REMODULIN 5 MGML

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

Active ingredient:

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

disorder.

For treatment of pulmonary hypertension resulting from a congenital heart defect.

Therapeutic group:

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

cough.

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

operate machinery.

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

liver function.

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

section 6.

3. How to use the medicine?

Always use according to the doctor's instructions. Check with the doctor or pharmacist if you are

not sure.

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

to treatment.

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

overdose.

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,

rash, itching.

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:

Subcutaneous administration:

Pain or infection at the injection site, local reaction including redness, hardness and/or rash.

Intravenous administration:

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

administration.

Bleeding/ hematoma.

Tingling sensation.

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:

https://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectMedic@moh.gov.il

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.

Storage conditions:

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

ingredients:

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.

003002-I

FULL PRESCRIBING INFORMATION

REMODULIN

®

(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

treatment of

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

2.1 General

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)].

2.5 Administration

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

not use.

Subcutaneous Infusion

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

subcutaneously

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:

Subcutaneous

Infusion Rate

(mL/hr)

=

Dose (ng/kg/min)

x

Weight (kg)

x

0.00006*

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:

Example 1:

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:

Subcutaneous

Infusion Rate

(mL/hr)

=

1.25 ng/kg/min

x

60 kg

x

0.00006

= 0.005 mL/hr

1 mg/mL

Example 2:

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:

Subcutaneous

Infusion Rate

(mL/hr)

=

40 ng/kg/min

x

65 kg

x

0.00006

= 0.031 mL/hr

5 mg/mL

Intravenous Infusion

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:

Step 1

Diluted

Intravenous

Remodulin

Concentration

(mg/mL)

=

Dose

(ng/kg/min)

x

Weight

(kg)

x

0.00006

Intravenous Infusion Rate

(mL/hr)

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:

Step 2

Volume of

Remodulin

Injection

(mL)

=

Diluted Intravenous

Remodulin

Concentration

(mg/mL)

x

Total Volume of Diluted

Remodulin Solution in

Reservoir

(mL)

Remodulin Vial

Strength

(mg/mL)

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:

Example 3:

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:

Step 1

Diluted

Intravenous

Remodulin

Concentration

(mg/mL)

=

5 ng/kg/min

x

60 kg

x

0.00006

= 0.018

mg/mL

(18,000

ng/mL)

1 mL/hr

The Volume

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:

Step 2

Amount of

Remodulin Injection

(mL)

0.018 mg/mL

x 50 mL = 0.9 mL

1 mg/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.

Example 4:

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:

Step 1

Diluted

Intravenous

Remodulin

Concentration

(mg/mL)

=

30 ng/kg/min

x

75 kg

x

0.00006

= 0.0675 mg/mL

(67,500 ng/mL)

2 mL/hr

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:

Step 2

Volume of

Remodulin Injection

(mL)

0.0675 mg/mL

x 100 mL = 2.7 mL

2.5 mg/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

Step

Flolan Dose

Remodulin Dose

Unchanged

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).

4. CONTRAINDICATIONS

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

administration.

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

guidelines.

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

Pharmacology (12.3)].

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

Pharmacology (12.3)].

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

treatment.

Table 2: Percentages of subjects reporting subcutaneous infusion site adverse events

Reaction

Pain

Placebo

Remodulin

Placebo

Remodulin

Severe

Requiring narcotics*

NA**

NA**

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.

Adverse Reaction

Remodulin

(N=236)

Percent of Patients

Placebo

(N=233)

Percent of Patients

Infusion Site Pain

Infusion Site Reaction

Headache

Diarrhea

Nausea

Rash

Jaw Pain

Vasodilatation

Edema

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

treated population.

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

reported.

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

http://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectMedic@moh.gov.il

7. DRUG INTERACTIONS

Pharmacokinetic/pharmacodynamic interaction studies have been conducted with treprostinil

administered subcutaneously (Remodulin) and orally (treprostinil diethanolamine).

Pharmacodynamics

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.

7.2 Anticoagulants

Since treprostinil inhibits platelet aggregation, there may be an increased risk of bleeding,

particularly among patients receiving anticoagulants.

Pharmacokinetics

7.3 Bosentan

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.

7.4 Sildenafil

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

Precautions (5.4)].

Remodulin has not been studied in conjunction with Flolan or Tracleer

(bosentan).

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

8.1 Pregnancy

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

Pharmacology (12.3)].

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)].

10. OVERDOSAGE

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

of Remodulin.

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.

11. DESCRIPTION

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.

12.2 Pharmacodynamics

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

observed.

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

been established.

12.3 Pharmacokinetics

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.

Absorption

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.

Distribution

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

Interactions (7.5)].

Special Populations

Hepatic Insufficiency

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

that

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.

Renal Insufficiency

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

individually.

Hemodynamic Effects

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

Hemodynamic

Parameter

Baseline

Mean change from baseline at

Week 12

Remodulin

(N=204-231)

Placebo

(N=215-235)

Remodulin

(N=163-199)

Placebo

(N=182-215)

(L/min/m

0.88

0.74

+0.12

0.58*

-0.06

0.55

PAPm

(mmHg)

17.6

14.8

-2.3

7.3*

+0.7

RAPm

(mmHg)

-0.5

5.0*

+1.4

PVRI

(mmHg/L/min/m

-3.5

8.2*

+1.2

SVRI

(mmHg/L/min/m

-3.5

-0.80

+2.0

-1.4

SAPm

(mmHg)

-1.7

-1.0

(bpm)

-0.5

-0.8

*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.

Clinical Effects

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

Injection.

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

(epoprostenol sodium).

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.