Tyvaso Starter Kit

Prostacyclin Analogs/Receptor Agonists for PAH

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).

For oral inhalation use only.
If a scheduled dose is missed or interrupted, resume therapy as soon as possible at the usual dose.
 
Nebulizer Solution for Inhalation (e.g., Tyvaso)
NOTE: Treprostinil nebulizer solution 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 be trained and 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 nebulizer solution with other medications in the Tyvaso Inhalation System. Compatibility with other medications has not been studied.
One ampule of treprostinil nebulizer solution 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 Tyvason Inhalation System device must be cleaned each day according to the "Instructions for Use".
Each treatment session will take 2 to 3 minutes.
 
Dry Powder Inhaler for Oral Inhalation (e.g., Tyvaso DPI)
NOTE: Cartridges containing treprostinil powder for inhalation must be used only with the Tyvaso DPI inhaler device.
The inhaler comes with "Instructions for Use". Instruct patients in the administration process including dosing and the DPI Inhaler setup, operation, cleaning, and maintenance, according to the "Instructions for Use".
Select the proper cartridge for the dose: 16 mcg (1 purple cartridge), 32 mcg (1 dark blue cartridge), 48 mcg (1 light blue cartridge), or 64 mcg (1 light green cartridge). If a dose is greater than 64 mcg, then more than 1 cartridge will be needed to make the dose. Example, an 80 mcg dose will require 1 dark blue cartridge (32 mcg) and 1 light blue cartridge (64 mcg).
The DPI inhaler may be used for 7 days. Advise patients that after 7 days of use, the DPI inhaler must be discarded in the trash and replaced with a new inhaler. Never wash the inhaler; it must always remain dry. If needed, the inhaler may be wiped with a clean, dry cloth only.
Storage: Store the inhaler in a clean, dry place with the mouthpiece cover in place at either room temperature of 20 to 25 degrees C (68 to 77 degrees F) or under refrigeration at 2 to 8 degrees C (36 to 46 degrees F). Unopened blister cards may be stored under refrigeration or at room temperature. Unopened blister cards may be stored for 5 weeks; discard after 5 weeks. Opened blister strips may be stored for 3 days at room temperature.
DPI Inhaler setup:
Tear along the perforation to remove 1 blister strip from the blister card and check the expiration date on the strip. Do not use if it is past the expiration date.
If the cartridges and inhaler have been stored under refrigeration, remove from the refrigerator and allow them to remain at room temperature for 10 minutes before use to remove condensation.
Remove the cartridge from the blister strip by pushing on the white plastic blister to push the cartridge out; this will not damage the cartridge.
Make sure to remove the correct number of cartridges for the dose.
Following removal of the cartridge(s), any unused cartridges that remain in the blister strip should be stored at room temperature. Do not put a blister strip back into the refrigerator after being opened. An opened blister strip must be used within 3 days.
Do not open cartridges; the inhaler device will open the cartridges. Do not place the cartridges in the mouth or swallow them.
Place the inhaler on a flat surface and open by lifting the mouthpiece.
Hold the cartridge with the cup facing down. Line up the cartridge with the opening in the inhaler; the pointed end of the cartridge should line up with the pointed end within the inhaler. Place the cartridge into the inhaler so that it lies flat.
Close the inhaler; this will open the cartridge. You should feel a snap when the inhaler is closed.
Keep the inhaler level to avoid loss of treprostinil powder. Do not turn inhaler upside down, point the mouthpiece down, shake, or drop the inhaler.
If any powder spills from the inhaler, throw the cartridge into household trash and repeat the above steps with a new cartridge. If the powder comes into contact with your hands, wash your hands right away.
Administration:
While keeping the inhaler level, remove the blue mouthpiece cover by pulling it straight off. Continue to keep the inhaler level as it is picked up and brought near a cheek. Do not place in front of the mouth. Holding the inhaler away from the mouth, fully blow out.
Keep head level as the mouthpiece is placed into the mouth and lips are closed around the mouthpiece forming a seal. Tilt the inhaler slightly downward while keeping the head level; this helps to prevent the powder being blocked by the tongue.
Inhale deeply, remove the mouthpiece from the mouth, and hold breath for as long as comfortably able to do so. Then blow out and continue to breath normally.
Replace the mouthpiece cover, open the inhaler, and remove the cartridge from the blue base. The cup should now be in the middle of the cartridge. You can tell that a cartridge has been used when the cup has moved from the front to the middle of the cartridge. Throw the used cartridge into the trash after use. Do not leave or store cartridges in the inhaler.
If dose requires more than one cartridge, repeat the above steps with each cartridge. The cartridges may be used in any order, regardless of cartridge strength. Inhale 1 cartridge at a time.
Treprostinil cartridges are for single-use only; use a new cartridge for each treatment session.

injection site reaction / Rapid / 38.0-38.0
GI bleeding / Delayed / 1.3-1.3
bronchospasm / Rapid / Incidence not known
angioedema / Rapid / Incidence not known

edema / Delayed / 9.0-9.0
dyspnea / Early / 7.8-7.8
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
thrombocytopenia / Delayed / Incidence not known
phlebitis / Rapid / Incidence not known
wheezing / Rapid / Incidence not known
bone pain / Delayed / Incidence not known

headache / Early / 15.7-75.0
diarrhea / Early / 10.0-69.0
cough / Delayed / 35.0-54.0
flushing / Rapid / 11.0-45.0
nausea / Early / 5.9-40.0
vomiting / Early / 3.0-36.0
throat irritation / Early / 25.0-25.0
rash / Early / 14.0-14.0
abdominal pain / Early / 3.0-12.0
pruritus / Rapid / 8.0-8.0
syncope / Early / 6.0-6.0
asthenia / Delayed / 3.0
dizziness / Early / 9.0
anorexia / Delayed / 3.0
paresthesias / Delayed / Incidence not known
maculopapular rash / Early / Incidence not known
dyspepsia / Early / Incidence not known
infection / Delayed / Incidence not known
nasal irritation / Early / Incidence not known
epistaxis / Delayed / Incidence not known
musculoskeletal pain / Early / Incidence not known
arthralgia / Delayed / Incidence not known
myalgia / Early / Incidence not known

Orenitram, Remodulin, Tyvaso, TYVASO DPI, Tyvaso Refill Kit, Tyvaso Starter Kit

Rx

Analog of epoprostenol (prostacyclin) for treatment of pulmonary hypertension and pulmonary hypertension associated with interstitial lung disease
Given by inhalation (nebulizer solution or dry powder oral inhaler), continuous subcutaneous or IV infusion, and an oral extended-release tablet
Major advantage over IV epoprostenol is ease of use and less potential for serious infections

Oral treprostinil:
Mild hepatic insufficiency (Child-Pugh Class A): Reduce the initial dose to 0.125 mg PO twice daily; increase by 0.125 mg increments twice daily, but not more frequently than every 3 to 4 days.
Moderate hepatic insufficiency (Child-Pugh Class B): Avoid use.
Severe hepatic impairment (Child-Pugh Class C): Do not use; contraindicated.
 
Injectable treprostinil:
Mlld to moderate hepatic insufficiency: Reduce the initial dose of treprostinil injection to 0.625 ng/kg/minute (using ideal body weight) subcutaneously or IV, and cautiously titrate upward. Follow the usual titration guidelines for indication.
Severe hepatic impairment: Treprostinil for injection or inhalation has not been studied in severe hepatic impairment.
 
Inhalational treprostinil:
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.

No dosage adjustments are required.
 
Hemodialysis
Treprostinil is not removed by dialysis.

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; Aspirin: (Moderate) When used concurrently with anticoagulants or platelet inhibitors, treprostinil may increase the risk of bleeding.
Acetaminophen; Aspirin; Diphenhydramine: (Moderate) When used concurrently with anticoagulants or platelet inhibitors, treprostinil may increase the risk of bleeding.
Acetaminophen; Ibuprofen: (Moderate) NSAIDs may decrease the effect of antihypertensive agents through various mechanisms, including renal and peripheral vasoactive pathways.
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; 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; Caffeine: (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.
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.
Bupivacaine; Meloxicam: (Moderate) NSAIDs may decrease the effect of antihypertensive agents through various mechanisms, including renal and peripheral vasoactive pathways.
Butalbital; Aspirin; Caffeine; Codeine: (Moderate) When used concurrently with anticoagulants or platelet inhibitors, treprostinil may increase the risk of bleeding.
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.
Celecoxib; Tramadol: (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.
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.
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.
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.
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.
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.
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.
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; Famotidine: (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.
Methenamine; Sodium Salicylate: (Moderate) When used concurrently with anticoagulants or platelet inhibitors, treprostinil may increase the risk of bleeding.
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.
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.
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.
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.
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.

Orenitram Oral Tab ER: 0.125mg, 0.25mg, 1mg, 2.5mg
Remodulin/Treprostinil/Treprostinil Sodium Intravenous Inj Sol: 1mL, 1mg, 2.5mg, 5mg, 10mg
Remodulin/Treprostinil/Treprostinil Sodium Subcutaneous Inj Sol: 1mL, 1mg, 2.5mg, 5mg, 10mg

Titrate parenteral dose to patient response, doses up to 290 ng/kg/min have been studied; 12 breaths of solution for inhalation via oral inhalation/treatment session, given 4 times daily; titrate powder for inhalation to clinical response and tolerability, maximum dose not specified by manufacturer; titrate oral tablets to clinical response and tolerability, doses up to 21 mg PO twice daily have been studied.

Titrate parenteral dose to patient response, doses up to 290 ng/kg/min have been studied; 12 breaths of solution for inhalation via oral inhalation/treatment session, given 4 times daily; titrate powder for inhalation to clinical response and tolerability, maximum dose not specified by manufacturer; titrate oral tablets to clinical response and tolerability, doses up to 21 mg PO 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.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

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. 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.
 
Data also 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, as an oral inhalation via a dry powder inhaler (DPI), 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. 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.
 
Affected cytochrome P450 isoenzymes and drug transporters: CYP2C8, CYP2C9
Treprostinil undergoes extensive metabolism 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 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.

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.

Solution for Inhalation
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. Plasma exposure was determined in 2 studies at the target dose of 54 mcg; mean Cmax was 0.91 and 1.32 ng/mL, the mean Tmax was 0.25 and 0.12 hour, and the mean AUC was 0.81 ng/mL/hour and 0.97 ng/mL/hour, respectively.
 
Powder for Inhalation
In a 6-treatment, 6-period, 6-sequence, crossover study involving healthy patients, the mean Cmax for the 16 mcg, 48 mcg, and 64 mcg doses were 0.39 ng/mL, 1.11 ng/mL, and 1.33 ng/mL, respectively, and the median Tmax was 0.17 hours. In addition, the mean AUC for the 16 mcg, 48 mcg, and 64 mcg doses were 0.275 ng/mL/hour, 0.774 ng/mL/hour, and 0.964 ng/mL/hour. Following a single treprostinil dose, the mean terminal half-life ranged from 27 to 50 minutes.

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). 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. Oral administration of treprostinil diolamine has been associated with adverse fetal effects in animal studies. Oral administration of treprostinil at doses of 10 mg/kg/day or greater (approximately 15 times the human exposure at the dose of 3.5 mg twice daily on an AUC basis) to pregnant rats resulted in decreased pregnancy rate, increased post-implantation loss, and decreased fetal viability and growth. Following oral treprostinil at doses of 1.5 mg/kg/day and 3 mg/kg/day to pregnant rabbits, teratogenicity (external fetal and soft tissue malformations, fetal skeletal malformations), decreased fetal weight, and decreased fetal viability and growth were observed. The dose of 1.5 mg/kg/day is approximately 7 times the human exposure at a dose of 3.5 mg twice daily. In animal studies, no adverse reproductive and developmental effects were seen for treprostinil nebulizer solution at 9 or greater times and 145 or greater times the human exposure when based on Cmax and AUC, respectively, following a single dose of 54 mcg. In animal studies, no adverse reproductive and developmental effects were seen for treprostinil powder for inhalation at 8 or greater times and 134 or greater times the human exposure when based on Cmax and AUC, respectively, following a single dose of 64 mcg. 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.

Specific recommendations are not available for treprostinil use in breast-feeding patients. There are no data on the presence of treprostinil in human milk, the effects on the breastfed infant, or the effects on milk production.