Veletri

epoprostenol sodium

Dosage Form: injection, powder, lyophilized, for solution
FULL PRESCRIBING INFORMATION

Indications and Usage for Veletri

Veletri is indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) to improve exercise capacity. Studies establishing effectiveness included predominantly patients with NYHA Functional Class III-IV symptoms and etiologies of idiopathic or heritable PAH or PAH associated with connective tissue diseases.

Veletri Dosage and Administration

Important Note: Reconstitute Veletri only as directed with Sterile Water for Injection, USP, or Sodium Chloride 0.9% Injection, USP. Do not dilute reconstituted solutions of Veletri or administer it with other parenteral solutions or medications [see Warnings and Precautions (5.1)].

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 a 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. 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 Reconstitution (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.

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 use only; discard any unused solution.

Use after storage of the reconstituted solution

Prior to use, Veletri solutions reconstituted with 5 mL diluent must be protected from light and can be refrigerated at 2° to 8°C (36° to 46°F) for as long as 5 days or held at up to 25°C (77°F) for up to 48 hours prior to use. Do not freeze reconstituted solutions of Veletri. Discard any reconstituted solution that has been frozen. Discard any reconstituted solution if it has been refrigerated for more than 5 days, or if held at room temperature for more than 48 hours.

Before administration, reconstituted solutions are further diluted to the final concentration.

During use, a single reservoir of diluted solution of 15000 ng/mL or above of Veletri prepared as directed can be administered at room temperature for up to 24 hours. (If lower concentrations are chosen, pump reservoirs should be changed every 12 hours when administered at room temperature.) Do not expose this solution to direct sunlight.

Use after reconstitution and immediate dilution to final concentration

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 per the conditions of use as outlined in Table 1.

Table 1: Maximum duration of administration (hours) at room temperature (25°C/ 77°F) of fully diluted solutions in the drug delivery reservoir

Final concentration range	Immediate administration	If stored at 2° to 8°C (36° to 46°F) for 1 day	If stored at 2° to 8°C (36° to 46°F) for 7 days
≥3,000 ng/mL and <6,000 ng/mL	12 hours	"Do not use"	"Do not use"
≥ 6,000 ng/mL and < 9,000 ng/mL	24 hours	12 hours	"Do not use"
≥ 9,000 ng/mL and < 12,000 ng/mL	24 hours	12 hours	12 hours
≥12,000 ng/mL and < 30,000 ng/mL	24 hours	24 hours	12 hours
≥30,000 ng/mL	72 hours	48 hours	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 for up to a 72-hour period. Each vial is for single use only; 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.
3,000 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 1 mL of the vial contents and add to a sufficient volume of the identical diluent to make a total of 100 mL.
6,000 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 2 mL of the vial contents and add to a sufficient volume of the identical diluent to make a total of 100 mL.
9,000 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 3 mL of the vial contents and add to a sufficient volume of the identical diluent to make a total of 100 mL.
12,000 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 4 mL of the vial contents and add to a sufficient volume of the identical diluent to make a total of 100 mL.
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 8 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 8, 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

	Dose or Drug Delivery Rate (ng/kg/min)
Patient weight (kg)	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 6,000 ng/mL

	Dose or Drug Delivery Rate (ng/kg/min)
Patient weight (kg)	2	3	4	5
	Infusion Delivery Rate (mL/hr)
20	---	---	---	---
30	---	---	1.2	1.5
40	---	1.2	1.6	2.0
50	1.0	1.5	2.0	2.5
60	1.2	1.8	2.4	3.0
70	1.4	2.1	2.8	3.5
80	1.6	2.4	3.2	4.0
90	1.8	2.7	3.6
100	2.0	3.0	4.0

Table 5: Infusion Rates for Veletri at a Concentration of 9,000 ng/mL

	Dose or Drug Delivery Rate (ng/kg/min)
Patient weight (kg)	3	6	9
	Infusion Delivery Rate (mL/hr)
20	---	---	---
30	---	1.2	1.8
40	---	1.6	2.4
50	1.0	2.0	3.0
60	1.2	2.4	3.6
70	1.4	2.8
80	1.6	3.2
90	1.8	3.6
100	2.0	4.0

Table 6: Infusion Rates for Veletri at a Concentration of 12,000 ng/mL

	Dose or Drug Delivery Rate (ng/kg/min)
Patient weight (kg)	4	6	8	10
	Infusion Delivery Rate (mL/hr)
20	---	---	---	---
30	---	---	1.2	1.5
40	---	1.2	1.6	2.0
50	1.0	1.5	2.0	2.5
60	1.2	1.8	2.4	3.0
70	1.4	2.1	2.8	3.5
80	1.6	2.4	3.2	4.0
90	1.8	2.7	3.6
100	2.0	3.0	4.0

Table 7: Infusion Rates for Veletri at a Concentration of 15,000 ng/mL

	Dose or Drug Delivery Rate (ng/kg/min)
Patient weight (kg)	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 8: Infusion Rates for Veletri at a Concentration of 30,000 ng/mL

	Dose or Drug Delivery Rate (ng/kg/min)
Patient weight (kg)	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

Dosage Forms and Strengths

Veletri contains epoprostenol sodium equivalent to 1.5 mg (1,500,000 ng) epoprostenol and is supplied as a sterile lyophilized material in a 10 mL vial with a red flip-off seal.

Contraindications

A large study evaluating the effect of epoprostenol on survival in NYHA Class III and IV patients with congestive heart failure due to severe left ventricular systolic dysfunction was terminated after an interim analysis of 471 patients revealed a higher mortality in patients receiving epoprostenol plus conventional therapy than in those receiving conventional therapy alone. The chronic use of Veletri in patients with congestive heart failure due to severe left ventricular systolic dysfunction is therefore contraindicated.

Some patients with pulmonary hypertension have developed pulmonary edema during dose initiation, which may be associated with pulmonary veno-occlusive disease. Veletri should not be used chronically in patients who develop pulmonary edema during dose initiation.

Veletri is also contraindicated in patients with known hypersensitivity to the drug or to structurally related compounds.

Warnings and Precautions

General

Reconstitute Veletri only as directed using Sterile Water for Injection, USP, or Sodium Chloride 0.9% Injection, USP. Do not mix Veletri with any other parenteral medications or solutions prior to or during administration.

Veletri should be used only by clinicians experienced in the diagnosis and treatment of pulmonary hypertension. Carefully establish the diagnosis of idiopathic or heritable PAH or PAH/CTD.

Dose Initiation

Veletri is a potent pulmonary and systemic vasodilator. Initiate Veletri in a setting with adequate personnel and equipment for physiologic monitoring and emergency care. Dose initiation has been performed during right heart catheterization and without cardiac catheterization. During dose initiation, asymptomatic increases in pulmonary artery pressure coincident with increases in cardiac output occurred rarely. In such cases, consider dose reduction, but such an increase does not imply that chronic treatment is contraindicated.

Chronic Use and Dose Adjustment

During chronic use, deliver Veletri continuously on an ambulatory basis through a permanent indwelling central venous catheter. Unless contraindicated, administer anticoagulant therapy to patients receiving Veletri to reduce the risk of pulmonary thromboembolism or systemic embolism through a patent foramen ovale. To reduce the risk of infection, use aseptic technique in the reconstitution and administration of Veletri and in routine catheter care. Because epoprostenol is metabolized rapidly, even brief interruptions in the delivery of Veletri may result in symptoms associated with rebound pulmonary hypertension including dyspnea, dizziness, and asthenia. Intravenous therapy with Veletri will likely be needed for prolonged periods, possibly years, so consider the patient's capacity to accept and care for a permanent intravenous catheter and infusion pump.

Based on clinical trials, the acute hemodynamic response (reduction in pulmonary artery resistance) to epoprostenol did not correlate well with improvement in exercise tolerance or survival during chronic use of epoprostenol. Adjust dosage of Veletri during chronic use at the first sign of recurrence or worsening of symptoms attributable to pulmonary hypertension or the occurrence of adverse events associated with epoprostenol [see Dosage and Administration (2)]. Following dosage adjustments, monitor standing and supine blood pressure and heart rate closely for several hours.

Withdrawal Effects

Abrupt withdrawal (including interruptions in drug delivery) or sudden large reductions in dosage of Veletri may result in symptoms associated with rebound pulmonary hypertension, including dyspnea, dizziness, and asthenia. In clinical trials, one Class III primary pulmonary hypertension patient's death was judged attributable to the interruption of epoprostenol. Avoid abrupt withdrawal.

Sepsis

See Adverse Reactions (6.1)

Adverse Reactions

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

During clinical trials, adverse events were classified as follows: (1) adverse events during dose initiation and escalation, (2) adverse events during chronic dosing, and (3) adverse events associated with the drug delivery system.

Adverse Events during Dose Initiation and Escalation

During early clinical trials, epoprostenol was increased in 2-ng/kg/min increments until the patients developed symptomatic intolerance. The most common adverse events and the adverse events that limited further increases in dose were generally related to vasodilation, the major pharmacologic effect of epoprostenol. The most common dose-limiting adverse events (occurring in ≥1% of patients) were nausea, vomiting, headache, hypotension, and flushing, but also include chest pain, anxiety, dizziness, bradycardia, dyspnea, abdominal pain, musculoskeletal pain, and tachycardia. Table 9 lists the adverse events reported during dose initiation and escalation in decreasing order of frequency.

Table 9: Adverse Events during Dose Initiation and Escalation

Adverse Events Occurring in ≥1% of Patients	Epoprostenol (n = 391)
Flushing	58%
Headache	49%
Nausea/vomiting	32%
Hypotension	16%
Anxiety, nervousness, agitation	11%
Chest pain	11%
Dizziness	8%
Bradycardia	5%
Abdominal pain	5%
Musculoskeletal pain	3%
Dyspnea	2%
Back pain	2%
Sweating	1%
Dyspepsia	1%
Hypesthesia/paresthesia	1%
Tachycardia	1%

Adverse Events during Chronic Administration:

Interpretation of adverse events is complicated by the clinical features of PAH, which are similar to some of the pharmacologic effects of epoprostenol (e.g., dizziness, syncope). Adverse events which may be related to the underlying disease include dyspnea, fatigue, chest pain, edema, hypoxia, right ventricular failure, and pallor. Several adverse events, on the other hand, can clearly be attributed to epoprostenol. These include hypotension, bradycardia, tachycardia, pulmonary edema, bleeding at various sites, thrombocytopenia, headache, abdominal pain, pain (unspecified), sweating, rash, arthralgia, jaw pain, flushing, diarrhea, nausea and vomiting, flu-like symptoms, anxiety/nervousness, and agitation. In addition, chest pain, fatigue, and pallor have been reported during epoprostenol therapy, and a role for the drug in these events cannot be excluded.

Adverse Events during Chronic Administration for Idiopathic or Heritable PAH:

In an effort to separate the adverse effects of the drug from the adverse effects of the underlying disease, Table 10 lists adverse events that occurred at a rate at least 10% greater on epoprostenol than on conventional therapy in controlled trials for idiopathic or heritable PAH.

Table 10: Adverse Events Regardless of Attribution Occurring in Patients with Idiopathic or Heritable PAH with ≥ 10% Difference between Epoprostenol and Conventional Therapy Alone

Adverse Event	Epoprostenol (n = 52)	Conventional Therapy (n = 54)
Occurrence More Common With Epoprostenol
General
Chills/fever/sepsis/flu-like symptoms	25%	11%
Cardiovascular
Tachycardia	35%	24%
Flushing	42%	2%
Gastrointestinal
Diarrhea	37%	6%
Nausea/vomiting	67%	48%
Musculoskeletal
Jaw pain	54%	0%
Myalgia	44%	31%
Nonspecific musculoskeletal pain	35%	15%
Neurological
Anxiety/nervousness/tremor	21%	9%
Dizziness	83%	70%
Headache	83%	33%
Hypesthesia, hyperesthesia, paresthesia	12%	2%

Thrombocytopenia has been reported during uncontrolled clinical trials in patients receiving epoprostenol.

Adverse Events during Chronic Administration for PAH/SSD

In an effort to separate the adverse effects of the drug from the adverse effects of the underlying disease, Table 11 lists adverse events that occurred at a rate at least 10% greater on epoprostenol in the controlled trial.

Table 11: Adverse Events Regardless of Attribution Occurring in Patients with PAH/SSD With ≥10% Difference Between Epoprostenol and Conventional Therapy Alone

Adverse Event	Epoprostenol (n = 56)	Conventional Therapy (n = 55)
Cardiovascular
Flushing	23%	0%
Hypotension	13%	0%
Gastrointestinal
Anorexia	66%	47%
Nausea/vomiting	41%	16%
Diarrhea	50%	5%
Musculoskeletal
Jaw pain	75%	0%
Pain/neck pain/arthralgia	84%	65%
Neurological
Headache	46%	5%
Skin and Appendages
Skin ulcer	39%	24%
Eczema/rash/urticaria	25%	4%

Although the relationship to epoprostenol administration has not been established, pulmonary embolism has been reported in several patients taking epoprostenol and there have been reports of hepatic failure.

Adverse Events Attributable to the Drug Delivery System

Chronic infusions of epoprostenol are delivered using a small, portable infusion pump through an indwelling central venous catheter. During controlled PAH trials of up to 12 weeks' duration, the local infection rate was about 18%, and the rate fo