Caripul

PACKAGE LEAFLET
SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT

CARIPUL 0.5 mg, Powder and Solvent for Solution for Infusion
CARIPUL 1.5 mg, Powder and Solvent for Solution for Infusion

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial contains 0.531 mg of epoprostenol sodium equivalent to 0.5 mg of epoprostenol.
One mL of reconstituted solution contains 0.1 milligram of epoprostenol (as epoprostenol sodium)
(0.5 mg epoprostenol in 5 mL of solvent).
Each vial contains 1.593 mg of epoprostenol sodium equivalent to 1.5 mg of epoprostenol.
One mL of reconstituted solution contains 0.3 milligrams of epoprostenol (as epoprostenol sodium)
(1.5 mg epoprostenol in 5 mL of solvent).
Each solvent vial contains 100 mL of water for injections.
For the complete list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Powder for solution for infusion
White to almost white powder
Solvent for parenteral use
Clear, colourless solution
For the pH of the diluted solution, see section 4.4

4. CLINICAL INFORMATION

4.1 Therapeutic Indications
CARIPUL is indicated for:
Pulmonary Arterial Hypertension
CARIPUL is indicated for the treatment of pulmonary arterial hypertension (PAH) (idiopathic or hereditary
PAH and PAH associated with connective tissue diseases) to improve exercise capacity in patients with
symptoms corresponding to WHO Functional Classes III-IV (see section 5.1).
Renal Dialysis
CARIPUL is indicated for use in haemodialysis in emergency situations when the use of heparin poses a high
risk of causing or exacerbating bleeding or in the presence of other contraindications to heparin use (see
section 5.1).

4.2 Posology and Method of Administration
Posology
Pulmonary Arterial Hypertension
CARIPUL is indicated only for continuous intravenous infusion.
Treatment must be initiated and monitored only by a physician experienced in the management of pulmonary
arterial hypertension.
Short-term (acute) dosing interval
This procedure must be performed in a hospital equipped with adequate resuscitation facilities. A short-term
procedure with dose-ranging administered via a peripheral or central venous catheter is required to determine
the infusion rate for long-term treatment.
The initial infusion rate is 2 nanograms/kg/min and should be increased in increments of 2
nanograms/kg/min every 15 minutes or more, until maximum haemodynamic benefit or dose-limiting
pharmacological effects are reached.
If the initial infusion rate of 2 nanograms/kg/min is not tolerated, a lower dose that is tolerated by the patient
should be identified.
Long-term continuous infusion
Long-term continuous infusion of CARIPUL must be administered via a central venous catheter. Temporary
peripheral intravenous infusions may be used until central access is established. Long-term infusions should
be initiated at a rate 4 nanograms/kg/min lower than the maximum tolerated infusion rate determined during
the short-term dose-ranging procedure. If the maximum tolerated infusion rate is equal to or less than 5
nanograms/kg/min, long-term infusion should be initiated at 1 ng/kg/min.
Dose adjustment
Adjustments to the long-term infusion rate should be based on the persistence, recurrence, or worsening of
symptoms related to pulmonary arterial hypertension or the occurrence of an adverse reaction due to excessive
doses of CARIPUL.
In general, over time, an increase in dose from the initial dose may be required. Dose increases should be
considered if symptoms of pulmonary arterial hypertension persist or recur after initial improvement. The
infusion rate should be increased in increments of 1 to 2 nanograms/kg/min at intervals sufficient to assess
clinical response; such intervals should be at least 15 minutes. After establishing a new infusion rate, the
patient must be clinically observed, and blood pressure in supine and upright positions and heart rate should be
monitored for several hours to confirm tolerance of the new dose.
During long-term infusion, the occurrence of dose-related pharmacological events similar to those observed
during the dose-titration period may necessitate a reduction in the infusion rate; however, adverse reactions
may occasionally resolve without any dose modification. Dose reductions should be performed gradually, with
decrements of 2 nanograms/kg/min every 15 minutes or more, until dose-limiting effects resolve. Abrupt
discontinuation of CARIPUL or significant and sudden reductions in infusion rate must be avoided due to the
risk of potentially fatal rebound effects (see section 4.4). Except in life-threatening situations (e.g., loss of
consciousness, collapse, etc.), CARIPUL infusion rates should only be modified under medical supervision.

Renal Dialysis
CARIPUL is suitable only for continuous infusion, either intravascularly or into the blood flowing into the
dialyser.
In adults, the following infusion regimen has proven effective:

• Before dialysis: 4 nanograms/kg/min intravenously for 15 minutes
• During dialysis: 4 nanograms/kg/min into the arterial access of the dialyser

Infusion should be discontinued at the end of dialysis.
The recommended dose for renal dialysis should only be exceeded under careful monitoring of the patient’s
blood pressure.

Elderly
Specific information on the use of CARIPUL in patients over 65 years of age, in either renal dialysis or
pulmonary arterial hypertension, is not available. In general, dose identification in elderly patients should be
performed with caution, taking into account the higher frequency of hepatic, renal (in case of pulmonary
arterial hypertension), or cardiac impairment, concomitant diseases, or other pharmacological therapies.

Paediatric population
The safety and efficacy of epoprostenol in children under 18 years of age have not yet been established.

Method of Administration
Long-term administration of epoprostenol must be performed intravenously via a central venous catheter using
an ambulatory infusion pump. The patient must be adequately trained in aspects related to central venous
catheter care, aseptic preparation of the injectable intravenous solution of CARIPUL, and preparation and
replacement of the infusion pump reservoir and its extension set.
Further information on potentially suitable materials, ambulatory pumps, and instructions for connecting
intravenous access systems to be used for CARIPUL administration are described in section 6.6.
Reduction of catheter-related bloodstream infection risk
Particular attention must be paid to the recommendations in section 4.4 and following, in order to reduce the
risk of catheter-related bloodstream infection.
Care of the central venous catheter and its external connection site must follow established medical procedures.
Only extension devices equipped with an in-line 0.22 micron filter placed between the infusion pump and the
central venous catheter should be used. Use of filters with hydrophilic polyethersulfone membrane is
recommended. The extension device and in-line filter must be replaced at least every 48 hours (see section
6.6).
Preparation of the intravenous injectable solution of CARIPUL
Reconstituted solutions must be immediately further diluted to the final concentration. The reconstituted
solution should be inspected before further dilution. Use is prohibited if discoloration or particulate matter is
present.
For instructions on reconstitution and dilution of the medicinal product before administration, see section 6.6.
Epoprostenol must not be administered as an injectable bolus.

4.3 Contraindications
CARIPUL is contraindicated in patients:

• with known hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
• with congestive heart failure due to severe left ventricular dysfunction.
• CARIPUL must not be used chronically in patients who develop pulmonary oedema during dose-ranging.

4.4 Special Warnings and Precautions for Use
The pH of diluted "ready-to-use" solutions decreases with dilution and ranges from 12.0 at concentrations of
90,000 ng/mL to 11.7 at 45,000 ng/mL, down to 11.0 at 3,000 ng/mL.
Therefore, peripheral intravenous use should be limited and of short duration, and low concentrations should be
used.
Due to the high pH of final infusion solutions, care must be taken during administration to avoid extravasation
and the consequent risk of tissue damage.
CARIPUL is a potent pulmonary and systemic vasodilator. Cardiovascular effects occurring during infusion
resolve within 30 minutes after discontinuation.
CARIPUL is a potent inhibitor of platelet aggregation; therefore, an increased risk of haemorrhagic
complications should be considered, especially in patients with additional haemorrhagic risk factors (see
section 4.5).
If excessive hypotension occurs during CARIPUL administration, the dose should be reduced or the infusion
discontinued. In case of overdose, hypotension may be severe and may lead to loss of consciousness (see
section 4.9).
Blood pressure and heart rate must be monitored during CARIPUL infusion.
CARIPUL may either decrease or increase heart rate. This change is thought to depend on both baseline heart
rate and the infusion rate at which CARIPUL is administered.
The effects of CARIPUL on heart rate may be masked by concomitant use of drugs acting on cardiovascular
reflexes.
Extreme caution is advised in patients with coronary artery disease.
Elevated serum glucose levels have been reported (see section 4.8).
The solvent does not contain preservatives; therefore, each vial must be used once only and then discarded.

Pulmonary Arterial Hypertension
Some patients with pulmonary arterial hypertension have developed pulmonary oedema during dose
titration, which may be associated with pulmonary veno-occlusive disease. CARIPUL must not be used
chronically in patients who develop pulmonary oedema during dose titration (see section 4.3).
Abrupt cessation or interruption of infusion must be avoided, except in life-threatening situations. Abrupt
discontinuation of therapy may lead to rebound pulmonary hypertension, resulting in dizziness, asthenia,
increased dyspnoea, and may lead to death (see section 4.2).
CARIPUL is continuously infused via a permanent central venous catheter using a small portable infusion
pump. Therefore, CARIPUL therapy requires patient commitment to sterile drug reconstitution, administration,
care of the permanent central venous catheter, and ongoing, careful training in these practices.
Aseptic conditions must be maintained during drug preparation and catheter care. Even brief interruptions in
CARIPUL delivery may result in rapid worsening of symptoms. The decision to administer CARIPUL for
pulmonary arterial hypertension must be carefully considered, taking into account the patient’s awareness
that prolonged therapy, possibly lasting years, is highly likely, and the patient’s ability to accept proper
management of both the permanent intravenous catheter and the infusion pump.

Renal Dialysis
The hypotensive effect of CARIPUL may be enhanced by the use of acetate buffer in the dialysate during renal
dialysis.
During renal dialysis with CARIPUL, care must be taken to ensure adequate increase in cardiac output so that
oxygen delivery to peripheral tissues is not reduced.
CARIPUL is not a conventional anticoagulant. Epoprostenol has been successfully used as a substitute for
heparin in renal dialysis, but in a small percentage of cases, clot formation in the dialysis circuit has occurred,
requiring dialysis interruption. When epoprostenol is used alone, tests such as activated whole blood
coagulation time may not be reliable.

Sodium
This medicinal product contains less than 1 mmol (23 mg) of sodium per vial, i.e., essentially 'sodium-free'.

4.5 Interaction with Other Medicinal Products and Other Forms of Interaction
When administering CARIPUL to patients receiving anticoagulants concurrently, standard monitoring of
coagulation parameters is recommended.
The vasodilatory effects of CARIPUL may be increased or enhanced by concomitant use of other
vasodilators.
As reported with other prostaglandin analogues, CARIPUL may reduce the thrombolytic efficacy of tissue
plasminogen activator (t-PA) by increasing hepatic clearance of t-PA.
When non-steroidal anti-inflammatory drugs (NSAIDs) or other drugs affecting platelet aggregation are used
concomitantly, CARIPUL may increase the risk of bleeding.
Patients receiving digoxin may experience increased digoxin concentrations after initiation of CARIPUL
therapy, which, although transient, may be clinically relevant in patients predisposed to digoxin toxicity.

4.6 Fertility, Pregnancy and Lactation
Pregnancy
Data on the use of epoprostenol in pregnant women are limited.
Animal studies do not indicate harmful effects on reproductive toxicity (see section 5.3).
In the absence of alternative therapies, epoprostenol may be used in women who choose to continue their
pregnancy despite the known risks associated with pulmonary arterial hypertension during pregnancy.

Lactation
It is not known whether epoprostenol or its metabolites are excreted in human milk. Risk to the infant cannot
be excluded. Breastfeeding must be discontinued during treatment with CARIPUL.

Fertility
There are no data on the effects of epoprostenol on fertility in humans. Reproduction studies in animal models
have not shown effects on fertility (see section 5.3).

4.7 Effects on Ability to Drive and Use Machines
Pulmonary arterial hypertension and its therapeutic treatment may impair the ability to drive vehicles and use
machinery.
There are no data on the effect of CARIPUL, when used in renal dialysis, on the ability to drive vehicles and use
machinery.

4.8 Undesirable Effects
Undesirable effects are listed below by system organ class and frequency. Frequencies are defined as
follows: very common ≥ 1/10 (≥ 10%); common ≥ 1/100 and < 1/10 (≥ 1% and < 10%); uncommon ≥ 1/1,000
and < 1/100 (≥ 0.1% and < 1%); rare ≥ 1/10,000 and < 1/1,000 (≥ 0.01% and < 0.1%); very rare < 1/10,000
(< 0.01%); not known (frequency cannot be estimated from the available data).

* Associated with the epoprostenol delivery system
Infections related to catheter use have been reported caused by organisms not always considered pathogenic (including Micrococcus).
Tachycardia has been reported following administration of epoprostenol at doses of 5 nanograms/kg/min and lower doses.
In healthy volunteers, bradycardia has been described with epoprostenol doses greater than 5 nanograms/kg/min, sometimes accompanied by orthostatic hypotension. In conscious healthy volunteers, intravenous administration of an epoprostenol dose equivalent to 30 nanograms/kg/min has been associated with bradycardia and a marked decrease in systolic and diastolic arterial pressure.

Reporting of suspected adverse reactions
Reporting of suspected adverse reactions occurring after medicinal product authorization is important, as it allows continuous monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions via:
Website: http://www.agenziafarmaco.gov.it/content/come-segnalare-una-sospetta-reazione-avversa

4.9 Overdose
The main symptom of overdose is likely to be hypotension.
In general, events observed following overdose of CARIPUL represent exaggerated pharmacological effects of the drug (e.g., hypotension and complications of hypotension).
In case of overdose, the dose should be reduced or the infusion stopped, and appropriate supportive therapeutic measures initiated; for example, plasma volume expansion and/or adjustment of the pump flow rate.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic Properties
Pharmacotherapeutic category: Antithrombotic agents; platelet aggregation inhibitors excluding heparin, ATC code: B01AC09
The pH value of CARIPUL is higher than the pH of other epoprostenol-containing products.
Compared to other diluted epoprostenol solutions buffered with glycine, Caripul contains L-arginine, which has lower buffering capacity. This results in a broader range of pH values for the diluted solution. Following dilution, the pH decreases from 12.0 at concentrations of 90,000 ng/mL to 11.7 at concentrations of 45,000 ng/mL, and down to 11.0 at concentrations of 3,000 ng/mL.
The studies described below under "Pharmacodynamic effects" refer to studies conducted with epoprostenol solutions buffered with glycine and having a pH between 10.3 and 10.8 (Flolan).

Mechanism of Action
Sodium epoprostenol, the monosodium salt of epoprostenol, is a naturally occurring prostaglandin normally produced by the vascular intima. Epoprostenol is the most potent known inhibitor of platelet aggregation. It is also a potent vasodilator.
Many of epoprostenol's actions occur through stimulation of adenylate cyclase, resulting in increased intracellular levels of 3',5'-cyclic adenosine monophosphate (cAMP). In human platelets, sequential stimulation of adenylate cyclase followed by activation of phosphodiesterase has been described. Elevated cAMP levels regulate intracellular calcium concentrations by stimulating calcium removal; thus, platelet aggregation is ultimately inhibited by reducing cytoplasmic calcium, which is required for platelet shape change, aggregation, and release reaction.

Pharmacodynamic Effects
An infusion of 4 nanograms/kg/min for 30 minutes has shown no significant effect on heart rate or blood pressure, although facial flushing may occur at these doses.

Pulmonary Arterial Hypertension (PAH)
Intravenous infusions of epoprostenol lasting up to 15 minutes have demonstrated dose-dependent increases in cardiac index (CI) and stroke volume (SV), and dose-dependent reductions in pulmonary vascular resistance (PVR), total pulmonary resistance (TPR), and mean systemic arterial pressure (SAPm). In patients with idiopathic or hereditary pulmonary arterial hypertension, the effects of epoprostenol on mean pulmonary artery pressure (PAPm) were variable and minimal.

Renal Dialysis
Administration of epoprostenol intravenously at doses of 2–16 ng/kg/min produces dose-dependent effects on platelet aggregation. At doses equal to or greater than 4 ng/kg/min, significant inhibition of adenosine diphosphate-induced aggregation is also observed.
The effects on platelets disappear within 2 hours after discontinuation of the infusion, and hemodynamic changes due to epoprostenol return to baseline within 10 minutes after termination of a 60-minute infusion at doses between 1 and 16 ng/kg/min.
Higher circulating doses of epoprostenol (20 ng/kg/min) cause dispersion of circulating platelet aggregates and increase the skin bleeding time up to twice the normal duration.
Epoprostenol potentiates the anticoagulant activity of heparin by approximately 50%, likely through reduction in the release of the heparin-neutralizing factor.

Clinical Efficacy and Safety

Pulmonary Arterial Hypertension (PAH)
Chronic continuous infusions of epoprostenol in patients with idiopathic or hereditary PAH were studied in two prospective, open-label, randomized trials of 8 and 12 weeks' duration (N=25 and N=81, respectively), comparing epoprostenol plus conventional therapy versus conventional therapy alone. Conventional therapy varied among patients and included some or all of the following: anticoagulants in nearly all patients; oral vasodilators, diuretics, and digoxin in half to two-thirds of patients; and supplemental oxygen in approximately half of the patients. Except for 2 patients in New York Heart Association (NYHA) Functional Class II, all patients were in Functional Class III or IV. As results were similar in both studies, combined analysis results are described. Baseline median values for the 6-minute walk test (6MWT) were 266 meters in the conventional therapy group and 301 meters in the epoprostenol plus conventional therapy group.
Improvements from baseline in cardiac index (0.33 vs -0.12 l/min/m²), stroke volume (6.01 vs -1.32 mL/beat), arterial oxygen saturation (1.62 vs -0.85%), mean pulmonary artery pressure (-5.39 vs 1.45 mmHg), mean right atrial pressure (-2.26 vs 0.59 mmHg), total pulmonary resistance (-4.52 vs 1.41 Wood Units), pulmonary vascular resistance (-3.60 vs 1.27 Wood Units), and systemic vascular resistance (-4.31 vs 0.18 Wood Units) were statistically different between patients receiving chronic epoprostenol and those not receiving it. Mean systemic arterial pressure was not significantly different between the two groups (-4.33 vs -3.05 mmHg). These hemodynamic improvements appeared to be sustained when epoprostenol was administered for at least 36 months in an open-label, non-randomized study.
A statistically significant improvement was observed in exercise capacity (p=0.001), measured by the 6MWT, in patients receiving continuous intravenous epoprostenol in combination with conventional therapy (N=52) for 8 or 12 weeks compared to patients receiving conventional therapy alone (N=54) (combined change at 8 and 12 weeks from baseline—median: 49 vs -4 meters; mean: 55 vs -4 meters). Improvements were evident as early as the first week of treatment. At the end of the treatment period in the 12-week study, survival was improved in NYHA Functional Class III and IV patients. Eight of 40 (20%) patients receiving conventional therapy alone died, whereas none of the 41 patients receiving epoprostenol died (p=0.003).

Chronic continuous infusions of epoprostenol in patients with PAH/SSD were studied in a prospective, open-label, randomized 12-week trial comparing epoprostenol plus conventional therapy (N=56) versus conventional therapy alone (N=55). Except for 5 patients in NYHA Functional Class II, all patients were in Functional Class III or IV. Conventional therapy varied among patients and included some or all of the following: anticoagulants in nearly all patients, supplemental oxygen and diuretics in two-thirds of patients, oral vasodilators in 40% of patients, and digoxin in one-third of patients. The primary efficacy endpoint was improvement in the 6MWT. Baseline median values were 240 meters in the conventional therapy group and 270 meters in the epoprostenol plus conventional therapy group. After 12 weeks of treatment, patients receiving chronic epoprostenol showed statistically significant increases in CI and statistically significant reductions in PAPm, RAPm, PVR, and SAPm compared to those not receiving epoprostenol.
Over 12 weeks, a statistically significant difference (p < 0.001) in change from baseline in 6MWT was observed in the group receiving epoprostenol plus conventional therapy compared to the group receiving conventional therapy alone (median: 63.5 vs -36.0 meters; mean: 42.9 vs -40.7 meters).
In some patients, improvements were evident by the end of the first week of therapy. Increases in exercise capacity were accompanied by statistically significant improvements in dyspnea, measured using the Borg Dyspnea Index. At week 12, NYHA functional class had improved in 21 of 51 patients (41%) treated with epoprostenol compared to none of the 48 patients treated with conventional therapy alone. However, more patients in both treatment groups (28/51 [55%] with epoprostenol and 35/48 [73%] with conventional therapy alone) showed no change in functional class, and 2/51 (4%) with epoprostenol and 13/48 (27%) with conventional therapy alone worsened.
No statistically significant difference in survival was observed over 12 weeks between PAH/SSD patients treated with epoprostenol versus those treated with conventional therapy alone. At the end of the treatment period, 4 of 56 patients (7%) who received epoprostenol died compared to 5 of 55 (9%) patients treated with conventional therapy alone.

Renal Dialysis
Six controlled studies with heparin and five emergency studies investigated the role of epoprostenol in the management of renal dialysis, using various techniques. Primary efficacy measurements included intradialytic removal of blood urea nitrogen (BUN) and creatinine, intradialytic fluid removal (ultrafiltration), and coagulation within the extracorporeal circuit.
Major clots (permanently interrupting dialysis or requiring modification of the artificial kidney) occurred in approximately 9% (n = 56) of all dialysis sessions with epoprostenol and in <1% (n = 1) of dialysis sessions with heparin in the main controlled and emergency studies. The majority of dialysis sessions with epoprostenol requiring replacement of the artificial kidney (67%) were subsequently completed with epoprostenol without further clotting. However, 9 out of 27 dialysis sessions with epoprostenol failed after several attempts.
Regardless of rare technical difficulties occurring with both treatments, major clots limiting dialysis did not occur in 93% of all dialysis sessions with epoprostenol and in 99% of all dialysis sessions with heparin.
Minor clots (requiring intervention but not permanent interruption of dialysis or modification of the artificial kidney) were reported more frequently during dialysis with epoprostenol than during dialysis with heparin. None of the dialysis sessions using heparin and 5% (n = 32) of those using epoprostenol experienced minor clots.
Visible clots (not requiring intervention) were reported in another 31% of dialysis sessions with epoprostenol and in 5% of dialysis sessions with heparin.

To determine whether patients undergoing renal dialysis at increased risk of bleeding bleed less frequently with epoprostenol than with heparin, two large prospective controlled studies were conducted. Each patient was randomly assigned to a sequence of dialysis sessions with heparin or epoprostenol and received up to 6 dialysis sessions of each type in one study and up to 3 sessions of each type in the other study.
Bleeding risk was defined as:

• Very high risk – presence of active bleeding at the time of initiation of dialysis
• High risk – active bleeding within the 3 days prior to dialysis that ceased during the predialysis phase or presence of surgical or traumatic wounds within the 3 days prior to dialysis

In major controlled studies, twelve patients at very high risk of bleeding underwent 35 dialysis sessions with epoprostenol and eleven patients underwent 28 dialysis sessions with heparin. In emergency studies, sixteen patients underwent 24 dialysis sessions with epoprostenol.
In the main controlled studies, when all dialysis sessions were combined for each treatment (heparin or epoprostenol), more patients receiving heparin bled the day before dialysis (N = 13/17 vs 8/23), on the day of dialysis (N = 25/28 vs 16/35), and the day after dialysis (N = 16/24 vs 5/24), compared to patients treated with epoprostenol during the same time periods.
Patients who continued to bleed were evaluated for changes in bleeding severity. Bleeding severity improved more frequently with epoprostenol the day before dialysis and on the day of dialysis (predialysis: N = 4/8; dialysis: N = 6/16) than with heparin (predialysis: N = 4/13; dialysis: N = 4/25). However, the opposite trend was observed in the days following dialysis with epoprostenol (N = 1/5) compared to heparin (N = 8/16). With epoprostenol, bleeding severity worsened during only one dialysis day (N = 1/16), whereas with heparin, severity worsened during 5 dialysis days (N = 5/25) and during 2 predialysis days (N = 2/13).

Patients who had no evident signs of bleeding just before dialysis in the first study but who had bled within the previous 3 days were classified as being at high risk of bleeding. In the main controlled studies, nineteen patients received 51 dialysis sessions with heparin and nineteen patients received 44 dialysis sessions with epoprostenol.
When all dialysis data were combined, a slightly higher number of patients treated with epoprostenol bled during the days before dialysis (N = 12/25 vs 8/32), on dialysis days (23/44 vs 14/51), and after dialysis (8/34 vs 5/44), compared to patients treated with heparin during the same periods.

5.2 Pharmacokinetic Properties
Due to the chemical instability, high potency, and short half-life of epoprostenol, no precise and accurate analytical method has been identified as suitable for quantifying epoprostenol in biological fluids.
Intravenously administered epoprostenol is rapidly distributed from blood to tissues.
At normal physiological pH and temperature, epoprostenol spontaneously dissociates into 6-oxo-prostaglandin F_α, although some enzymatic degradation into other products also occurs.
After administration of radiolabeled epoprostenol in humans, at least 16 metabolites have been detected, 10 of which have been structurally identified.
Unlike many other prostaglandins, epoprostenol is not metabolized during passage through the pulmonary circulation.
The half-life for spontaneous dissociation into 6-oxo-prostaglandin F_α in humans should not exceed 6 minutes and may be as short as 2–3 minutes, as estimated from the degradation rate of epoprostenol in vitro in human whole blood culture.
After administration of radiolabeled epoprostenol in humans, urinary and fecal excretion of radioactivity accounted for 82% and 4%, respectively.

5.3 Preclinical Safety Data
Preclinical data reveal no particular risk for humans based on conventional studies of safety pharmacology, repeated-dose toxicity, genotoxicity, reproductive and developmental toxicity. No long-term animal studies have been conducted to assess the carcinogenic potential of epoprostenol.

6. PHARMACEUTICAL INFORMATION

6.1 List of excipients
Powder for solution for infusion:
Sucrose
Arginine
Sodium hydroxide (for pH adjustment)

Solvent for parenteral use:
Water for injections

6.2 Incompatibilities
This medicinal product must not be mixed with other medicinal products except those mentioned in
section 6.6.

6.3 Shelf life
Powder and solvent for solution for infusion: 3 years.
Stability of the reconstituted product/diluted solution for infusion:
The reconstituted solution must be immediately further diluted to achieve the final concentration.
The diluted solution should be stored in the dedicated reservoir of the drug delivery system to protect it from light and may be stored for up to 8 days at a temperature between 2 and 8 °C.

6.4 Special precautions for storage
Do not freeze.
The solvent does not contain preservatives; therefore, each vial must be used once only and then discarded.
The reconstituted solution must be immediately further diluted to achieve the final concentration (see section 4.2, section 6.3 and section 6.6).
CARIPUL diluted to the final concentration in the dedicated reservoir of the drug delivery system, as per instructions, may be administered at room temperature (25 °C) immediately after dilution or stored for up to 8 days at a temperature between 2 and 8 °C, as indicated in the use conditions reported in Table 2, section 6.6. Do not expose the diluted solution at the final concentration to direct sunlight.

6.5 Nature and contents of container
Powder for solution for infusion:
10 mL in a clear type I glass vial closed with a rubber stopper and an aluminum cap with a removable seal (with a white disc in the 0.5 mg/vial formulation and a red disc in the 1.5 mg/vial formulation).

Solvent for parenteral use:
Low-density polyethylene plastic container. The vial is closed with a latex-free rubber stopper (Type I) secured by a cap.

Packaging:
Pulmonary Arterial Hypertension
For the treatment of pulmonary arterial hypertension, the following 4 pack sizes are available:

• One vial containing 0.5 mg of powder and one vial of solvent.
• One vial containing 1.5 mg of powder and one vial of solvent.
• One vial containing 0.5 mg of powder.
• One vial containing 1.5 mg of powder.

Renal Dialysis
The following 2 pack sizes are available for use in renal dialysis:

• One vial containing 0.5 mg of powder and one vial of solvent.
• One vial containing 0.5 mg of powder.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and handling
The ambulatory infusion pumps suitable for the administration of CARIPUL are:

• CADD-Legacy 1
• CADD-Legacy PLUS
• CADD-Solis VIP (variable infusion profile)

Manufactured by Smiths Medical.

The pump accessories compatible with the administration of CARIPUL are:

• CADD disposable medication reservoir cassette 50 mL; 100 mL from Smith Medical.
• CADD extension set with in-line 0.2 micron filter (CADD extension set with male luer connector, 0.2 micron air-eliminating filter, clamp and integral anti-siphon valve with male luer connector) from Smith Medical.

Based on available data from internal testing and the manufacturers' instructions for use of the accessories, materials that appear to be compatible for preparation and administration include:

• Acrylics
• Acrylonitrile butadiene styrene (ABS)
• Polycarbonate
• Polyethersulfone
• Polypropylene
• Polytetrafluoroethylene (PTFE)
• Polyurethane
• Polyvinyl chloride (PVC) (plasticized with DEHP)
• Silicone

It is not known whether polyethylene terephthalate (PET) and glycol-modified polyethylene terephthalate (PETG) are compatible with CARIPUL, as these materials have not been tested with CARIPUL; therefore, the use of such materials is not recommended.
It is recommended that the infusion pump should not be in permanent contact with the skin to avoid changes in the reservoir temperature.
When connecting the extension set, ensure that no diluted solution is present in the space between the EV access system and the luer lock connector. The first drops from the extension set must be carefully removed before connecting the extension set to the EV access system.
Unused medicinal product and waste materials arising from its use must be disposed of in accordance with local regulations.
The solvent does not contain preservatives; therefore, each vial must be used once only and then discarded.
The stability of the CARIPUL solution is dependent on the pH value.
The powder for solution for infusion must be reconstituted using the solvent supplied with the pack.
Further dilution must be performed using the same diluent used to reconstitute the sterile lyophilized powder.

Reconstitution, dilution and calculation of infusion rate:
Particular attention must be paid to the preparation of the infusion and the calculation of the infusion rate. The procedure described below must be strictly followed.
Reconstitution and dilution must be carried out under aseptic conditions.

Renal Dialysis
Two pack sizes are available for use in renal dialysis:

• One vial containing sterile lyophilized CARIPUL equivalent to 0.5 mg of CARIPUL, supplied with a 100 mL solvent vial.
• One vial containing sterile lyophilized CARIPUL equivalent to 0.5 mg of CARIPUL, supplied in a single pack.

Reconstitution:
Withdraw 5 mL of diluent into a sterile syringe, inject the syringe contents into the vial containing CARIPUL and gently shake until the powder is completely dissolved. Any unused reconstituted solution must be discarded in accordance with local regulations. The reconstituted solution must be inspected before further dilution. Use must be avoided if there is any change in color or presence of particles.

Dilution:
The reconstituted solution must be immediately further diluted to the final concentration.
Further dilution must be performed using the same diluent used to reconstitute the sterile lyophilized powder.

Calculation of infusion rate:
The infusion rate can be calculated using the following formula:
Infusion rate (mL/min) = Dose (ng/kg/min) × body weight (kg)
Concentration of solution (ng/mL)
Infusion rate (mL/hour) = Infusion rate (mL/min) × 60
The commonly used dilution is 2,000 nanograms/mL of CARIPUL:

Pulmonary Arterial Hypertension
For the treatment of pulmonary arterial hypertension, the following 4 pack sizes are available:

• One vial containing CARIPUL, sterile lyophilized powder equivalent to 0.5 mg of CARIPUL, supplied with one 100 mL solvent vial.
• One vial containing CARIPUL, sterile lyophilized powder equivalent to 1.5 mg of CARIPUL, supplied with one 100 mL solvent vial.
• One vial containing CARIPUL, sterile lyophilized powder equivalent to 0.5 mg of CARIPUL, supplied alone.
• One vial containing CARIPUL, sterile lyophilized powder equivalent to 1.5 mg of CARIPUL, supplied alone.

At the beginning, the pack containing solvent for parenteral use should be used. During chronic therapy
with CARIPUL, the final concentration of the solution may be increased by adding further vials of
lyophilized CARIPUL powder (0.5 mg or 1.5 mg).
Reconstitution:
Withdraw 5 mL of diluent into a sterile syringe, inject the syringe contents into the vial containing
CARIPUL, and gently swirl until complete dissolution occurs. Use is prohibited if there is any change in
colour or presence of particles. Any reconstituted unused solution must be disposed of in accordance
with local regulations.
Dilution:
The reconstituted solution must be immediately further diluted to the final concentration.
Further dilutions must be performed using the same diluent used for reconstitution of the
sterile lyophilized powder. When administered chronically, CARIPUL must be prepared
in the dedicated reservoir of a drug delivery system compatible with an infusion pump.
Only extension sets equipped with an in-line 0.22 micron filter placed between the infusion pump and the catheter should be used.
Hydrophilic polyethersulfone membrane filters are recommended. The extension set and in-line filter must be replaced at least every 48 hours
(see section 4.4).
The vial containing 0.5 mg of epoprostenol should be used for the preparation of solutions with
final concentrations below 15,000 ng/mL.
Table 1 provides examples for the preparation of commonly used CARIPUL concentrations.
The contents of each vial must be used only once.
Table 1. Commonly Used Concentrations – Examples of Reconstitution and Dilution

* Solutions with higher final concentrations may be necessary for patients who have been receiving
CARIPUL for a long time.
CARIPUL, diluted to the final concentration in the drug delivery system reservoir, can be administered immediately at room temperature (25°C) or, if stored, for up to a maximum of 8 days at a temperature between 2 and 8°C, according to the conditions of use reported in Table 2.
Table 2. Maximum Duration of Administration (hours) at Room Temperature (25°C) of Fully Diluted Solutions Stored in the Drug Delivery System Reservoir

Do not expose the fully diluted solution to direct sunlight.
Calculation of infusion rate:
The infusion rate can be calculated using the following formula:
Infusion rate (mL/min) = Dose (ng/kg/min) x body weight (kg)
Concentration of the solution (ng/mL)
Infusion rate (mL/h) = Infusion rate (mL/min) x 60
Examples of some commonly used concentrations in pulmonary arterial hypertension are provided below.
Table 3. Infusion Rate of CARIPUL at a Concentration of 5,000 ng/mL

Table 4. Infusion Rate of CARIPUL at a Concentration of 15,000 nanograms/mL

Table 5. Infusion Rate of CARIPUL at a Concentration of 30,000 nanograms/mL

Higher doses, and therefore more concentrated solutions, may be required for long-term administration of CARIPUL.

7. MARKETING AUTHORISATION HOLDER

Janssen-Cilag International NV
Turnhoutseweg 30
B-2340 Beerse
Belgium

8. MARKETING AUTHORISATION NUMBER(S)

0.5 mg powder and solvent for solution for infusion - AIC No. 042119038
1.5 mg powder and solvent for solution for infusion - AIC No. 042119040

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation:
22 February 2014
Date of most recent renewal:

10. DATE OF TEXT REVISION

Package leaflet: information for the user

CARIPUL 0.5 mg, Powder for Solution for Infusion, 1.5 mg, Powder for Solution for Infusion

epoprostenol
Please read this leaflet carefully before using this medicine as it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor, pharmacist, or nurse.
• This medicine has been prescribed for you only. Do not give it to others, even if their symptoms are the same as yours, as it could be harmful.
• If you experience any side effects, including those not listed in this leaflet, tell your doctor, pharmacist, or nurse. See section 4.

Contents of this leaflet:

1. What CARIPUL is and what it is used for
2. What you need to know before taking CARIPUL
3. How to take CARIPUL
4. Possible side effects
5. How to store CARIPUL
6. Contents of the pack and other information

1. What CARIPUL is and what it is used for

CARIPUL contains the active substance epoprostenol, which belongs to a group of medicines called prostaglandins. Prostaglandins help prevent blood from clotting and cause blood vessels to widen.
CARIPUL is used to treat a condition called "pulmonary arterial hypertension", which occurs when there is increased pressure in the blood vessels of the lungs. CARIPUL works by dilating the blood vessels, thereby reducing blood pressure in the lungs.
CARIPUL is also used to prevent blood clotting during renal dialysis when heparin cannot be used.

2. What you need to know before taking CARIPUL

Do not take CARIPUL

• if you are allergic to CARIPUL or to any of the other ingredients of this medicine (listed in section 6).
• if you suffer from heart failure.
• if, after starting this treatment, fluid has started to accumulate in your lungs causing shortness of breath.

If you think any of these situations apply to you, do not take CARIPUL until you have
consulted your doctor.
Warnings and precautions
Before being given CARIPUL, your doctor needs to know:

• if you have ever had any problems with bleeding.

Tissue damage at the injection site
CARIPUL is injected into a vein. It is important that this medicine does not leak out of the vein into the
surrounding tissues. If this happens, the skin may be damaged. Symptoms include:

• tenderness
• burning
• sensation like a pinprick
• swelling
• redness.

These symptoms may be followed by blistering and skin peeling. During treatment with CARIPUL, it is important to monitor the injection site.
Contact the hospital immediately for medical advice if the area becomes irritated, painful or swollen, or if you notice blistering or skin peeling.
Effect of CARIPUL on blood pressure and heart rate
CARIPUL may cause your heartbeat to speed up or slow down. Your blood pressure may also drop significantly. During treatment with CARIPUL, your heart rate and blood pressure should be monitored. Symptoms of low blood pressure include dizziness and fainting.
Inform your doctor if you experience these symptoms. It may be necessary to reduce the dose or stop the infusion.
Children and adolescents
The safety and efficacy of CARIPUL in children have not yet been established.
Other medicines and CARIPUL
Inform your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines, including medicines obtained without a prescription.
Some medicines may interfere with the way CARIPUL works, or may increase the risk of side effects. CARIPUL may also interfere with the action of other medicines if taken at the same time. These medicines include:

• medicines used to treat high blood pressure
• medicines used to prevent the formation of blood clots
• medicines used to dissolve blood clots
• medicines used to treat inflammation or pain (also called “NSAIDs”)
• digoxin (used to treat heart disease). Inform your doctor or pharmacist if you are taking any of these medicines.

Pregnancy and breastfeeding
If you are pregnant, suspect you may be pregnant, planning to become pregnant, or are breastfeeding, consult your doctor or pharmacist before taking this medicine, as your symptoms may worsen during pregnancy.
It is not known whether the components of CARIPUL can pass into breast milk. Breastfeeding must be discontinued
during treatment with CARIPUL.
Driving and using machines
This treatment may affect your ability to drive or operate machinery.
Do not drive or operate machinery unless you feel well.
CARIPUL contains sodium
This medicine contains less than 1 mmol (23 mg) of sodium per vial, i.e. essentially ‘sodium-free’.

3. How to take CARIPUL

Take this medicine exactly as directed by your doctor or pharmacist. If you have
any doubts, consult your doctor or pharmacist.
CARIPUL comes as a powder in a glass vial. The powder must be dissolved before
use.
CARIPUL must not be administered via rapid intravenous injection. It must always
be given by slow intravenous infusion.
Your doctor will determine the appropriate dose of CARIPUL. The dose administered
varies according to body weight and the type of disease. Your dose may be increased or decreased depending on your response to
treatment.
CARIPUL is administered by slow (drop-by-drop) infusion into a vein.
Pulmonary arterial hypertension
Your first treatment will be given in hospital. This is because your doctor needs to
monitor you and identify the appropriate dose for you.
You will start with an infusion of CARIPUL. The dose will be gradually increased until symptoms are relieved and any side effects can be managed. Once the appropriate dose has been established, a small permanent tube (catheter) will be inserted into a vein. Treatment can then begin using an infusion pump.
Renal dialysis
You will receive a CARIPUL infusion throughout the entire dialysis session.
Home use of CARIPUL (only for the treatment of Pulmonary Arterial Hypertension)
If treatment is carried out at home, your doctor or nurse will show you how to prepare and use
CARIPUL. They will also advise you on how to stop treatment, if necessary.
Stopping CARIPUL must be done gradually. It is very important to carefully follow
all of their instructions.
CARIPUL comes as a powder in a glass vial. Before use, the powder must be dissolved in the liquid provided. The liquid does not contain preservatives. If any liquid remains unused, it must be discarded.
Care of the infusion site
If a catheter has been inserted into a vein, it is very important to keep this area clean, otherwise infection may occur. Your doctor or nurse will show you how to clean the catheter and the surrounding area. It is very important to carefully follow all their instructions. It is also very important that you carefully follow all instructions on how to change the drug delivery system reservoir and that you always use, as instructed by your doctor, an infusion device with an in-line filter, in order to reduce the risk of infection. When reconnecting the extension device, always remove any excess drops to ensure no liquid remains in the external space between the extension device and the infusion line connectors, as this could damage the materials.
If you take more CARIPUL than you should
Contact your doctor urgently if you think you have taken or been given too much
CARIPUL. Symptoms of overdose may include headache, nausea, vomiting, rapid heartbeat, sensation of warmth or tingling, or feeling faint (experiencing
fatigue/dizziness).
If you forget to take CARIPUL
Do not take a double dose to make up for the forgotten dose.
If you stop treatment with CARIPUL
Stopping CARIPUL must be done gradually. If treatment is stopped too quickly, serious side effects may occur, including dizziness, feeling weak, and breathing difficulties. If there are problems with the infusion pump or the infusion line (catheter) that interrupt or prevent treatment with CARIPUL, contact your doctor, nurse, or hospital
immediately.
If you have any doubts about using this medicine, contact your doctor, pharmacist, or
nurse immediately.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone gets them.

Very common side effects
May affect more than 1 in 10 people:

• headache
• jaw pain
• pain
• vomiting
• nausea
• diarrhoea
• facial flushing (hot flushes)

Common side effects
May affect up to 1 in 10 people:

• blood infection ( septicaemia )
• increased heart rate
• slowed heart rate
• low blood pressure
• bleeding at various sites, for example from the nose or gums, and bruising more easily than normal
• stomach discomfort or pain
• chest pain
• joint pain
• anxiety, nervousness
• skin redness
• pain at injection site

Side effects that may be detected by blood tests

• decrease in the number of platelets (cells that help blood to clot)

Uncommon side effects
May affect up to 1 in 100 people:

• sweating
• dry mouth

Rare side effects
May affect up to 1 in 1,000 people:

• infection at injection site

Very rare side effects
May affect up to 1 in 10,000 people:

• sensation of tightness in the chest
• feeling of tiredness, weakness
• restlessness
• pale skin
• redness at injection site
• overactivity of the thyroid gland
• blockage of the infusion catheter

Other side effects
Frequency is unknown:

• enlargement or overactivity of the spleen
• fluid buildup in the lungs (pulmonary oedema)
• increased blood sugar (glucose)
• ascites (fluid accumulation in the abdomen)
• excessive pumping of blood from the heart leading to breathlessness, fatigue, swelling of the legs and abdomen due to fluid retention, persistent cough
• skin rashes (urticaria)

Reporting of side effects

Immediately inform your doctor or nurse, as these may be signs of blood infection, low blood pressure, or severe bleeding:

• If you feel your heart is beating too hard, or if you have chest pain or shortness of breath.
• If you feel dizzy or tired, especially when standing up.
• If you have fever or chills.
• If you have episodes of bleeding that are more frequent or longer than usual.

If you experience any side effect, including those not listed in this leaflet, talk to your doctor or pharmacist. You can also report side effects directly via the reporting system at: http://www.agenziafarmaco.gov.it/content/come-segnalare-una-sospetta-reazione-avversa
By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store CARIPUL

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the packaging after EXP. The expiry date refers to the
last day of that month.
Do not freeze.
The solvent does not contain preservatives; therefore each vial must be used only once and then discarded.
The reconstituted solution must be immediately further diluted to the final concentration (see Information for Healthcare Professionals).
For instructions on the storage of the medicinal product after reconstitution and dilution, see Information for Healthcare Professionals.
Do not use this medicine if you notice particles in the reconstituted solution.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

6. Contents of the pack and other information

What CARIPUL contains
CARIPUL 0.5 mg, Powder for Solution for Infusion

• The active substance is epoprostenol (as sodium epoprostenol). Each vial contains 0.531 mg of sodium epoprostenol, equivalent to 0.5 mg of epoprostenol. One mL of reconstituted solution contains 0.1 milligrams of epoprostenol (as sodium epoprostenol).
  CARIPUL 1.5 mg, Powder for Solution for Infusion
• The active substance is epoprostenol (as sodium epoprostenol). Each vial contains 1.593 mg of sodium epoprostenol, equivalent to 1.5 mg of epoprostenol. One mL of reconstituted solution contains 0.3 milligrams of epoprostenol (as sodium epoprostenol).
• The other components are sucrose, arginine, and sodium hydroxide (for pH adjustment).

Description of the appearance of CARIPUL and contents of the pack
White to off-white powder in a clear glass vial closed with a rubber stopper and an aluminium crimp cap.
Each pack contains one vial with 0.5 mg of powder.
Each pack contains one vial with 1.5 mg of powder.

Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder:
Janssen-Cilag International NV
Turnhoutseweg 30
B-2340 Beerse
Belgium
Manufacturer:
Janssen Pharmaceutica NV
Turnhoutseweg 30
B-2340 Beerse
Belgium

This medicinal product is authorised in the European Economic Area and in the United Kingdom (Northern Ireland) under the following names:
Belgium, Czech Republic, France, Germany, Greece, Hungary, Ireland, Luxembourg, Netherlands, Poland, Portugal, Slovakia, Spain, United Kingdom (Northern Ireland): VELETRI
Italy: CARIPUL

The following information is intended exclusively for healthcare professionals:

INFORMATION FOR HEALTHCARE PROFESSIONALS
Renal Dialysis
One package is available for use in renal dialysis:

• One glass vial containing sterile, lyophilized CARIPUL equivalent to 0.5 mg of CARIPUL, supplied in a single-dose container.

Reconstitution:
Withdraw 5 mL of diluent into a sterile syringe, inject the syringe contents into the vial containing CARIPUL, and gently agitate until the powder is completely dissolved. Any unused reconstituted solution must be disposed of in accordance with applicable local regulations. The reconstituted solution must be inspected prior to further dilution. Its use is prohibited if there are changes in color or if particulate matter is present.
Dilution:
The reconstituted solution must be immediately further diluted to achieve the final concentration. Further dilution must be performed using the same solvent used for reconstitution of the sterile lyophilized powder.
Infusion Rate Calculation:
The infusion rate can be calculated using the following formula:
Infusion rate (mL/min) = Dose (ng/kg/min) × body weight (kg)
Concentration of solution (ng/mL)
Infusion rate (mL/h) = infusion rate (mL/min) × 60

Pulmonary Arterial Hypertension
For use in the treatment of pulmonary arterial hypertension, the following 4 packages are available:

• One vial containing sterile, lyophilized CARIPUL equivalent to 0.5 mg of CARIPUL, supplied individually.
• One vial containing sterile, lyophilized CARIPUL equivalent to 1.5 mg of CARIPUL, supplied individually.

Reconstitution:
Withdraw 5 mL of solvent into a sterile syringe, inject the syringe contents into the vial containing CARIPUL, and gently agitate until the powder is completely dissolved. Any unused reconstituted solution must be discarded in accordance with applicable local regulations.
Dilution:
The reconstituted solution must be immediately further diluted to achieve the final concentration. Further dilution must be performed using the same solvent used for reconstitution of the sterile lyophilized powder.
When used for chronic therapy, CARIPUL must be prepared in the dedicated reservoir of a drug delivery system compatible with an infusion pump.
The ambulatory pumps suitable for administration of CARIPUL are:

• CADD-Legacy 1
• CADD-Legacy PLUS
• CADD-Solis VIP (variable infusion profile)

Manufactured by Smiths Medical.
The pump accessories compatible with the administration of CARIPUL are:

• CADD disposable medication reservoir cassette 50 mL; 100 mL from Smith Medical.
• CADD extension set with in-line 0.2 micron filter (CADD extension set with male luer connector, 0.2 micron air-eliminating filter, clamp, and integrated anti-siphon valve with male luer connector) from Smith Medical.

Based on available internal testing data and manufacturers' instructions for use of accessories, materials that appear to be compatible for preparation and administration include:

• Acrylics
• Acrylonitrile butadiene styrene (ABS)
• Polycarbonate
• Polyethersulfone
• Polypropylene
• Polytetrafluoroethylene (PTFE)
• Polyurethane
• Polyvinyl chloride (PVC) (plasticized with DEHP)
• Silicone

It is unknown whether polyethylene terephthalate (PET) and glycol-modified polyethylene terephthalate (PETG) are compatible with CARIPUL, as these materials have not been tested with CARIPUL; therefore, the use of such materials is not recommended.
Only extension sets equipped with an in-line 0.22 micron filter placed between the infusion pump and the catheter should be used. The use of filters with hydrophilic polyethersulfone membrane is recommended. The extension set and in-line filter must be replaced at least every 48 hours.
The vial containing 0.5 mg of epoprostenol should be used for the preparation of solutions with final concentrations below 15,000 ng/mL.
Table 1 provides examples for the preparation of commonly used CARIPUL solution concentrations. Each vial must be used only once.
Table 1. Commonly Used Concentrations – Examples of Reconstitution and Dilution

* Solutions with higher final concentrations may be necessary in patients receiving
CARIPUL for prolonged periods.
CARIPUL diluted to the final concentration in the drug delivery system reservoir as
indicated, can be administered immediately at room temperature (25°C), or may be
stored for up to 8 days at a temperature between 2 and 8°C, as specified under the use conditions
described in Table 2.
Table 2. Maximum Duration of Administration (hours) at Room Temperature (25°C) of Fully Diluted Solutions Stored in the Drug Delivery System Reservoir

Do not expose the fully diluted solution to direct sunlight.
Special storage precautions
Do not freeze.
The reconstituted solution must be immediately further diluted to achieve the final concentration.
Reconstitution and dilution must be carried out immediately before use.
Diluted epoprostenol solutions freshly prepared for the treatment of pulmonary arterial hypertension may be administered immediately at 25°C or stored protected from light in the dedicated reservoir of the drug delivery system for up to 8 days at a temperature between 2 and 8°C, as indicated in the use conditions described in Table 2.