Dilsatan

Dilsatan 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 (peripheral arterial disease Fontaine stage II).

Dilsatan is for second-line use, in patients in whom lifestyle modifications (including stopping smoking and [supervised] exercise programs) and other appropriate interventions have failed to sufficiently improve their intermittent claudication symptoms.

Posology

The recommended dosage of Dilsatan is 100 mg twice a day.

The physician should reassess the patient after 3 months of treatment with a view to discontinuing Dilsatan where an inadequate effect is observed or symptoms have not been improved.

Patients receiving treatment with Dilsatan should continue with their life-style modifications (smoking cessation and exercise), and pharmacological interventions (such as lipid lowering and antiplatelet treatment) to reduce the risk of cardiovascular events. Dilsatan is not a substitute for such treatments. Reduction of the dose to 50 mg twice daily is recommended in patients receiving medicines that strongly inhibit CYP3A4, for example some macrolides, azole antifungals, protease inhibitors, or medicines that strongly inhibit CYP2C19, for example omeprazole.

elderly

There are no special dosage requirements for the elderly.

Paediatric population

The safety and efficacy of Dilsatan in children have not yet been established.

Renal impairment

No dose adjustment is necessary in patients with a creatinine clearance of > 25 ml/min. Dilsatan 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 Dilsatan is extensively metabolised by hepatic enzymes, it is contraindicated in patients with moderate or severe hepatic impairment.

Method of administration

Dilsatan should be taken 30 minutes before breakfast and the evening meal. Taking Dilsatan with food has been shown to increase the maximum plasma concentrations (C_max) of Dilsatan, which may be associated with an increased frequency of adverse reactions.

- Severe renal impairment: creatinine clearance of ≤ 25 ml/min

- Moderate or severe hepatic impairment

- Congestive heart failure

- Pregnancy

- Patients with any known predisposition to bleeding (e.g. active peptic ulceration, recent [within six months] haemorrhagic stroke, proliferative diabetic retinopathy, poorly controlled hypertension)

- Patients with any history of ventricular tachycardia, ventricular fibrillation or multifocal ventricular ectopics, whether or not adequately treated, and in patients with prolongation of the QTc interval

- Patients with a history of severe tachyarrhythmia

- Patients treated concomitantly with two or more additional antiplatelet or anticoagulant agents (e.g. 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 Dilsatan should be carefully considered alongside other treatment options such as revascularisation.

Based on its mechanism of action, Dilsatan may induce tachycardia, palpitation, tachyarrhythmia and/or hypotension. The increase in heart rate associated with Dilsatan 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 Dilsatan, while the use of Dilsatan 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 Dilsatan 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.5 for further information on bleeding risks.

Due to Dilsatan'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 anti-platelet effect is not necessary, Dilsatan 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 Dilsatan. 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. Dilsatan 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 Dilsatan were shown to be increased.).

Caution is needed when co-administering Dilsatan 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 Dilsatan with any other agents that inhibit platelet aggregation.5.

Dilsatan may cause dizziness and patients should be warned to exercise caution before they drive or operate machinery.

The most commonly reported adverse reactions in clinical trials 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 in clinical trials and in the post-marketing period are included in the table below.

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 <1/1,000)

Very rare (<1/10,000)

not known (cannot be estimated from the available data)

The frequencies of reactions observed in the post-marketing period are considered unknown (cannot be estimated from the available data).

An increase in the frequency of palpitation and peripheral oedema was observed when Dilsatan 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 Dilsatan was headache. Other frequent causes of discontinuation included palpitation and diarrhoea (both 1.1%).

Dilsatan 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 diarrhoea and palpitation has been found in patients older than 70 years.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Information on acute overdose in humans is limited. The signs and symptoms can be anticipated to be severe headache, diarrhoea, tachycardia and possibly cardiac arrhythmias.

Patients should be observed and given supportive treatment. The stomach should be emptied by induced vomiting or gastric lavage, as appropriate.

Pharmacotherapeutic group: Antithrombotic agents, platelet aggregation inhibitor excl. heparin.

ATC code: B01A C23

From data generated in nine placebo-controlled studies (where 1,634 patients were exposed to Dilsatan), it has been demonstrated that Dilsatan 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, Dilsatan 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 Dilsatan 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 Dilsatan to have vasodilator effects and this has been demonstrated in small studies in man where ankle blood flow was measured by strain gauge plethysmography. Dilsatan 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 Dilsatan 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 Dilsatan recovery of aggregation occurred within 48-96 hours, without rebound hyperaggregability. Effects on circulating plasma lipids have been examined in patients taking Dilsatan. After 12 weeks, as compared to placebo, Dilsatan 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 Dilsatan, with focus on mortality and safety. In total, 1,439 patients with intermittent claudication and no heart failure have been treated with Dilsatan 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 Dilsatan and 6.8% (95% CI of 1.9 to 11.5%) on placebo. Long-term treatment with Dilsatan did not raise safety concerns.

Absorption

Following multiple doses of Dilsatan 100 mg twice daily in patients with peripheral vascular disease, steady state is achieved within 4 days.

Distribution

Dilsatan is 95-98% protein bound, predominantly to albumin. The dehydro metabolite and 4'-trans- hydroxy metabolite are 97.4% and 66% protein bound respectively.

Biotransformation

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 Dilsatan concentrations.

Elimination

The apparent elimination half-life of Dilsatan is 10.5 hours.

There are two major metabolites, a dehydro-Dilsatan and a 4'-transhydroxy Dilsatan, both of which have similar apparent half-lives.

Dilsatan 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 Dilsatan is excreted in the urine, and less than 2% of the dose is excreted as the dehydro-Dilsatan 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.

Linearity/non-linearity

The Cmax of Dilsatan and its primary circulating metabolites increase less than proportionally with increasing doses. However, the AUC for Dilsatan and its metabolites increase approximately proportionately with dose.

There is no evidence that Dilsatan induces hepatic microsomal enzymes.

The pharmacokinetics of Dilsatan 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 Dilsatan 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 Dilsatan 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. There are no data in patients with moderate to severe hepatic impairment and since Dilsatan is extensively metabolised by hepatic enzymes, the medicine must not be used in such patients.

Dilsatan 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, Dilsatan 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 Dilsatan 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 Dilsatan 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.

Dilsatan 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.

Not applicable.

No special requirements.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.