Sakure

Sakure is indicated for the treatment of hypertension either alone or in combination with other antihypertensive agents, including ß-adrenoceptor antagonists, diuretics, and ACE-inhibitors.

Posology

Adults

The treatment of hypertension should be adapted to the severity of the condition, and according to the individual response.

The recommended initial dose is 2 mg once daily. The dose may be increased to 4 mg (and then, if necessary, to 6 mg) after adequate time has been allowed for the full pharmacological effect to occur. In practice, this should not be less than 3 to 4 weeks. Daily doses above 6 mg have not been shown to be significantly more effective. Sakure tablets should be taken at the same time each day, preferably in the morning. Treatment with Sakure may be continued indefinitely.

Patients with hepatic impairment

Sakure is metabolised primarily by the liver and therefore in patients with hepatic impairment, the bioavailability of Sakure may be increased and the hypotensive effect enhanced. These patients should be carefully monitored, and in severe cases, a dose reduction may be necessary.

Patients with kidney disease

As Sakure is not cleared by the kidneys, the dose does not require modification in patients with kidney disease.

Paediatric population

The safety and efficacy of Sakure in children and adolescents aged below 18 have not been estabilished. No data are available.

Method of administration

For oral administration

Sakure tablets are contraindicated in patients with known hypersensitivity to any ingredient of the preparation.

Sakure should only be used with great care in patients with a previous allergic reaction to another dihydropyridine because there is a theoretical risk of cross-reactivity.

As with other calcium antagonists, Sakure should be discontinued in patients who develop cardiogenic shock and unstable angina. In addition, dihydropyridines have been shown to reduce coronary arterial blood-flow in patients with aortic stenosis and in such patients Sakure is contraindicated.

Sakure should not be used during or within one month of a myocardial infarction.

In specialised studies Sakure has been shown not to affect the spontaneous function of the SA node or to cause prolonged conduction within the AV node. However, the theoretical potential for a calcium antagonist to affect the activity of the SA and AV nodes should be noted, and therefore Sakure should be used with caution in patients with pre-existing abnormalities in the activity of the SA and AV nodes.

As has been reported with other dihydropyridine calcium channel antagonists, Sakure should be used with caution in patients with congenital or documented acquired QT prolongation. Sakure should also be used with caution in patients treated concomitantly with medications known to prolong the QT interval such as class I and III antiarrhythmics, tricyclic antidepressants, some antipsychotics, antibiotics (e.g. erythromycin) and some antihistamines (e.g. terfenadine).

As with other calcium antagonists, Sakure should be used with caution in patients with poor cardiac reserve.

There is no evidence that Sakure is useful for secondary prevention of myocardial infarction.

The efficacy and safety of Sakure in the treatment of malignant hypertension has not been established.

Sakure should be used with caution in patients with impaired liver function because antihypertensive effect may be increased.

There is no evidence that Sakure impairs glucose tolerance or alters diabetic control.

Excipients

This product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Sakure tablets may cause dizziness. Patients should be warned not to drive or operate machinery if they experience dizziness or related symptoms.

Sakure tablets are generally well tolerated.

Some individuals may experience minor side effects which are related to its known pharmacological action of peripheral vasodilation. Such effects, indicated by a hash #, are usually transient and usually disappear with continued administration of Sakure at the same dosage.

Data from large clinical studies (internal and published) were used to determine the frequency adverse effects.

Adverse effects have been ranked under headings of frequency using the following convention:

In each group adverse effects are presented with decreasing severity.

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: www.mhra.gov.uk/yellowcard.

Symptoms

There have been no recorded cases of Sakure tablets overdosage. The expected symptoms could comprise prolonged peripheral vasodilation associated with hypotension and tachycardia. Bradycardia or prolonged AV conduction could occur.

Therapy

There is no specific antidote. Standard general measures for monitoring cardiac function and appropriate supportive and therapeutic measures should be used.

Pharmacotherapeutic group: Calcium channel blockers, dihydropyridine derivatives

ATC code: C08CA09

Mechanism of action

Sakure is a specific and potent calcium antagonist with a predominant selectivity for calcium channels in the vascular smooth muscle.

Pharmacodynamic effects

Its main action is to dilate peripheral arterioles, reducing peripheral vascular resistance and lowering blood pressure.

In a study of ten patients with a renal transplant, Sakure has been shown to prevent an acute decrease in renal plasma flow and glomerular filtration rate about six hours after administering oral cyclosporin. During the trough phase of cyclosporin treatment, there was no difference in renal plasma flow and glomerular filtration rate between patients with or without Sakure.

Following the oral administration of 4 mg Sakure to volunteer subjects, a minimal prolongation of QTc interval has been observed (mean QTcF increase between 3.44 and 9.60 ms in young and elderly volunteers). This was not associated with any adverse clinical effects or cardiac arrhythmias on monitoring.

Absorption

Sakure is a highly lipophilic compound; it is rapidly absorbed from the gastrointestinal tract following oral dosing.

Absolute bioavailability averages about 10% due to extensive first-pass metabolism in the liver.

Peak plasma concentrations are reached between 30 and 150 minutes.

Biotransformation

The principal four metabolites possess little, if any, pharmacodynamic activity.

The drug is eliminated primarily by hepatic metabolism (involving cytochrome P450 CYP3A4). There is no evidence that Sakure causes either induction or inhibition of hepatic enzymes.

Elimination

Approximately 70% of the administered dose is eliminated as metabolites in the faeces and the remainder as metabolites in the urine.

The average terminal half-life of Sakure ranges from between 13 and 19 hours at steady state.

In acute toxicity studies, Sakure has shown a wide safety margin.

In repeated dose toxicological studies, findings in animals, related to the safety profile of Sakure in man, were reversible and reflected the pharmacodynamic effect of Lacydipine.

No data of clinical relevance have been gained from in vivo and in vitro studies on reproduction toxicity, genetic toxicity or oncogenicity.

Not applicable.

The tablets should not be removed from their foil pack until required for administration.

No special requirements for disposal.

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