Usual Adult Dose for Pulmonary Hypertension

ORAL:
Extended-release tablets:

• Initial dose: 0.25 mg orally every 12 hours or 0.125 mg every 8 hours
• Maintenance dose: Titrate to the highest tolerated dose in increments of 0.25 or 0.5 mg twice a day or 0.125 mg 3 times a day every 3 to 4 days

Comments:

• If dose increments are not tolerated, consider titrating slower.
• Appropriate maintenance dose determined by tolerability.
• If intolerable effects occur, decrease the dose in increments of 0.25 mg to avoid abrupt discontinuation.
• When discontinuing use, reduce the dose in steps of 0.5 to 1 mg per day.

Inhalation:

• Initial dose: 3 breaths (18 mcg) per treatment session 4 times a day; if 3 breaths are not tolerated, reduce to 1 or 2 breaths and subsequently increase to 3 breaths as tolerated
• Maintenance dose: Increase by an additional 3 breaths at about 1 to 2 week intervals as tolerated until the target dose of 9 breaths (54 mcg) is reached per treatment session 4 times a day
• Maximum dose: 9 breaths (54 mcg) per treatment session 4 times a day

Comments:

• Administer in 4 separate, equally spaced (about 4 hours apart) treatment sessions each day during waking hours.
• This drug should be continued at the highest tolerated dose.
• Use only with the Tyvaso(R) Inhalation System.

PARENTERAL:
Patients New to Prostacyclin Infusion Therapy:

• Initial dose: 1.25 ng/kg/min via continuous subcutaneous or IV infusion; if this dose cannot be tolerated, reduce to 0.625 ng/kg/min
• Maintenance dose: Increase infusion rate by 1.25 ng/kg/min per week for the first 4 weeks and thereafter, by 2.5 ng/kg/min per week for the remaining duration of infusion

Comments:

• May be administered as a continuous subcutaneous infusion or continuous IV infusion; however, high risks associated with chronic indwelling central venous catheters (e.g., serious blood stream infections).
• Administration by continuous subcutaneous infusion is the preferred and continuous IV infusion should be reserved for patients in which the subcutaneous route is not tolerated due to severe site pain or reaction, or in whom the above risks are considered warranted.
• The goal of chronic dose adjustments is to establish a dose at which pulmonary arterial hypertension (PAH) symptoms are improved and excessive pharmacological effects are minimized.
• Dose adjustments may be undertaken more often if tolerated.

Patients Transitioning from Epoprostenol:

• Initial dose: Initiate treprostinil at a recommended dose of 10% of the current epoprostenol dose and then escalate as the epoprostenol dose is decreased; the manufacturer product information should be consulted for appropriate recommended titration doses

Comments: Transition from epoprostenol to treprostinil is accomplished by initiating the infusion of treprostinil and increasing it, while simultaneously reducing the dose of IV epoprostenol and should take place in a hospital setting.

Use: For the treatment of PAH (WHO Group 1) to improve exercise capacity

Renal Dose Adjustments

No adjustment recommended, however, doses should be titrated slowly in patients with renal insufficiency.

Liver Dose Adjustments

Extended-release tablets:

• Mild liver dysfunction (Child-Pugh Class A): Initiate at 0.125 mg orally twice a day with 0.125 mg twice a day dose increments every 3 to 4 days
• Moderate liver dysfunction (Child-Pugh Class B): Avoid use
• Severe liver dysfunction (Child-Pugh Class C): Contraindicated

Oral inhalation: Titrate dose slowly in patients with liver dysfunction

Parenteral:

• Mild to moderate liver dysfunction: Decrease initial subcutaneous or IV dose to 0.625 ng/kg/min ideal body weight
• Severe liver dysfunction: Data not available

Dose Adjustments

Conversion from parenteral treprostinil to oral extended-release tablets:

• Decrease the dose of the parenteral product by up to 30 ng/kg/min per day while simultaneously increasing the dose of the extended-release tablets by up to 6 mg per day (2 mg orally 3 times a day) if tolerated.
• To estimate a comparable total daily dose of the extended-release tablets, the following equation is provided by the manufacturer:

Oral (extended-release tablets) total daily dose (mg) = 0.0072 x Parenteral treprostinil dose (ng/kg/min) x weight (kg)

Coadministration with strong CYP450 2C8 inhibitors (e.g., gemfibrozil):
Extended-release tablets:

• Initial dose: 0.125 mg orally twice a day with 0.125 mg twice a day dose increments every 3 to 4 days

Interruptions and discontinuation:

• During planned short-term treatment interruption for patients unable to take oral medications, consider a temporary infusion of subcutaneous or intravenous treprostinil.
• To calculate the total daily dose (mg) for parenteral use, the manufacturer provides the following calculation:

Parenteral treprostinil (ng/kg/min) = 139 x Oral extended-release tablet total daily dose (mg) divided by weight (kg)

Precautions

Oral Inhalation and Extended-release Tablets: Safety and efficacy have not been established in patients younger than 18 years.

Consult WARNINGS section for additional precautions.

Dialysis

Extended-release tablets: No adjustment recommended.

Parenteral and oral inhalation: Data not available

Other Comments

Administration Advice:

• Do not abruptly discontinue any formulation of this drug.
• The manufacturer product information should be consulted for individual formulations.

ER Tablets:

• Swallow whole with food; do not crush, split, or chew tablets.

Parenteral:

• Undiluted treprostinil is administered subcutaneously by continuous infusion without further dilution, via a subcutaneous catheter, using an infusion pump designed for subcutaneous drug delivery.
• Diluted treprostinil is administered IV by continuous infusion via a surgically placed indwelling central venous catheter using an infusion pump designed for IV drug delivery.
• If clinically necessary, a temporary peripheral IV cannula, preferably placed in a large vein, may be used for short term administration.
• Restarting infusion within a few hours after an interruption can be done using the same dose rate; interruptions for longer periods may require the dose to be re-titrated.
• Patients must have immediate access to a backup infusion pumps and infusion sets to avoid interruption of therapy.
• The ambulatory infusion pump should be small and lightweight, be adjustable to about 0.002 mL/hr (subcutaneous only), have occlusion/no delivery, low battery, programming error, and motor malfunction alarms, have delivery accuracy of +/- 6% or better, and be positive pressure driven.
• The reservoir should be made of polyvinyl chloride, polypropylene, or glass.
• The manufacturer product information should be consulted for proper infusion rates.

Inhalation:

• Use only with the Tyvaso(R) Inhalation System.
• Access to a back-up inhalation system device should be available to avoid interruptions in drug delivery.
• Following the last treatment session of the day, the medicine cup and any remaining medication must be discarded and the device cleaned according to instructions for use.
• One ampule should be used each day; after an ampule is opened and transferred to the medicine cup, the solution should remain in the device for no more than one day (24 hours).
• Avoid mixing other medications in the inhalation system.
• Prior to first treatment session, twist off top of a single ampule and squeeze entire contents into medicine cup.
• Between each of the 4 treatment sessions per day, the device should be capped and stored upright with remaining medication inside.
• Advise patients to carefully follow the instructions for use and be adequately trained.
• If a dose is missed, therapy should be resumed as soon as possible.

Storage requirements:

• Inhalation: Ampules should be used within 7 days of opening foil pack; store unopened ampules in the foil pouch to protect from light.
• Parenteral: A single vial should be used for no more than 30 days after initial introduction into the vial. During use, a single undiluted syringe can be administered up to 72 hours at 37C (98.6F)

Reconstitution/preparation techniques:

• Subcutaneous: To be administered without further dilution when used for subcutaneous administration.
• IV: Manufacturer product information should be consulted for proper dilution techniques when used for IV infusion.

IV compatibility: The manufacturer product information should be consulted.

Patient advice:

• Avoid abrupt discontinuation of therapy.
• Avoid skin or eye contact with inhalation solution and do not orally ingest.
• Follow the instructions for use for operation of the inhalation system and for daily cleaning of the device components after the last treatment session of each day.