These highlights do not include all the information needed to use VELETRI safely and effectively. See full prescribing information for VELETRI.
VELETRI (epoprostenol) for Injection
Initial U.S. Approval: 1995
INDICATIONS AND USAGE
VELETRI is a prostanoid vasodilator 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. (1)
DOSAGE AND ADMINISTRATION
Dosage
-
Infusion of VELETRI should be initiated at 2 ng/kg/min and increased in increments of 2 ng/kg/min every 15 minutes or longer until dose-limiting pharmacologic effects are elicited or until a tolerance limit to the drug is established. (2.1)
-
If symptoms of pulmonary hypertension persist or recur after improving - the infusion should be increased 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. (2.2)
Administration
-
VELETRI is administered by continuous intravenous infusion via a central venous catheter using an ambulatory infusion pump. (2.3)
-
Do not mix with any other parenteral medications or solutions prior to or during administration. (2.4)
-
During initiation of treatment, VELETRI may be administered peripherally. (2.3)
Reconstitution
-
Reconstituted in vial with only 5 mL of either Sterile Water for Injection or Sodium Chloride 0.9% Injection. This solution may be refrigerated at 2°C 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. (2.4)
-
Reconstituted product should be further diluted as directed with the same diluent used for reconstitution. This solution of 15000 ng/mL or above of VELETRI may be used for up to 24 hours at room temperature. (Lower concentrations may be used with pump reservoir changed every 12 hours when used at room temperature). (2.4)
-
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. (2.4 )
-
Solution for chronic delivery should be prepared in a drug delivery reservoir appropriate for the infusion pump. (2.4)
DOSAGE FORMS AND STRENGTHS
1.5 mg (1,500,000 ng) VELETRI is in a 10 mL vial with a red flip-off seal. (3)
CONTRAINDICATIONS
Congestive heart failure due to severe left ventricular systolic dysfunction (4)
Pulmonary edema (4)
Hypersensitivity to the drug or to structurally related compounds (4)
WARNINGS AND PRECAUTIONS
VELETRI should be used only by clinicians experienced in the diagnosis and treatment of pulmonary hypertension. (5.1)
Reconstitute only as directed, with Sterile Water for Injection or Sodium Chloride 0.9% Injection.(5.1)
Do not abruptly lower the dose or withdraw dosing. All dosing initiation and changes should be closely monitored. (5.3, 5.4)
Chronic Dosing: Headache, jaw pain, flushing, diarrhea, nausea and vomiting, flu-like symptoms, and anxiety/nervousness (6.1)
To report SUSPECTED ADVERSE REACTIONS, please contact: ACTELION at 1-866-228-3546 or FDA at 1-800-FDA-1088, or http://www.fda.gov/medwatch
DRUG INTERACTIONS
Diuretics, antihypertensive agents, or other vasodilators: reduction in blood pressure (7)
Antiplatelet agents or anticoagulants: increase the risk of bleeding (7)
Patients on digoxin: elevations of digoxin concentrations clinically significant in patients prone to digoxin toxicity (7)
USE IN SPECIFIC POPULATIONS
See 8 for USE IN SPECIFIC POPULATIONS
See 17 for PATIENT COUNSELING INFORMATION
Revised: 06/2011
Back to Highlights and Tabs
FULL PRESCRIBING INFORMATION: CONTENTS*
* Sections or subsections omitted from the full prescribing information are not listed
1 INDICATIONS AND USAGE
2DOSAGE AND ADMINISTRATION
2.1 Dosage
2.2Dosage Adjustments
2.3 Administration
2.4 Reconstitution
3DOSAGE FORMS AND STRENGTHS
4CONTRAINDICATIONS
5WARNINGS AND PRECAUTIONS
5.1General
5.2Dose Initiation
5.3Chronic Use and Dose Adjustment
5.4Withdrawal Effects
5.5Sepsis
6ADVERSE REACTIONS
6.1 Clinical Trials Experience
6.2 Post-Marketing Experience
7DRUG INTERACTIONS
8USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.2 Labor and Delivery
8.3 Nursing Mothers
8.4Pediatric Use
8.5Geriatric Use
10OVERDOSAGE
11DESCRIPTION
12CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis and Mutagenesis and Impairment of Fertility
14CLINICAL STUDIES
14.1 Clinical Trials in Pulmonary Arterial Hypertension (PAH)
16HOW SUPPLIED / STORAGE AND HANDLING
16.1 How Supplied
16.2 Storage and Stability
17PATIENT COUNSELING INFORMATION
FULL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE
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.
2DOSAGE 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)].
2.1 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.
2.2Dosage 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.
2.3 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.
2.4 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
