Veletri Dosage

Dosage

Prepare continuous chronic infusion of VELETRI as directed, and administer through a central venous catheter. Temporary peripheral intravenous infusion may be used until central access is established. Initiate chronic infusion of VELETRI at 2 ng/kg/min and increase in increments of 2 ng/kg/min every 15 minutes or longer until a tolerance limit to the drug is established or further increases in the infusion rate are not clinically warranted. If dose-limiting pharmacologic effects occur, then decrease the infusion rate until VELETRI is tolerated. In clinical trials, the most common dose-limiting adverse events were nausea, vomiting, hypotension, sepsis, headache, abdominal pain, or respiratory disorder (most treatment-limiting adverse events were not serious). If the initial infusion rate of 2 ng/kg/min is not tolerated, use a lower dose.

In the controlled 12-week trial in PAH/SSD, for example, the dose increased from a mean starting dose of 2.2 ng/kg/min. During the first 7 days of treatment, the dose was increased daily to a mean dose of 4.1 ng/kg/min on day 7 of treatment. At the end of week 12, the mean dose was 11.2 ng/kg/min. The mean incremental increase was 2 to 3 ng/kg/min every 3 weeks.

Dosage Adjustments

Base changes in the chronic infusion rate on persistence, recurrence, or worsening of the patient's symptoms of pulmonary hypertension and the occurrence of adverse events due to excessive doses of VELETRI. In general, expect increases in dose from the initial chronic dose.

Consider increments in dose if symptoms of pulmonary hypertension persist or recur. Adjust the infusion by 1- to 2-ng/kg/min increments at intervals sufficient to allow assessment of clinical response; these intervals should be at least 15 minutes. In clinical trials, incremental increases in dose occurred at intervals of 24 to 48 hours or longer. Following establishment of new chronic infusion rate, observe the patient, and monitor standing and supine blood pressure and heart rate for several hours to ensure that the new dose is tolerated.

During chronic infusion, the occurrence of dose-limiting pharmacological events may necessitate a decrease in infusion rate, but the adverse event may occasionally resolve without dosage adjustment. Make dosage decreases gradually in 2-ng/kg/min decrements every 15 minutes or longer until the dose-limiting effects resolve [see Adverse Reactions (6.1 and 6.2)]. Avoid abrupt withdrawal of VELETRI or sudden large reductions in infusion rates. Except in life-threatening situations (e.g., unconsciousness, collapse, etc.), infusion rates of VELETRI should be adjusted only under the direction of a physician.

In patients receiving lung transplants, doses of epoprostenol were tapered after the initiation of cardiopulmonary bypass.

Administration

VELETRI, once prepared as directed [see Dosage and Administration (2.4)], is administered by continuous intravenous infusion via a central venous catheter using an ambulatory infusion pump. During initiation of treatment, VELETRI may be administered peripherally.

Infusion sets with an in-line 0.22 micron filter should be used.

The ambulatory infusion pump used to administer VELETRI should: (1) be small and lightweight, (2) be able to adjust infusion rates in 2-ng/kg/min increments, (3) have occlusion, end-of-infusion, and low-battery alarms, (4) be accurate to ±6% of the programmed rate, and (5) be positive pressure-driven (continuous or pulsatile) with intervals between pulses not exceeding 3 minutes at infusion rates used to deliver VELETRI. The reservoir should be made of polyvinyl chloride, polypropylene, or glass. The infusion pump used in the most recent clinical trials was the CADD-1 HFX 5100 (SIMS Deltec). A 60-inch microbore non-DEHP extension set with proximal antisyphon valve, low priming volume (0.9 mL), and in-line 0.22 micron filter was used during clinical trials.

To avoid potential interruptions in drug delivery, the patient should have access to a backup infusion pump and intravenous infusion sets. Consider a multi-lumen catheter if other intravenous therapies are routinely administered.

Reconstitution

VELETRI is stable only when reconstituted as directed using Sterile Water for Injection, USP, or Sodium Chloride 0.9% Injection, USP. Do not reconstitute or mix VELETRI with any other parenteral medications or solutions prior to or during administration. Each vial is for single-dose; discard any unused solution.

Use after reconstitution and immediate dilution to final concentration.

Use at room temperature (77°F/25°C)

VELETRI solution reconstituted with 5 mL of Sterile Water for Injection, USP or Sodium Chloride 0.9% Injection, and immediately diluted to the final concentration in the drug delivery reservoir can be administered at room temperature per the conditions of use as outlined in Table 1.

Table 1: Maximum Duration of Administration (hours) at Room Temperature (77°F/ 25°C) of Fully Diluted Solutions in the Drug Delivery Reservoir*

Final concentration range	Immediate administration	If stored for up to 8 days at 36° to 46°F (2° to 8°C)
* Short excursions at 104°F (40°C) are permitted for up to: 2 hours for concentrations below 15,000 ng/mL 4 hours for concentrations between 15,000 ng/mL and 60,000 ng/mL 8 hours for concentrations above 60,000 ng/mL
0.5 mg vial
≥3,000 ng/mL and <15,000 ng/mL	48 hours	24 hours
1.5 mg vial
≥15,000 ng/mL and <60,000 ng/mL	48 hours	48 hours
≥60,000 ng/mL	72 hours	48 hours

Use at higher temperatures >77°F up to 104°F (>25° to 40°C)

Temperatures greater than 77°F and up to 86°F (>25°C to 30°C): A single reservoir of fully diluted solution of 60,000 ng/mL or above of VELETRI prepared as directed can be administered (either immediately or after up to 8 days storage at 36° to 46°F (2° to 8°C)) for up to 48 hours. For diluted solutions of less than 60,000 ng/mL, pump reservoirs should be changed every 24 hours.

Temperatures up to 104°F (40°C): Fully diluted solutions of 60,000 ng/mL or above of VELETRI, prepared as directed, can be immediately administered for periods up to 24 hours.

Do not expose this solution to direct sunlight.

A concentration for the solution of VELETRI should be selected that is compatible with the infusion pump being used with respect to minimum and maximum flow rates, reservoir capacity, and the infusion pump criteria listed above. VELETRI, when administered chronically, should be prepared in a drug delivery reservoir appropriate for the infusion pump. Outlined in Table 2 are directions for preparing different concentrations of VELETRI.

Each vial is for single-dose; discard any unused solution.

Table 2: Reconstitution and Dilution Instructions

To make 100 mL of solution with Final Concentration (ng/mL) of:	Directions
* Higher concentrations may be prepared for patients who receive VELETRI long-term.
Using the 0.5 mg vial
3,000 ng/ml	Dissolve contents of one 0.5 mg vial with 5 mL of Sterile Water for Injection, USP or Sodium Chloride 0.9% Injection, USP. Withdraw 3 mL of the vial contents and add to a sufficient volume of the identical diluent to make a total of 100 mL.
5,000 ng/mL	Dissolve contents of one 0.5 mg vial with 5 mL of Sterile Water for Injection, USP, or Sodium Chloride 0.9% Injection, USP. Withdraw entire vial contents and add to a sufficient volume of the identical diluent to make a total of 100 mL.
10,000 ng/mL	Dissolve contents of two 0.5 mg vials each with 5 mL of Sterile Water for Injection, USP, or Sodium Chloride 0.9% Injection, USP. Withdraw entire vial contents and add to a sufficient volume of the identical diluent to make a total of 100 mL.
Using the 1.5 mg vial
15,000 ng/mL*	Dissolve contents of one 1.5 mg vial with 5 mL of Sterile Water for Injection, USP, or Sodium Chloride 0.9% Injection, USP. Withdraw entire vial contents and add to a sufficient volume of the identical diluent to make a total of 100 mL.
30,000 ng/mL*	Dissolve contents of two 1.5 mg vials each with 5 mL of Sterile Water for Injection, USP, or Sodium Chloride 0.9% Injection, USP. Withdraw entire vial contents and add to a sufficient volume of the identical diluent to make a total of 100 mL.

Infusion rates may be calculated using the following formula:

Infusion Rate (mL/hr)=	[Dose (ng/kg/min)×Weight (kg)×60 min/hr]
	Final Concentration (ng/mL)

Tables 3 to 7 provide infusion delivery rates for doses up to 16 ng/kg/min based upon patient weight, drug delivery rate, and concentration of the solution of VELETRI to be used. These tables may be used to select the most appropriate concentration of VELETRI that will result in an infusion rate between the minimum and maximum flow rates of the infusion pump and that will allow the desired duration of infusion from a given reservoir volume. For infusion/dose rates lower than those listed in Tables 3 to 7, it is recommended that the pump rate be set by a healthcare professional such that steady state is achieved in the patient, keeping in mind the half-life of epoprostenol is no more than six minutes. Higher infusion rates, and therefore, more concentrated solutions may be necessary with long-term administration of VELETRI.

Table 3: Infusion Rates for VELETRI at a Concentration of 3,000 ng/mL

Patient weight (kg)	Dose or Drug Delivery Rate (ng/kg/min)
	2	3	4	5
	Infusion Delivery Rate (mL/hr)
20	–	1.2	1.6	2.0
30	1.2	1.8	2.4	3.0
40	1.6	2.4	3.2	4.0
50	2.0	3.0	4.0	–
60	2.4	3.6	–	–
70	2.8	–	–	–
80	3.2	–	–	–
90	3.6	–	–	–
100	4.0	–	–	–

Table 4: Infusion Rates for VELETRI at a Concentration of 5,000 ng/mL

Patient weight (kg)	Dose or Drug Delivery Rate (ng/kg/min)
	2	4	6	8	10	12	14
	Infusion Delivery Rate (mL/hr)
20	–	1.0	1.4	1.9	2.4	2.9	3.4
30	–	1.4	2.2	2.9	3.6	–	–
40	1.0	1.9	2.9	3.8	–	–	–
50	1.2	2.4	3.6	–	–	–	–
60	1.4	2.9	–	–	–	–	–
70	1.7	3.4	---	---	---	---	---
80	1.9	3.8	---	---	---	---	---
90	2.2	–	---	---	---	---	---
100	2.4	–	---	---	---	---	---

Table 5: Infusion Rates for VELETRI at a Concentration of 10,000 ng/mL

Patient weight (kg)	Dose or Drug Delivery Rate (ng/kg/min)
	4	6	8	10	12	14	16
	Infusion Delivery Rate (mL/hr)
20	–	–	1.0	1.2	1.4	1.7	1.9
30	–	1.1	1.4	1.8	2.2	2.5	2.9
40	1.0	1.4	1.9	2.4	2.9	3.4	3.8
50	1.2	1.8	2.4	3.0	3.6	–	–
60	1.4	2.2	2.9	3.6	–	–	–
70	1.7	2.5	3.4	–	–	–	–
80	1.9	2.9	3.8	–	–	–	–
90	2.2	3.2	–	–	–	–	–
100	2.4	3.6	–	–	–	–	–

Table 6: Infusion Rates for VELETRI at a Concentration of 15,000 ng/mL

Patient weight (kg)	Dose or Drug Delivery Rate (ng/kg/min)
	4	6	8	10	12	14	16
	Infusion Delivery Rate (mL/hr)
20	–	–	–	–	1.0	1.1	1.3
30	–	–	1.0	1.2	1.4	1.7	1.9
40	–	1.0	1.3	1.6	1.9	2.2	2.6
50	–	1.2	1.6	2.0	2.4	2.8	3.2
60	1.0	1.4	1.9	2.4	2.9	3.4	3.8
70	1.1	1.7	2.2	2.8	3.4	3.9	–
80	1.3	1.9	2.6	3.2	3.8	–	–
90	1.4	2.2	2.9	3.6	–	–	–
100	1.6	2.4	3.2	4.0	–	–	–

Table 7: Infusion Rates for VELETRI at a Concentration of 30,000 ng/mL

Patient weight (kg)	Dose or Drug Delivery Rate (ng/kg/min)
	6	8	10	12	14	16
30	–	–	–	–	–	1.0
40	–	–	–	1.0	1.1	1.3
50	–	–	1.0	1.2	1.4	1.6
60	–	1.0	1.2	1.4	1.7	1.9
70	–	1.1	1.4	1.7	2.0	2.2
80	1.0	1.3	1.6	1.9	2.2	2.6
90	1.1	1.4	1.8	2.2	2.5	2.9
100	1.2	1.6	2.0	2.4	2.8	3.2