1. Name Of The Medicinal Product
SYSCOR MR 10
2. Qualitative And Quantitative Composition
Film-coated tablet containing 10mg nisoldipine
3. Pharmaceutical Form
Modified (extended) release tablets for oral administration.
4. Clinical Particulars
4.1 Therapeutic Indications
For the first-line treatment of mild to moderate arterial essential hypertension and the prophylaxis of chronic stable angina pectoris.
4.2 Posology And Method Of Administration
For oral administration, the tablets should be swallowed whole with a little liquid. The tablets should be taken once-daily at approximately 24-hour intervals, i.e. at the same time each day, preferably during the morning. Syscor MR tablets must be swallowed whole, under no circumstances should they be bitten, chewed or broken up. Syscor MR tablets should not be taken with grapefruit juice.
A food interaction has been observed with Syscor MR, with an increase in peak plasma concentration and decrease in the area under the plasma concentration/time curve (AUC). It is therefore preferable to administer Syscor MR in the fasting state, i.e. before breakfast.
The recommended initial dose in angina pectoris is 10mg once daily. The usual maintenance dose is 20-40mg once daily. The maximum recommended dose is 40mg once daily.
In hypertension, the recommended initial dose is one 10mg tablet once daily. If necessary, the dosage can be increased according to individual requirements up to a maximum of 40mg once daily.
Patients should be assessed at least one week after starting on any dosage before titration to a higher dosage.
Patients with renal impairment should not require adjustment of dosage. Nisoldipine is highly protein-bound (> 99%) and is not dialysable. Therefore, dose adjustment is not usually required in patients on dialysis.
An alteration of the pharmacokinetics of nisoldipine may be seen in the elderly with peak plasma concentrations and area under the plasma concentration/time curve being increased in some individuals, although there is no alteration of peak : trough fluctuation in plasma levels. Therefore, therapeutic plasma concentrations can be achieved with lower doses without compromising efficacy and safety. Therapy in the elderly with either angina pectoris or hypertension should commence with 10mg once daily, titration to higher doses being possible if clinically warranted and according to tolerability.
Treatment may be continued indefinitely.
4.3 Contraindications
Syscor MR should not be administered to patients with known hypersensitivity to nisoldipine or other dihydropyridines because of the theoretical risk of cross-reactivity, or hypersensitivity to any components of the tablets.
Syscor MR should not be administered to pregnant women, to nursing mothers or to children (aged less than 12 years).
Syscor MR should not be used in cardiogenic shock, unstable angina or during or within one week of a myocardial infarction.
Syscor MR should not be used for the treatment of acute attacks of angina.
The safety of Syscor MR in malignant hypertension has not been established.
Syscor MR should not be used for secondary prevention of myocardial infarction.
Syscor MR is contra-indicated in cases where there is a fixed cardiac output obstruction, such as aortic stenosis, as the decrease in peripheral resistance cannot be compensated by an increase in cardiac output, with ensuing risk of severe hypotension.
Syscor MR should not be used in patients receiving rifampicin or long-term treatment with phenytoin.
Syscor MR should not be administered to patients receiving ketoconazole or its congeners itraconazole and fluconazole.
Owing to the duration of action of the formulation, Syscor MR should not be administered to patients with hepatic impairment.
4.4 Special Warnings And Precautions For Use
Syscor MR tablets must be swallowed whole, under no circumstances should they be bitten, chewed or broken up.
Caution should be exercised in patients with symptomatic heart failure (NYHA Class III-IV). The safety of Syscor MR in patients with symptomatic heart failure has not been established.
There are no data to support the use of Syscor MR as monotherapy for the treatment of hypertension and chronic stable angina pectoris during or within one month of a myocardial infarction.
Caution should be exercised in patients with hypotension as there is a risk of further reduction in blood pressure.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Syscor MR may be used in combination with beta-blocking drugs, but the possibility of an additive effect resulting in postural hypotension should be borne in mind. If Syscor MR is administered at the same time as beta-blockers, the patient should be carefully monitored since severe hypotension can occur; in isolated cases, signs of heart failure can also occur. Syscor MR may not prevent possible rebound effects after cessation of other antihypertensive therapy. A study of the interaction of Syscor MR with propranolol did not suggest a significant interaction of either drug on each other's pharmacokinetics, but a possible additive effect of the two drugs must be borne in mind.
The antihypertensive effect of Syscor MR may be potentiated by simultaneous administration of cimetidine. No interaction has been observed with ranitidine.
Syscor MR does not influence the pharmacokinetics of quinidine, whilst quinidine may cause a small decrease in the AUC of Syscor MR. The clinical relevance of this interaction is probably small but it should be borne in mind that the dose of Syscor MR may need to be increased when using the two drugs concomitantly, to achieve the desired clinical effect.
As an interaction has been observed on concomitant administration of carbamazepine with other calcium antagonists, the possibility of an interaction with Syscor MR cannot be excluded.
Chronic concomitant intake of phenytoin reduces the bioavailability of nisoldipine. Therefore, nisoldipine must not be given concomitantly with phenytoin.
No interaction has been observed with concomitant administration of Syscor MR and warfarin or digoxin.
The concomitant intake of grapefruit juice may potentiate the effects of Syscor MR during the first 6-8 hours and therefore should not be taken. This effect may be due to a constituent of grapefruit juice that inhibits cytochrome P450.
4.6 Pregnancy And Lactation
The use of Syscor MR during pregnancy is contra-indicated.
The safety of Syscor MR for use in human pregnancy has not been established (Category B3). Evaluation of experimental animal studies has shown reproductive toxicity consisting of increased occurrence of phalangeal defects at maternally toxic doses.
Syscor MR is contra-indicated in nursing mothers, as nisoldipine may be present in breast milk.
4.7 Effects On Ability To Drive And Use Machines
As with some other antihypertensives, reactions may vary from individual to individual which can impair the ability to drive or to operate machinery. This applies particularly at the start of therapy, on changing medication, and in combination with alcohol.
4.8 Undesirable Effects
Gravitational oedema, headache, flushing, tachycardia and palpitation may occur, particularly on commencement of treatment. Gravitational oedema is caused by peripheral dilatation and is not associated with heart failure or weight gain. Most vasodilatory side-effects improve or regress after a few weeks with continuation of therapy. Gravitational oedema may take longer to develop and may remain for longer than other acute vasodilatory side-effects.
Dizziness, asthenia, chest pain, dyspnoea and nausea may also occur. Other less frequently reported side-effects include: paraesthesia, hypotension, myalgia, nervousness, tremor, increased urinary frequency, allergic skin reactions (rash, urticaria, pruritus), gastrointestinal disorders such as dyspepsia, abdominal pain, constipation, diarrhoea and vomiting.
As with other sustained release dihydropyridines, exacerbation of angina pectoris may rarely occur at the start of treatment with nisoldipine. The occurrence of myocardial infarction has been described although it is not possible to distinguish such an event from the natural course of ischaemic heart disease.
Disturbances of the enzymes AST (SGOT), ALT (SGPT) and CPK may occur on Syscor MR. The abnormalities are usually slight increases in enzyme levels, which tend to return to normal with continuation of therapy. If these abnormalities do not regress, or increase within a few weeks, treatment should be discontinued. Enzyme elevations usually regress on discontinuation of the drug.
Abnormal vision, liver function test abnormalities, gynaecomastia and gum hyperplasia have also been observed rarely.
Syscor MR has a mild hypouricaemic effect.
Increased diuresis has been observed in isolated cases.
Anaphylactic reactions including angioedema may occur very rarely.
4.9 Overdose
Overdosage with Syscor MR has not been reported.
Symptoms of nisoldipine overdosage might include a fall in blood pressure, disturbances of cardiac rhythm and shock.
General measures to be taken in the event of nisoldipine overdosage include gastric lavage with the addition of activated charcoal and support of vital functions, with administration of oxygen, possibly mechanical ventilation and volume replacement.
Cardiac rhythm disturbances, especially bradycardia, may be treated symptomatically with beta-sympathomimetics. If these disturbances represent a danger to the patient, a temporary pacemaker may be necessary.
Hypotension due to cardiogenic shock and arterial vasodilatation may be treated with 10-20ml of a 10% calcium gluconate solution administered slowly, intravenously. This can raise the serum calcium level to the high-normal or slightly elevated range. If the effect is insufficient, vasoconstrictive sympathomimetics such as dopamine or noradrenaline must be given in addition. The dosage of these drugs should be determined by the clinical effect observed.
Nisoldipine is not dialysable (protein-binding > 99%).
Extracorporeal detoxification by haemoperfusion or plasmapheresis is unlikely to be successful since the volume of distribution in an adult weighing 70 kg is about 300 litres.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Nisoldipine is a specific and potent calcium antagonist of the dihydropyridine class. Nisoldipine has a selective blocking effect on the slow, voltage-dependent, calcium channels. The anti-anginal and antihypertensive effects of nisoldipine are determined by its high vascular selectivity, its vasodilatory action and consequent reduction of cardiac afterload, and by its natriuretic properties.
Nisoldipine has a coronary-selective action, dilating coronary vessels more potently than peripheral arterial vessels. Consequently, when nisoldipine is used to treat coronary heart disease, there is an improvement in myocardial oxygen supply as a result of coronary dilatation. There is also a reduction in oxygen consumption as a result of the reduction of afterload.
At therapeutic doses, nisoldipine has no negative inotropic effect and does not modify impulse generation or conduction in the heart.
In clinical trials, Syscor MR was well tolerated in patients with compensated left ventricular dysfunction (NYHA Class I-II) associated with ischaemic heart disease.
In hypertension, the main effect of nisoldipine is to dilate the peripheral arterial vessels and thus reduce peripheral resistance.
There is no evidence of tolerance developing with Syscor MR during long-term therapy.
5.2 Pharmacokinetic Properties
General characteristics:
Orally administered nisoldipine is almost completely absorbed in the gastrointestinal tract. Nisoldipine undergoes marked first-pass metabolism in the liver and gastrointestinal tract, giving a systemic availability of approximately 4-8% after oral administration of a solution. Non-metabolised nisoldipine can be detected in the plasma 15-30 minutes after administration of a solution. Nisoldipine is eliminated through metabolism, 70-80% of its metabolites being excreted in the urine. The elimination kinetics are linear within the dosage range proposed. The intrinsic half-lives for nisoldipine are approximately 2 hours (beta-phase) and 10-12 hours (gamma-phase). Over 99% of nisoldipine is bound by plasma proteins.
The Syscor MR tablet is formulated to release nisoldipine in a controlled way to enable once-daily administration.
The pharmacokinetic profile of this formulation is characterised by low peak : trough fluctuation. 0-24 hour plasma-concentration versus time profiles at steady state are plateau-shaped, rendering the MR tablet appropriate for once-daily administration. Bioavailability of the drug in the MR formulation is 5.5%.
Characteristics in patients:
There are age-related changes in pharmacokinetics of nisoldipine with the AUC of the drug being increased two- to three-fold in the elderly. However, the peak : trough fluctuation is similar to that in the non-elderly, and thus clinical effect may be achieved with lower doses without compromising safety.
There are no significant differences in the pharmacokinetics of nisoldipine between healthy subjects and subjects with renal impairment including anuric patients on haemodialysis. The latter indicates that dosage adjustment is not needed in these patients. Renal dysfunction does not influence the protein binding of nisoldipine.
Nisoldipine is partly metabolised in the liver. In patients with cirrhosis, Cmax and AUC may be increased approximately three- to four-fold. Owing to the duration of action of the formulation, Syscor MR should not be administered to patients with hepatic impairment.
5.3 Preclinical Safety Data
In acute oral administration of nisoldipine, the active ingredient is only slightly toxic.
In subacute and subchronic studies in rats, nisoldipine was tolerated without damage at doses of up to 100mg/kg p.o. Chronic administration to mice (21 months) and rats (2 years) provided no evidence of a drug related carcinogenic effect.
In chronic studies in dogs, with treatment lasting up to one year, the substance was tolerated without damage at doses up to and including 3mg/kg p.o.
In studies of fertility, embryotoxicity, and perinatal and postnatal development in rats, doses of up to 10mg/kg were tolerated without damage.
Studies in rabbits have not revealed any general embryotoxic or specific teratogenic effects after doses of up to 10mg/kg p.o.
In an embryotoxicity study in monkeys, a dose which was maternally toxic (100mg/kg p.o.) also induced phalangeal defects.
In in-vitro and in-vivo tests, nisoldipine has not been associated with mutagenic properties.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Lactose
Crospovidone
Magnesium stearate
Maize starch
Microcrystalline cellulose
Sodium lauryl sulphate
Polyvidone 25
Hydroxypropylcellulose (low viscosity)
Hydroxypropylcellulose (medium viscosity)
Methylhydroxypropylcellulose
Polyethylene glycol 4000
Iron oxide yellow (E172)
Titanium dioxide (E171)
6.2 Incompatibilities
Not applicable
6.3 Shelf Life
Shelf life of the product as packaged for sale:
|
| |||
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
6.4 Special Precautions For Storage
The tablets should be protected from strong light and stored in the manufacturer's original container.
6.5 Nature And Contents Of Container
Calendar packs of PP or PVC, each containing 28 tablets (professional sample pack of 14 tablets also available).
6.6 Special Precautions For Disposal And Other Handling
The light-sensitive active ingredient of Syscor MR tablets is protected from light by film-coating the tablets. Nevertheless, it is advisable not to remove the tablets from the manufacturer's original container until immediately before use.
Syscor MR must not be used after the expiry date.
Keep out of the reach of children.
7. Marketing Authorisation Holder
|
|
|
|
8. Marketing Authorisation Number(S)
PL 0108/0117
9. Date Of First Authorisation/Renewal Of The Authorisation
7 December 1998
10. Date Of Revision Of The Text
August 1998
11. Legal Category
POM
No comments:
Post a Comment