Cylos

Cilostazol.

Each Tablet Contains: Cilostazol, USP 100mg.
Cilostazol (Cylos) is a quinolinone derivative which inhibits cellular phosphodiesterase (more specific for phosphodiesterase 3).
Molecular formula: C₂₀H₂₇N₅O₂.
Molecular wt: 369.47.
CAS: 73963-72-1.
The IUPAC name for cilostazol is 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone.

Pharmacotherapeutic group: Antithrombotic agents, platelet aggregation inhibitor.
Pharmacology: Pharmacodynamics: Animal studies have shown Cilostazol to have vasodilator effects and this has been demonstrated in small studies in man where ankle blood flow was measured by strain gauge plethysmography. Cilostazol also inhibits smooth muscle cell proliferation in rat and human smooth muscle cells in vitro, and inhibits the release of platelet-derived growth factor and PF-4 from human platelets.
Studies in animals (in vivo and ex vivo) have shown that Cilostazol causes inhibition of platelet aggregation. The inhibition is effective against a range of aggregants (including shear stress, arachidonic acid, collagen, ADP and adrenaline); in man the inhibition lasts for up to 12 hours, and on cessation of administration of Cilostazol recovery of aggregation occurs within 48-96 hours, without rebound hyperaggregability.
Pharmacokinetics: Absorption: The Cmax of cilostazol and its primary circulating metabolites increase less than proportionally with increasing doses.
However, the AUC for cilostazol and its metabolites increase approximately proportionately with dose.
Distribution: Cilostazol is 95-98% protein bound, predominantly to albumin. The dehydro metabolite and 4'-transhydroxy metabolite are 97.4% and 66% protein bound respectively.
Biotransformation: The apparent elimination half-life of cilostazol is 10.5 hours. There are two major metabolites, a dehydro-cilostazol and a 4'-trans-hydroxy cilostazol, both of which have similar apparent half-lives.
The dehydro metabolite is 4-7 times as active a platelet antiaggregant as the parent compound and the 4'-trans-hydroxymetabolite is one fifth as active. Plasma concentrations (as measured by AUC) of the dehydro and 4'-trans-hydroxy metabolites are ~41% and ~12% of cilostazol concentrations.
Cilostazol is eliminated predominantly by metabolism and subsequent urinary excretion of metabolites. The primary isoenzymes involved in its metabolism are cytochrome P-450 CYP3A4, to a lesser extent, CYP2C19, and to an even lesser extent CYP1A2.
Elimination: The primary route of elimination is urinary (74%) with the remainder excreted in the faeces. No measurable amount of unchanged cilostazol is excreted in the urine, and less than 2% of the dose is excreted as the dehydro-cilostazol metabolite. Approximately 30% of the dose is excreted in the urine as the 4'-trans-hydroxy metabolite. The remainder is excreted as metabolites, none of which exceed 5% of the total excreted.
There is no evidence that cilostazol induces hepatic microsomal enzymes.
Older people: The pharmacokinetics of cilostazol and its metabolites were not significantly affected by age or gender in healthy subjects aged between 50-80 years.
In subjects with severe renal impairment, the free fraction of cilostazol was 27% higher and both Cmax and AUC were 29% and 39% lower respectively than in subjects with normal renal function. The Cmax and AUC of the dehydro metabolite were 41% and 47% lower respectively in the severely renally impaired subjects compared to subjects with normal renal function. The Cmax and AUC of 4'-trans-hydroxy cilostazol were 173% and 209% greater in subjects with severe renal impairment. The medicine must not be administered to patients with a creatinine clearance <25ml/min.
Hepatic impairment: There are no data in patients with moderate to severe hepatic impairment and since cilostazol is extensively metabolised by hepatic enzymes, the medicine must not be used in such patients.

Cilostazol (Cylos) is indicated for the improvement of the maximal and pain-free walking distances in patients with intermittent claudication, who do not have rest pain and who do not have evidence of peripheral tissue necrosis.
Cilostazol (Cylos) is for second-line use, in patients for whom lifestyle modifications (including stopping smoking and supervised exercise programs) and other appropriate interventions have failed to sufficiently improve their intermittent claudication symptoms.

The recommended dosage of Cilostazol (Cylos) is 100 mg twice a day. Doses of 150 mg twice daily were investigated, however 100 mg twice daily provided the optimal risk to benefit ratio.
Cilostazol (Cylos) should be taken 30 minutes before or two hours after breakfast and the evening meal. Taking Cilostazol with food has been shown to increase the maximum plasma concentrations (Cmax) of Cilostazol (Cylos), which may be associated with an increased incidence of adverse effects.
Cilostazol (Cylos) treatment should be initiated by a physician experienced in the management of intermittent claudication. The patient should be reassessed after 3 months of treatment with a view to discontinuing Cilostazol (Cylos) where an inadequate effect is observed or symptoms have not improved.
Patients should continue with their lifestyle modifications (smoking cessation and exercise), and pharmacological interventions (such as lipid lowering and antiplatelet treatment) to reduce the risk of cardiovascular events. Cilostazol (Cylos) is not a substitute for such treatments.
Renal Insufficiency: No dose adjustment is necessary in patients with a creatinine clearance of >25 ml/min. Cilostazol is contraindicated in patients with a creatinine clearance of <25 ml/min.
Hepatic Impairment: No dosage adjustment is necessary in patients with mild hepatic disease. There are no data in patients with moderate or severe hepatic impairment. Since Cilostazol is extensively metabolised by hepatic enzymes, it is contraindicated in patients with moderate or severe hepatic impairment.
Paediatric use: Safety and efficacy in children have not been established.
Use in the Elderly: There are no special dosage requirements for the elderly.

Information on acute overdose in humans is limited. The signs and symptoms can be anticipated to be severe headache, diarrhea, tachycardia and possibly cardiac arrhythmia.
Patients should be observed and given supportive treatment. The stomach should be emptied by induced vomiting or gastric lavage, as appropriate.

Known hypersensitivity to Cilostazol or to any of the excipients.
Severe renal impairment: creatinine clearance of < 25 ml/min.
Moderate or severe hepatic impairment.
Congestive heart failure of any grade or severity.
Pregnancy and lactation.
Patients taking inhibitors of CYP3A4 or of CYP2C19 (e.g. cimetidine, diltiazem, erythromycin, ketoconazole, lansoprazole, omeprazole and inhibitors of HIV-1 proteases).
Patients with a known predisposition to bleeding (e.g. active peptic ulceration, recent (within six months) haemorrhagic stroke, surgery within the previous three months, proliferative diabetic retinopathy, poorly controlled hypertension) or any active or uncontrolled bleeding.
Patients with a history of ventricular tachycardia, ventricular fibrillation or multifocal ventricular ectopic beats, whether or not adequately treated.
Patients with a history of severe tachyarrhythmia.
Patients treated concomitantly with two or more additional antiplatelet or anticoagulant agents (eg acetylsalicylic acid, clopidogrel, heparin, warfarin, acenocoumarol, dabigatran, rivaroxaban or apixaban).
Patients with unstable angina pectoris, myocardial infarction within the last 6 months, or a coronary intervention in the last 6 months

The suitability of treatment with cilostazol should be carefully considered alongside other treatment options such as revascularisation.
Based on its mechanism of action, cilostazol may induce tachycardia, palpitation, tachyarrhythmia and/or hypotension. The increase in heart rate associated with cilostazol is approximately 5 to 7 bpm; in patients at risk this consequently may induce angina pectoris.
Patients who may be at increased risk for serious cardiac adverse events as a result of increased heart rate, e.g. patients with stable coronary disease, should be closely monitored during treatment with cilostazol, while the use of cilostazol in patients with unstable angina pectoris, or myocardial infarction/coronary intervention within the last 6 months, or a history of severe tachyarrhythmia is contraindicated.
Caution should be exercised when prescribing cilostazol for patients with atrial or ventricular ectopy and patients with atrial fibrillation or flutter.
Patients should be warned to report any episode of bleeding or easy bruising whilst on therapy. In case of retinal bleeding administration of cilostazol should be stopped.
Due to cilostazol's platelet aggregation inhibitory effect it is possible that an increased bleeding risk occurs in combination with surgery (including minor invasive measurements like tooth extraction). If a patient is to undergo elective surgery and antiplatelet effect is not necessary, cilostazol should be stopped 5 days prior to surgery.
There have been rare or very rare reports of haematological abnormalities including thrombocytopenia, leucopenia, agranulocytosis, pancytopenia and aplastic anaemia. Most patients recovered on discontinuation of cilostazol. However, some cases of pancytopenia and aplastic anaemia had a fatal outcome.
In addition to reporting episodes of bleeding and easy bruising, patients should be warned to promptly report any other signs which might also suggest the early development of blood dyscrasia such as pyrexia and sore throat. A full blood count should be performed if infection is suspected or there is any other clinical evidence of blood dyscrasia. Cilostazol should be discontinued promptly if there is clinical or laboratory evidence of haematological abnormalities.
In the case of patients receiving strong inhibitors for CYP3A4 or CYP2C19, plasma levels of cilostazol were shown to be increased. In such cases, a cilostazol dosage of 50 mg twice daily is recommended.
Caution is needed when co-administering cilostazol with any other agent which has the potential to reduce blood pressure due to the possibility that there may be an additive hypotensive effect with a reflex tachycardia.
Caution should be exercised when co-administering cilostazol with any other agents that inhibit platelet aggregation.
Effects on Ability to Drive and Use Machines: Cilostazol (Cylos) may cause dizziness and patients should be warned to exercise caution before they drive or operate machinery.

The most commonly reported adverse reactions in were headache (in > 30%), diarrhoea and abnormal stools (in >15% each). These reactions were usually of mild to moderate intensity and were sometimes alleviated by reducing the dose.
Adverse reactions reported as being at least possibly drug-related and occurring more commonly with Cilostazol (Cylos) 100 mg b.i.d. than in the placebo groups are listed as follows.
The frequencies correspond with: Very common: (≥1/10); Common (≥1/100 to <1/10); Uncommon (≥1/1,000 to <1/100); Rare (≥1/10,000 to <1/1000); Very rare (<1/10,000).
Blood and the lymphatic system disorders: Common: Ecchymosis.
Uncommon: Anaemia.
Rare: Bleeding time increased, thrombocythemia.
Immune system disorders: Uncommon: Allergic reaction.
Psychiatric disorders: Uncommon: Anxiety.
Metabolism and nutrition disorders: Common: Oedema (peripheral, face).
Uncommon: Hyperglycaemia.
Nervous system disorders: Common: Dizziness.
Uncommon: Insomnia, anxiety, abnormal dreams.
Eye disorders: Unknown: Conjunctivitis.
Cardiac disorders: Common: Palpitation, tachycardia, angina pectoris, arrhythmia, ventricular extrasystoles.
Uncommon: Myocardial infarction, atrial fibrillation, congestive heart failure, supraventricular tachycardia, ventricular tachycardia, syncope, postural hypotension.
Vascular disorders: Uncommon: Eye haemorrhage, epistaxis, gastrointestinal haemorrhage, haemorrhage unspecified, orthostatic hypotension.
Unknown: Hot flushes, hypertension, hypotension, cerebral haemorrhage, pulmonary haemorrhage, muscle haemorrhage, respiratory tract haemorrhage, subcutaneous haemorrhage.
Respiratory, thoracic and mediastinal disorders: Common: Rhinitis, pharyngitis.
Uncommon: Dyspnoea, pneumonia, cough.
Gastrointestinal disorders: Very Common: Diarrhoea, abnormal stools.
Common: Nausea and vomiting, dyspepsia, flatulence.
Uncommon: Gastritis.
Hepato-biliary disorders: Unknown: Hepatitis, hepatic function abnormal, jaundice.
Skin and subcutaneous tissue disorders: Common: Rash, pruritus.
Musculoskeletal, connective tissue and bone disorders: Uncommon: Myalgia.
Renal and urinary disorders: Rare: Renal failure, renal impairment.
General disorders and administration site conditions: Common: Chest pain, asthenia.
Uncommon: Chills, malaise.
Unknown: Pyrexia, pain.
An increase in the incidence of palpitation and peripheral oedema was observed when Cilostazol (Cylos) was combined with other vasodilators that cause reflex tachycardia e.g. dihydropyridine calcium channel blockers.
The only adverse event resulting in discontinuation of therapy in < 3% of patients treated with Cilostazol (Cylos) was headache. Other frequent causes of discontinuation included palpitation and diarrhea (both 1.1%).
Cilostazol (Cylos) per se may carry an increased risk of bleeding and this risk may be potentiated by co-administration with any other agent with such potential.
The risk of intraocular bleeding may be higher in patients with diabetes.
An increase in the frequency of diarrhea and palpitation has been found in patients older than 70 years.

Inhibitors of platelet aggregation: Cilostazol is a PDE III inhibitor with anti-platelet activity. In a clinical study in healthy subjects, Cilostazol 150mg b.i.d. for five days did not result in prolongation of bleeding time.
Aspirin: Short term (≤4 days) co-administration of aspirin with Cilostazol suggested a 23-25% increase in inhibition of ADP-induced ex vivo platelet aggregation when compared to aspirin alone. There was no additive or synergistic effect on arachidonic acid induced platelet aggregation when compared to aspirin alone.
There were no apparent trends toward a greater incidence of haemorrhagic adverse effects in patients taking Cilostazol and aspirin compared to patients taking placebo and equivalent doses of aspirin. Nonetheless, patients taking Cilostazol in combination with aspirin should be monitored for bleeding events.
Clopidogrel and other antiplatelet drugs: Concomitant administration of Cilostazol 150 mg b.i.d. and clopidogrel 75 mg daily for five days did not have a notable effect on the pharmacokinetics of Cilostazol, with an increase in AUC of only 9%. However, the AUC of the dehydro metabolite, which has about 4 times the potency of cilostazol in inhibiting platelet aggregation, increased by 24%. Concomitant administration of Cilostazol and clopidogrel did not have an appreciable effect on platelet count, prothrombin time (PT) or activated partial thromboplastin time (aPTT). All healthy subjects in the study had a prolongation of bleeding time on clopidogrel alone and concomitant administration with Cilostazol did not result in a significant additional effect on bleeding time. Caution is advised when co-administering Cilostazol with any drug that inhibits platelet aggregation. Consideration should be given to monitoring the bleeding time at intervals during co-administration. Cilostazol treatment is contraindicated in patients receiving two or more additional antiplatelet/anticoagulant agents. A higher rate of haemorrhage was observed with the concomitant use of clopidogrel, aspirin and cilostazol in the CASTLE trial.
Cilostazol has not been evaluated in circumstances where clopidogrel coadministration and a high bleeding risk co-exist, such as at the time of coronary stent insertion.
Anticoagulants: In a single-dose clinical study, no inhibition of the metabolism of warfarin or an effect on the coagulation parameters (PT, aPTT, bleeding time) was observed. However, caution is advised in patients receiving both Cilostazol and any anticoagulant agent, and frequent monitoring is required to reduce the possibility of bleeding. Cilostazol treatment is contraindicated in patients receiving two or more additional antiplatelet/anticoagulant agents.
Cytochrome P-450 (CYP) enzyme inhibitors and substrates: Cilostazol is extensively metabolised by CYP enzymes, particularly CYP3A4 and CYP2C19 and to a lesser extent CYP1A2. The dehydro metabolite, which has 4-7 times the potency of cilostazol in inhibiting platelet aggregation, appears to be formed primarily via CYP3A4. The 4'-trans-hydroxy metabolite, with potency one-fifth that of cilostazol, appears to be formed primarily via CYP2C19. Therefore, drugs inhibiting CYP3A4 (e.g., some macrolides, azole antifungals, protease inhibitors) or CYP2C19 (like proton pump inhibitors, PPIs) increase the total pharmacological activity and could have the potential to enhance the undesirable effects of cilostazol. Consequently, for patients concomitantly taking strong CYP3A4 or CYP2C19 inhibitors the recommended dose is 50 mg twice daily.
Administration of cilostazol with erythromycin (an inhibitor of CYP3A4) resulted in an increase in the AUC of cilostazol by 72%, accompanied by a 6% increase in AUC of the dehydro metabolite and a 119% increase in AUC of the 4'-trans-hydroxy metabolite.
Based on AUC, the overall pharmacological activity of cilostazol increases 34% when coadministered with erythromycin. Based on these data, the recommended dose of cilostazol is 50 mg bid in the presence of erythromycin and similar agents (e.g., clarithromycin).
Co-administration of ketoconazole (an inhibitor of CYP3A4 with cilostazol resulted in a 117% increase in the AUC of cilostazol, accompanied by a 15% decrease in the AUC of the dehydro metabolite and a 87% increase in the AUC of the 4'-trans-hydroxy metabolite. Based on AUC, the overall pharmacological activity of cilostazol increases 35% when co-administered with ketoconazole. Based on these data, the recommended dose of cilostazol is 50 mg bid in the presence of ketoconazole and similar agents (e.g., itraconazole).
Administration of cilostazol with diltiazem (a weak inhibitor of CYP3A4) resulted in an increase in the AUC of cilostazol of 44%, accompanied by a 4% increase in AUC of the dehydro metabolite and a 43% increase in the AUC of the 4'-trans-hydroxy metabolite.
Based on AUC, overall pharmacological activity of cilostazol increases 19 % when co-administered with diltiazem. Based on these data, no dose adjustment is necessary.
Administration of a single dose of 100 mg cilostazol with 240 ml grapefruit juice (an inhibitor of intestinal CYP3A4) did not have a notable effect on the pharmacokinetics of cilostazol. Based on these data, no dose adjustment is necessary. A clinically relevant effect on cilostazol is still possible at higher quantities of grapefruit juice.
Administration of cilostazol with omeprazole (an inhibitor of CYP2C19) increased the AUC of cilostazol by 22%, accompanied by a 68% increase in the AUC of the dehydro metabolite and a decrease of 36% in the AUC of the 4'-trans hydroxy metabolite. Based on AUC, the overall pharmacological activity increases by 47% when co-administered with omeprazole. Based on these data, the recommended dose of cilostazol is 50 mg bid in the presence of omeprazole.
Cytochrome P-450 enzyme substrates: Cilostazol has been shown to increase the AUC of lovastatin (sensitive substrate for CYP3A4) and its β-hydroxy acid by 70%. Caution is advised when cilostazol is co-administered with CYP3A4 substrates with a narrow therapeutic index (e.g., cisapride, halofantrine, pimozide, ergot derivates). Caution is advised in case of co-administration with statins metabolised by CYP3A4, for example simvastatin, atorvastatin and lovastatin.
Cytochrome P-450 enzyme inducers: The effect of CYP3A4 and CYP2C19 inducers (such as carbamazepine, phenytoin, rifampicin and St. John's wort) on cilostazol pharmacokinetics has not been evaluated. The antiplatelet effect may theoretically be altered and should be carefully monitored when cilostazol is co-administered with CYP3A4 and CYP2C19 inducers.
In clinical trials, smoking (which induces CYP1A2) decreased cilostazol plasma concentrations by 18%.
Other potential interactions: Caution is needed when co-administering cilostazol with any other agent which has the potential to reduce blood pressure due to the possibility that there may be an additive hypotensive effect with a reflex tachycardia.

Store at temperatures not exceeding 30°C.

Anticoagulants, Antiplatelets & Fibrinolytics (Thrombolytics)

B01AC23 - cilostazol ; Belongs to the class of platelet aggregation inhibitors excluding heparin. Used in the treatment of thrombosis.

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