Treprostinil

Pronunciation: tre-PROST-i-nil
Class: Vasodilator

Trade Names

Remodulin
- Injection 1 mg/mL (as treprostinil sodium)
- Injection 2.5 mg/mL (as treprostinil sodium)
- Injection 5 mg/mL (as treprostinil sodium)
- Injection 10 mg/mL (as treprostinil sodium)

Tyvaso
- Solution for inhalation 0.6 mg/mL

Pharmacology

Treprostinil directly vasodilates pulmonary and systemic arterial vascular beds and inhibits platelet aggregation.

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Pharmacokinetics

Absorption

Relatively rapid and complete absorption after subcutaneous infusion; absolute bioavailability is approximately 100%. Steady state is achieved in approximately 10 h. For inhalation, absolute systemic bioavailability is approximately 64% (18 mcg) and 72% (36 mcg); C _max at the target dose (54 mcg) was 0.91 and 1.32 ng/mL in 2 studies with a corresponding T _max of 0.25 and 0.12 h, respectively.

Distribution

Vd is approximately 14 L; 91% bound to human plasma proteins.

Metabolism

Substantially metabolized by the liver; 5 metabolites identified but biological activity and metabolic fate unknown.

Elimination

Biphasic elimination; terminal half-life is approximately 4 h. Approximately 79% excreted in urine, 4% as unchanged drug; approximately 13% excreted in feces. Cl approximately 30 L/h.

Special Populations

No studies have been performed.

Cl reduced up to 80% in patients with hepatic impairment. C _max increased 2-fold in patients with mild impairment and 4-fold in patients with moderate impairment. Treprostinil has not been studied in patients with severe hepatic impairment.

Indications and Usage

Treatment of pulmonary arterial hypertension (PAH) in patients with New York Heart Association (NYHA) class II to IV symptoms (injection) and class III symptoms (inhalation) to diminish symptoms associated with exercise; to diminish the rate of clinical deterioration in patients requiring transition from epoprostenol (injection).

Contraindications

Standard considerations.

Dosage and Administration

Subcutaneous or IV Initial dose: 1.25 ng/kg/min; reduce to 0.625 ng/kg/min if initial dose is not tolerated. Titrate dose in increments of no more than 1.25 ng/kg/min/wk for first 4 wk, then by no more than 2.5 ng/kg/min/wk to establish dose at which PAH symptoms are improved, while minimizing excessive pharmacologic adverse reactions. Little experience with doses higher than 40 ng/kg/min. Inhalation Initial dose: 3 breaths (18 mcg) per treatment session 4 times daily; reduce to 1 or 2 breaths if initial dose is not tolerated. Titrate dose by an additional 3 breaths at approximately 1- to 2-wk intervals, if tolerated, until a target dose of 9 breaths (54 mcg) is reached per treatment session 4 times daily (max dose, 9 breaths per treatment session 4 times daily).

Reduce initial dose to 0.625 ng/kg/min in patients with mild to moderate hepatic impairment and increase dose cautiously.

IV Initiate the infusion of treprostinil and increase it while simultaneously decreasing the dose of IV epoprostenol. This transition should take place in a hospital with constant observation. Treprostinil is initiated at 10% of current epoprostenol dose and then escalated as epoprostenol dose is decreased. The transition is as follows:

• Step 1 - Epoprostenol dose is unchanged and treprostinil dose is 10% of epoprostenol dose.
• Step 2 - Administer 80% of starting epoprostenol dose and treprostinil dose is 30% of starting epoprostenol dose.
• Step 3 - Administer 60% of starting epoprostenol dose and treprostinil dose is 50% of starting epoprostenol dose.
• Step 4 - Administer 40% of starting epoprostenol dose and treprostinil dose is 70% of starting epoprostenol dose.
• Step 5 - Administer 20% of starting epoprostenol dose and treprostinil dose is 90% of starting epoprostenol dose.
• Step 6 - Administer 5% of starting epoprostenol dose and treprostinil dose is 110% of starting epoprostenol dose.
• Step 7 - Administer 0% of starting epoprostenol dose and treprostinil dose is 110% of starting epoprostenol dose plus additional 5% to 10% increments as needed.

General Advice

• Injection
• For subcutaneous or IV infusion only. IV infusion is for those who are not able to tolerate subcutaneous infusion (severe site pain or reaction).
• Administer as supplied (undiluted) for subcutaneous infusion. Administer via self-inserted subcutaneous catheter using an infusion pump designed for subcutaneous drug delivery.
• Calculate subcutaneous infusion rate using the following formula: subcutaneous infusion rate (mL/h) = (dose [ng/kg/min] × weight [kg] × 0.00006)/treprostinil vial strength (mg per mL).
• For IV infusion, dilute with sterile water for injection, sodium chloride 0.9% injection, or epoprosenol sterile diluent for injection. Administer via surgically placed indwelling central venous catheter using an infusion pump designed for IV drug delivery.
• Visually inspect for particulate matter and discoloration; do not use if particulate matter or discoloration is noted.
• First, calculate diluted IV treprostinil concentration using the following formula: diluted IV treprostinil concentration (mg/mL) = (dose [ng/kg/min] × weight [kg] × 0.00006)/IV infusion rate (mL/min); then calculate amount of treprostinil injection needed using the following formula: amount of treprostinil injection (mL) = (diluted IV concentration [mg/mL]/treprostinil vial strength [mg/mL]) × total volume of diluted treprostinil solution in reservoir (mL).
• Add calculated amount of treprostinil injection to reservoir along with sufficient volume of sterile water for injection, sodium chloride 0.9% injection, or epoprostenol sterile diluent for injection to achieve desired total volume in reservoir.

• Inhalation
• Treprostinil must be used only with the treprostinil inhalation system.
• Do not mix treprostinil with other medications in the Optineb -ir device.
• Treprostinil is dosed in 4 separate, equally spaced treatment sessions per day during waking hours. The treatment sessions should be approximately 4 h apart.
• One ampule of treprostinil contains a sufficient volume of medication for all 4 treatment sessions in a single day. At the end of each day, the medicine cup and any remaining medication must be discarded.

Storage/Stability

Store vials at 59° to 86°F. During use, a single reservoir (syringe) of undiluted treprostinil can be administered for up to 72 h at 98.6°F; diluted treprostinil can be administered for up to 48 h at 98.6°F. A single vial should be used for no more than 30 days after initial introduction into the vial.

The ampules for inhalations should be stored at 59° to 86°F. After opening the foil pouch, treprostinil should be used within 7 days. Treprostinil is light sensitive; store unopened ampules in foil pouch. After an ampule is opened and transferred to the medicine cup, the solution should remain in the device for no more than 24 h.

Drug Interactions

The risk of bleeding may be increased. Use with caution in patients receiving anticoagulants. Monitor anticoagulant parameters and adjust the dose as needed.

The risk of symptomatic hypotension may be increased. Coadminister with caution. Monitor blood pressure. If an interaction is suspected, dosage adjustments or supportive treatment may be needed.

Treprostinil exposure may be decreased, decreasing the efficacy. Monitor the response of the patient and adjust the treprostinil treatment timing based on planned activity.

Treprostinil exposure may be increased, increasing the pharmacologic and adverse reactions. Monitor the response of the patient and adjust the treprostinil treatment timing based on planned activity.

The risk of symptomatic hypotension may be increased. Coadminister with caution. Monitor blood pressure. If an interaction is suspected, dosage adjustments or supportive treatment may be needed.

The risk of symptomatic hypotension may be increased. Coadminister with caution. Monitor blood pressure. If an interaction is suspected, dosage adjustments or supportive treatment may be needed.

Laboratory Test Interactions

None well documented.

Adverse Reactions

Cardiovascular

Flushing (15%); vasodilatation (11%); syncope (6%); hypotension (4%).

CNS

Headache (41%); dizziness (9%).

Dermatologic

Rash (14%); pruritus (8%); generalized rashes, sometimes macular or papular (postmarketing).

GI

Diarrhea (25%); nausea (22%).

Local

Infusion-site pain (85%); infusion-site reaction (83%); arm swelling, hematoma, pain, paresthesias (potentially related to mode of infusion), thrombophlebitis associated with peripheral IV infusion (postmarketing).

Respiratory

Cough (54%); pharyngolaryngeal pain, throat irritation (25%); epistaxis, hemoptysis, pneumonia, wheezing.

Miscellaneous

Jaw pain (13%); edema (9%); muscle, jaw, or bone pain; bone pain, cellulitis, thrombocytopenia (postmarketing).

Precautions

Pregnancy

Category B .

Lactation

Undetermined.

Children

Safety and efficacy not established.

Elderly

Dose selection should be cautious, reflecting the higher frequency of decreased hepatic, renal, or cardiac function, and of comorbidity.

Renal Function

Use with caution.

Hepatic Function

Use with caution.

Abrupt withdrawal

Avoid abrupt withdrawal or sudden large dose reductions because of risk of worsening of PAH symptoms.

Bleeding

May be at an increased risk of bleeding.

Hypotension

May produce symptomatic hypotension in patients with low systemic arterial pressure.

Initiating therapy

Initiate therapy in a setting with adequate personnel and equipment for physiological monitoring and emergency care.

Pulmonary disease

Use in patients with pulmonary disease (eg, asthma, COPD) has not been established.

Overdosage

Symptoms

Diarrhea, flushing, headache, hypotension, nausea, vomiting.

Patient Information

• Injection
• Advise patient that medication is administered as a continuous infusion through a catheter using an infusion pump and that therapy will be needed for a prolonged period of time, possibly years.
• Advise patient or caregiver that medication initially will be prepared by health care provider and administered in health care setting while the dose is being adjusted to provide optimal benefit.
• For home infusion, ensure that patient understands how to store, prepare, and administer the medication using the infusion pump, and how to dispose of used equipment and supplies.
• Ensure that patient has immediate access to backup infusion pump and infusion sets at all times, and knows how to change equipment if necessary.
• Advise patient that dose may be adjusted periodically by health care provider to maintain optimal benefit or to manage adverse reactions. Caution patient not to stop the infusion or change the dose unless advised by health care provider.
• Advise patient that if medication needs to be discontinued, it will be slowly withdrawn unless safety concerns (eg, rash) require a more rapid withdrawal.
• Advise patient or caregiver to immediately inform health care provider if chest pain, fatigue, injection-site pain or reaction, itching, skin rash, or worsening shortness of breath occurs during treatment.
• Advise patient or caregiver to report persistent diarrhea, dizziness, headache, or any other bothersome or unexplained sensation or feeling.

• Inhalation
• Ensure that patients are properly trained in the administration process, including dosing and Opetineb -ir device set-up, operation, cleaning, and maintenance.
• Advise patients that if a treatment session is missed or interrupted, to resume therapy as soon as possible.
• Advise patients to avoid skin or eye contact with treprostinil. If the medication comes in contact with the skin or eyes, instruct patient rinse with water immediately.

Copyright © 2009 Wolters Kluwer Health.