Aducil - instructions for use, doses, side effects, contraindications

Active substanceCilostazolumCilostazolum

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Aducil®

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SEM Pharmaceuticals Limited Cyprus

Pletasol®

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ESCO PHARMA, LLC

Dosage form: & nbsppills

Composition:

1 tablet of 50 mg contains:

Active substance: 50 mg of cilostazol.

Excipients: corn starch, cellulose microcrystalline 101, carmellose calcium, hypromellose, microcrystalline cellulose 12, magnesium stearate.

1 tablet of 100 mg contains:

Active substance: 100 mg of cilostazol.

Excipients: corn starch, cellulose microcrystalline 101, carmellose calcium, hypromellose, magnesium stearate.

Description:

Round, flat tablets with chamfer, white or almost white color, with engraving, with an inscription for tablets with a dosage of 50 mg: "50", for tablets with a dosage of 100 mg: "100".

Pharmacotherapeutic group:Antiaggregant agent

ATX: & nbsp

B.01.A.C.23 Cilostazolum

Pharmacodynamics:

The main mechanism of pharmacological action of cilostazol is the inhibition of phosphodiesterase type 3 (PTE-3) and, consequently, an increase in the intracellular content of cyclic adenosine monophosphate (cAMP) in various organs and tissues.

In experimental and small clinical studies, it has been established that cilostazol has a vasodilating effect. Cilostazolum inhibits the proliferation of smooth muscle cells in humans and rats under conditions in vitro.

In experimental and clinical studies in conditions in vivo and ex vivo determined that cilostazol increases the content of cAMP in platelets and causes a reversible antiaggregant effect. Besides, cilostazol blocks the release of human platelets platelet growth factor and platelet factor 4 (PF-4). Additional potentially useful effects of cilostazol, found in experimental and clinical studies, were a decrease in serum triglyceride concentration and an increase in cholesterol concentration in high-density lipoprotein (HDL). In a clinical study, taking cilostazol 100 mg twice daily for 12 weeks compared with placebo reduced blood triglyceride levels by an average of 0.33 mmol / L (by 15%) and increased the HDL cholesterol in the blood on average by 0.10 mmol / L (10%).

Cilostazol has a positive inotropic effect. In experimental studies cilostazol had a species-specific damaging effect on the cardiovascular system.

The efficacy of cilostazol in patients with intermittent claudication was confirmed in 9 placebo-controlled clinical trials.It has been established that cilostazol therapy at a dose of 100 mg twice a day for 24 weeks approximately doubles the maximum distance traveled (from 60.4 m to 129.1 m, the average absolute increase in the maximum distance traveled is 42 meters) and the distance traveled to the appearance of pain (from 47.3 m to 93.6 m). The effectiveness of the drug in patients with diabetes mellitus was lower than in persons without a violation of carbohydrate metabolism. In a prospective, double-blind clinical trial, it was found that cilostazol does not increase the mortality of patients with intermittent claudication.

Pharmacokinetics:

Absorption

In patients with occlusive diseases of peripheral arteries with a regular intake of cilostazol at a dose of 100 mg 2 times a day, the equilibrium concentration of the drug in the blood is reached after 4 days.

The maximum concentration (C_m_Oh) of cilostazol and its major metabolites increases less than the proportionally increased dose. In this case, the area under the "concentration-time" curve (AUC) Cilostazol and its major metabolites increase approximately in proportion to the increase in dose.

Distribution and Metabolism

Cilostazol is 95-98% bound to blood proteins, mainly albumin. Cilostazolum metabolized in the liver mainly by isoenzyme CYP3A4, to a lesser extent - isoenzyme CYP2C19, and to an even lesser extent - isoenzyme CYP1A2. Cilostazol is not an inducer of hepatic microsomal peroxidation enzymes.

The plasma concentration of dehydrocystostazole and 4'-trans-hydroxycylostasol (estimated on the basis of AUC) is approximately 41% and approximately 12% of the concentration of unchanged cilostazol, respectively. Dehydrocystolostazol and 4'-trans-hydroxycilostazol bind to blood proteins by 97.4% and 66%, respectively.

Excretion

Cilostazol is excreted from the body mainly by the kidneys (74%), the remaining drug is excreted through the intestine. Unchanged in urine cilostazol practically not determined. Less than 2% of the accepted dose of the drug is excreted by the kidneys in the form of dehydrocylostazole. Approximately 30% of the accepted dose is excreted by the kidneys in the form of 4'-trans-hydroxycylostasol. The remaining drug is excreted in the form of various metabolites, each of which is no more than 5% of the dose.

The half-life of cilostazol is 10.5 hours. The two main metabolites, dehydroxylostasol and 4'-trans-hydroxycylostazole, have similar half-lives.

Special patient groups

In studies involving healthy volunteers aged 50-80 years, it has been established that age and sex do not significantly affect the pharmacokinetics of cilostazol.

Renal insufficiency

It was found that in patients with severe renal failure, the free fraction of cilostazol is 27% higher, and the C_m_Oh and AUC unchanged cilostazol, respectively, by 29% and 39% lower than in individuals with normal renal function.

Indicators C_m_Oh and AUC dehydrocylostazole in patients with severe renal failure, respectively, 41% and 47% lower than patients with normal renal function. At the same time, the C_m_Oh and AUC 4'-trans-hydroxycylostasol (the main excreted by the kidney metabolite) in patients with severe renal insufficiency, respectively, increased by 173% and 209% compared with patients without renal dysfunction. The use of cilostazol is contraindicated in patients with severe renal insufficiency (creatinine clearance ≤25 ml / min).

Liver failure

In patients with moderate hepatic impairment, C_m_Oh in blood plasma and AUC increased by 25 and 10%, respectively, compared with healthy people. In patients with moderate renal failure, peak plasma concentrations and AUC increased by 50 and 16%, respectively, compared with healthy people. Data on the use of cilostazol in patients with moderate and severe hepatic insufficiency are absent. Because the cilostazol is largely metabolized by hepatic enzymes of microsomal oxidation, the use is contraindicated in patients with moderate or severe hepatic insufficiency.

Indications:

Symptomatic treatment of intermittent claudication.

Cilostazol is used to increase the maximum distance and distance traveled without pain, in patients with intermittent claudication, who have no pain at rest and there are no signs of necrosis of peripheral tissues (chronic ischemia of the lower extremities of the 2nd degree according to Fontaine's classification).

Cilostazol is intended for use as second-line therapy in patients with intermittent claudication, in whom lifestyle changes (including cessation and [under supervision specialist] physical rehabilitation programs) and other appropriate interventions were not sufficient to reduce the symptoms of intermittent claudication.

Contraindications:

- Hypersensitivity to cilostazol or any other component of the drug;

- Severe renal failure (creatinine clearance ≤ 25 mL / min);

- Moderate or severe hepatic impairment;

- Chronic heart failure;

- Predisposition to bleeding (for example, peptic ulcer of the stomach or duodenum in the acute stage, recently (during the last 6 months), a hemorrhagic stroke, proliferative diabetic retinopathy, poorly controlled arterial hypertension);

- Ventricular tachycardia, ventricular fibrillation or polytopic ventricular extrasystole in history (regardless of the presence or absence of adequate antiarrhythmic therapy);

- Extended interval QT on the ECG;

- Severe tachyarrhythmia in the anamnesis;

- Unstable angina or myocardial infarction during the last 6 months;

- Invasive intervention on the coronary arteries during the last 6 months;

- Simultaneous administration of two or more antiplatelet agents or anticoagulant drugs (eg, acetylsalicylic acid, clopidogrel, heparin, warfarin, acenocoumarol, dabigatran, rivaroxaban or apixaban);

- Simultaneous application of powerful inhibitors CYP3A4 or CYP2C19 (eg, cimetidine, diltiazem, erythromycin, ketoconazole, lansoprazole, omeprazole, and HIV-1 protease inhibitors);

- Pregnancy;

- The period of breastfeeding;

- Age younger than 18 years (safety and efficacy not studied).

Carefully:

- Hepatic insufficiency of mild severity;

- Chronic ischemic heart disease (in particular, stable angina of stress);

- Atrial or ventricular extrasystole, atrial fibrillation and flutter;

- Diabetes;

- Simultaneous use of drugs that lower blood pressure;

- Simultaneous use of drugs that reduce blood coagulability;

- Simultaneous application of substrates CYP3A4 or CYP2C19 (e.g., cisapride, midazolam, nifedipine, verapamil);

- Elderly age.

Pregnancy and lactation:

Pregnancy

There are no data on the use of cilostazol in pregnant women.

In experimental animal studies, it has been established that Cilostazol has reproductive toxicity. Application Cilostazolum during pregnancy is contraindicated.

Breastfeeding period

In experimental animal studies, it has been established that Cilostazol penetrates into breast milk. It is not known whether the Cilostazol in human breast milk. In connection with possible adverse effects on the newborn, the use of Cilostazol in the period of breastfeeding is contraindicated.

Fertility

In experimental studies it was established that cilostazol not had an adverse effect on the fertility of laboratory animals.

Dosing and Administration:

The recommended dose of cilostazol is 100 mg twice daily. Should be taken cilostazol 30 minutes before meals. When taking cilostazol while eating, there is an increase in C_m_Oh in the blood plasma, which can be associated with an increase in the number of adverse events. Therapy with cilostazol should be started under the supervision of a physician with experience in the treatment of intermittent claudication.

The doctor should reassess the patient's condition after 3 months of treatment. If cilostazol therapy does not have an adequate effect or if there is no decrease in the symptoms of intermittent claudication, cilostazol and consider other ways of treatment.

Patients treated with cilostazol should continue to follow recommendations for lifestyle changes (quitting, physical exercises) and drug therapy (the use of lipid-lowering and antiplatelet drugs) aimed at reducing the risk of cardiovascular complications. Cilostazolum is not a substitute for this treatment.

Skipping the next dose

1. If it's less than 6 hours after missing the next dose, you should immediately take the missed dose of the drug, and then take the next dose at the usual time.

2. If more than 6 hours have passed after missing the next dose, the patient should take the next dose at the usual time (do not take a double dose).

The use of cilostazol in specific patient groups

Elderly age

Correction of the dose of cilostazol in elderly patients is not required.

Children

The safety and effectiveness of cilostazol in children under the age of 18 years have not been studied.

Renal insufficiency

In patients with creatinine clearance> 25 ml / min, a dose change is not required. Cilostazolum contraindicated for use in patients with creatinine clearance ≤ 25 ml / min.

Liver failure

In patients with mild hepatic insufficiency, a dose change is not required. There are no data on the use of cilostazol in patients with moderate and severe hepatic insufficiency. As cilostazol is largely metabolized by enzymes of microsomal oxidation of the liver, the use of the drug is contraindicated in patients with moderate and severe hepatic insufficiency.

Simultaneous administration of potent inhibitors CYP3A4 or CYP2C19

Patients receiving drugs that have a strong blocking effect on CYP3A4 (for example, some macrolides), or drugs that have a strong blocking effect on CYP2C19 (eg, omeprazole) should reduce the dose of cilostazol to 50 mg twice a day.

Side effects:

In clinical trials, the most common adverse reactions were headache (30%), diarrhea (15%), and stool disorder (15%). These unwanted reactions usually differed slightly or moderately, and sometimes their severity decreased with a lower dose of the drug.

Other side effects reported in clinical research and post-marketing use of cilostazol preparations are given below.

Undesirable reactions by frequency of occurrence have been classified as follows:

Very frequent: ≥1 / 10

Frequent: from ≥1 / 100 to <1/10

Infrequent: from ≥1 / 1,000 to <1/100

Rare: from ≥1 / 10,000 to <1 / 1,000

Very rare: <1 / 10,000

Frequency unknown: can not be determined based on available data

The adverse reactions observed in the post-marketing use of cilostazol drugs are classified as side effects effects with unknown frequency (the frequency can not be determined by based on available data).

On the part of the blood and lymphatic system	Frequent	Ecchymosis
	Infrequent	Anemia
	Rare	Increased bleeding time, thrombocytosis
	Frequency unknown	Inclination to bleeding, thrombocytopenia, granulocytopenia, agranulocytosis, leukopenia, pancytopenia, aplastic anemia
Immune system disorders	Infrequent	Allergic reactions
Disorders from the metabolism and nutrition	Frequent	Edema (peripheral edema, edema of the face), anorexia
Disorders from the metabolism and nutrition	Infrequent	Hyperglycemia, diabetes mellitus
Disorders of the psyche	Infrequent	Anxiety
Disturbances from the nervous system	Very Frequent	Headache
	Frequent	Dizziness
	Infrequent	Insomnia, sleep disturbance (unusual dreams)
	Frequency unknown	Paresis, hyperesthesia
Disturbances on the part of the organ of sight	Frequency unknown	Conjunctivitis
Hearing disorders and labyrinthine disorders	Frequency unknown	Tinnitus
Heart Disease	Frequent	Heart palpitations, tachycardia, angina pectoris, arrhythmia, ventricular extrasystole
	Infrequent	Myocardial infarction, atrial fibrillation, chronic heart failure, supraventricular tachycardia, ventricular tachycardia, syncope
	Frequency unknown	Polymorphic ventricular tachycardia of the "pirouette" type and prolongation of the QTc interval (in patients with cardiovascular diseases).
Vascular disorders	Frequent	Ocular hemorrhage, epistaxis, gastrointestinal bleeding, orthostatic hypotension
Vascular disorders	Infrequent	Hot flushes, arterial hypertension, arterial hypotension, intracranial hemorrhage, pulmonary hemorrhage, intramuscular hematomas, bleeding from the respiratory tract, subcutaneous hemorrhage
Disturbances from the respiratory system, chest and mediastinal organs	Frequent	Rhinitis, pharyngitis
	Infrequent	Shortness of breath (dyspnoea), pneumonia, cough
	Frequency unknown	Interstitial pneumonia
Disorders from the gastrointestinal tract	Very Frequent	Diarrhea, stool disorders
	Frequent	Nausea, vomiting, indigestion, flatulence, abdominal pain
	Infrequent	Gastritis
Disturbances from the liver and bile ducts	Frequency unknown	Hepatitis, deviation of liver function indicators from normal values, jaundice
Disturbances from the skin and subcutaneous tissues	Frequent	Skin rash, itchy skin
Disturbances from the skin and subcutaneous tissues	Infrequent	Eczema, skin rashes, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria
Disturbances from musculoskeletal and connective tissue	Infrequent	Myalgia
Disorders from the kidneys and urinary tract	Rare	Renal failure, impaired renal function
Disorders from the kidneys and urinary tract	Frequency unknown	Hematuria, pollakiuria
General disorders and disorders at the site of administration	Frequent	Chest pain, asthenia
	Infrequent	Chills, malaise
	Frequency unknown	Hyperthermia, pain
Laboratory and instrumental data	Frequency unknown	Increased uric acid in the blood, increased urea levels in the blood, increased levels of creatinine in the blood

Cilostazol has an increased risk of causing bleeding and this risk may be exacerbated by simultaneous use with other drugs with similar effects.

The risk of intraocular bleeding may be higher in patients with diabetes mellitus.

An increase in the frequency of diarrhea and palpitation is noted in patients older than 70 years.

Overdose:

Information on acute overdose in humans is limited. The expected symptoms are severe headache, diarrhea, tachycardia and, possibly, heart rhythm disturbances.

It is necessary to clean the stomach by inducing vomiting, or to perform gastric lavage in accordance with generally accepted recommendations.

Patient monitoring and supportive care are necessary.

Interaction:

Inhibitors of platelet aggregation

Cilostazol is an inhibitor of PDE-3 with antithrombotic activity. Its use in healthy individuals at a dose of 150 mg for 5 days did not lead to an extension of bleeding time.

Acetylsalicylic acid

Short-term (for ≤ 4 days) concurrent use of cilostazol and acetylsalicylic acid leads to an increase in blocking by 23-25% of ADP-induced platelet aggregation under conditions ex vivo compared with monotherapy with acetylsalicylic acid. There was no obvious tendency to increase hemorrhagic side effects in patients who received cilostazol and aspirin compared with patients taking placebo and an equivalent dose of acetylsalicylic acid.

Clopidogrel and other antiplatelet drugs

In a study in healthy volunteers, concurrent use of cilostazol with clopidogrel had no effect on platelet count, prothrombin time (PT), and activated partial thromboplastin time (APTT). When using clopidogrel in both monotherapy and in combination with cilostazol, the time of bleeding increased in healthy volunteers.The administration of cilostazol did not lead to an additional significant lengthening of bleeding time. Nevertheless, caution should be exercised when using concurrent use of cilostazol with any agent that inhibits aggregation thrombocytes. It is recommended to regularly monitor bleeding time. The use of cilostazol is contraindicated in patients receiving simultaneously two or more antiplatelet agents and / or anticoagulant medications.

Oral anticoagulants

In a clinical study, a single administration of cilostazol did not inhibit warfarin metabolism and did not affect blood clotting parameters (PT, APTT, bleeding time). Nevertheless, caution is advised when using concurrent use of cilostazol with any anticoagulant drug. The use of cilostazol is contraindicated in patients receiving simultaneously two or more antiplatelet agents and / or anticoagulant medications.

Inhibitors of cytochrome P-450 isoenzymes

In the liver cilostazol is mainly metabolized by the action of cytochrome P-450 enzymes, mainly CYP3A4 and CYP2C19 and, to a lesser extent, CYP1A2. It is believed that dehydrocylostazole, 4-7 times greater than cilostazol on the ability to inhibit platelet aggregation, is formed mainly with the participation of CYP3A4. 4'-trans-hydroxycilostazol, having a five-fold less pronounced ability to inhibit platelet aggregation, is formed mainly by the action of CYP2C19. Accordingly, drugs that inhibit CYP3A4 (for example, some macrolides [erythromycin, clarithromycin], azole antifungals [ketoconazole, itraconazole], protease inhibitors) and CYP2C19 (eg, proton pump inhibitors [omeprazole, esomeprazole]) increase the overall pharmacological activity of cilostazol and can enhance its undesirable effects. Accordingly, patients receiving powerful inhibitors CYP3A4 or CYP2C19, it is recommended to appoint cilostazol in a dose of 50 mg 2 times a day.

With the simultaneous administration of cilostazol with erythromycin (a potent inhibitor CYP3A4) indicators AUC cilostazol, dehydrocystolostazol and 4'-trans-hydroxycylostazole increased by 72%, 6% and 119%, respectively. Based on changes in indicators AUC It was established that the total pharmacological activity of cilostazol, when applied simultaneously with erythromycin, is increased by 34%.Based on these data, it is recommended that cilostazol in a dose of 50 mg twice daily with erythromycin or similar drugs (eg clarithromycin).

With concurrent administration of cilostazol with ketoconazole (a potent inhibitor CYP3A4) index AUC Cystic acid is increased by 117%, the index AUC dehydrocystostiazol decreases by 15%, the index AUC 4'-trans-hydroxycylostasol increases by 87%. Based on changes in indicators AUC It was found that the total pharmacological activity of cilostazol, when used concomitantly with ketoconazole, is increased by 35%. Based on these data, it is recommended to apply cilostazol in a dose of 50 mg twice a day with simultaneous administration with ketoconazole or similar medications (eg, itraconazole).

With concomitant administration of cilostazol with diltiazem (a weak inhibitor CYP3A4) indicators AUC Cilostazolum, dehydrocystolostazol and 4'-trans-hydroxycylostazol increased by 44%, 4% and 43%, respectively. Based on changes in indicators AUC It was established that the total pharmacological activity of cilostazol, when used simultaneously with diltiazem, is increased by 19%.Correction of the dose of cilostazol with simultaneous application with diltiazem is not required.

With a single admission of 100 mg of cilostazol concurrently with 240 ml of grapefruit juice (an inhibitor of the intestinal CYP3A4) there was no significant change in pharmacokinetic indices of cilostazol. Correction of the dose of cilostazol is not required. Nevertheless, the intake of grapefruit juice in a larger amount may affect the pharmacokinetics of cilostazol.

With concurrent administration of cilostazol with omeprazole (a potent inhibitor CYP2C19) indicators AUC Cilostazol and dehydrocylostazole increased by 22% and 68%, respectively, while AUC 4'-trans-hydroxycilostazole decreases by 36%. Based on changes in indicators AUC It has been established that the total pharmacological activity of cilostazol when applied simultaneously with omeprazole is increased by 47%. It is recommended to reduce the dose of cilostazol to 50 mg 2 times a day with simultaneous application with omeprazole.

Substrates of cytochrome P-450 isoenzymes

Cilostazol increases the indices AUC lovastatin (substrate CYP3A4) and its beta-hydroxyl metabolite by 70%, caution should be exercised when using cilostazol with substrates at the same time CYP3A4, having a narrow therapeutic range (such as cisapride, halofantrine, pimozide, ergot alkaloids). It is also advisable to use caution while using cilostazol with HMG-CoA reductase inhibitors (statins), metabolizing with the participation of CYP3A4 (simvastatin, atorvastatin and lovastatin).

Inductors of cytochrome P-450 isoenzymes

The effects of drugs that increase activity CYP3A4 and CYP2C19 (such as carbamazepine, phenytoin, rifampicin, preparations of St. John's wort perfumed), on the pharmacokinetics of cilostazol has not been studied. With simultaneous admission, it is theoretically possible to reduce the antiplatelet effect of cilostazol, therefore, it is necessary to regularly monitor bleeding time. In clinical studies, it has been established that smoking (an activity enhancing factor CYP1A2) reduces the concentration of cilostazol in the blood plasma by 18%.

Other medicines

Caution should be exercised when combined use of cilostazol with antihypertensive drugs, as well as any other drugs that potentially reduce blood pressure (including nitrates and phosphodiesterase-5 inhibitors), since an additive hypotensive effect is possible with the development of reflex tachycardia.An increase in heart rate and peripheral edema was noted with simultaneous use of cilostazol and other vasodilating agents, for example, dihydropyridine calcium channel blockers.

Special instructions:

Before starting treatment with cilostazol, other methods of treatment, such as surgical revascularization or conservative therapy, should be evaluated.

Due to the mechanism of pharmacological action cilostazol can cause tachycardia, palpitation, tachyarrhythmia and / or arterial hypotension. When taking cilostazol, the heart rate may increase by 5-7 beats per minute. In patients at risk (for example, in patients with stable angina) increased heart rate may trigger an attack of angina pectoris. Care must be taken to monitor the condition of such patients.

Caution should be exercised when prescribing cilostazol to patients with atrial or ventricular extrasystole, as well as patients with atrial fibrillation or atrial flutter.

It is necessary to warn patients about the need to report any case of bleeding or the appearance of "bruise" (subcutaneoushematoma) with a small bruise. In the case of development of hemorrhage in the retina of the eye, the use of cilostazol should be discontinued.

Because the cilostazol is an inhibitor of platelet aggregation, increases the risk of bleeding during surgical interventions (including small invasive procedures such as tooth extraction). At planned surgical interventions (if antiaggregant effect is undesirable) cilostazol should be canceled 5 days before surgery. There have been reports of rare or very rare cases of hematological disorders, including thrombocytopenia, leukopenia, agranulocytosis, pancytopenia, or aplastic anemia. In most cases, these disorders occurred after discontinuation of cilostazol. However, in several cases, pancytopenia and aplastic anemia led to death.

The patient should be warned about the need to report immediately to the doctor any symptoms that may be early manifestations of hematologic complications, such as high fever (pyrexia) and tonsillitis. An extensive blood test should be done if there is a suspicion of infection or if clinical symptoms of hematologic complications appear.Immediately stop taking cilostazol in case of clinical symptoms or laboratory signs of hematological complications.

Caution should be exercised when concurrent use of cilostazol with drugs that lower blood pressure (the possibility of additive antihypertensive action with the development of reflex tachycardia) as well as reducing blood clotting or inhibiting platelet aggregation.

Effect on the ability to drive transp. cf. and fur:

Cilostazol can cause dizziness. It is advisable to use caution when driving vehicles or operating machinery during the treatment period.

Form release / dosage:

Tablets of 50 mg and 100 mg.

Packaging:

For 10 tablets in PVC / PVDC / Aluminum blister.

For 3, 6 blisters together with instructions for use in a cardboard box.

Storage conditions:

Store at a temperature not exceeding 25 ° C.

Keep out of the reach of children.

Shelf life:

4 of the year.

Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-004878

Date of registration:05.06.2018

Expiration Date:05.06.2023

The owner of the registration certificate:SEM Pharmaceuticals LimitedSEM Pharmaceuticals Limited Cyprus

Manufacturer: & nbsp

PABIANICE PHARMACEUTICAL WORKS POLFA Poland

Representation: & nbspSEM Pharmaceuticals LimitedSEM Pharmaceuticals LimitedRussia

Information update date: & nbsp21.06.2018

Illustrated instructions

Instructions

Aducil® (Aducil®)