Treprostinil Sodium

Trade Names:
Remodulin
- Injection 1 mg/mL
- Injection 2.5 mg/mL
- Injection 5 mg/mL
- Injection 10 mg/mL

Pharmacology

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

Pharmacokinetics

Absorption

Relatively rapid and complete absorption after subcutaneous infusion; absolute bioavailability is approximately 100%. Steady state is achieved in approximately 10 h.

Distribution

Vd is approximately 14 L; 91% bound to 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 to diminish symptoms associated with exercise; to diminish the rate of clinical deterioration in patients requiring transition from epoprostenol.

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.

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

• 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 either particulate matter or discoloration is noted.
• First, calculate diluted IV treprostinil concentration using 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 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.

Storage/Stability

Store 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.

Drug Interactions

The risk of bleeding may be increased.

Reduction in BP associated with these agents may be exacerbated by treprostinil.

Laboratory Test Interactions

None well documented.

Adverse Reactions

Cardiovascular

Vasodilatation (11%); hypotension (4%).

CNS

Headache (27%); 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).

Miscellaneous

Jaw pain (13%); edema (9%); 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.

Initiating therapy

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

Overdosage

Symptoms

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

Patient Information

• 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 dispose of used equipment and supplies.
• Ensure that patient has immediate access to back-up 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 occur during treatment.
• Advise patient or caregiver to report persistent diarrhea, dizziness, headache, or any other bothersome or unexplained sensation or feeling.

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