Treprostinil

TREPROSTINIL- treprostinil injection, solution
Teva Parenteral Medicines, Inc.

1 INDICATIONS AND USAGE

1.1 Pulmonary Arterial Hypertension

Treprostinil Injection is indicated for the treatment of pulmonary arterial hypertension (PAH; WHO Group 1) to diminish symptoms associated with exercise. Studies establishing effectiveness included patients with NYHA Functional Class II-IV symptoms and etiologies of idiopathic or heritable PAH (58%), PAH associated with congenital systemic-to-pulmonary shunts (23%), or PAH associated with connective tissue diseases (19%) [see Clinical Studies (14.1)].

1.2 Pulmonary Arterial Hypertension in Patients Requiring Transition from Epoprostenol

In patients with PAH requiring transition from epoprostenol, Treprostinil Injection is indicated to diminish the rate of clinical deterioration. Consider the risks and benefits of each drug prior to transition.

2 DOSAGE AND ADMINISTRATION

2.1 General

Treprostinil Injection can be administered with or without further dilution with Sterile Diluent for Remodulin^® or similar approved high-pH glycine diluent (e.g. Sterile Diluent for Flolan^® or Sterile Diluent for Epoprostenol), Sterile Water for Injection, or 0.9% Sodium Chloride Injection prior to administration. See Table 1 below for storage and administration time limits for the different diluents.

Diluted Treprostinil Injection has been shown to be stable at ambient temperature when stored for up to 14 days using high-pH glycine diluent at concentrations as low as 0.004 mg/mL (4,000 ng/mL).

Table 1: Selection of Diluent

Diluent	Storage Limits	Administration Limits
None	See Section 16	16 weeks at 40°C
Sterile Diluents for Remodulin® , Flolan® , or Epoprostenol	14 days at room temperature	48 hours at 40°C
Sterile Water for Injection 0.9% Sodium Chloride for Injection	4 hours at room temperature or 24 hours refrigerated	48 hours at 40°C

2.2 Initial Dose for Patients New to Prostacyclin Infusion Therapy

Treprostinil Injection is indicated for subcutaneous or intravenous use only as a continuous infusion. Treprostinil Injection is preferably infused subcutaneously, but can be administered by a central intravenous line if the subcutaneous route is not tolerated, because of severe site pain or reaction. The infusion rate is initiated at 1.25 ng/kg/min. If this initial dose cannot be tolerated because of systemic effects, reduce the infusion rate to 0.625 ng/kg/min.

2.3 Initial Dose for Patients Transitioning to an Implantable Intravenous Infusion Pump

​ The initial dose of Treprostinil Injection should be the same as the current dose the patient is receiving using the external infusion pump at the time of transition.

2.4 Dosage Adjustments

The goal of chronic dosage adjustments is to establish a dose at which PAH symptoms are improved, while minimizing excessive pharmacologic effects of Treprostinil Injection (headache, nausea, emesis, restlessness, anxiety and infusion site pain or reaction).

The infusion rate should be increased in increments of 1.25 ng/kg/min per week for the first four weeks of treatment and then 2.5 ng/kg/min per week for the remaining duration of infusion, depending on clinical response. Dosage adjustments may be undertaken more often if tolerated. Avoid abrupt cessation of infusion [see Warnings and Precautions (5.2)]. Restarting a Treprostinil Injection infusion within a few hours after an interruption can be done using the same dose rate. Interruptions for longer periods may require the dose of Treprostinil Injection to be re-titrated.

2.5 Patients with Hepatic Insufficiency

In patients with mild or moderate hepatic insufficiency, decrease the initial dose of Treprostinil Injection to 0.625 ng/kg/min ideal body weight. Treprostinil Injection has not been studied in patients with severe hepatic insufficiency [see Warnings and Precautions (5.3), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].

2.6 Administration

Inspect parenteral drug products for particulate matter and discoloration prior to administration whenever solution and container permit. If either particulate matter or discoloration is noted, do not use.

Preparation

Treprostinil Injection is administered by subcutaneous or intravenous infusion at a calculated rate based on a patient’s dose (ng/kg/min), weight (kg) and the Treprostinil Injection concentration (mg/mL).

For administration of Undiluted Treprostinil Injection the rate is calculated using the following formula:

​

Undiluted Infusion Rate (mL/hour)	=	Dose (ng/kg/min)	x	Weight (kg)	x	0.00006*
		Treprostinil Vial Strength (mg/mL)
*Conversion factor of 0.00006 = 60 min/hour x 0.000001 mg/ng

For administration of Diluted Treprostinil Injection, the concentration is calculated using the following formula:

Step 1

Diluted Treprostinil Concentration (mg/mL)	=	Dose (ng/kg/min)	x	Weight (kg)	x	0.00006
		Infusion Rate (mL/hour)

The volume of Treprostinil Injection needed to make the required diluted Treprostinil concentration for the given reservoir size can then be calculated using the following formula:

Step 2

V olume of Treprostinil Injection (mL)	=	D il uted Treprostinil Concentration (mg/mL)	x	T otal Volume of Diluted Treprostinil Solution in Reservoir (mL)
		Treprostinil Vial Strength (mg/mL)

The calculated volume of Treprostinil Injection is then added to the reservoir along with the sufficient volume of diluent to achieve the desired total volume in the reservoir.

Subcutaneous Infusion

Treprostinil Injection is administered subcutaneously by continuous infusion, via a subcutaneous catheter, using an infusion pump designed for subcutaneous drug delivery. The infusion pump should: (1) be adjustable to approximately 0.002 mL/hour, (2) have occlusion/no delivery, low battery, programming error and motor malfunction alarms, (3) have delivery accuracy of ±6% or better, (4) be positive pressure-driven, and (5) have a reservoir made of polyvinyl chloride, polypropylene or glass. Alternatively, use an infusion pump cleared for use with Treprostinil Injection. To avoid potential interruptions in drug delivery, the patient must have immediate access to a backup infusion pump and subcutaneous infusion sets.

Intravenous Infusion

External Intravenous Infusion Pump:

Treprostinil Injection is administered intravenously by continuous infusion via a surgically placed indwelling central venous catheter using an external infusion pump designed for intravenous drug delivery. If clinically necessary, a temporary peripheral intravenous cannula, preferably placed in a large vein, may be used for short term administration of Treprostinil Injection. Use of a peripheral intravenous infusion for more than a few hours increases the risk of thrombophlebitis. The infusion pump used to administer Treprostinil Injection should: (1) have occlusion/no delivery, low battery, programming error and motor malfunction alarms, (2) have delivery accuracy of ±6% or better, (3) be positive pressure driven, and (4) have a reservoir made of polyvinyl chloride, polypropylene or glass. Alternatively, use an infusion pump cleared for use with Treprostinil Injection. To avoid potential interruptions in drug delivery, the patient must have immediate access to a backup infusion pump and infusion sets.

Infusion sets with an in-line 0.22 or 0.2 micron pore size filter should be used.

​ Implantable Intravenous Infusion Pump:

Use an implantable intravenous infusion pump approved for use with Treprostinil Injection. Refer to the pump manufacturer’s manual for specific instructions regarding preparation, programing, implantation, and refilling.