Endoprost

Package leaflet: Information for the patient

Endoprost 0.05 mg/0.5 ml concentrate for solution for infusion

Iloprost
Please read this leaflet carefully before you are given this medicine
because it contains important information for you.

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

Contents of this leaflet:

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

1. What Endoprost is and what it is used for

Endoprost contains the active substance iloprost, a compound belonging to a group of medicines called "antiplatelet agents". It is a synthetic analogue of a substance naturally present in the body (prostacyclin) and exerts several actions, including inhibition of blood coagulation when there is a risk of thrombosis and embolism in veins or arteries, dilation of small blood vessels, and stimulation of the physiological mechanisms that dissolve blood clots (thrombi).

Endoprost is used for:

• Treatment of advanced stage thromboangiitis obliterans (Buerger's disease) with critical limb ischemia when revascularization surgery is not indicated. Thromboangiitis obliterans is an inflammatory disease affecting small and medium-sized arteries and veins in the extremities (hands and feet).

• Treatment of Raynaud's phenomenon (extreme constriction of blood vessels in the fingers of the hands and feet) secondary to scleroderma (a chronic autoimmune disease causing hardening and thickening of the skin).

• Treatment of severe chronic arterial ischemia of the lower limbs in patients at risk of amputation when surgical intervention or angioplasty (a procedure to dilate a narrowing in a blood vessel) is not indicated.

2. What you need to know before you are given Endoprost

Endoprost must not be administered to you
if you are allergic to iloprost or to any of the other ingredients of this medicine (listed
in section 6);
if you are pregnant;
if you are breastfeeding;
if you are at risk of bleeding, for example in case of active peptic ulcer, trauma,
intracranial bleeding;
if there is suspicion that you may have pulmonary congestion;
if you have a heart condition, such as:

• if you suffer from reduced blood flow to the heart muscle, such as severe coronary artery disease or unstable angina (symptoms may include chest pain);
• if you have had a heart attack (myocardial infarction) within the last six months;
• if you have a weak heart (acute or chronic congestive heart failure in NYHA classes II to IV);
• if you suffer from severe or prognostically relevant cardiac arrhythmias.

Warnings and precautions
Talk to your doctor or nurse before you are given Endoprost.
Pay particular attention if any of the following apply to you:
if you require urgent amputation (e.g. in case of infected gangrene);
if you smoke. It is strongly recommended not to smoke during treatment with Endoprost;
if you have low blood pressure; in this case, you must take special care to avoid further drops in blood pressure;
if you have a serious heart disease. In this case, you must be closely monitored by your doctor;
if you suffer from dizziness upon standing (orthostatic hypotension). You should rise slowly to help your body adjust to the new position;
if you have had a severe stroke (transient ischemic attack, cerebrovascular accidents) within the last 3 months (see Endoprost must not be administered to you); your doctor will carefully evaluate the risk-benefit ratio.
Infusion of the concentrated solution outside the blood vessels may cause local changes at the injection site.
Avoid oral administration and contact with skin and mucous membranes. In case of contact with the skin, Endoprost may cause persistent skin redness (erythema), without pain. If the medicine comes into contact with the skin, immediately wash the affected area thoroughly with water or physiological saline solution.
For athletes : the use of medicines containing ethyl alcohol may lead to positive results in doping tests, depending on the blood alcohol concentration limits indicated by certain sports federations.
Children and adolescents
Currently, only limited data are available on the use in children and adolescents.
Other medicines and Endoprost
Inform your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines, including those purchased without a prescription or dietary supplements.
Endoprost may affect how other medicines work. Conversely, some medicines may affect how Endoprost works.
In particular, talk to your doctor if you are taking:
medicines used to treat high blood pressure (antihypertensives) or heart conditions (such as beta-blockers, calcium antagonists, vasodilators, and ACE inhibitors). Your blood pressure may drop further; therefore, your doctor may need to adjust the dose of Endoprost;
medicines that thin the blood (anticoagulants and antiplatelet agents) that prevent blood clotting, such as heparin, coumarin-like anticoagulants, acetylsalicylic acid, or other non-steroidal anti-inflammatory drugs, phosphodiesterase inhibitors, and nitrovasodilators, for example molsidomine. The risk of bleeding may increase. If you experience bleeding, treatment with Endoprost must be stopped.
Endoprost and alcohol
As with all medicines, concomitant intake of alcohol should be avoided.
Fertility, pregnancy, and breastfeeding
If you are pregnant, suspect you may be pregnant, are planning a pregnancy, or are breastfeeding, consult your doctor before you are given this medicine.
Pregnancy
Endoprost must not be administered during pregnancy (see “Endoprost must not be administered to you”).
There are insufficient data on the use of this medicine in pregnant women. Since the potential risk of therapeutic use of Endoprost during pregnancy is unknown, if you are of childbearing age, use appropriate contraceptive methods during treatment.
Breastfeeding
It is not known whether the medicine passes into breast milk. Endoprost must not be administered if you are breastfeeding (see “Endoprost must not be administered to you”).
Driving and using machines
Not applicable.
Endoprost contains sodium and ethanol
This medicine contains less than 1 mmol (23 mg) of sodium per dose, i.e. it is practically “sodium-free”.
This medicine contains small amounts of ethanol (alcohol), less than 100 mg per dose.

3. How Endoprost is used

Use this medicine exactly as instructed by your doctor or pharmacist. If you have
any doubts, consult your doctor or pharmacist.
Endoprost will be administered to you by your doctor or nurse in a hospital or properly
equipped outpatient setting, under close supervision.
If you are a woman of childbearing age, pregnancy must be ruled out before starting
treatment.
Recommended dose: as prescribed by the doctor.
The medicine is administered through a vein, as a daily infusion lasting 6 hours.
The duration of treatment is 4 weeks.
Shorter treatment periods (from 3 to 5 days) are often sufficient in Raynaud's phenomenon to achieve improvement lasting several weeks.
Blood pressure and heart rate will be measured at the beginning of the infusion and after each dose increase.

Use in patients with renal insufficiency, dialysis, or hepatic cirrhosis:
Dose adjustment is required (e.g., half of the recommended dose).

If you are given more Endoprost than you should
Since Endoprost will be administered by a doctor or nurse, it is unlikely that you will receive too much medicine.
However, if you think you have been given an excessive dose of Endoprost, contact your doctor or nurse immediately. Symptoms that may occur include: drop in blood pressure (hypotensive reaction), headache, flushing, nausea, vomiting, and diarrhea. An increase in blood pressure, slow heart rate (bradycardia), or fast heart rate (tachycardia), pain in the limbs or back, sudden paleness, sweating, and abdominal pain may also occur.
A specific antidote is not known.
In case of overdose, discontinuation of Endoprost administration is recommended, along with monitoring and symptomatic treatment.

If you miss a dose of Endoprost
Do not receive a double dose to make up for the missed dose.
If you have any doubts about how to use this medicine, consult your doctor or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.
The most frequently observed adverse reactions are headache, skin flushing, nausea, vomiting and excessive sweating (hyperhidrosis).
These side effects are likely to occur during dose titration at the beginning of treatment, to identify the optimal tolerable dose for each patient. However, all these adverse effects resolve rapidly upon dose reduction.
Overall, the more serious adverse reactions include stroke (cerebrovascular accident), heart attack (myocardial infarction), blood clots in the lungs (pulmonary embolism), cardiac arrest, seizures, low blood pressure (hypotension), rapid heartbeat (tachycardia), asthma, chest pain (angina pectoris), difficulty breathing (dyspnoea), and fluid accumulation in the lungs (pulmonary oedema).
Another group of adverse effects relates to local reactions at the infusion site. For example, redness and pain at the infusion site or cutaneous vasodilation may occur, which can lead to visible superficial striated redness along the course of the vein.

Very common (may affect more than 1 in 10 people)

• headache
• flushing
• nausea and vomiting
• excessive sweating (hyperhidrosis)

Common (may affect up to 1 in 10 people)

• loss of appetite
• apathy (lack of emotion, motivation or enthusiasm)
• confusion
• dizziness and vertigo
• altered sensation (paraesthesia)
• sensation of pulsation
• increased skin sensitivity (hyperaesthesia)
• burning sensation
• restlessness
• agitation
• sedation
• somnolence
• rapid heartbeat (tachycardia*)
• slow heartbeat (bradycardia)
• chest pain (angina pectoris*)
• low blood pressure (hypotension*)
• increased blood pressure (hypertension)
• difficulty breathing (dyspnoea*)
• diarrhoea
• abdominal discomfort/abdominal pain
• jaw pain, jaw spasms (trismus)
• muscle pain (myalgia)
• joint pain (arthralgia)
• pain, fever (pyrexia), increased body temperature, feeling of warmth
• weakness (asthenia), malaise
• chills, fatigue, tiredness
• thirst
• reaction at infusion site (redness, pain or inflammation of the vein)

Uncommon (may affect up to 1 in 100 people)

• reduced number of platelets in the blood (thrombocytopenia)
• excessive allergic-type sensitivity (hypersensitivity)
• anxiety, depression, hallucinations
• seizures*, fainting or brief loss of consciousness (syncope), tremor, one-sided headache (migraine)
• blurred vision, eye irritation, eye pain
• heart attack (myocardial infarction*), cardiac arrest*, irregular heartbeat (arrhythmia or extrasystoles)
• stroke (cerebrovascular accident*) or reduced blood flow to the brain (cerebral ischaemia)
• blood clots in the lungs (pulmonary embolism*), blood clots in the leg veins (deep vein thrombosis)
• asthma*, fluid accumulation in the lungs (pulmonary oedema*)
• diarrhoea with blood in stool (haemorrhagic diarrhoea), rectal bleeding, indigestion (dyspepsia), rectal tenesmus (painful spasm of the anus accompanied by a feeling of urgent need to defecate), constipation
• eructation, difficulty swallowing (dysphagia), dry mouth
• altered taste (dysgeusia)
• yellowish discoloration of the skin, mucous membranes and whites of the eyes due to liver disorders (jaundice)
• itching
• muscle cramps (tetany), muscle spasms, increased muscle tone (hypertonia)
• kidney pain, painful urination, abnormal urine, difficulty urinating (dysuria), urinary tract disorders

Rare (may affect up to 1 in 1,000 people)

• vestibular disorders (part of the ear responsible for balance)
• cough
• inflammation of the rectum (proctitis)

* Fatal and/or life-threatening cases have been reported.
Endoprost may cause chest pain due to angina pectoris, especially in patients suffering from reduced blood flow to the heart muscle (coronary disorders).
The risk of bleeding is higher in patients who are concomitantly receiving medications that thin the blood (platelet aggregation inhibitors, heparin or coumarin-like anticoagulants) (see “Other medicines and Endoprost”).

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor, pharmacist or nurse. You can also report side effects directly via the national reporting system at the website: http://www.agenziafarmaco.gov.it/it/responsabili. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Endoprost

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the packaging after the term
"EXP". The expiry date refers to the last day of that month.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. This will help protect the environment.

6. Package contents and other information

What Endoprost contains

• The active substance is iloprost. Each 0.5 ml vial contains 0.067 mg (67 micrograms) of iloprost tromethamine, equivalent to 0.050 mg (50 micrograms) of iloprost.
• The other components are: tromethamine, ethanol 96% (v/v), sodium chloride, hydrochloric acid (1N), water for injections.

Description of the appearance of Endoprost and contents of the pack
Endoprost is a concentrate for solution for infusion.
The pack contains 1 vial of 0.5 ml, concentrate for solution for infusion 0.050 mg.
Marketing Authorization Holder
Italfarmaco S.p.A. - Viale F. Testi, 330 – 20126 Milan
Manufacturer
Berlimed SA - Alcalà de Henares, Madrid (Spain)

• • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • The following information is intended exclusively for physicians or healthcare professionals:

Other medicines and Endoprost
In healthy volunteers, oral pretreatment with acetylsalicylic acid up to 300 mg daily for 8 days had no impact on the pharmacokinetic clearance (mL/min/kg) of iloprost.
In an animal study, iloprost was shown to reduce steady-state plasma concentrations of t-PA.
Results from studies in patients demonstrate that iloprost infusions have no effect on the pharmacokinetics of digoxin in patients receiving multiple oral doses, and that iloprost has no impact on the pharmacokinetics of co-administered t-PA.
In animal studies, the vasodilatory effect of iloprost was reduced following pretreatment with glucocorticoids, while its inhibitory activity on platelet aggregation remained unchanged. The clinical significance of this observation is not yet known.
Although no clinical studies have been conducted, in vitro studies evaluating the potential inhibitory effect of iloprost on cytochrome P450 enzyme activity have shown that a significant inhibition by iloprost of drug metabolism mediated by these enzymes is not expected.

Dosage and method of administration
Endoprost must be administered, after dilution, as an intravenous infusion for 6 hours daily, into a peripheral vein or via a central venous catheter.
The ready-to-use infusion solution must be prepared daily to ensure sterility.

• Dilution instructions: The contents of the vial and the diluent must be thoroughly mixed.

Dilution of Endoprost for use with an infusion pump
For this purpose, the contents of one 0.5 ml vial of ENDOPROST (i.e., 50 mcg) are diluted with 250 ml of sterile physiological saline solution or 5% glucose solution.
Dilution of Endoprost for use with a syringe pump
In this case, the contents of one 0.5 ml vial of ENDOPROST (i.e., 50 mcg) are diluted with 25 ml of sterile physiological saline solution or 5% glucose solution.
The dose must be adjusted according to individual patient tolerance within an infusion rate range of 0.5 to 2 ng iloprost/kg/min over 6 hours daily.
The infusion solution must be prepared daily to ensure sterility.
The contents of the vial and the diluent must be thoroughly mixed.
Blood pressure and heart rate must be monitored at the start of infusion and after each dose increase.
During the first 2–3 days of treatment, the maximally tolerated dose should be determined. Infusion is initiated at a rate of 0.5 ng/kg/min for 30 minutes.
Dose increases of 0.5 ng/kg/min may then be made every 30 minutes, up to a maximum of 2.0 ng/kg/min. The exact infusion rate must be calculated based on body weight to achieve an infusion within the range of 0.5 to 2.0 ng/kg/min (see tables below for use with infusion pump or syringe pump).
If adverse effects such as headache, nausea, or hypotension occur, the infusion rate must be reduced until the tolerated dose is reached. If adverse effects are severe, the infusion must be suspended.
After the individual dose has been established during the first 2–3 days, it should be maintained throughout the treatment cycle (usually for 4 weeks).
Two different dilutions of the vial contents are available, depending on the infusion technique used. One of these dilutions is 10 times less concentrated than the other (0.2 mcg/ml vs. 2 mcg/ml) and can only be administered using an infusion pump (e.g., Infusomat). Conversely, the more concentrated solution is administered using a syringe pump (e.g., Infonde or Perfusor).

Infusion rate (mL/hour) for different doses using an infusion pump
Generally, the ready-to-use infusion solution is administered intravenously via an infusion pump (e.g., Infusomat). For dilution instructions for use with an infusion pump, see above.
With an ENDOPROST concentration of 0.2 mcg/mL, the required infusion rate must be determined according to the table below to achieve a dose within the range of 0.5 to 2.0 ng/kg/min.
The following table can be used to calculate the infusion rate corresponding to the patient's body weight and the required dose. Identify the patient's actual body weight, then adjust the infusion rate to the desired dose in ng/kg/min.

Body weight Dose (ng/kg/min)
(kg) 0.5 1.0 1.5 2.0
Infusion rate (mL/hour)
40 6.0 12 18.0 24
50 7.5 15 22.5 30
60 9.0 18 27.0 36
70 10.5 21 31.5 42
80 12.0 24 36.0 48
90 13.5 27 40.5 54
100 15.0 30 45.0 60
110 16.5 33 49.5 66

Infusion rate (mL/hour) for different doses using a syringe pump
A syringe pump with a syringe calibrated up to 25.5 mL (e.g., Infonde) or a syringe pump with a 50 mL syringe (e.g., Perfusor) may also be used. For dilution instructions for use with a syringe pump, see above.
With an ENDOPROST concentration of 2 mcg/mL, the required infusion rate must be determined according to the table below to achieve a dose within the range of 0.5 to 2.0 ng/kg/min.
The following table can be used to calculate the infusion rate corresponding to the patient's body weight and the required dose. Identify the patient's actual body weight, then adjust the infusion rate to the desired dose in ng/kg/min.

Dose (ng/kg/min)
Body weight (kg) 0.5 1.0 1.5 2.0
Infusion rate (mL/hour)
40 0.60 1.2 1.80 2.4
50 0.75 1.5 2.25 3.0
60 0.90 1.8 2.70 3.6
70 1.05 2.1 3.15 4.2
80 1.20 2.4 3.60 4.8
90 1.35 2.7 4.05 5.4
100 1.50 3.0 4.50 6.0
110 1.65 3.3 4.95 6.6

The duration of treatment should not exceed 4 weeks.
The safety and efficacy of treatment lasting longer than 4 weeks or of repeated treatment cycles have not been established.
Shorter treatment periods (from 3 to 5 days) are often sufficient in Raynaud's phenomenon to achieve improvement lasting several weeks.
Continuous infusion over several days is not recommended due to the potential development of tachyphylaxis regarding the effect on platelets and the possibility of rebound platelet hyperaggregation at the end of treatment, although no clinical complications associated with these phenomena have ever been observed.

• Patients with renal or hepatic impairment
  It should be considered that in patients with renal insufficiency undergoing dialysis and in those with hepatic cirrhosis, elimination of iloprost is reduced. In these patients, a dose reduction is necessary (e.g., half the recommended dose).

There is no experience with the use of ENDOPROST in children.
Patient Information Leaflet: Information for the patient

Endoprost 0.1 mg/1 ml concentrate for solution for infusion

Iloprost
Please read this leaflet carefully before this medicine is administered to you
because it contains important information for you.

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

Contents of this leaflet:

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

1. What Endoprost is and what it is used for

Endoprost contains the active substance iloprost, a compound belonging to a group of medicines called "antiplatelet agents". It is a synthetic analogue of a substance naturally present in the body (prostacyclin) and exerts several actions, including inhibition of blood coagulation when there is a risk of thrombosis and embolism in veins or arteries, dilation of small blood vessels, and stimulation of the physiological mechanisms that dissolve blood clots (thrombi).

Endoprost is used for:

• the treatment of advanced thromboangiitis obliterans (Buerger's disease) with critical limb ischemia when revascularization surgery is not indicated. Thromboangiitis obliterans is an inflammatory disease affecting the small and medium arteries and veins of the extremities (hands and feet).

• the treatment of Raynaud's phenomenon (extreme constriction of blood vessels in the fingers and toes) secondary to scleroderma (a chronic autoimmune disease causing hardening and thickening of the skin).

• the treatment of severe chronic arterial ischemia of the lower limbs in patients at risk of amputation, when surgical intervention or angioplasty (a procedure used to widen a narrowed blood vessel) is not indicated.

2. What you should know before being administered Endoprost

Endoprost must not be administered to you
if you are allergic to iloprost or to any of the other ingredients of this medicine (listed
in section 6);
if you are pregnant;
if you are breastfeeding;
if you are at risk of bleeding, for example in case of active peptic ulcer, trauma,
intracranial bleeding;
if there is suspicion that you have pulmonary congestion;
if you have a heart condition, such as:

• if you suffer from poor blood flow to the heart muscle, such as severe coronary artery disease or unstable angina (symptom may be chest pain);
• if you have had a heart attack (myocardial infarction) within the last six months;
• if you have a weak heart (acute or chronic congestive heart failure in NYHA classes II to IV);
• if you suffer from severe or prognostically relevant cardiac arrhythmias.

Warnings and precautions
Talk to your doctor or nurse before being administered Endoprost.
Exercise particular caution if any of the following apply to you:
if you require urgent amputation (e.g., in case of infected gangrene);
if you smoke. It is strongly recommended not to smoke during treatment with Endoprost.
if you have low blood pressure; in this case, you must take particular care to
avoid further drops in blood pressure.
if you have a serious heart disease. In this case, you must be closely monitored by
your doctor.
if you suffer from dizziness upon standing (orthostatic hypotension). You should rise slowly to
help your body adjust to the new position.
if you have had a severe stroke (transient ischemic attack, cerebrovascular accidents) within the
last 3 months (see Endoprost must not be administered to you); your doctor will carefully
evaluate the risk-benefit ratio.
Infusion of the concentrated solution outside the blood vessels may cause local reactions at the
injection site.
Avoid oral administration and contact with skin and mucous membranes. In case of contact with the skin,
Endoprost may cause persistent skin redness (erythema), without pain. If the medicine comes into contact with the skin, immediately wash the affected area thoroughly with water or physiological saline solution.
For athletes: the use of medicinal products containing ethyl alcohol may result in a positive doping test, depending on the alcohol concentration limits set by certain sports federations.
Children and adolescents
Currently, only sporadic data are available on the use in children and adolescents.
Other medicines and Endoprost
Inform your doctor or pharmacist if you are taking, have recently taken, or might take
any other medicines, including those purchased without a prescription or dietary supplements.
Endoprost may affect how other medicines work. Conversely, some medicines may
affect how Endoprost works.
In particular, talk to your doctor if you are taking:
medicines used to treat high blood pressure (antihypertensives) or heart conditions (such as
beta-blockers, calcium antagonists, vasodilators, and ACE inhibitors). Your blood pressure may
drop further; therefore, your doctor may adjust the dose of Endoprost.
medicines that thin the blood (anticoagulants and antiplatelet agents) that prevent blood
clotting, such as heparin, coumarin-like anticoagulants, acetylsalicylic acid, or other
non-steroidal anti-inflammatory drugs, phosphodiesterase inhibitors, and nitrovasodilators, for
example molsidomine. This may increase the risk of bleeding. If you start bleeding,
treatment with Endoprost must be stopped.
Endoprost and alcohol
As with all medicines, concomitant intake of alcohol should be avoided.
Fertility, pregnancy, and breastfeeding
If you are pregnant, suspect you may be pregnant, are planning a pregnancy, or are breastfeeding,
consult your doctor before being administered this medicine.
Pregnancy
Endoprost must not be administered during pregnancy (see “Endoprost must not be administered to you”).
There are insufficient data on the use of this medicine in pregnant women. Since the potential risk of therapeutic use of Endoprost during pregnancy is unknown, if you are of childbearing age, use adequate contraceptive methods during treatment.
Breastfeeding
It is not known whether the medicine passes into breast milk. Endoprost must not be administered if you are
breastfeeding (see “Endoprost must not be administered to you”).
Driving and using machines
Not applicable.
Endoprost contains sodium and ethanol
This medicine contains less than 1 mmol (23 mg) of sodium per dose, i.e., it is practically “sodium-free”.
This medicine contains small amounts of ethanol (alcohol), less than 100 mg per dose.

3. How Endoprost is used

Use this medicine exactly as instructed by your doctor or pharmacist. If you have
any doubts, consult your doctor or pharmacist.
Endoprost will be administered to you by a doctor or nurse in a hospital or properly
equipped outpatient setting, under close supervision.
If you are a woman of childbearing age, pregnancy must be ruled out before starting
treatment.
The recommended dose is: as prescribed by the doctor.
The medicine is administered through a vein, as a daily infusion lasting 6 hours.
The duration of treatment is 4 weeks.
Shorter treatment periods (from 3 to 5 days) are often sufficient in Raynaud's phenomenon to achieve improvement lasting for several weeks.
Blood pressure and heart rate will be measured at the beginning of the infusion and after each dose increase.

Use in patients with renal impairment, dialysis, or hepatic cirrhosis:
Dose adjustment is required (e.g., half of the recommended dose).

If you are given more Endoprost than you should
Since Endoprost will be administered by a doctor or nurse, it is unlikely that you will receive too much medicine.
However, if you think an excessive dose of Endoprost has been administered, contact your doctor or nurse immediately. Possible symptoms include: drop in blood pressure (hypotensive reaction), headache, flushing, nausea, vomiting, and diarrhea. An increase in blood pressure, slowed heart rate (bradycardia), or accelerated heart rate (tachycardia), pain in the limbs or back, sudden pallor, sweating, and abdominal pain may also occur.
No specific antidote is known.
In case of overdose, discontinuation of Endoprost administration is recommended, along with monitoring and symptomatic treatment.

If you miss a dose of Endoprost
Do not administer a double dose to make up for the missed dose.
If you have any doubts about the use of this medicine, consult your doctor or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone gets them.
The most frequently observed adverse reactions are headache, skin flushing, nausea, vomiting and excessive sweating (hyperhidrosis).
These side effects are likely to occur during dose titration at the beginning of treatment, in order to identify the optimal tolerable dose for each patient. However, all these side effects resolve rapidly upon dose reduction.
Overall, the more serious adverse reactions include stroke (cerebrovascular accident), heart attack (myocardial infarction), blood clots in the lungs (pulmonary embolism), cardiac arrest, seizures, low blood pressure (hypotension), rapid heartbeat (tachycardia), asthma, chest pain (angina pectoris), difficulty breathing (dyspnea), and fluid accumulation in the lungs (pulmonary edema).
Another group of adverse effects relates to local reactions at the infusion site. For example, redness and pain at the infusion site or cutaneous vasodilation may occur, which can lead to visible superficial streaking redness along the course of the vein.
Very common (may affect more than 1 in 10 patients)

• headache
• flushing
• nausea and vomiting
• excessive sweating (hyperhidrosis)

Common (may affect up to 1 in 10 patients)

• loss of appetite
• apathy (lack of emotion, motivation or enthusiasm)
• confusion
• dizziness and vertigo
• altered sensation (paraesthesia)
• sensation of pulsation
• increased skin sensitivity (hyperaesthesia)
• burning sensation
• restlessness
• agitation
• sedation
• somnolence
• rapid heartbeat (tachycardia*)
• slow heartbeat (bradycardia)
• chest pain (angina pectoris*)
• low blood pressure (hypotension*)
• increased blood pressure (hypertension)
• difficulty breathing (dyspnea*)
• diarrhoea
• abdominal discomfort/abdominal pain
• jaw pain, jaw spasms (trismus)
• muscle pain (myalgia)
• joint pain (arthralgia)
• pain, fever (pyrexia), increased body temperature, feeling of warmth
• weakness (asthenia), malaise
• chills, fatigue, tiredness
• thirst
• infusion site reaction (redness, pain or inflammation of the vein)

Uncommon (may affect up to 1 in 100 patients)

• reduced number of platelets in the blood (thrombocytopenia)
• excessive allergic-type sensitivity (hypersensitivity)
• anxiety, depression, hallucinations
• seizures*, fainting or brief loss of consciousness (syncope), tremor, one-sided headache (migraine)
• blurred vision, eye irritation, eye pain
• heart attack (myocardial infarction*), cardiac arrest*, irregular heartbeat (arrhythmia or extrasystoles)
• stroke (cerebrovascular accident*) or reduced blood flow to the brain (cerebral ischaemia)
• blood clots in the lungs (pulmonary embolism*), blood clots in the leg veins (deep vein thrombosis)
• asthma*, fluid accumulation in the lungs (pulmonary edema*)
• diarrhoea with blood in stools (haemorrhagic diarrhoea), rectal bleeding, indigestion (dyspepsia), rectal tenesmus (painful spasm of the anus accompanied by a feeling of urgent need to defecate), constipation
• eructation, difficulty swallowing (dysphagia), dry mouth
• altered taste (dysgeusia)
• yellowish discoloration of the skin, mucous membranes and whites of the eyes due to liver disorders (jaundice)
• itching
• muscle cramps (tetany), muscle spasms, increased muscle tone (hypertonia)
• kidney pain, painful urination, abnormal urine, difficulty urinating (dysuria), urinary tract disorders

Rare (may affect up to 1 in 1,000 patients)

• vestibular disorders (part of the ear responsible for balance)
• cough
• inflammation of the rectum (proctitis)

* Fatal and/or life-threatening cases have been reported
Endoprost may cause chest pain due to angina pectoris, especially in patients suffering from reduced blood flow to the heart muscle (coronary disorders).
The risk of bleeding is higher in patients who are concomitantly receiving medicines that thin the blood (platelet aggregation inhibitors, heparin or coumarin-like anticoagulants) (see “Other medicines and Endoprost”).
Reporting of side effects
If you experience any side effects, including those not listed in this leaflet, talk to your doctor, pharmacist or nurse. You can also report side effects directly via the national reporting system at the website
http://www.agenziafarmaco.gov.it/it/responsabili. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Endoprost

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the packaging after the word "EXP". The expiry date refers to the last day of that month.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

6. Package Contents and Other Information

What Endoprost Contains

• The active substance is iloprost. Each 1 ml vial contains 0.134 mg (134 micrograms) of iloprost tromethamine, equivalent to 0.100 mg (100 micrograms) of iloprost.
• The other components are: tromethamine, ethanol 96% (v/v), sodium chloride, hydrochloric acid (1N), water for injections.

Description of the Appearance of Endoprost and Contents of the Package
Endoprost is a concentrate for solution for infusion.
The pack contains 1 vial of 1 ml, concentrate for infusion solution 0.1 mg.
Marketing Authorization Holder
Italfarmaco S.p.A. - Viale F. Testi, 330 – 20126 Milan
Manufacturer
Berlimed SA - Alcalá de Henares, Madrid (Spain)

• • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • The following information is intended exclusively for physicians or healthcare professionals:

Other Medicines and Endoprost
In healthy volunteers, oral pretreatment with acetylsalicylic acid up to 300 mg daily for 8 days had no effect on the pharmacokinetic clearance (mL/min/kg) of iloprost.
In an animal study, iloprost was found to reduce plasma concentrations of t-PA at steady state.
Results from studies in patients show that iloprost infusions have no effect on the pharmacokinetics of digoxin in patients receiving multiple oral doses, and that iloprost does not affect the pharmacokinetics of co-administered t-PA.
In animal studies, the vasodilatory effect of iloprost was reduced following pretreatment with glucocorticoids, although its inhibitory activity on platelet aggregation remained unchanged. The clinical significance of this observation is not yet known.
Although no clinical studies have been conducted, in vitro studies evaluating the potential inhibitory effect of iloprost on cytochrome P450 enzyme activity have shown that clinically relevant inhibition of drug metabolism by iloprost via these enzymes is unlikely.

Dosage and Administration
Endoprost must be administered, after dilution, as an intravenous infusion over 6 hours daily, into a peripheral vein or via a central venous catheter.
The ready-to-use infusion solution must be prepared daily to ensure sterility.

• Dilution Instructions: The contents of the vial and the diluent must be mixed thoroughly.

Dilution of Endoprost for use with an infusion pump
For this purpose, the contents of one 1 ml vial of ENDOPROST (i.e., 100 mcg) should be diluted with 500 ml of sterile physiological saline solution or 5% glucose solution.
Dilution of Endoprost for use with a syringe pump
In this case, the contents of one 1 ml vial of ENDOPROST (i.e., 100 mcg) should be diluted with 50 ml of sterile physiological saline solution or 5% glucose solution.
The dose should be adjusted according to individual patient tolerance within an infusion rate range of 0.5 to 2 ng iloprost/kg/min over 6 hours daily.
The infusion solution must be prepared daily to ensure sterility.
The contents of the vial and the diluent must be mixed thoroughly.
Blood pressure and heart rate must be monitored at the start of infusion and after each dose increase.
During the first 2–3 days of treatment, the individually maximally tolerated dose should be determined. Infusion should begin at a rate of 0.5 ng/kg/min for 30 minutes.
Dose increases of 0.5 ng/kg/min may then be made every 30 minutes up to a maximum of 2.0 ng/kg/min. The exact infusion rate must be calculated based on body weight to achieve an infusion within the range of 0.5 to 2.0 ng/kg/min (see tables below for use with infusion pump or syringe pump).
If adverse effects such as headache, nausea, or hypotension occur, the infusion rate should be reduced until the tolerated dose is reached. If adverse effects are severe, the infusion should be suspended.
After determining the individual dose during the first 2–3 days, this dose should be maintained throughout the treatment cycle (usually for 4 weeks).
Two different dilutions of the vial contents are available depending on the infusion technique used. One of these dilutions is 10 times less concentrated than the other (0.2 mcg/ml vs. 2 mcg/ml) and can only be administered using an infusion pump (e.g., Infusomat). Conversely, the more concentrated solution is administered using a syringe pump (e.g., Perfusor).

Infusion Rates (mL/hour) for Different Doses Using an Infusion Pump
In general, the ready-to-use infusion solution is administered intravenously using an infusion pump (e.g., Infusomat). For dilution instructions for use with an infusion pump, see above.
With a concentration of ENDOPROST of 0.2 mcg/mL, the required infusion rate should be determined according to the table below to achieve a dose within the range of 0.5 to 2.0 ng/kg/min.
The following table can be used to calculate the infusion rate corresponding to the patient's body weight and required dose. Identify the patient’s actual body weight, then adjust the infusion rate to the desired dose in ng/kg/min.

| Body Weight (kg) | Dose (ng/kg/min) | | | | |----------------------|----------------------|---------|---------|---------|---------| | | 0.5 | 1.0 | 1.5 | 2.0 | | Infusion Rate (mL/hour) | | | | | | 40 | 6.0 | 12 | 18.0 | 24 | | 50 | 7.5 | 15 | 22.5 | 30 | | 60 | 9.0 | 18 | 27.0 | 36 | | 70 | 10.5 | 21 | 31.5 | 42 | | 80 | 12.0 | 24 | 36.0 | 48 | | 90 | 13.5 | 27 | 40.5 | 54 | | 100 | 15.0 | 30 | 45.0 | 60 | | 110 | 16.5 | 33 | 49.5 | 66 |

Infusion Rates (mL/hour) for Different Doses for Use with a Syringe Pump
A syringe pump with a 50 mL syringe (e.g., Perfusor) may also be used. For dilution instructions for use with a syringe pump, see above.
With a concentration of ENDOPROST of 2 mcg/mL, the required infusion rate should be determined according to the table below to achieve a dose within the range of 0.5 to 2.0 ng/kg/min.
The following table can be used to calculate the infusion rate corresponding to the patient's body weight and required dose. Identify the patient’s actual body weight, then adjust the infusion rate to the desired dose in ng/kg/min.

| Body Weight (kg) | Dose (ng/kg/min) | | | | |----------------------|----------------------|---------|---------|---------|---------| | | 0.5 | 1.0 | 1.5 | 2.0 | | Infusion Rate (mL/hour) | | | | | | 40 | 0.60 | 1.2 | 1.80 | 2.4 | | 50 | 0.75 | 1.5 | 2.25 | 3.0 | | 60 | 0.90 | 1.8 | 2.70 | 3.6 | | 70 | 1.05 | 2.1 | 3.15 | 4.2 | | 80 | 1.20 | 2.4 | 3.60 | 4.8 | | 90 | 1.35 | 2.7 | 4.05 | 5.4 | | 100 | 1.50 | 3.0 | 4.50 | 6.0 | | 110 | 1.65 | 3.3 | 4.95 | 6.6 |

The duration of treatment should not exceed 4 weeks.
The safety and efficacy of treatment longer than 4 weeks or of repeated treatment cycles have not been established.
Shorter treatment periods (3 to 5 days) are often sufficient in Raynaud's phenomenon to achieve improvement lasting several weeks.
Continuous infusion over several days is not recommended due to the potential development of tachyphylaxis regarding platelet effects and the possibility of rebound platelet hyperaggregability at the end of treatment, although no clinical complications associated with these phenomena have ever been observed.

• Patients with Renal or Hepatic Impairment
  It should be considered that iloprost elimination is reduced in patients with renal impairment undergoing dialysis and in those with hepatic cirrhosis. In these patients, dose reduction is necessary (e.g., half the recommended dose).

There is no experience with the use of ENDOPROST in children.