Active ingredients: Iloprost
Endoprost 0.05 mg / 0.5 ml concentrate for solution for infusion
Indications Why is Endoprost used? What is it for?
Endoprost contains the active substance iloprost, a substance that belongs to a group of medicines called 'antiplatelet agents'. It is a synthetic analogue of a substance normally present in the body (prostacyclin) and exerts numerous actions including inhibiting blood clotting when there is a risk of thrombosis and embolism in the veins or arteries, a dilation of small blood vessels and a stimulus to the physiological mechanisms that dissolve blood clots (thrombi).
Endoprost is used for:
- the treatment of thromboangiitis obliterans (Bürger's disease) in advanced stage with critical limb ischemia when revascularization is not indicated. Thrombangiitis obliterans is an inflammatory disease of the small and medium-sized arteries and veins of the extremities of the body (hands and feet).
- the treatment of Raynaud's phenomenon (extreme contraction of the blood vessels in the fingers and toes) secondary to scleroderma (chronic autoimmune disease that causes hardening and thickening of the skin).
- the treatment of severe chronic arterial ischemia (sharp reduction in blood flow) of the lower limbs, in patients at risk of amputation and when surgery or angioplasty is not indicated (surgery that allows a narrowing of a blood vessel to be dilated).
Contraindications When Endoprost should not be used
You must not be given Endoprost
- if you are allergic to iloprost or any of the other ingredients of this medicine;
- if you are pregnant;
- if you are breast-feeding;
- if you are at risk of bleeding, for example in the case of an active peptic ulcer, trauma, bleeding inside the skull;
- if there is a suspicion that you have pulmonary congestion.
- if you have a heart problem, such as:
- if you suffer from poor blood flow to the heart muscle, such as severe coronary heart disease or unstable angina (chest pain may be the symptom);
- if you have suffered a heart attack (myocardial infarction) in the past six months;
- if you have a weak heart (acute or chronic congestive heart failure in NYHA classes II to IV);
- if you suffer from heart rhythm disturbances (arrhythmias) that are severe or relevant to prognosis.
Precautions for use What you need to know before taking Endoprost
Talk to your doctor or nurse before you are given Endoprost. Take special care if any of the following apply to you:
- if you need an "urgent amputation (for example in case of infected gangrene);
- if you smoke. It is strongly recommended that you do not smoke while taking Endoprost.
- if you have low blood pressure; in this case you must pay particular attention to avoid further drops in blood pressure.
- if you have serious heart disease. In this case it must be carefully monitored by the doctor.
- if you suffer from dizziness when standing up (orthostatic hypotension). It has to get up slowly in order to help the body get used to its new position.
- if you have had a severe stroke (transient ischemic attack, cerebro-vascular accidents) in the past 3 months (see You must not be given Endoprost); the doctor will carefully evaluate the risk-benefit ratio.
Infusing the concentrated solution outside the vessels may cause local changes at the injection site.
Avoid oral administration and contact with skin and mucous membranes. In case of skin contact, Endoprost may cause persistent redness of the skin (erythema), without pain. If the medicine comes into contact with the skin, wash the affected area immediately with plenty of water or saline.
For those who carry out sports activities
The use of medicines containing ethyl alcohol can determine positive doping tests in relation to the alcohol concentration limits indicated by some sports federations.
Children and adolescents
Currently, only sporadic data are available on use in children and adolescents.
Interactions Which drugs or foods can modify the effect of Endoprost
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines, including those you buy without a prescription or dietary supplements.
Endoprost can affect the way other medicines work. Conversely, some medicines can affect the way Endoprost works.
In particular, talk to your doctor if you are taking:
- medicines used to treat high blood pressure (antihypertensives) or heart disease (such as beta blockers, calcium channel blockers, vasodilators and ACE inhibitors). Your blood pressure may drop further, so your doctor can change the dose of Endoprost.
- blood-thinning medicines (anticoagulants and antithrombotics) that prevent blood clotting such as heparin, coumarin-like anticoagulants, acetylsalicylic acid or other non-steroidal anti-inflammatory drugs, phosphodiesterase inhibitors and nitro-vasodilators, for example molsidomin. It can increase the risk of bleeding. If bleeding occurs, treatment with Endoprost should be stopped.
Endoprost with alcohol
As with all medicines, concomitant alcohol intake should be avoided.
Warnings It is important to know that:
Fertility, pregnancy and breastfeeding
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before being given this medicine.
Pregnancy
Edoprost must not be given to you if you are pregnant (see "You must not be given Endoprost").
There are no adequate data on the use of this medicinal product in pregnant women. As the potential risk of the therapeutic use of Endoprost in pregnancy is unknown, if you are of childbearing age use adequate contraceptive methods during treatment.
Feeding time
It is not known whether the medicine passes into breast milk. You must not be given Endoprost if you are breastfeeding (see "You must not be given Endoprost").
Driving and using machines
Not relevant.
Endoprost contains sodium and ethanol
This medicinal product contains less than 1 mmol (23 mg) sodium per dose, ie it is essentially "sodium-free". This medicine contains small amounts of ethanol (alcohol) less than 100 mg per dose.
Dosage and method of use How to use Endoprost: Posology
Always use this medicine exactly as your doctor or pharmacist has told you. If in doubt, consult your doctor or pharmacist.
Your doctor or nurse will administer Endoprost to you in suitably equipped hospital and outpatient clinics, under close supervision.
If you are a woman of childbearing potential, the possibility of an ongoing pregnancy must be ruled out prior to treatment.
The recommended dose is: according to medical prescription.
The medicine is given through a vein as a daily infusion for 6 hours. The duration of treatment is 4 weeks.
Shorter treatment periods (3 to 5 days) are often sufficient in Raynaud's phenomenon to achieve improvement over several weeks.
Your blood pressure and heart rate will be measured at the start of the infusion and after each dose increase.
Use in patients with renal insufficiency, dialysis or liver cirrhosis: Dose adjustment (e.g. half the recommended dose) is required.
If you forget to receive Endoprost
You should not receive a double dose to make up for a forgotten dose.
If you have any further questions on the use of this medicine, ask your doctor or nurse.
Overdose What to do if you have taken too much Endoprost
As Endoprost will be given to you by a doctor or nurse, it is therefore unlikely that you will receive too much medicine.
However, if you think that you have been given too much Endoprost, contact your doctor or nurse immediately. Symptoms that may occur are: drop in blood pressure (hypotensive reaction), headache, redness, nausea, vomiting and diarrhea.Increased blood pressure, slow (bradycardia) or rapid (tachycardia) heartbeat, pain in limbs or back, sudden paleness, sweating and stomach pain are also possible.
A specific antidote is not known.
In the event of overdose, it is recommended that Endoprost be discontinued, followed by monitoring and treatment of symptoms.
Side Effects What are the side effects of Endoprost
Like all medicines, this medicine can cause side effects, although not everybody gets them.
The most frequently observed adverse reactions are headache, skin redness (flushing), nausea, vomiting and excessive sweating (hyperhidrosis). These undesirable effects are likely to occur during dose adjustment at the start of treatment to find the best tolerable dose for each patient. However, all these side effects disappear quickly by reducing the dose.
Overall, the most serious adverse reactions are stroke (cerebrovascular accident), heart attack (myocardial infarction), blood clots in the lungs (pulmonary embolism), cardiac arrest, seizures, low blood pressure (hypotension), rapid heart beat ( tachycardia), asthma, chest pain (angina pectoris), difficulty in breathing (dyspnoea) and accumulation of fluid in the lungs (pulmonary edema).
Another group of undesirable effects relates to local reactions at the infusion site. For example, there may be redness and pain at the infusion site or skin vasodilation which can lead to superficial striated redness along the course of the vein.
Very common (may affect more than 1 in 10 patients)
- headache
- redness
- nausea and vomit,
- excessive sweating (hyperhidrosis)
Common (may affect up to 1 in 10 patients)
- loss of appetite
- apathy (lack of emotion, motivation, or enthusiasm)
- confusional state
- dizziness and vertigo,
- impaired sensation (paraesthesia)
- throbbing sensation,
- increased sensitivity of the skin (hyperesthesia)
- burning sensation
- restlessness
- agitation
- sedation
- drowsiness
- rapid heartbeat (tachycardia *)
- slow heart rate (bradycardia)
- chest pain (angina pectoris *)
- low blood pressure (hypotension *)
- increased blood pressure (hypertension)
- difficulty in breathing (dyspnoea *)
- diarrhea,
- abdominal discomfort / abdominal pain
- jaw pain, jaw twitching (trismus)
- muscle aches (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)
- allergic-type excessive sensitivity (hypersensitivity)
- anxiety, depression, hallucinations
- seizures *, fainting or loss of consciousness for a short period of time (syncope), tremor, one-sided headache (migraine)
- blurred vision, eye irritation, eye pain
- heart attack (myocardial infarction *), cardiac arrest *, irregular heart rhythm (arrhythmia or extrasystole)
- stroke (cerebrovascular accident *) or reduced blood flow to the brain (cerebral ischaemia),
- blood clots in the lungs (pulmonary embolism *), clots in the blood vessels of the legs (deep vein thrombosis)
- asthma *, accumulation of fluid in the lungs (pulmonary edema *)
- diarrhea with blood in the stool (haemorrhagic diarrhea), rectal bleeding, indigestion (dyspepsia), rectal tenesmus (painful spasm of the anus accompanied by a feeling of urgent need to defecate), constipation (constipation)
- belching, difficulty swallowing (dysphagia), dry mouth
- taste disturbance (dysgeusia)
- yellowing of the skin, mucous membranes and whites of the eyes due to liver disorders (jaundice)
- itch
- muscle cramps (tetany), muscle spasms, increased muscle tension (hypertonia)
- kidney pain, painful urination, abnormal urine, difficulty passing urine (dysuria), urinary tract disorder
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 can cause chest pain due to angina pectoris, especially in patients who suffer from poor blood flow to the heart muscle (coronary artery disease).
The risk of bleeding is higher in patients who are given concomitantly blood-thinning medicines (platelet aggregation inhibitors, heparin or coumarin-like anticoagulants) (see "Other medicines and Endoprost").
Reporting of side effects
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system at www.agenziafarmaco.it/ it / responsible. By reporting side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the carton after "EXP". The expiry date refers to the last day of that month.
Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
Other Information
What Endoprost contains
The active ingredient is iloprost. Each 0.5 ml vial contains 0.067 mg (67 micrograms) of iloprost trometamol equivalent to 0.050 mg (50 micrograms) of iloprost.
The other ingredients are: trometamol, ethanol 96% (v / v), sodium chloride, hydrochloric acid (1N), water for injections.
What Endoprost looks like and contents of the pack
Endoprost comes in the form of a solution for infusion.
The pack contains 1 ampoule of 0.5 ml, 0.050 mg concentrate for solution for infusion.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
ENDOPROST 0.05 MG / 0.5 ML CONCENTRATE FOR SOLUTION FOR INFUSION
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
0.5 ml of aqueous solution contains 67 mcg of iloprost trometamol (equal to 50 mcg of iloprost).
Excipients with known effects: ethanol, 96% (v / v), sodium chloride.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Concentrate for solution for infusion.
Clear, free of particles.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Treatment of thromboangiitis obliterans (Bürger's disease) in advanced stage with critical limb ischemia when revascularization is not indicated.
Treatment of Raynaud's phenomenon secondary to scleroderma.
Treatment of severe chronic arterial ischaemia of the lower limbs in patients at risk of amputation and when surgery or angioplasty is not indicated.
04.2 Posology and method of administration
ENDOPROST must be used under strict medical supervision in adequately equipped hospitals and clinics.
The possibility of an existing pregnancy must be ruled out before treatment of women of childbearing age.
ENDOPROST should be administered, after dilution, as described in section 6.6 "Special precautions for disposal and handling", as an intravenous infusion over 6 hours per day, into a peripheral vein or via a catheter into a central vein.
The dose should be adjusted based on the individual patient's tolerability over an infusion range of 0.5 to 2 ng iloprost / kg / min for 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 should be measured at the start of the infusion and after each dose increase.
The maximum individually tolerated dose should be sought in the first 2-3 days of treatment. For this purpose, the infusion is started at a rate of 0.5 ng / kg / min for 30 min.
Increases of further 0.5 ng / kg / min are therefore possible every 30 minutes up to a maximum of 2.0 ng / kg / min. The exact infusion rate must be calculated on the basis of body weight to perform an "infusion" within the range of 0.5 to 2.0 ng / kg / min (see tables below for use with infusion pump or for " use with syringe pump).
In the event of the onset of side effects such as headache, nausea or drop in blood pressure, the rate of infusion should be reduced until the tolerated dose is reached. If the side effects are severe, the infusion must be stopped.
After establishing the individual dose in the first 2-3 days, this will be maintained for the duration of the therapeutic cycle (usually for 4 weeks).
There are two different dilutions of the contents of a vial depending on the infusion technique used. One of these dilutions is 10 times less concentrated than the other (0.2 mcg / ml versus 2 mcg / ml) and can only be administered with an infusion pump (eg Infusomat). Conversely, the more concentrated solution is administered with a syringe pump (eg Infonde or Perfusor), for instructions for use and handling see section 6.6 "Special precautions for disposal and handling".
Infusion rate (ml / hour) for different doses using an infusion pump.
In general, the ready-to-use solution for infusion is infused intravenously via an infusion pump (eg Infusomat). For instructions for dilution for use with the infusion pump see section 6.6 " Special precautions for disposal and handling ".
In the case of an ENDOPROST concentration of 0.2 mcg / ml, the required infusion rate must be determined according to the scheme below to obtain a dose in the range between 0.5 and 2.0 ng / kg / min.
The following table can be used to calculate the infusion rate corresponding to the patient's individual weight and the dose to be infused. Identify the patient's actual weight, then adjust the infusion rate to the dose in ng / kg / min.
Infusion rates (ml / hour) for different doses for use with syringe pump
A syringe pump with graduated syringe up to 25.5 ml (eg Infuse) or also a syringe pump with 50 ml syringe (eg Perfusor) can be used. For instructions for dilution for use with a syringe pump see section 6.6 "Special precautions for disposal and handling".
In the case of an ENDOPROST concentration of 2 mcg / ml, the required infusion rate must be determined according to the scheme below to obtain a dose in the range between 0.5 and 2.0 ng / kg / min.
The following table can be used to calculate the infusion rate corresponding to the patient's individual weight and the dose to be infused. Identify the actual weight of the patient, then adjust the infusion rate to the dose in ng / kg / min.
The duration of treatment should not last beyond 4 weeks.
The safety and efficacy of treatment lasting more than 4 weeks or of repeated treatment courses has not been established.
Shorter treatment periods (3 to 5 days) are often sufficient in Raynaud's phenomenon to achieve improvement over several weeks.
Continuous infusion for several days is not recommended due to the possible development of tachyphylaxis in relation to the effect on platelets and the possibility of a "rebound" platelet hyperaggregability at the end of treatment, although no clinical complications associated with these have never been observed. phenomena.
• Patients with renal or hepatic insufficiency
It should be taken into account that in patients with renal insufficiency undergoing dialysis and in those with cirrhosis of the liver, the elimination of iloprost is reduced. In these patients a dose reduction (eg half the recommended dose) is required.
There is no experience with the use of ENDOPROST in children (see section 4.4 "Special warnings and precautions for use").
04.3 Contraindications
- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
- Pregnancy;
- Feeding time;
- Conditions in which the effects of iloprost on platelets may increase the risk of bleeding (eg active peptic ulcer, trauma, intracranial haemorrhage);
- Severe coronary heart disease or unstable angina;
- Myocardial infarction within the previous six months;
- Acute or chronic congestive heart failure (NYHA II - IV);
- Severe or significant arrhythmias for prognosis;
- Suspicion of pulmonary congestion;
04.4 Special warnings and appropriate precautions for use
Special warnings
In patients in whom amputation is urgently required (eg in infected gangrene) the surgery should not be postponed.
Patients should be strongly advised not to smoke.
Particular attention should be paid to hypotensive patients in order to avoid further drops in blood pressure; patients with major heart disease must be carefully monitored.
The possibility of orthostatic hypotension should be considered in cases where the patient changes from the supine to the standing position at the end of the administration.
A "careful risk-benefit assessment should be made for patients who have had a cerebrovascular event (eg transient ischemic attack, stroke) in the past 3 months (see 4.3" Contraindications ": risk of haemorrhage, eg intracranial haemorrhage ).
Precautions for use
Currently, only sporadic data are available on use in children and adolescents.
The extravascular infusion of the concentrated solution may cause local changes at the injection site.
Avoid oral administration and contact with mucous membranes. In case of skin contact, iloprost may cause long lasting painless erythema. Therefore, appropriate precautions must be taken to prevent the product from coming into contact with the skin. In the event that this occurs, the affected area must be washed immediately with plenty of water or physiological solution.
Important information about some of the excipients
This medicinal product contains less than 1 mmol (23 mg) sodium per dose, ie essentially "sodium-free".
This medicine contains small amounts of ethanol (alcohol) less than 100 mg per dose.
04.5 Interactions with other medicinal products and other forms of interaction
Iloprost may increase the antihypertensive activity of beta-blockers, calcium channel blockers, vasodilators and ACE inhibitors. If significant hypotension occurs, this can be corrected by reducing the dose of iloprost.
Since iloprost inhibits platelet function, concomitant use of anticoagulants (such as heparin, coumarin-like anticoagulants), or other inhibitors of platelet aggregation (such as acetylsalicylic acid, other non-steroidal anti-inflammatory drugs, phosphodiesterase inhibitors and nitro-vasodilators eg. molsidomina), may increase the risk of bleeding. In this case, iloprost administration should be discontinued.
In healthy volunteers, oral pretreatment with acetylsalicylic acid up to 300 mg per day for a period of 8 days has no impact on iloprost clearance (mL / min / kg).
In an animal study, iloprost was found to lead to a reduction in steady-state plasma t-PA concentration.
The results of studies in patients demonstrate that iloprost infusions have no effect on the pharmacokinetics of digoxin in patients treated with 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, although the inhibitory activity on platelet aggregation remained unchanged. The significance of this observation in clinical use is not yet known.
Although no clinical studies have been performed, in vitro studies evaluating the inhibitory potential of iloprost on the activity of cytochrome P450 enzymes have shown that no relevant inhibition by iloprost on drug metabolism mediated by iloprost is to be expected. these enzymes.
04.6 Pregnancy and breastfeeding
ENDOPROST must not be administered during pregnancy or lactation (see section 4.3 "Contraindications").
• Pregnancy
There are no adequate data on the use of iloprost in pregnant women.
Preclinical studies showed fetotoxicity in rats but not in rabbits and monkeys (see section 5.3 "Preclinical safety data").
Since the potential risk of the therapeutic use of iloprost in pregnancy is unknown, women of childbearing potential should use effective contraceptive methods during treatment.
• Feeding time
It is not known whether iloprost passes into breast milk. Iloprost should not be given to women who are breastfeeding.
04.7 Effects on ability to drive and use machines
Not relevant.
04.8 Undesirable effects
Overall safety profile
The overall safety profile of Endoprost is based on data from post-registration observation and data from the analysis of clinical studies.
The crude incidences are calculated on a database that includes a total of 3,325 patients who received iloprost either in controlled or uncontrolled clinical trials or in a compassionate use program related to patients in general elderly and with multiple associated diseases and presenting with arterial ischaemia chronic disease of the lower limbs in advanced stages III and IV and, again, in patients with thromboangiitis obliterans, according to what is reported in detail in table 1.
The most frequently observed adverse drug reactions (≥10%) in patients receiving iloprost in clinical trials are headache, skin flushing (flushing), nausea, vomiting and hyperhidrosis.
These side effects are likely to occur during dose titration at the start of treatment to find the best tolerable dose for each patient. However, all of these side effects disappear quickly by reducing the dose.
Overall, the most serious adverse drug reactions in patients receiving iloprost are cerebrovascular accident, myocardial infarction, pulmonary embolism, cardiac arrest, convulsion, hypotension, tachycardia, asthma, angina pectoris, dyspnoea and pulmonary edema.
Another group of undesirable effects relates to local reactions at the infusion site. For example, there may be redness and pain at the infusion site or skin vasodilation which can lead to the emergence of superficial striated erythema along the course of the seat vein. d "infusion.
Table of adverse reactions
Adverse drug reactions observed with Endoprost are shown in the table below by system organ class (MedDRA 14.1). The more appropriate MedDRA term is used to describe a certain reaction with its symptoms and related conditions. Adverse drug reactions from clinical trials are classified according to their frequency, frequency groups are defined according to the following conventions: very common (≥1 / 10), common (≥1 / 100,
Table 1: Adverse Drug Reactions Reported in Clinical Studies or Post-Registration Observation in Patients Treated with Endoprost
* fatal and / or life-threatening cases have been reported
Iloprost can cause angina pectoris, especially in patients with coronary heart disease.
The risk of haemorrhage is greater in patients who are administered concomitantly with platelet aggregation inhibitors, heparin or coumarin-like anticoagulants.
04.9 Overdose
• Symptoms
A hypotensive reaction can be expected as well as headache, redness, nausea, vomiting and diarrhea. An increase in blood pressure, bradycardia or tachycardia, pain in the limbs or back, sudden paleness, sweating and cramping abdominal pain is possible.
• Treatment
A specific antidote is not known.
Interruption of iloprost administration, monitoring and treatment of symptoms is recommended.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: antiplatelet agents, excluding heparin.
ATC code: B01A C.
Iloprost is a synthetic analogue of prostacyclin of which the following pharmacological activities have been observed:
• inhibition of platelet aggregation, adhesion and release reaction
• dilation of arterioles and venules
• increase in capillary density and reduction in vascular hyperpermeability caused by mediators such as serotonin or histamine at the microcirculation level
• stimulation of the endogenous fibrinolytic potential
• anti-inflammatory effects such as inhibition of the adhesion of leukocytes after an endothelial lesion or of the accumulation of leukocytes in the injured tissues and reduction of the release of tumor necrosis factor.
05.2 Pharmacokinetic properties
• Distribution
Plasma levels of iloprost reach steady-state as early as 10-20 minutes from the start of the intravenous infusion and follow a linear trend in relation to the infusion rate. At an infusion rate of 3 ng / kg / min. corresponds to a plasma level of 135 ± 24 pg / ml.
The rapid metabolism of iloprost leads to a rapid drop in its plasma concentration soon after the end of the infusion. The metabolic clearance of the substance from the plasma is approximately 20 ± 5 ml / kg / min.
The terminal phase half-life is 0.5 hours, therefore, already 2 hours after the end of the infusion, the plasma levels of the substance are reduced to less than 10% of the equilibrium concentration.
Interactions with other drugs at the level of binding with plasma proteins appear unlikely as most of iloprost is bound to plasma albumin (protein binding: 60%) and also due to the low concentration reached by the substance.
Interference of iloprost on the biotransformation of other drugs is also extremely unlikely due to both the metabolic pathways followed and the low dose administered.
•Metabolism
Iloprost is extensively metabolised mainly by beta-oxidation of the side carboxyl chain.
Unchanged substance is not eliminated.
The main metabolite is tetranoriloprost which is found in the urine in free and conjugated form in 4 diastereoisomers. Tetranoiloprost is pharmacologically inactive as demonstrated by animal experiments. In vitro studies suggest that the lung metabolite of iloprost is similar both after intravenous administration and after inhalation.
• Elimination
In subjects with normal renal and hepatic function, the elimination of iloprost following intravenous infusion is characterized in most cases by a biphasic profile with mean half-lives of 3 to 5 minutes and 15 to 30 minutes. The total clearance of iloprost is approximately 20 ml / kg / min, indicating an extrahepatic contribution to the metabolism of iloprost.
A mass balance study was conducted using 3H-iloprost in healthy subjects. Following intravenous infusion of 2 ng / kg / min for 4 hours, recovery of total radioactivity is 81%, 68% in urine and 12% in faeces. The metabolites are eliminated from plasma and urine in 2 phases, for which the half-lives were calculated, respectively of about 2 and 5 hours (plasma) and of 2 and 18 hours (urine).
• Special conditions
Renal dysfunction:
In an intravenous infusion study of iloprost, patients with end stage renal insufficiency undergoing intermittent dialysis treatment demonstrated significantly lower clearance (mean CL = 5 ± 2 ml / min / kg) than that observed in patients with renal failure not undergoing intermittent dialysis treatment (mean CL = 18 ± 2 ml / min / kg).
Hepatic dysfunction:
Since iloprost is extensively metabolised by the liver, plasma levels of the drug are affected by changes in liver function. In an intravenous study, results were collected on 8 patients with liver cirrhosis. The mean clearance of iloprost is estimated to be 10 ml / min / kg.
Age and gender:
Age and gender have no clinical relevance in iloprost pharmacokinetics.
05.3 Preclinical safety data
On the basis of studies in animals, the risk of acute toxicity phenomena in humans appears to be minimal, taking into account the total absolute dose administered during therapy and the quantity of the substance contained in the vial. It must also be considered that administration takes place only under conditions of accurate medical surveillance.
Repeated dose systemic toxicity studies (continuous intravenous infusion) have shown slight reductions in blood pressure only at doses above 14 ng / min and the appearance of serious undesirable effects (hypotension, respiratory function disorders) only at extremely high doses compared to at the therapeutic dose (two orders of magnitude higher than the therapeutic dose).
In vitro and in vivo genotoxicity studies did not demonstrate any mutagenic potential.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Trometamol;
ethanol, 96% (v / v);
sodium chloride;
hydrochloric acid, 1N;
water for injections.
06.2 Incompatibility
To avoid the possibility of interactions, no other drugs should be added to the ready-to-use solution for infusion.
06.3 Period of validity
4 years.
06.4 Special precautions for storage
This medicine does not require any special storage conditions.
06.5 Nature of the immediate packaging and contents of the package
1 ml colorless ampoule, class I glass, containing 0.5 ml of concentrate for solution for infusion.
• Packaging:
1 ampoule containing 0.5 ml of concentrate for solution for infusion
06.6 Instructions for use and handling
• Instructions for Use
ENDOPROST should only be used after dilution.
The ready-to-use infusion solution must be prepared daily to ensure sterility.
• Instructions for dilution
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 content of a 0.5 ml vial of ENDOPROST (i.e. 50 mcg) is diluted with 250 ml of sterile physiological saline or 5% glucose solution.
Dilution of ENDOPROST for use with a syringe pump
In this case, the content of a 0.5 ml vial of ENDOPROST (i.e. 50 mcg) is diluted with 25 ml of sterile physiological saline or 5% glucose solution.
07.0 MARKETING AUTHORIZATION HOLDER
ITALFARMACO S.p.A. - Viale Fulvio Testi 330 -20126 Milan
Licensed by Bayer Pharma AG - Berlin (Germany)
08.0 MARKETING AUTHORIZATION NUMBER
1 ampoule of 0.5 ml / 0.05 mg AIC n. 027184023
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
31.10.1994/19.08.2007
10.0 DATE OF REVISION OF THE TEXT
November 2013
