Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2018 Publisher: Consilient Health Limited, 5<sup>th</sup> Floor, Beaux Lane House, Mercer Street Lower, Dublin 2, Ireland
Pharmacotherapeutic group: Antithrombotic agents, platelet aggregation inhibitor excl. heparin.
ATC code: B01AC23
From data generated in nine placebo-controlled studies (where 1,634 patients were exposed to cilostazol), it has been demonstrated that cilostazol improves exercise capacity as judged by changes in Absolute Claudication Distance (ACD, or maximal walking distance) and Initial Claudication Distance (ICD, or pain-free walking distance) upon treadmill testing. Following 24 weeks treatment, cilostazol 100 mg b.i.d. increases in mean ACD ranged from 60.4-129.1 metres, whilst mean ICD increases ranged from 47.3-93.6 metres.
A meta-analysis based on weighted mean differences across the nine studies indicated that there was a significant absolute overall post-baseline improvement of 42 m in maximal walking distance (ACD) for cilostazol 100 mg b.i.d. over the improvement seen under placebo. This corresponds to a relative improvement of 100% over placebo. This effect appeared lower in diabetics than in non-diabetics.
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 platelet release reaction of platelet-derived growth factor and PF-4 in human platelets.
Studies in animals and in man (in vivo and ex vivo) have shown that cilostazol causes reversible 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 occurred within 48-96 hours, without rebound hyperaggregability. Effects on circulating plasma lipids have been examined in patients taking cilostazol. After 12 weeks, as compared to placebo, cilostazol 100 mg b.i.d. produced a reduction in triglycerides of 0.33 mmol/L (15%) and an increase in HDL-cholesterol of 0.10mmol/L (10%).
A randomized, double-blind, placebo-controlled Phase IV study was conducted to assess the long-term effects of cilostazol, with focus on mortality and safety. In total, 1,439 patients with intermittent claudication and no heart failure have been treated with cilostazol or placebo for up to three years. With respect to mortality, the observed 36-month Kaplan-Meier event rate for deaths on study drug with a median time on study drug of 18 months was 5.6% (95%CI of 2.8 to 8.4%) on cilostazol and 6.8% (95% CI of 1.9 to 11.5%) on placebo. Long-term treatment with cilostazol did not raise safety concerns.
Following multiple doses of cilostazol 100 mg twice daily in patients with peripheral vascular disease, steady state is achieved within 4 days.
Cilostazol is 95-98% protein bound, predominantly to albumin. The dehydro metabolite and 4'-trans-hydroxy metabolite are 97.4% and 66% protein bound respectively.
The primary isoenzymes involved in its metabolism are cytochrome P-450 CYP3A4, to a lesser extent, CYP2C19, and to an even lesser extent CYP1A2. There are two major metabolites, the dehydro metabolite is 4-7 times as active a platelet anti-aggregant as the parent compound and the 4'-trans-hydroxy metabolite 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.
The apparent elimination half-life of cilostazol is 10.5 hours.
There are two major metabolites, a dehydro-cilostazol and a 4'-transhydroxy cilostazol, both of which have similar apparent half-lives.
Cilostazol is eliminated predominantly by metabolism and subsequent urinary excretion of metabolites. 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.
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.
There is no evidence that cilostazol induces hepatic microsomal enzymes.
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 (see section 4.3). 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 (see section 4.3).
Cilostazol and several of its metabolites are phosphodiesterase III inhibitors which suppress cyclic AMP degradation, resulting in increased cAMP in a variety of tissues including platelets and blood vessels. As with other positive inotropic and vasodilator agents, cilostazol produced cardiovascular lesions in dogs. Such lesions were not seen in rats or monkeys and are considered species specific. Investigation of QTc in dogs and monkeys showed no prolongation after administration of cilostazol or its metabolites.
Mutagenicity studies were negative in bacterial gene mutation, bacterial DNA repair, mammalian cell gene mutation and mouse in vivo bone marrow chromosomal aberrations. In in vitro tests on Chinese ovary hamster cells cilostazol produced a weak but significant increase in chromosome aberration frequency. No unusual neoplastic outcomes were observed in two-year carcinogenicity studies in rats at oral (dietary) doses up to 500 mg/kg/day, and in mice at doses up to 1000 mg/kg/day.
Cilostazol inhibited mouse oocyte maturation in vitro, and in female mice caused a reversible impairment of fertility. No effect on fertility was observed in rats or in non-human primates. The relevance to humans is unknown.
In rats dosed during pregnancy, foetal weights were decreased. In addition, an increase in foetuses with external, visceral and skeletal abnormalities was noted at high dose levels. At lower dose levels, retardations of ossification were observed. Exposure in late pregnancy resulted in an increased frequency of stillbirths and lower offspring weights. An increased frequency of retardation of ossification of the sternum was observed in rabbits.
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