Israel - English - Ministry of Health
Patient Leaflet According to the Pharmacists' Regulations (Preparations) - 1986
This medicine is sold with a doctor's prescription only.
Remodulin 2.5 mg/ml
Remodulin 5 mg/ml
Remodulin 10 mg/ml
Solution for injection administrated subcutaneously or intravenously
Remodulin 2.5 mg/ml: Each ml contains 2.5 mg Treprostinil (as sodium).
Remodulin 5 mg/ml: Each ml contains 5 mg Treprostinil (as sodium).
Remodulin 10 mg/ml: Each ml contains 10 mg Treprostinil (as sodium).
For a list of inactive ingredients, please see section 6.
See also 'Important information about some of the medicine's ingredients' in section 2.
Read this entire leaflet carefully before using this medicine.
This leaflet contains concise information about the medicine. If you have any further questions,
contact the doctor or pharmacist.
This medicine has been prescribed for treating your illness. Do not pass it on to others. It may
harm them, even if it seems to you that their illness is similar to yours.
1. What is the medicine intended for?
This medicine is intended:
For treatment of primary pulmonary arterial hypertension.
For treatment of pulmonary arterial hypertension associated with connective tissue
For treatment of pulmonary hypertension resulting from a congenital heart defect.
Synthetic prostacyclin analog, platelet aggregation inhibitor.
2. Before using the medicine
Do not use the medicine if:
Do not use if you are sensitive (allergic) to the active ingredient or to any of the other ingredients
this medicine contains (for a list of inactive ingredients, please see section 6).
Do not use the medicine if the solution is not clear, if it is cloudy, there is a change in the solution color,
the solution contains foreign particles and/or if there is any defect in the vial.
Special warnings regarding the use of this medicine:
When Remodulin is administrated by IV infusion there is a risk of blood infection and sepsis. This
condition may be life threatening. Contact a doctor or a hospital emergency room immediately if
signs which may indicate an infection develop (see Side effects section). The medical staff will
guide you how to reduce this risk.
The medicine may reduce the blood pressure. Contact a doctor if you experience a decrease in
your blood pressure.
Contact a doctor immediately if you experience worsening of breathing difficulties or persistent
Inform all your doctors and pharmacists that you are treated with Remodulin.
Before the treatment with Remodulin tell your doctor:
If you suffer or have previously suffered from kidneys/urinary system problems or liver problems.
If you suffer or have previously suffered from problems of the blood system (such as coagulation
problems), heart and/or blood vessels.
If you receive or have previously received epoprostenol.
If you are taking or have recently taken any other medicines, including non-prescription
medicines and nutrition supplements, please tell your doctor or pharmacist. Especially
inform your doctor or pharmacist if you are taking the following medicines (it should be noted that
the following list mentions the active ingredients of the medicines. If you are unsure whether you
are using one of these medicines, please consult with your doctor or pharmacist):
Medicines used to treat high blood pressure, medicines that dilate blood vessels or diuretics:
Combined use increases the risk of blood pressure decrease.
Anticoagulants: Combined use increases the risk of bleeding.
Gemfibrozil - increases exposure to Remodulin.
Rifampicin - decreases exposure to Remodulin.
Pregnancy and breastfeeding:
It is not known whether the medicine is secreted into breast milk. Since many medicines are
secreted into breast milk, care should be taken upon administration to breastfeeding women.
If you are pregnant or breastfeeding, consult your doctor prior to using this medicine.
Driving and use of machinery:
Use of this medicine may cause a decrease in your blood
pressure including dizziness and/or fainting. If you experience these effects, do not drive or
Use in children:
The safety and efficacy of this medicine was not examined in children.
Use in special populations:
Consult a doctor regarding dose adjustment in elderly patients, patients with impaired kidney or
Important information about some of the medicine's ingredients:
Consult a doctor if you consume a low sodium diet, since the medicine contains sodium. See
3. How to use the medicine?
Always use according to the doctor's instructions. Check with the doctor or pharmacist if you are
The dosage and the manner of treatment will be determined by the doctor only.
Remodulin is administered as continuous infusion using a pump, subcutaneously via a small cannula,
or intravenously via a catheter.
Treatment with Remodulin is initiated at the hospital under close medical supervision by a doctor or a
nurse, who will give you detailed instructions regarding the manner of use, appropriate dosage,
medicine administration rate appropriate for you specifically and the pump setting.
The medical staff will instruct you regarding proper use of the pump, and what to do if you cannot
operate it adequately.
Use the pump type recommended to you by the doctor. Read the instructions enclosed with the infusion
pump and follow them. Ensure availability of another infusion pump and infusion set to avoid the
situation of not receiving regular delivery of the medicine in case of device failure.
The standard dosage is usually: The dosage of Remodulin (infusion rate and dose) will be
determined by the doctor in accordance with your age, weight, health condition and your response
Subcutaneous infusion: The medicine is delivered without further dilution at a rate to be determined
by the doctor. The medicine is stable in a syringe without dilution for 72 hours.
Intravenous infusion: Dilute the medicine solution with sterile water for injection or physiological
saline (0.9% sodium chloride solution).
Infuse at the rate determined by the doctor. Diluted
medicine is stable for 48 hours.
Do not exceed the recommended dose.
If you experience a change in your health condition, or concerned that the medicine is no longer
helpful for you – contact the doctor.
For your attention!
Rinsing the infusion cannula when the cannula is already connected to the body may cause an
Instructions for use:
Remodulin is used for either subcutaneous infusion or intravenous infusion by an appropriate
infusion pump enabling slow and continuous infusion.
The treatment is for long term, therefore you must ensure that you know how to use the pump and
how to place the infusion set according to the instructions.
Use an infusion set suitable for the pump. Replace the infusion set according to the instructions you
receive from the medical staff.
Remodulin solution is dispensed in a multiple use vial (containing more than one dose). Therefore,
to prevent the penetration of pathogens into the vial due to repeated use, wipe the vial stopper with
an alcohol sponge before and after piercing the stopper by the needle.
The solution must be visually inspected to ensure that it is free of foreign particles or color changes.
Do not use Remodulin if the solution is not clear, if it contains foreign particles and/or if a change in
the solution color is observed (see also section 'Do not use the medicine if').
Prior to injection, thoroughly wash your hands and the site intended for needle insertion with soap
and water to prevent any infection at the infusion site.
While refilling the infusion, ensure that no large air bubbles were left in the syringe or catheter.
Replace the infusion set (catheter and needle) according to the doctor's instructions.
Ensure availability of another pump and infusion set in case of pump system failure.
If you have accidentally used a higher dosage than that determined for you, you may
experience symptoms of overdose, including: Flushing, headache, low blood pressure (which
may be manifested by dizziness, light-headedness and/or fainting), nausea, vomiting, diarrhea,
seizures, loss of consciousness.
In case of an overdose, immediately contact a doctor or a hospital.
Continue with the treatment as recommended by the doctor.
Even if your health condition improves, do not stop the treatment with this medicine without
consulting your doctor.
If you stop using Remodulin:
Do not stop using the medicine without consulting your doctor.
Abrupt withdrawal or extreme reduction in the dosage of Remodulin without consulting the doctor may
result in recurrence of pulmonary hypertension symptoms and worsening of your condition.
Do not take or use medicines in the dark! Check the label and the dose each time you take or use
a medicine. Wear glasses if you need them.
If you have any further questions regarding the use of the medicine, contact the doctor or pharmacist.
4. Side effects
Like any medicine, the use of Remodulin may cause side effects in some users. If the side
effects are bothersome, get worse or persist, consult your doctor. Do not be alarmed while
reading the list of side effects, you may not suffer from any of them.
Contact your doctor or a hospital emergency room immediately if during intravenous
infusion symptoms which may indicate an infection develop, such as: fever, redness, swelling,
pain, bleeding/ hematoma and/or tenderness to touch at the catheter site.
Additional side effects:
Diarrhea, nausea, reduced appetite, vomiting, weakness, abdominal pain.
Pain in the jaw, headache, dizziness, edemas, widening of blood vessels, low blood pressure,
Decrease in platelets count (thrombocytopenia) which may cause bleeding; pain in the bones,
inflammation of subcutaneous tissue (cellulitis).
Breathing difficulties, tiredness, chest pain, heart failure (of the right ventricular), pallor. These
effects may be related to the underlying disease.
Additional side effects related to the route of administration:
Pain or infection at the injection site, local reaction including redness, hardness and/or rash.
Infection related to intravenous administration (these signs may include fever, redness, swelling,
pain and/or tenderness to touch at the catheter site) - see also 'Special warnings regarding the use of
this medicine', in section 2.
Vein inflammation related to thrombus (thrombophlebitis) if a peripheral vein is used for
Side effects which may be caused by problems in the infusion system:
Signs of recurrence of pulmonary hypertension, such as breathing difficulties.
Signs of medicine excess, such as nausea (see overdose symptoms in section 'If you have
accidentally used a higher dosage').
In any case you experience side effects that are not mentioned in this leaflet or if there is a
change in your general feeling, consult the doctor immediately!
Side effects may be reported to the Ministry of Health by clicking on the link “reporting side effects following
drug treatment” on the Ministry of Health homepage (www.health.gov.il) which leads to an online form for
reporting side effects, or by entering the link:
5. How to store the medicine?
Avoid poisoning! This medicine and any other medicine must be stored in a safe place out of the
reach of children and/or infants, to avoid poisoning. Do not induce vomiting unless explicitly instructed
to do so by a doctor.
Do not use the medicine after the expiry date (exp. date) stated on the package. The expiry date
refers to the last day of that month.
Store below 25
After the first opening, the solution in the vial may be used for up to 30 days.
Undiluted solution in a syringe may be kept for 72 hours at 37
Diluted solution in a syringe (
dilution up to
0.004 mg/ml) may be kept for 48 hours at 25
Do not use the medicine if you notice any signs which may indicate a defect in the medicine such
as: the solution is not clear, cloudy, there is a change in the solution color, the solution contains
foreign particles and/or if there is any defect in the vial.
6. Additional Information
In addition to the active ingredient, this medicine also contains the following inactive
Sodium citrate, sodium chloride, metacresol, water for injection, sodium hydroxide, hydrochloric acid.
Each vial contains about 58.6 mg sodium.
What does the medicine look like and what does the package contain?
A clear colorless or yellowish solution in a package containing a transparent glass vial of 20 ml
with a rubber stopper and colored cap.
Remodulin 2.5 mg/ml: blue cap.
Remodulin 5 mg/ml: green cap.
Remodulin 10 mg/ml: red cap.
Manufacturer: United Therapeutics Corp., USA.
Registration Holder: Rafa Laboratories Ltd., P.O. Box 405, Jerusalem 9100301
Drug registration number at the national medicines registry of the Ministry of Health:
Remodulin 2.5 mg/ml: 1265730563
Remodulin 5 mg/ml: 1265630562
Remodulin 10 mg/ml: 1355531251
This leaflet was checked and approved by the Ministry of Health in June 2015.
FULL PRESCRIBING INFORMATION
(treprostinil) solution for injection
COMPOSITION: Remodulin is supplied in 20 mL vials in three strengths containing 50mg, 100 mg
or 200 mg (2.5 mg/mL, 5 mg/mL or 10 mg/mL) of treprostinil (as sodium).
For the full list of ingredients see section 11.
1. INDICATIONS AND USAGE
Remodulin® is indicated as a continuous subcutaneous infusion or intravenous infusion for the
Primary pulmonary arterial hypertension
Pulmonary arterial hypertension associated with connective tissue disorders
Pulmonary arterial hypertension associated with congenital systemic to pulmonary shunts.
2. DOSAGE AND ADMINISTRATION
Remodulin can be administered without further dilution for subcutaneous administration, or
diluted for intravenous infusion with Sterile Water for Injection or 0.9% Sodium Chloride Injection,
prior to administration.
2.2 Initial Dose for Patients New to Prostacyclin Infusion Therapy
Remodulin is indicated for subcutaneous (SC) or intravenous (IV) use only as a continuous
infusion. Remodulin is preferably infused subcutaneously, but can be administered by a central
intravenous line if the subcutaneous route is not tolerated, because of severe site pain or
reaction. The infusion rate is initiated at 1.25 ng/kg/min. If this initial dose cannot be tolerated
because of systemic effects, reduce the infusion rate to 0.625 ng/kg/min.
2.3 Dosage Adjustments
The goal of chronic dosage adjustments is to establish a dose at which PAH symptoms are
improved, while minimizing excessive pharmacologic effects of Remodulin (headache, nausea,
emesis, restlessness, anxiety and infusion site pain or reaction).
The infusion rate should be increased in increments of 1.25 ng/kg/min per week for the first four
weeks of treatment and then 2.5 ng/kg/min per week for the remaining duration of infusion,
depending on clinical response. Dosage adjustments may be undertaken more often if tolerated.
Avoid abrupt cessation of infusion [see Warnings and Precautions (5.4)]. Restarting a Remodulin
infusion within a few hours after an interruption can be done using the same dose rate.
Interruptions for longer periods may require the dose of Remodulin to be re-titrated.
2.4 Patients with Hepatic Insufficiency
In patients with mild or moderate hepatic insufficiency, decrease the initial dose of Remodulin to
0.625 ng/kg/min ideal body weight. Remodulin has not been studied in patients with severe
hepatic insufficiency [see Warnings and Precautions (5.3), Use In Specific Populations (8.6) and
Clinical Pharmacology (12.3)].
Inspect parenteral drug products for particulate matter and discoloration prior to administration
whenever solution and container permit. If either particulate matter or discoloration is noted, do
Remodulin is administered subcutaneously by continuous infusion without further dilution, via a
subcutaneous catheter, using an infusion pump designed for subcutaneous drug delivery. To
avoid potential interruptions in drug delivery, the patient must have immediate access to a backup
infusion pump and subcutaneous infusion sets. The ambulatory infusion pump used to administer
Remodulin should: (1) be small and lightweight, (2) be adjustable to approximately 0.002 mL/hr,
(3) have occlusion/no delivery, low battery, programming error and motor malfunction alarms,
(4) have delivery accuracy of ±6% or better and (5) be positive pressure driven. The reservoir
should be made of polyvinyl chloride, polypropylene or glass.
Remodulin is administered
by continuous infusion at a calculated Subcutaneous
Infusion Rate (mL/hr) based on a patient's Dose (ng/kg/min), Weight (kg), and the Vial Strength
(mg/mL) of Remodulin being used. During use, a single reservoir (syringe) of undiluted
Remodulin can be administered up to 72 hours at 37
C. The Subcutaneous Infusion rate is
calculated using the following formula:
Remodulin Vial Strength (mg/mL)
*Conversion factor of 0.00006 = 60 min/hour x 0.000001 mg/ng
Example calculations for Subcutaneous Infusion are as follows:
For a 60 kg person at the recommended initial dose of 1.25 ng/kg/min using the 1 mg/mL
Remodulin, the infusion rate would be calculated as follows:
= 0.005 mL/hr
For a 65 kg person at a dose of 40 ng/kg/min using the 5 mg/mL Remodulin, the infusion
rate would be calculated as follows:
= 0.031 mL/hr
Remodulin must be diluted with either Sterile Water for Injection or 0.9% Sodium Chloride
Injection and is administered intravenously by continuous infusion, via a surgically placed
indwelling central venous catheter using an infusion pump designed for intravenous drug delivery.
If clinically necessary, a temporary peripheral intravenous cannula, preferably placed in a large
vein, may be used for short term administration of Remodulin. Use of a peripheral intravenous
infusion for more than a few hours may be associated with an increased risk of thrombophlebitis.
To avoid potential interruptions in drug delivery, the patient must have immediate access to a
backup infusion pump and infusion sets. The ambulatory infusion pump used to administer
Remodulin should: (1) be small and lightweight, (2) have occlusion/no delivery, low battery,
programming error and motor malfunction alarms, (3) have delivery accuracy of ±6% or better of
the hourly dose, and (4) be positive pressure driven. The reservoir should be made of polyvinyl
chloride, polypropylene or glass.
Infusion sets with an in-line 0.22 or 0.2 micron pore size filter should be used.
Diluted Remodulin has been shown to be stable at ambient temperature for up to 48 hours at
concentrations as low as 0.004 mg/mL (4,000 ng/mL).
Select the intravenous infusion rate to allow for a desired infusion period length of up to 48 hours
between system changeovers. Typical intravenous infusion system reservoirs have volumes of 50
or 100 mL. With this selected Intravenous Infusion Rate (mL/hr) and the patient’s Dose
(ng/kg/min) and Weight (kg), the Diluted Intravenous Remodulin Concentration (mg/mL) can be
calculated using the following formula:
Intravenous Infusion Rate
The Volume of Remodulin Injection needed to make the required Diluted Intravenous Remodulin
Concentration for the given reservoir size can then be calculated using the following formula:
Total Volume of Diluted
Remodulin Solution in
The calculated volume of Remodulin Injection is then added to the reservoir along with the
sufficient volume of diluent (Sterile Water for Injection or 0.9% Sodium Chloride Injection) to
achieve the desired total volume in the reservoir.
Example calculations for Intravenous Infusion are as follows:
For a 60 kg person at a dose of 5 ng/kg/min, with a predetermined intravenous infusion
rate of 1 mL/hr and a reservoir of 50 mL, the Diluted Intravenous Remodulin
Concentration would be calculated as follows:
of Remodulin Injection (using 1 mg/mL Vial Strength) needed for a total
Diluted Remodulin Concentration of 0.018 mg/mL and a total volume of 50 mL would be
calculated as follows:
x 50 mL = 0.9 mL
The Diluted Intravenous Remodulin Concentration for the person in Example 3 would
thus be prepared by adding 0.9 mL of 1 mg/mL Remodulin Injection to a suitable
reservoir along with a sufficient volume of diluent to achieve a total volume of 50 mL in
the reservoir. The pump flow rate for this example would be set at 1 mL/hr.
For a 75 kg person at a dose of 30 ng/kg/min, with a predetermined intravenous infusion
rate of 2 mL/hr, and a reservoir of 100 mL, the Diluted Intravenous Remodulin
Concentration would be calculated as follows:
= 0.0675 mg/mL
The Volume of Remodulin Injection (using 2.5 mg/mL Vial Strength) needed for a total
Diluted Remodulin Concentration of 0.0675 mg/mL and a total volume of 100 mL would
be calculated as follows:
x 100 mL = 2.7 mL
The Diluted Intravenous Remodulin Concentration for the person in Example 4 would
thus be prepared by adding 2.7 mL of 2.5 mg/mL Remodulin Injection to a suitable
reservoir along with a sufficient volume of diluent to achieve a total volume of 100 mL in
the reservoir. The pump flow rate for this example would be set at 2 mL/hr.
2.6 Patients Requiring Transition from Flolan
Transition from Flolan to Remodulin is accomplished by initiating the infusion of Remodulin and
increasing it, while simultaneously reducing the dose of intravenous Flolan. The transition to
Remodulin should take place in a hospital with constant observation of response (e.g., walk
distance and signs and symptoms of disease progression). Initiate Remodulin at a recommended
dose of 10% of the current Flolan dose, and then escalate as the Flolan dose is decreased (see
Table 1 for recommended dose titrations).
Patients are individually titrated to a dose that allows transition from Flolan therapy to Remodulin
while balancing prostacyclin-limiting adverse events. Increases in the patient’s symptoms of PAH
should be first treated with increases in the dose of Remodulin. Side effects normally associated
with prostacyclin and prostacyclin analogs are to be first treated by decreasing the dose of Flolan.
Table 1: Recommended Transition Dose Changes
10% Starting Flolan Dose
80% Starting Flolan Dose
30% Starting Flolan Dose
60% Starting Flolan Dose
50% Starting Flolan Dose
40% Starting Flolan Dose
70% Starting Flolan Dose
20% Starting Flolan Dose
90% Starting Flolan Dose
5% Starting Flolan Dose
110% Starting Flolan Dose
110% Starting Flolan Dose + additional 5-10%
increments as needed
3. DOSAGE FORMS AND STRENGTHS
20-mL vial containing 50 mg treprostinil (2.5 mg per mL).
20-mL vial containing 100 mg treprostinil (5 mg per mL).
20-mL vial containing 200 mg treprostinil (10 mg per mL).
Remodulin is contraindicated in patients with known hypersensitivity to the drug ,to structurally
related compounds or to any of the excipients listed in section 11.
5. WARNINGS AND PRECAUTIONS
5.1 Risk of Catheter-Related Bloodstream Infection
Chronic intravenous infusions of Remodulin are delivered using an indwelling central venous
catheter. This route is associated with the risk of blood stream infections (BSIs) and sepsis, which
may be fatal. Therefore, continuous subcutaneous infusion (undiluted) is the preferred mode of
In an open-label study of IV treprostinil (n=47), there were seven catheter-related line infections
during approximately 35 patient years, or about 1 BSI event per 5 years of use. A CDC survey of
seven sites that used IV treprostinil for the treatment of PAH found approximately 1 BSI (defined
as any positive blood culture) event per 3 years of use. Administration of IV Remodulin with a
high pH glycine diluent has been associated with a lower incidence of BSIs when compared to
neutral diluents (sterile water, 0.9% sodium chloride) when used along with catheter care
5.2 Worsening PAH upon Abrupt Withdrawal or Sudden Large Dose Reduction
Avoid abrupt withdrawal or sudden large reductions in dosage of Remodulin, which may result in
worsening of PAH symptoms.
5.3 Patients with Hepatic or Renal Insufficiency
Titrate slowly in patients with hepatic or renal insufficiency, because such patients will likely be
exposed to greater systemic concentrations relative to patients with normal hepatic or renal
function [see Dosage and Administration (2.4), Use In Specific Populations (8.6, 8.7), and Clinical
5.4 Effect of Other Drugs on Treprostinil
Co-administration of a cytochrome P450 (CYP) 2C8 enzyme inhibitor (e.g., gemfibrozil) increases
exposure (both C
and AUC) to treprostinil. Co-administration of a CYP2C8 enzyme inducer
(e.g., rifampin) decreases exposure to treprostinil. [see Drug Interactions (7.5, 7.6) and Clinical
6. ADVERSE REACTIONS
The following adverse reactions are discussed elsewhere in labeling: Infections associated with
intravenous administration [see Warnings and Precautions (5.1)].
6.1 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.
Adverse Events with Subcutaneously Administered Remodulin
Patients receiving Remodulin as a subcutaneous infusion reported a wide range of adverse
events, many potentially related to the underlying disease (dyspnea, fatigue, chest pain, right
ventricular heart failure, and pallor). During clinical trials with subcutaneous infusion of
Remodulin, infusion site pain and reaction were the most common adverse events among those
treated with Remodulin. Infusion site reaction was defined as any local adverse event other than
pain or bleeding/bruising at the infusion site and included symptoms such as erythema, induration
or rash. Infusion site reactions were sometimes severe and could lead to discontinuation of
Table 2: Percentages of subjects reporting subcutaneous infusion site adverse events
Leading to discontinuation
based on prescriptions for narcotics, not actual use
medications used to treat infusion site pain were not distinguished from those used to
treat site reactions
Other adverse events included diarrhea, jaw pain, edema, vasodilatation and nausea, and these
are generally considered to be related to the pharmacologic effects of Remodulin, whether
administered subcutaneously or intravenously.
Adverse Reactions during Chronic Dosing
Table 3 lists adverse reactions defined by a rate of at least 3% more frequent in patients treated
with subcutaneous Remodulin than with placebo in controlled trials in PAH.
Table 3: Adverse Reactions in Controlled 12-Week Studies of Subcutaneous Remodulin
and at least 3% more frequent than on Placebo.
Percent of Patients
Percent of Patients
Infusion Site Pain
Infusion Site Reaction
Reported adverse reactions (at least 3% more frequent on drug than on placebo) are included
except those too general to be informative, and those not plausibly attributable to the use of the
drug, because they were associated with the condition being treated or are very common in the
While hypotension occurred in both groups, the event was experienced twice as frequently in the
Remodulin group as compared to the placebo group (4% in Remodulin treatment group verses
2% in placebo-controlled group). As a potent vasodilator, hypotension is possible with the
administration of Remodulin.
The safety of Remodulin was also studied in a long-term, open-label extension study in which 860
patients were dosed for a mean duration of 1.6 years, with a maximum exposure of 4.6 years.
Twenty-nine (29%) percent achieved a dose of at least 40 ng/kg/min (max: 290 ng/kg/min). The
safety profile during this chronic dosing study was similar to that observed in the 12-week placebo
controlled study except for the following suspected adverse drug reactions (occurring in at least
3% of patients): anorexia, vomiting, infusion site infection, asthenia, and abdominal pain.
Adverse Events Attributable to the Drug Delivery System
In controlled studies of Remodulin administered subcutaneously, there were no reports of
infection related to the drug delivery system. There were 187 infusion system complications
reported in 28% of patients (23% Remodulin, 33% placebo); 173 (93%) were pump related and
14 (7%) related to the infusion set. Eight of these patients (4 Remodulin, 4 Placebo) reported
non-serious adverse events resulting from infusion system complications. Adverse events
resulting from problems with the delivery systems were typically related to either symptoms of
excess Remodulin (e.g., nausea) or return of PAH symptoms (e.g., dyspnea). These events were
generally resolved by correcting the delivery system pump or infusion set problem such as
replacing the syringe or battery, reprogramming the pump, or straightening a crimped infusion
line. Adverse events resulting from problems with the delivery system did not lead to clinical
instability or rapid deterioration. In addition to these adverse events due to the drug delivery
system during subcutaneous administration, the following adverse events may be attributable to
the IV mode of infusion including arm swelling, paresthesias, hematoma and pain [see Warnings
and Precautions (5.1)].
6.2 Post-Marketing Experience
In addition to adverse reactions reported from clinical trials, the following events have been
identified during post-approval use of Remodulin. Because they are reported voluntarily from a
population of unknown size, estimates of frequency cannot be made. The following events have
been chosen for inclusion because of a combination of their seriousness, frequency of reporting,
and potential connection to Remodulin. These events are thrombophlebitis associated with
peripheral intravenous infusion, thrombocytopenia, bone pain, pruritus and dizziness. In addition,
generalized rashes, sometimes macular or papular in nature, and cellulitis have been infrequently
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It
allows continued monitoring of the benefit/risk balance of the medicinal product.
Any suspected adverse events should be reported to the Ministry of Health according to the National
Regulation by using an online form
7. DRUG INTERACTIONS
Pharmacokinetic/pharmacodynamic interaction studies have been conducted with treprostinil
administered subcutaneously (Remodulin) and orally (treprostinil diethanolamine).
7.1 Antihypertensive Agents or Other Vasodilators
Concomitant administration of Remodulin with diuretics, antihypertensive agents or other
vasodilators may increase the risk of symptomatic hypotension.
Since treprostinil inhibits platelet aggregation, there may be an increased risk of bleeding,
particularly among patients receiving anticoagulants.
In a human pharmacokinetic study conducted with bosentan (250 mg/day) and an oral
formulation of treprostinil (treprostinil diethanolamine), no pharmacokinetic interactions between
treprostinil and bosentan were observed.
In a human pharmacokinetic study conducted with sildenafil (60 mg/day) and an oral formulation
of treprostinil (treprostinil diethanolamine), no pharmacokinetic interactions between treprostinil
and sildenafil were observed.
7.5 Effect of Treprostinil on Cytochrome P450 Enzymes
In vitro studies of human hepatic microsomes showed that treprostinil does not inhibit cytochrome
P450 (CYP) isoenzymes CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1
and CYP3A. Additionally, treprostinil does not induce cytochrome P450 isoenzymes CYP1A2,
CYP2B6, CYP2C9, CYP2C19, and CYP3A. Thus Remodulin is not expected to alter the
pharmacokinetics of compounds metabolized by CYP enzymes.
7.6 Effect of Cytochrome P450 Inhibitors and Inducers on Treprostinil
Human pharmacokinetic studies with an oral formulation of treprostinil (treprostinil
diethanolamine) indicated that co-administration of the cytochrome P450 (CYP) 2C8 enzyme
inhibitor gemfibrozil increases exposure (both C
and AUC) to treprostinil. Co-administration of
the CYP2C8 enzyme inducer rifampin decreases exposure to treprostinil. It has not been
determined if the safety and efficacy of treprostinil by the parenteral (subcutaneously or
intravenously) route are altered by inhibitors or inducers of CYP2C8 [see Warnings and
Remodulin has not been studied in conjunction with Flolan or Tracleer
7.7 Effect of Other Drugs on Treprostinil
Drug interaction studies have been carried out with treprostinil (oral or subcutaneous) co-
administered with acetaminophen (4 g/day), warfarin (25 mg/day), and fluconazole (200 mg/day),
respectively in healthy volunteers. These studies did not show a clinically significant effect on the
pharmacokinetics of treprostinil. Treprostinil does not affect the pharmacokinetics or
pharmacodynamics of warfarin. The pharmacokinetics of R- and S- warfarin and the INR in
healthy subjects given a single 25 mg dose of warfarin were unaffected by continuous
subcutaneous infusion of treprostinil at an infusion rate of 10 ng/kg/min.
8. USE IN SPECIFIC POPULATIONS
Pregnancy Category B - In pregnant rats, continuous subcutaneous infusions of treprostinil during
organogenesis and late gestational development, at rates as high as 900 ng treprostinil/kg/min
(about 117 times the starting human rate of infusion, on a ng/m
basis and about 16 times the
average rate achieved in clinical trials), resulted in no evidence of harm to the fetus. In pregnant
rabbits, effects of continuous subcutaneous infusions of treprostinil during organogenesis were
limited to an increased incidence of fetal skeletal variations (bilateral full rib or right rudimentary
rib on lumbar 1) associated with maternal toxicity (reduction in body weight and food
consumption) at an infusion rate of 150 ng treprostinil/kg/min (about 41 times the starting human
rate of infusion, on a ng/m
basis, and 5 times the average rate used in clinical trials). In rats,
continuous subcutaneous infusion of treprostinil from implantation to the end of lactation, at rates
of up to 450 ng treprostinil/kg/min, did not affect the growth and development of offspring. Animal
reproduction studies are not always predictive of human response,
8.2 Labor and Delivery
No treprostinil treatment-related effects on labor and delivery were seen in animal studies. The
effect of treprostinil sodium on labor and delivery in humans is unknown.
8.3 Nursing Mothers
It is not known whether treprostinil is excreted in human milk or absorbed systemically after
ingestion. Many drugs are excreted in human milk.
8.4 Pediatric Use
Safety and effectiveness in pediatric patients have not been established. Clinical studies of
Remodulin did not include sufficient numbers of patients aged ≤16 years to determine whether
they respond differently from older patients.
8.5 Geriatric Use
Clinical studies of Remodulin did not include sufficient numbers of patients aged 65 and over to
determine whether they respond differently from younger patients. In general, dose selection for
an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic,
renal, or cardiac function, and of concomitant disease or other drug therapy.
8.6 Patients with Hepatic Insufficiency
Remodulin clearance is reduced in patients with hepatic insufficiency. In patients with mild or
moderate hepatic insufficiency, decrease the initial dose of Remodulin to 0.625 ng/kg/min ideal
body weight, and monitor closely. Remodulin has not been studied in patients with severe hepatic
insufficiency [see Dosage and Administration (2.4), Warnings and Precautions (5.5) and Clinical
8.7 Patients with Renal Insufficiency
No studies have been performed in patients with renal insufficiency. No specific advice about
dosing in patients with renal impairment can be given. [see Clinical Pharmacology (12.3)].
Signs and symptoms of overdose with Remodulin during clinical trials are extensions of its
dose-limiting pharmacologic effects and include flushing, headache, hypotension, nausea,
vomiting, and diarrhea. Most events were self-limiting and resolved with reduction or withholding
In controlled clinical trials, seven patients received some level of overdose and in open-label
follow-on treatment seven additional patients received an overdose; these occurrences resulted
from accidental bolus administration of Remodulin, errors in pump programmed rate of
administration, and prescription of an incorrect dose. In only two cases did excess delivery of
Remodulin produce an event of substantial hemodynamic concern (hypotension, near-syncope).
One pediatric patient was accidentally administered 7.5 mg of Remodulin via a central venous
catheter. Symptoms included flushing, headache, nausea, vomiting, hypotension and seizure-like
activity with loss of consciousness lasting several minutes. The patient subsequently recovered.
Remodulin (treprostinil) Injection is a sterile solution of treprostinil formulated for subcutaneous or
intravenous administration. Remodulin is supplied in 20 mL multidose vials in three strengths,
containing 50 mg, 100 mg or 200 mg (2.5 mg/mL, 5 mg/mL or 10 mg/mL ) of treprostinil. Each
mL also contains 5.3 mg sodium chloride (except for the 10 mg/mL strength which contains 4.0
mg sodium chloride) , 3 mg metacresol, 6.3 mg sodium citrate, and water for injection. Sodium
hydroxide and hydrochloric acid may be added to adjust pH between 6.0 and 7.2.
Treprostinil is chemically stable at room temperature and neutral pH.
Treprostinil is (1R,2R,3aS,9aS)-[[2,3,3a,4,9,9a-Hexahydro-2-hydroxy-1-[(3S)-3-hydroxyoctyl]-1H-
benz[f]inden-5-yl]oxy]acetic acid. Treprostinil has a molecular weight of 390.52 and a molecular
formula of C
12. CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
The major pharmacologic actions of treprostinil are direct vasodilation of pulmonary and systemic
arterial vascular beds, and inhibition of platelet aggregation.
In animals, the vasodilatory effects reduce right and left ventricular afterload and increase cardiac
output and stroke volume. Other studies have shown that treprostinil causes a dose-related
negative inotropic and lusitropic effect. No major effects on cardiac conduction have been
Treprostinil produces vasodilation and tachycardia. Single doses of treprostinil up to 84 mcg by
inhalation produce modest and short-lasting effects on QTc, but this is apt to be an artifact of the
rapidly changing heart rate. Treprostinil administered by the subcutaneous or intravenous routes
has the potential to generate concentrations many-fold greater than those generated via the
inhaled route; the effect on the QTc interval when treprostinil is administered parenterally has not
The pharmacokinetics of continuous subcutaneous Remodulin are linear over the dose range of
1.25 to 125 ng/kg/min (corresponding to plasma concentrations of about 15 pg/mL to 18,250
pg/mL) and can be described by a two-compartment model. Dose proportionality at infusion rates
greater than 125 ng/kg/min has not been studied.
Subcutaneous and intravenous administration of Remodulin demonstrated bioequivalence at
steady state at a dose of 10 ng/kg/min.
Remodulin is relatively rapidly and completely absorbed after subcutaneous infusion, with an
absolute bioavailability approximating 100%. Steady-state concentrations occurred in
approximately 10 hours. Concentrations in patients treated with an average dose of 9.3 ng/kg/min
were approximately 2,000 pg/mL.
The volume of distribution of the drug in the central compartment is approximately 14L/70 kg ideal
body weight. Remodulin at in vitro concentrations ranging from 330-10,000 mcg/L was 91%
bound to human plasma protein.
Metabolism and Excretion
Treprostinil is substantially metabolized by the liver,
primarily by CYP2C8. In a study conducted in
healthy volunteers using [
C] treprostinil, 78.6% and 13.4% of the subcutaneous dose was
recovered in the urine and feces, respectively, over 10 days. Only 4% was excreted as
unchanged treprostinil in the urine. Five metabolites were detected in the urine, ranging from
10.2% to 15.5% and representing 64.4% of the dose administered. Four of the metabolites are
products of oxidation of the 3-hydroxyloctyl side chain and one is a glucuroconjugated derivative
(treprostinil glucuronide). The identified metabolites do not appear to have activity.
The elimination of treprostinil (following subcutaneous administration) is biphasic, with a terminal
elimination half-life of approximately 4 hours using a two compartment model. Systemic clearance
is approximately 30 L/hr for a 70 kg person.
Based on in vitro studies treprostinil does not inhibit or induce major CYP enzymes [see Drug
In patients with portopulmonary hypertension and mild (n=4) or moderate (n=5) hepatic
insufficiency, Remodulin at a subcutaneous dose of 10 ng/kg/min for 150 minutes had a C
was 2-fold and 4-fold, respectively, and an AUC
that was 3-fold and 5-fold, respectively values
observed in healthy subjects. Clearance in patients with hepatic insufficiency was reduced by up
to 80% compared to healthy adults.
No studies have been performed in patients with renal insufficiency, so no specific advice about
dosing in such patients can be given. Although only 4% of the administered dose is excreted
unchanged in the urine, the five identified metabolites are all excreted in the urine.
13. NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term studies have not been performed to evaluate the carcinogenic potential of treprostinil.
In vitro and in vivo genetic toxicology studies did not demonstrate any mutagenic or clastogenic
effects of treprostinil.
Treprostinil did not affect fertility or mating performance of male or female
rats given continuous subcutaneous infusions at rates of up to 450 ng treprostinil/kg/min [about
59 times the recommended starting human rate of infusion (1.25 ng/kg/min) and about 8 times
the average rate (9.3 ng/kg/min) achieved in clinical trials, on a ng/m
basis]. In this study, males
were dosed from 10 weeks prior to mating and through the 2-week mating period. Females were
dosed from 2 weeks prior to mating until gestational day 6.
14. CLINICAL STUDIES
14.1 Clinical Trials in Pulmonary Arterial Hypertension (PAH)
Two 12-week, multicenter, randomized, double-blind studies compared continuous subcutaneous
infusion of Remodulin to placebo in a total of 470 patients with NYHA Class II (11%), III (81%), or
IV (7%) pulmonary arterial hypertension (PAH). PAH was idiopathic/heritable in 58% of patients,
associated with connective tissue diseases in 19%, and the result of congenital systemic-to-
pulmonary shunts in 23%. The mean age was 45 (range 9 to 75 years). About 81% were female
and 84% were Caucasian. Pulmonary hypertension had been diagnosed for a mean of 3.8 years.
The primary endpoint of the studies was change in 6-minute walking distance, a standard
measure of exercise capacity. There were many assessments of symptoms related to heart
failure, but local discomfort and pain associated with Remodulin may have substantially unblinded
those assessments. The 6-minute walking distance and an associated subjective measurement
of shortness of breath during the walk (Borg dyspnea score) were administered by a person not
participating in other aspects of the study. Remodulin was administered as a subcutaneous
infusion, described in Section 2, DOSAGE AND ADMINISTRATION, and the dose averaged
9.3 ng/kg/min at Week 12. Few subjects received doses > 40 ng/kg/min. Background therapy,
determined by the investigators, could include anticoagulants, oral vasodilators, diuretics, digoxin,
and oxygen but not an endothelin receptor antagonist or epoprostenol. The two studies were
identical in design and conducted simultaneously, and the results were analyzed both pooled and
As shown in Table 4, chronic therapy with Remodulin resulted in small hemodynamic changes
consistent with pulmonary and systemic vasodilation.
Table 4: Hemodynamics during Chronic Administration of Remodulin in Patients with PAH
in 12-Week Studies
Mean change from baseline at
*Denotes statistically significant difference between Remodulin and placebo, p<0.05.
CI = cardiac index; PAPm = mean pulmonary arterial pressure; PVRI = pulmonary vascular
resistance indexed; RAPm = mean right atrial pressure; SAPm = mean systemic arterial
pressure; SVRI = systemic vascular resistance indexed; SvO2 = mixed venous oxygen
saturation; HR = heart rate.
The effect of Remodulin on 6-minute walk, the primary end point of the 12-week studies, was
small and did not achieve conventional levels of statistical significance. For the combined
populations, the median change from baseline on Remodulin was 10 meters and the median
change from baseline on placebo was 0 meters from a baseline of approximately 345 meters.
Although it was not the primary endpoint of the study, the Borg dyspnea score was significantly
improved by Remodulin during the 6-minute walk, and Remodulin also had a significant effect,
compared with placebo, on an assessment that combined walking distance with the Borg
dyspnea score. Remodulin also consistently improved indices of dyspnea, fatigue and signs and
symptoms of pulmonary hypertension, but these indices were difficult to interpret in the context of
incomplete blinding to treatment assignment resulting from infusion site symptoms.
14.2 Flolan-To-Remodulin Transition Study
In an 8-week, multicenter, randomized, double-blind, placebo-controlled study, patients on stable
doses of Flolan were randomly withdrawn from Flolan to placebo or Remodulin. Fourteen
Remodulin and 8 placebo patients completed the study. The primary endpoint of the study was
the time to clinical deterioration, defined as either an increase in Flolan dose, hospitalization due
to PAH, or death. No patients died during the study.
During the study period, Remodulin effectively prevented clinical deterioration in patients
transitioning from Flolan therapy compared to placebo (Figure 1). Thirteen of 14 patients in the
Remodulin arm were able to transition from Flolan successfully, compared to only 1 of 8 patients
in the placebo arm (p=0.0002).
Figure 1: Time to Clinical Deterioration for PAH Patients Transitioned from Flolan to
Remodulin or Placebo in an 8-Week Study
16. HOW SUPPLIED / STORAGE AND HANDLING
Remodulin is supplied in 20 mL multidose vials containing 50, 100 or 200 mg of treprostinil at
concentrations of 2.5 mg/mL, 5 mg/mL and 10 mg/mL treprostinil, respectively, as sterile
solutions in water for injection, individually packaged in cartons.
Unopened vials of Remodulin are stable until the date indicated when stored below 25
Shelf life after first opening – A single vial of Remodulin should be used for no more than 30 days
after the initial introduction into the vial.
During use, a single reservoir (syringe) of undiluted Remodulin can be administered up to 72
hours at 37
Shelf life after dilution – 48 hours
Diluted Remodulin has been shown to be stable at ambient temperature for up to 48 hours at
concentrations as low as 0.004 mg/mL (4,000 ng/mL).
Can be diluted
for intravenous infusion with Sterile Water for Injection or 0.9% Sodium Chloride
20-mL vial containing 50 mg treprostinil (2.5 mg treprostinil per mL), carton of 1.
20-mL vial containing 100 mg treprostinil (5 mg treprostinil per mL), carton of 1.
20-mL vial containing 200 mg treprostinil (10 mg treprostinil per mL), carton of 1.
17. PATIENT COUNSELING INFORMATION
Patients receiving Remodulin should be given the following information: Remodulin is infused
continuously through a subcutaneous or surgically placed indwelling central venous catheter, via
an infusion pump. Patients receiving intravenous infusion should use an infusion set with an in-
line filter. Therapy with Remodulin will be needed for prolonged periods, possibly years, and the
patient's ability to accept and care for a catheter and to use an infusion pump should be carefully
considered. In order to reduce the risk of infection, aseptic technique must be used in the
preparation and administration of Remodulin. Additionally, patients should be aware that
subsequent disease management may require the initiation of an alternative intravenous
prostacyclin therapy, Flolan
Manufacturer: United Therapeutics Corp., USA.
Registration Holder: Rafa Laboratories Ltd. P.O.Box 405, Jerusalem 9100301
Registration Numbers: Remodulin 2.5 mg/mL: 126 57 30563
Remodulin 5 mg/mL: 126 56 30562
Remodulin 10 mg/mL: 135 55 31251
The content of this leaflet was approved by the Ministry of Health in February 2015, and updated
according to the guidelines of the Ministry of Health in December 2017.