is biphasic, with a terminal half-life of approximately 4 hours. The majority of the dose is excreted as inactive metabolites in the urine with minimal amounts excreted as unchanged drug.
Among healthy volunteers, clinical and supratherapeutic doses of inhaled treprostinil prolonged the QTc by approximately 10 msec. The QTc effect rapidly dissipated as the concentration of treprostinil decreased. This effect on the QT interval may be an artifact of rapidly changing heart rate. The injectable and oral formulations of treprostinil have not been evaluated in a QT study.
The absolute bioavailability of treprostinil tablets is approximately 17%, with maximum plasma concentrations occurring between 4 and 6 hours following oral administration. Treprostinil absorption is affected by food. The extent of drug exposure increases by 49% and the maximum plasma concentration increases by about 13% when treprostinil is administered following a high-fat, high-calorie meal.
Intravenous Route
Subcutaneous and intravenous administration of treprostinil are bioequivalent at a steady state dose of 10 ng/kg/min. Treprostinil injection is rapidly absorbed with close to 100% bioavailability. Steady-state concentrations of treprostinil injection occur in approximately 10 hours. The average treprostinil parenteral dose of 9.3 ng/kg/min corresponds to a plasma concentration of 2 mcg/L.
Subcutaneous and intravenous administration of treprostinil are bioequivalent at a steady state dose of 10 ng/kg/min. The pharmacokinetics of continuous subcutaneous treprostinil are linear over the dose range 2.5 to 125 ng/kg/min (corresponding to a plasma concentration of roughly 260 pg/ml to 18,250 pg/mL). Treprostinil injection is rapidly absorbed with close to 100% bioavailability. Steady-state concentrations of treprostinil injection occur in approximately 10 hours. The average treprostinil parenteral dose of 9.3 ng/kg/min corresponds to a plasma concentration of 2 mcg/L.
Inhalation Route
Systemic bioavailability of treprostinil after inhalation has been estimated as a mean of 64% after 18 mcg and 72% after 36 mcg, with systemic exposure proportional to the dose administered.

redpajama_set_name: RedPajamaCommonCrawl


text:
Cobra in Its Dressing Room
By Sumathi Reddy
Updated April 2, 2011 12:01 am ET
The city has a newfound celebrity, but she won't be seen in public for at least another week.
The venomous Egyptian cobra whose missing status captured the city's imagination—to the point that someone launched a Twitter account under her identity—will likely be on exhibit beginning next weekend, according to Bronx Zoo officials.
In the meantime, the adolescent snake, just three ounces and less than 24 inches long, is being held in a quarantine unit in the reptile house. The good news: So far she's showing no signs of post-traumatic snake disorder.
"She looks like she's in fine condition and fine temperament," said Jim Breheny, director of the zoo. "She's back in the venomous snake holding room and we're just going to watch her probably for about a week and make sure she suffers no ill effects from her little foray into the wilds of the reptile house. We'll make sure she has a meal and feels comfortable and then we'll open the building and have her on exhibit."
A meal, Mr. Breheny said, is typically one or two mice or rat pups. (Although it looks like the snake has a different idea of a meal, per its Twitter feed on Friday. "A great cake recipe: 2 cups sugar, 4 eggs, 1 cup milk, 2 cups self-rising flour, 1 saw, 1 stick butter. And mix. Bring it by the zoo," wrote @BronxZoosCobra).


I know you've been waiting....here are some photos of Lucy and her kittens, just minutes after birth. It is now 2 weeks later and the kittens (there are 2) are fuzzy and just starting to walk. Their eyes are open and they are very sweet.


text:
Bord Bia's biggest ever showcase gets underway
More than 550 overseas buyers are due to attend some 5,000 meetings with 185 Irish food and drink companies in the RDS Dublin on Thursday as part of the Bord Bia's Marketplace event, writes Joe Dermody.
The week-long food and drink showcase got underway yesterday, with 300 of the international visitors embarking on the first of 28 different three-day group itineraries organised and hosted by Bord Bia. The event is expected to deliver €40m in new business for Irish food companies.
The sector-focused itineraries will allow buyers to see Irish farms, factories, retail stores and manufacturing facilities all around the country to showcase the very best of the Irish food and drink industry.
"Marketplace is an invaluable opportunity for Irish food and drink companies to meet with a large number of international buyers face to face," said Bord Bia CEO Tara McCarthy. "It is our prime platform for showing international buyers' first-hand what makes our products world-class."
Initiatives such as Marketplace have enabled the sustained growth of Irish food and drink exports for the past eight years, culminating in a record value of €12.6bn in 2017."
The visiting food buyers include representatives from Australia, Algeria, Bahrain, China, Indonesia, UAE, Japan, Singapore, Saudi Arabia, and South Africa.
Interest from UK buyers remains strong, with close to 50 attending. Visiting buyers represented every sector of the industry including from dairy and beef to alcohol, seafood and prepared foods.
A team of Bord Bia specialists, including its network of 13 international offices, spent six months preparing for Marketplace, including providing a comprehensive training programme for the 185 companies to ensure they were adequately prepared for meetings with potential buyers. Through a series of training workshops, Irish companies availed of advice on choosing export markets, logistics, and sales pitch techniques. Companies will then get to put these skills into action in pre-scheduled, 'speed-dating' style meetings with the buyers in the RDS.
OBR warns no-deal Brexit could push UK economy into recession
Asos warns on profits over warehouse problems
Warning economy close to overheating; think tank recommends taxing the rich
Angela Merkel criticises Donald Trump's 'go back' comments on Democratic lawmakers


When Associate Professor Dan Brener found the dental profession was lacking education for implant surgery, teaming up with BOQ Specialist helped him use his love of teaching to share his knowledge with others.
Associate Professor Dan Brener didn't plan to be a teacher, although he always had a passion for it. While working as a prosthodontist he identified a gap in dentists implant training and this was his primary drive to create the Brener Implant Institute (Bii).
Why was the Institute necessary?
There are several acknowledged areas of specialty in the dental profession. But implant dentistry isn't one of them.
The process has been made safer by huge advances in technology since those early days. "When I started, we were still placing implants with very roughly made guides, we didn't have three-dimensional software planning at all," says Associate Professor Brener. Now patients can be assessed on the spot using cone beam scans and 3D modelling.
"We can now trace nerves, and place implants electronically," he adds. "That is really taking out a lot of the human error that has been in implant dentistry." However, as Bii grew Associate Professor Brener realised that students faced another problem.
"It takes a significant amount of time, effort and money to set yourself up for implants," he says.
Associate Professor Brener chose BOQ Specialist because of his long standing business relationship with Sandy Constanti, dating back to when he started his very first practice.
When he first graduated from the University of Sydney and planned to open his own practice, he approached the major banks. All of them turned him down. "The four big banks and the non-specialist medical and dental lending centres, have no idea about the ins and outs of what we do as dentists and the potential that we have," he says.
It may have seemed simple to Associate Professor Brener, but a lot goes on behind the scenes at BOQ Specialist to make the purchase seamless. Knowing his practice, BOQ Specialist was able to help him buy the cone beam on his BOQ Specialist credit card—which also earned him Qantas Frequent Flyer points.
Want to finance the next level in your professional education? Click on the link to find out more about personal loans for dentists. Ready to take the next step? Contact us to find out how we can tailor a practice finance solution for you, or call us on 1300 131 141.
Learn about how Dr Andrea Zalan, a paediatrician and child psychiatrist, considered her patients' total wellbeing when building her dream practice.
Our dental practice purchase guide is a great tool designed to help dentists navigate the process of owning a practice, and understand the financial options available.
We understand the value of your professional standing and can lend against goodwill and equipment for your medical practice.
All the best advice on how to build a practice, delivered to your inbox.
The information contained in this article (Information) is general in nature and has been provided in good faith, without taking into account your personal circumstances. While all reasonable care has been taken to ensure that the information is accurate and opinions fair and reasonable, no warranties in this regard are provided.


text:
Ferguson Protesters File $40 Million Civil Rights Lawsuit [DOC]
By Paul Farrell
Updated Aug 28, 2014 at 6:18pm
A group of Ferguson protesters has filed a $40 million lawsuit alleging brutality and civil rights violations occurred as militarized police wantonly cracked down in the wake of the Michael Brown shooting.
The suit, on behalf of six plaintiffs, names the following defendants: Ferguson Police Chief Thomas Jackson, St. Louis County Police Chief Jon Belmar, Ferguson police officer Justin Cosma, various unnamed police officers (John Does), the city of Ferguson and St. Louis County.
The suit was filed by attorneys Gregory Lattimer, Malik Shabazz with Black Lawyers for Justice, and Reginald Green.
See the full lawsuit below, obtained by St. Louis Public Radio.
Michael Brown Autopsy: 5 Fast Facts You Need to Know
Published Aug 28, 2014 at 5:58pm
Breaking News, Civil Rights, Ferguson, Lawsuits, Michael Brown, Police, Racism
A group of protesters filed a $40 million lawsuit alleging civil rights violations by militarized police during the Ferguson, Missouri, protests.


With a productive wine area of over 30, 000 hectares New Zealand has become an important wine producing country over the last 30 years. The growth in the wine indusrty didn't happened by chance.
Right from the early beginning in the 1970's Kiwi's have adapted what they already knew to this new fledging industry. One great example was the universal use of stainless steel in winemaking adapted from the norms and standards of the New Zealand dairy industry. This Kiwi DIY attitutde meant that winemakers adapted and made use of the existing small-scale industrial infrastructure economically from the start.
Holdm® is another example of the "can do " attitude that Kiwi's are reknown for world wide.
Hold drip irrigation tubing or wires together.
foliage growth, holds strong, and is reliable and easy to use.
1-3 years of age. Allows vines to mature without girdling.
Holdm clips are marketed in packs of 10, 20's and 50's, mixed packs in the same numbers are also available.


text:
require 'test/unit'
require 'shoulda'
require 'jsontrim'

redpajama_set_name: RedPajamaGithub


Since 1978 The Painting Pros, Inc. has delivered expert service for interior and exterior painting in San Jose. Find out what our eco-friendly, precise craftsmanship can achieve for you: Call (408) 805-3372 or email us below to ask for a free estimate!
Are you a new customer? Yes, I am a potential new cusomter. No, I am a current existing cusomter. I'm neither.


Captain Rob Taylor believes his young team can push on an look at the promotion places in the second half of the season despite an up and down beginning to his reign as captain.
Twenty-year-old Nelson took over the captaincy from Tom Leeming over the winter and has inherited a talented squad of players in York Senior League Division Two North.
Wins have been difficult to come by over the opening three months of the summer, though, with Ripon sat in eighth place.
League leaders Selby were put under pressure by the Ripon bowlers at the weekend, but their class showed after the interval to collect a 51-run win.
Elliot Oates was Ripon's only batsman to withstand the Selby attack for a length of time as they collapsed for 101 in 39.3 overs.
Despite falling to defeat, Taylor was encouraged enough to suggest his side were capable of a dart at the top of the table in the second half of the season.
"It's all very tight at the moment and I am hoping we can get into the top half of the table and consolidate our position," he said.
Ben Crewe (4-25) and Jake Briscombe (3-22) were the front line bowlers doing the damage to Selby's usually prolific batsmen at the weekend as they bowled the leaders out for just 152.
Both bowlers drew praise from their young captain for the way they have began the campaign, but it has been the team dynamic that has Taylor beaming.
"I'm enjoying it. It's a good challenge and we have a good young team this year with a few new faces," the captain added.
Taylor admitted Saturday's trip to Easingwold was a step in the unknown, with a first pairing between the sides since the York Senior League regionalised its divisions.
Easingwold earned promotion into the northern tier of Division Two this season after finished second in Division Three north last year.
Taylor said: "We just have to take it as it comes, play to our strengths and bowl in the good areas that we know we can.
"We know we are going in the right direction.


text:
Q: How to target form elements other than by id, class or screen location? I am trying to fill out a form using Internet Explorer. The webpage contains no id's nor class names. So currently I move the mouse to a relative position based on the size of the screen. But this screen resolution dependency is undesired.
Given the webpage's (internal website) lack of classes/ids, how to target its HTML form inputs, text areas, combo boxes, drop downs, date pickers, and buttons other than by screen location?

A: You could iterate all input elements to identify the ones you need :
#include <IE.au3>
$oIE = _IECreate("http://www.google.com")
$oAs = _IETagnameGetCollection($oIE, "input")
$i = 1
For $oA In $oAs
   _IEPropertySet($oA, "innertext", $i)
   $i = $i + 1
Next

Next you could use the $i variable to set the right values. In this example the Google search field is the fourth input element so you could fill it out this way:
#include <IE.au3>
$oIE = _IECreate("http://www.google.com")
$oAs = _IETagnameGetCollection($oIE, "input")
$i = 1
For $oA In $oAs
   If $i = 4 Then _IEPropertySet($oA, "innertext", "MyValue")
   $i = $i + 1
Next

redpajama_set_name: RedPajamaStackExchange