Cilostazol

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Clinical Pharmacology

Pharmacodynamics
The main mechanism of the pharmacological action of Cilostazol is inhibition of type 3 phosphodiesterase 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. Cilostazol expands mainly the femoral arteries, to a lesser extent - the vertebral, carotid and superior mesenteric arteries. The renal arteries are not sensitive to the effects of Cilostazol. Cilostazol inhibits the proliferation of human and human smooth muscle cells in vitro.
In experimental and clinical studies in in vivo and ex vivo, it has been established that Cilostazol increases the amount of cAMP in platelets and causes a reversible antiplatelet effect. Cilostazol reversibly inhibits platelet aggregation caused by various stimuli, such as: thrombin, adenosine diphosphate, collagen, arachidonic acid, adrenaline and mechanical stress (hemodynamic shock). In addition, Cilostazol blocks the release of platelet-derived human growth factor and platelet-derived factor 4 (PF-4) by human platelets.
Additional potentially beneficial effects of Cilostazol, found in experimental and clinical studies, were a decrease in the serum triglyceride level and an increase in the concentration of cholesterol in the composition of high-density lipoprotein (HDL). In a clinical trial, the administration of Cilostazol in a dose of 100 mg twice a day for 12 weeks compared with placebo reduced the blood levels of triglycerides by an average of 0.33 mmol / l (15%) and increased the blood levels of HDL cholesterol 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 (found in dogs, but not detected in rats and monkeys). Cilostazol does not increase the QT interval in dogs and monkeys.
The effectiveness of Cilostazol in patients with intermittent claudication has been confirmed in 9 placebo-controlled clinical trials. It has been established that therapy with Cilostazol at a dose of 100 mg twice a day for 24 weeks approximately doubles the maximum walkable distance (from 60.4 m to 129.1 m; the average absolute increase of the maximum walkable distance is 42 meters) and the distance traveled to the appearance of pain (from 47.3 m to 93.6 m). The effectiveness of Cilostazol in patients with diabetes mellitus was lower than in individuals without disturbed carbohydrate metabolism. In a prospective, double-blind clinical study, it was found that Cilostazol does not increase the mortality of patients with intermittent claudication.
Pharmacokinetics
Cilostazol is easily absorbed when taken orally. Compared to taking the drug on an empty stomach, the maximum concentration (Cmax) is 16% higher after taking the drug 30 minutes after a meal and 93% when taken 2 hours after a meal.
The maximum concentration (Cmax) of Cilostazol and its major metabolites increases less than proportional to the dose increase. At the same time, the area under the concentration-time curve (AUC) of Cilostazol and its main metabolites increases approximately in proportion to the dose increase.
In patients with occlusive peripheral arterial disease, when taken regularly at a dose of 100 mg 2 times a day, the equilibrium concentration of Cilostazol in the blood is reached after 4 days.
Cilostazol has two pharmacologically active metabolites (dehydrocylostazol and 4’-trans-hydroxycylostazol). Dehydrocylostazol is 4–7 times as high as Cilostazol in its ability to inhibit platelet aggregation. 4`-trans-hydroxycylostazol, which has five times less pronounced ability to inhibit platelet aggregation compared to unchanged Cilostazol.The plasma concentration (measured by the magnitude of the AUC) of dehydrocylostazol and 4`-trans-hydroxycylostazol is ~ 41% and ~ 12%, respectively, of the concentration of cilostazol.
The connection of Cilostazol with plasma proteins (mainly albumin) is 95-98%. Dehydrocylostazol and 4`-trans-hydroxycylostazol bind to plasma proteins by 97.4% and 66%, respectively.
Cilostazol is actively metabolized mainly by the action of the CYP3A4 isoenzyme, to a lesser extent by the CYP2C19 isoenzyme, and to an even smaller extent by the CYP1A2 isoenzyme. Cilostazol is not an inducer of hepatic microsomal peroxidation enzymes.
Cilostazol is excreted mainly with urine (74%), the remaining drug is excreted with feces. In the urine unchanged Cilostazol is practically undetermined. Less than 2% of the dose taken is excreted in the urine in the form of dehydrocylostazol. About 30% of the dose taken is excreted in the urine in the form of 4’-trans-hydroxycylostazol. The remaining drug is displayed in the form of various metabolites, each of which is not more than 5% of the dose.
The observed half-life of cilostazol is 10.5 hours. The two major metabolites (dehydrocylostazol and 4’-trans-hydroxycylostazol) have similar observed half-life.
Special patient groups
Renal failure
It was established that in patients with severe renal insufficiency, the free fraction of Cilostazol is 27% higher, and the Cmax and AUC indices of unchanged Cilostazol are 29% and 39%, respectively, lower than in patients with normal renal function. The Cmax and AUC values of dehydrocylostazol in patients with severe renal insufficiency are, respectively, 41% and 47% lower than in patients with normal renal function. At the same time, Cmax and AUC 4’-trans-hydroxycylostazol (the main urinary excreted metabolite) in patients with severe renal insufficiency increase by 173% and 209% compared with patients without renal impairment. 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, peak plasma concentrations and AUC were increased by 25 and 10%, respectively, compared with healthy people. In patients with moderate renal failure, peak plasma concentrations and AUC were increased by 50 and 16%, respectively, compared with healthy people. Data on the use of Cilostazol in patients with moderate to severe hepatic insufficiency are not available. Since Cilostazol is extensively metabolized by hepatic enzymes of microsomal oxidation, use is contraindicated in patients with moderate or severe hepatic insufficiency.
Age and gender
In studies involving healthy volunteers aged 50–80 years, it was established that age and gender do not have a significant effect on the pharmacokinetics of Cilostazol.

Indications

Symptomatic treatment of intermittent claudication.
Cilostazol is used to increase the maximum distance and the distance traveled without pain in patients with intermittent claudication who have no pain at rest and no signs of necrosis of peripheral tissues (chronic ischemia of the lower limbs II degree according to Fontaine classification).
Cilostazol is intended for use as a second-line treatment for patients with intermittent claudication who have lifestyle changes (including smoking cessation and [supervised by a specialist] physical rehabilitation programs) and other appropriate interventions have not been sufficient to reduce the symptoms of intermittent claudication.

Composition

Active ingredient: Cilostazol 50.0 mg / 100.0 mg.Excipients: Pregelatinized potato starch, 81.8 mg / 84.0 mg, microcrystalline cellulose, 26.0 mg / 35.0 mg; calcium carmellose 1.5 mg / 2.2 mg; magnesium stearate 1.7 mg / 2.3 mg; hypromellose 19.0 mg / 26.5 mg.

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Dosage and Administration

For oral use.
The recommended dosage of Cilostazol is 100 mg twice a day.
Cilostazol should be taken 30 minutes before a meal. When taking Cilostazol during a meal, an increase in the maximum concentration (Cmax) in the blood plasma is noted, which may be associated with an increase in the frequency of adverse events.
If you miss the drug, you must take the next pill at the usual time. Do not take a double dose of Cilostazol.
Cilostazol therapy should be initiated under the supervision of a physician experienced in the treatment of intermittent claudication.
The physician must reassess the patient after 3 months of treatment. If Cilostazol therapy does not have an adequate effect or if there is no decrease in the severity of symptoms of intermittent claudication, Cilostazol should be discontinued and other treatments should be considered.
Patients receiving treatment with Cilostazol should continue to follow recommendations for lifestyle changes (quitting smoking, exercise) and drug therapy (taking lipid-lowering and antiplatelet drugs) aimed at reducing the risk of cardiovascular complications. Cilostazol is not a substitute for this treatment.
Use in special patient groups
Elderly age
There are no special requirements for changing the dosage of Cilostazol in elderly patients.
Renal failure
In patients with creatinine clearance> 25 ml / min, dosage change is not required. Cilostazol is contraindicated for use in patients with creatinine clearance <25 ml="" min="" br=""> Liver failure
In patients with mild hepatic impairment, a dosage change is not required. There is no experience in the use of Cilostazol in patients with moderate and severe hepatic insufficiency. Since 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 liver failure.
Concurrent use of potent inhibitors of CYP3A4 or CYP2C19
In patients receiving drugs that have a potent inhibitory effect on CYP3A4 (for example, some macrolides), or drugs that have a powerful inhibitory effect on CYP2C19 (for example, omeprazole), reduce the dose of Cilostazol to 50 mg twice a day.

Adverse reactions

The most commonly reported side effects in clinical studies were headache (> 30%), diarrhea, and stool disorders (> 15% each). These side effects were mild to moderate in intensity.
Adverse reactions by frequency of occurrence were classified as follows: very often (≥1 / 10), often (≥1 / 100 and <1/10), infrequently (≥1 / 1,000 and <1/100), rarely (≥1 / 10,000 and <1/1000), very rarely (<1 10="" 000="" the="" frequency="" is="" unknown="" cannot="" be="" determined="" from="" available="" data="" br=""> Violations of the blood and lymphatic system
Often: ecchymosis.
Infrequently: anemia.
Rarely: increased bleeding time, thrombocytosis.
Frequency unknown: bleeding tendency, thrombocytopenia, granulocytopenia, agranulocytosis, leukopenia, pancytopenia, aplastic anemia.
Immune system disorders
Infrequently: allergic reactions.
Metabolic and nutritional disorders
Often: edema (peripheral edema, swelling of the face), anorexia.
Infrequently: hyperglycemia, diabetes.
Mental disorders
Infrequently: anxiety.
Nervous system disorders
Very often: headache
Often: dizziness.
Infrequently: insomnia, sleep disturbance (unusual dreams), intracranial hemorrhage.
Frequency is unknown: paresis, hypesthesia.
Violations by the organ of vision
Often: intraocular hemorrhage.
Frequency unknown: conjunctivitis.
Disturbances from an organ of hearing and labyrinth disturbances
Frequency unknown: ringing in the ears.
Heart disorders
Often: heartbeat, tachycardia, stenocardia, arrhythmia, ventricular extrasystoles.
Infrequently: myocardial infarction, atrial fibrillation, chronic heart failure, supraventricular tachycardia, ventricular tachycardia, syncopal state.
Vascular disorders
Often: orthostatic hypotension.
Infrequently: flushes of heat, arterial hypertension, arterial hypotension.
Disorders of the respiratory system, organs of the chest and mediastinum
Often: rhinitis, pharyngitis.
Infrequently: shortness of breath (dyspnea), pneumonia, cough, pulmonary hemorrhage, airway bleeding.
Frequency unknown: interstitial pneumonia.
Disorders of the gastrointestinal tract
Very often: diarrhea, disturbed stool.
Often: nausea, vomiting, dyspepsia, flatulence, abdominal pain, gastrointestinal bleeding.
Infrequently: gastritis.
Disorders of the liver and biliary tract
Frequency is unknown: hepatitis, deviation of liver function indicators from normal values, jaundice.
Violations of the skin and subcutaneous tissue
Often: skin rash, skin itch.
Infrequently: eczema, skin rashes, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria, subcutaneous hemorrhage.
Disorders of the musculoskeletal and connective tissue
Infrequently: myalgia, intramuscular hematomas.
Kidney and urinary tract disorders
Rarely: renal failure, impaired renal function.
Frequency unknown: hematuria, pollauria.
General disorders and disorders at the site of administration
Often: chest pain, asthenia.
Infrequently: chills, malaise.
Frequency unknown: pyrexia, pain.
Laboratory and instrumental data
The frequency is unknown: an increase in the content of uric acid in the blood, an increase in the content of urea in the blood, an increase in the content of creatinine in the blood.
Increased heart rate and peripheral edema were observed when Cilostazol was used in combination with other vasodilators that cause reflex tachycardia (for example, with dihydropyridine blockers of “slow” calcium channels).
Cilostazol itself increases the risk of bleeding, and this risk can be further increased with simultaneous use of Cilostazol with any other drug that has the same potential.
The risk of intraocular hemorrhage can be increased in patients with diabetes.
A higher incidence of diarrhea and heart palpitations in patients older than 70 years has been established.

Contraindications

Hypersensitivity to Cilostazol or any other component of the drug;
Severe renal failure (creatinine clearance ≤ 25 ml / min);
Moderate or severe liver failure;
Chronic heart failure;
Predisposition to bleeding (for example, peptic ulcer or duodenal ulcer in the acute stage, recently [in the last 6 months] hemorrhagic stroke, proliferative diabetic retinopathy, poorly controlled arterial hypertension);
Ventricular tachycardia, ventricular fibrillation or polytopic ventricular premature beats in history (regardless of the presence or absence of adequate antiarrhythmic therapy);
Extended QT interval on ECG;
Severe tachyarrhythmia in history;
Unstable angina or myocardial infarction during the last 6 months;
Invasive intervention on the coronary arteries during the last 6 months;
The simultaneous use of two or more antiplatelet or anticoagulant drugs (for example, acetylsalicylic acid, clopidogrel, heparin, warfarin, acenocoumarol, dabigatran, rivaroxaban or apixaban);
Concurrent use of potent inhibitors of CYP3A4 or CYP2C19 (for example, cimetidine, diltiazem, erythromycin, ketoconazole, lansoprazole, omeprazole, and HIV-1 protease inhibitors);
Pregnancy;
Breastfeeding period;
Age under 18 years (safety and efficacy not studied).

Carefully

Hepatic failure mild severity;
Chronic ischemic heart disease (in particular, stable exertional angina);
Atrial or ventricular premature beats, atrial fibrillation and flutter;
Diabetes;
The simultaneous use of drugs that reduce blood pressure;
The simultaneous use of drugs that reduce blood clotting;
Simultaneous use of substrates of CYPZA4 or CYP2C19 (for example, cisapride, midazolam, nifedipine, verapamil);
Elderly age.

Drug interactions

Acetylsalicylic acid
Short-term (for ≤ 4 days) simultaneous use of Cilostazol and acetylsalicylic acid leads to an increase of 23-25% ADP-induced platelet aggregation under ex vivo conditions compared with acetylsalicylic acid monotherapy. Due to the increased risk of bleeding with simultaneous use with Cilostazol, careful monitoring is necessary.
Clopidogrel and other antiplatelet drugs
In a study of healthy volunteers, the simultaneous use of Cilostazol with clopidogrel had no effect on platelet count, prothrombin time (PT) and activated partial thromboplastin time (APTT). When clopidogrel was used both as monotherapy and in combination with Cilostazol, the bleeding time was increased in healthy volunteers. Receiving Cilostazol did not lead to an additional significant lengthening of the bleeding time. However, caution is advised while using Cilostazol with any drug that inhibits platelet aggregation. It is recommended to regularly monitor the bleeding time.
The use of Cilostazol is contraindicated in patients receiving at the same time two or more antiplatelet and / or anticoagulant drugs.
Oral anticoagulants
In a clinical study, a single dose of Cilostazol did not inhibit the metabolism of warfarin and had no effect on the blood clotting parameters (PT, APTT, bleeding time). However, caution is advised while using Cilostazol with any anticoagulant medication. The use of Cilostazol is contraindicated in patients receiving at the same time two or more antiplatelet and / or anticoagulant drugs.
Inhibitors of cytochrome P450 isoenzymes
In the liver, cilostazol is mainly metabolized by the action of cytochrome P450 enzymes, mainly CYP3A4 and CYP2C19 and, to a lesser extent, CYP1A2. It is believed that dehydrocylostazol, 4-7 times superior to Cilostazol in its ability to inhibit platelet aggregation, is formed mainly with the participation of CYP3A4. 4`-trans-hydroxycylostazol, which is five times less pronounced ability to inhibit platelet aggregation, is formed mainly under the action of CYP2C19. Accordingly, drugs that inhibit CYP3A4 (for example, some macrolides [erythromycin, clarithromycin], azole antifungal drugs [ketoconazole, itraconazole], HIV protease inhibitors) and CYP2C19 (for example, proton pump inhibitors [omeprazole, esomeprazole]) increase the total timeframe, you will be completely out of the challenge, you will have to leave the pharmacological problem, you will be completely out of the last problem and you’ll be a pharmacologic, you can’t stop the problem, you can’t stop using the same pharmacological process, you can’t stop using the same pharmacological process, you can’t stop using this method. may enhance its undesirable effects. Accordingly, patients receiving potent inhibitors of CYP3A4 or CYP2C19, it is recommended to appoint Cilostazol at a dose of 50 mg 2 times a day.
Erythromycin
While taking Cilostazol with erythromycin (a potent inhibitor of CYP3A4), the AUC of Cilostazol, dehydrocylostazol and 4`-trans-hydroxycylostazol increase by 72%, 6% and 119%, respectively. On the basis of changes in AUC, it was found that the total pharmacological activity of Cilostazol, while being used with erythromycin, is increased by 34%. It is recommended to reduce the dose of Cilostazol to 50 mg 2 times a day while using it with erythromycin and other drugs of this group (for example, clarithromycin).
Ketoconazole
While taking Cilostazol with ketoconazole (a potent CYP3A4 inhibitor), the AUC of Cilostazol increases by 117%, the AUC of dehydrocylostazol decreases by 15%, AUC 4`-trans-hydroxycylostazol increases by 87%. On the basis of changes in AUC, it was found that the total pharmacological activity of Cilostazol, while used with ketoconazole, is increased by 34%. It is recommended to reduce the dose of Cilostazol to 50 mg 2 times a day with simultaneous use with ketoconazole and other drugs of this group (for example, with itraconazole).
Diltiazem
While taking Cilostazol with diltiazem (a weak CYP3A4 inhibitor), the AUC of Cilostazol, dehydrocylostazol and 4`-trans-hydroxycystasol increases to 44%, 4% and 43%, respectively. On the basis of changes in AUC, it was found that the total pharmacological activity of Cilostazol, when used simultaneously with diltiazem, is increased by 19%. Correction of the dose of Cilostazol with simultaneous use with diltiazem is not required.
Grapefruit juice
With a single dose of 100 mg of Cilostazol simultaneously with 240 ml of grapefruit juice (intestinal inhibitor CYP3A4), no significant change in the pharmacokinetic parameters of Cilostazol was observed. Correction of the dose of Cilostazol is not required. However, taking more grape juice may have an effect on the pharmacokinetics of Cilostazol.
Omeprazole
While taking Cilostazol with omeprazole (a potent inhibitor of CYP2C19), the AUC values of Cilostazol and dehydrocylostazol increase by 22% and 68%, respectively, while the AUC 4`-trans-hydroxycylostasol decreases by 36%. On the basis of changes in AUC, it was found that the total pharmacological activity of Cilostazol, while used with omeprazole, is increased by 47%. It is recommended to reduce the dose of Cilostazol to 50 mg 2 times a day while using it with omeprazole.
Substrates of cytochrome P450 isoenzymes
Cilostazol increases the AUC of lovastatin (CYP3A4 substrate) and its beta-hydroxyl metabolite by 70%. It is recommended to use caution when applying Cilostazol with CYP3A4 substrates with a narrow therapeutic range (such as cisapride, halofantrine, pimozide, ergot alkaloids). It is also recommended that caution be taken with simultaneous use of Cilostazol with HMG-CoA reductase inhibitors (statins) that metabolize with CYP3A4 (simvastatin, atorvastatin and lovastatin).
Inductors of cytochrome P450 isoenzymes
The effect of drugs that increase the activity of CYP3A4 and CYP2C19 (such as carbamazepine, phenytoin, rifampicin, Hypericum perforatum drugs) on the pharmacokinetics of Cilostazol has not been studied. If taken simultaneously, it is theoretically possible to reduce the antiplatelet effect of Cilostazol, so it is necessary to regularly control the bleeding time. In clinical studies, it was found that smoking (a factor that enhances the activity of CYP1A2) reduces the plasma concentration of Cilostazol by 18%.
Other preparations
It is necessary to be careful at simultaneous use of Cilostazol with any drugs that reduce blood pressure (includingwith nitrates and phosphodiesterase-5 inhibitors), since an additive effect is possible with the development of arterial hypotension and reflex tachycardia.

Special instructions

Before starting therapy with Cilostazol, the possibility of prescribing other treatment methods, such as surgical revascularization or conservative therapy, should be evaluated.
Due to the mechanism of pharmacological action, cilostazol can cause tachycardia, palpitations, tachyarrhythmias and / or arterial hypotension. When taking Cilostazol, the heart rate can increase by 5-7 beats per minute, which can trigger an attack of angina in patients at risk (for example, in patients with stable angina).
Patients who are at increased risk of developing severe cardiovascular complications due to an increase in heart rate (for example, patients with stable coronary artery disease) need careful monitoring during treatment with Cilostazol. The use of Cilostazol is contraindicated in patients with unstable angina or myocardial infarction / invasive intervention on the coronary arteries during the last 6 months, as well as in patients with severe tachyarrhythmia in history.
Care must be taken when prescribing Cilostazol to patients with atrial or ventricular extrasystole, as well as patients with atrial fibrillation or atrial flutter.
The patient should be warned of the need to report any case of bleeding or the appearance of a bruise (subcutaneous hematoma) with a small injury. In case of development of retinal hemorrhage, Cilostazol should be discontinued.
Since Cilostazol is an inhibitor of platelet aggregation, the risk of bleeding during surgical interventions (including minor invasive procedures such as tooth extraction) increases. At planned surgical interventions (if the antiplatelet effect is undesirable), cilostazol should be canceled 5 days before the operation.
Rare or very rare cases of hematological disorders have been reported, including thrombocytopenia, leukopenia, agranulocytosis, pancytopenia, or aplastic anemia. In most cases, these violations occurred after discontinuation of cilostazol. However, in several cases, pancytopenia and aplastic anemia have been fatal.
The patient should be warned about the need to immediately inform the doctor about any symptoms that may be early manifestations of hematological complications, such as high fever (pyrexia) and angina. A complete blood count should be performed if an infection is suspected or if clinical symptoms of hematological complications appear. It is necessary to immediately stop taking Cilostazol in case of clinical symptoms or laboratory signs of hematological complications.
Caution should be exercised with the simultaneous use of Cilostazol with drugs that reduce blood pressure (the possibility of additive action with the development of arterial hypotension and reflex tachycardia) as well as reducing blood clotting or inhibiting platelet aggregation.
Influence on ability to steer vehicles, mechanisms
Cilostazol may cause dizziness. It is recommended to use caution when driving or working with mechanisms during treatment.

Overdosage

Symptoms
Information about acute overdose of cilostazol in humans is limited. Expected symptoms of overdose: severe headache, diarrhea, tachycardia, hypotension, cardiac arrhythmias.
Treatment
Symptomatic. In the event of an overdose, careful observation and examination of the patient is necessary.It is necessary to clear the stomach, causing vomiting, or perform a gastric lavage in accordance with generally accepted recommendations.
Due to the high degree of association with plasma proteins, hemodialysis and peritoneal dialysis are practically ineffective.