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Syscor® 1 film-coated tablet contains 5 mg nisoldipine
Syscor®10 1 film-coated tablet contains 10 mg nisoldipine
| Syscor® | Immediate release tablets, film-coated, for oral use |
|---|---|
| Syscor®10 | Immediate release tablets, film-coated, for oral use |
As far as possible the treatment must be tailored to the severity of the disease and the patient's responsiveness. To allow adjustment of the dose to suit each individual patient, the drug is available as Syscor containing 5 mg nisoldipine and Syscor 10 containing 10 mg nisoldipine.
Unless otherwise prescribed, the following dosage guidelines apply (the basic dose for adults is given):
- For chronic stable angina: 2 x 5-10 mg nisoldipine/day
If higher doses are needed the daily dose can be gradually increased to 2 x 20 mg nisoldipine, in accordance with individual requirements.
- For hypertension: 2 x 5-10 mg nisoldipine/day
If higher doses are needed the daily dose can be gradually increased to 2 x 20 mg nisoldipine, in accordance with individual requirements.
In patients with severe disturbances of liver function treatment must be initiated at the lowest dose (i.e. 1 x 5-10 mg nisoldipine/day) and the patient carefully monitored since the effects of the drug can be potentiated and prolonged.
Patients with renal impairment should not require adjustment of dosage.
Nisoldipine is generally well tolerated in patients over 65 years, but it may be advisable to titrate the dose more carefully. Treatment should start with the lowest dose.
The film-coated tablets are generally swallowed whole with a little liquid at mealtimes (preferably at breakfast and with the evening meal).
The tablets should not be taken with grapefruit juice.
No limit on the duration of use is envisaged.
Syscor must be withdrawn gradually, particularly if taken at high doses.
Syscor must not be administered:
- in cases of hypersensitivity to any component of the tablet
- in cases of shock
- in patients taking rifampicin (rifampin) or phenytoin chronically
- in patients taking ketoconazode, itraconazole, fluconazole
- during pregnancy and breastfeeding
As with other vasoactive substances, angina pectoris attacks may very rarely occur at the start of treatment with Syscor. The occurrence of myocardial infarction has been described in isolated cases, although it was not possible to distinguish this from the natural course of the underlying disease.
Care should be exercised in patients with very low blood pressure (severe hypotension: systolic pressure lower than 90 mm Hg) and in patients with severe aortic stenosis.
Safety of Syscor in patients with heart failure has not been established. Caution therefore should be exercised when using Syscor in patients with heart failure or compromised ventricular function, particularly in combination with a beta-blocker.
In patients with severe disturbances of liver function the activity of Syscor can be potentiated and prolonged. In these cases treatment must be initiated at the lowest dose and the patient carefully monitored during the therapy.
Children should not be treated with Syscor, as no findings are available in relation to the use of the drug in this age group.
Nisoldipine is metabolised via the cytochrome P450 3A4 system, located both in the intestinal mucosa and in the liver. Drugs that are known to either inhibit or to induce this enzyme system may therefore alter the first pass or the clearance of nisoldipine.
Other Drugs that affect Syscor
Demonstrated Interactions
Cimetidine
The effects of Syscor may be potentiated by simultaneous administration of cimetidine. The treatment of patients receiving cimetidine should start with the lowest dose of Syscor and should be carefully monitored.
Phenytoin
Chronic concomitant intake of phenytoin reduces the bioavailability of nisoldipine. Therefore, Syscor must not be given concomitantly.
Ketoconazole
Concomitant intake of ketoconazole 200 mg increases the bioavailability of nisoldipine by more than 20-fold. Due to the magnitude of the interaction a dose reduction of nisoldipine can not be recommended. Both drugs should not be given concomitantly.
Theoretical Potential Interactions
Itraconazole, Fluconazole
Both these drugs belong to the same class as ketoconazole which was shown to significantly increase nisoldipine bioavailability. Owing to similar inhibitory effects expected on the cytochrome P450 system, neither itraconazole nor fluconazole should be used in combination with Syscor.
Erythromycin
No interaction studies have been carried out between Syscor and erythromycin. As both nisoldipine and erythromycin undergo metabolism by CYP3A4, the potential for drug interaction cannot be ruled out at this stage. Erythromycin is known to inhibit CYP3A4 mediated metabolism of other drugs.
Valproic acid
From experience with the calcium antagonist nimodipine it has to be expected that valproic acid inhibits the metabolism of Syscor. The resulting increase in plasma-concentration can be expected to translate into increased efficacy.
Rifampicin (rifampin)
From experience with the calcium antagonist nifedipine it has to be expected that rifampicin (rifampin) accelerates the metabolism of Syscor due to enzyme induction. Thus, efficacy of Syscor could be reduced and additional therapy could become necessary.
Carbamazepine
No interaction studies have been carried out between Syscor and carbamazepine. As carbamazepine has been shown to reduce the plasma-concentrations of nimodipine due to enzyme-induction, a decrease in nisoldipine concentrations and efficacy cannot be excluded.
Phenobarbitone
As phenobarbitone has been shown to reduce the plasma-concentrations of nimodipine, a decrease in nisoldipine concentrations and efficacy cannot be ruled out.
Ranitidine
Ranitidine does not influence the pharmacokinetics of Syscor.
Beta-blockers
Pharmacokinetic interactions between nisoldipine and beta-blockers (atenolol, propranolol) were variable and no significant trends were observed. Syscor may be used in combination with beta-blocking drugs and other anti-hypertensive agents, but the possibility of an additive effect resulting in postural hypotension should be borne in mind.
If Syscor 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.
Quinidine
Syscor does not influence the pharmacokinetics of quinidine.
Digitalis glycosides
Syscor does not influence the pharmacokinetics of β-acetyl-digoxin or
Other interactions
Concomitant intake of grapefruit juice inhibits the oxidative metabolism of Syscor, resulting in increased plasma concentrations which can cause an increased blood pressure-lowering effect.
Syscor is contraindicated throughout pregnancy. Animal studies using clearly maternally toxic doses of nisoldipine have brought to light evidence of malformation.
Syscor is contraindicated during the breastfeeding period, because nisoldipine may pass into the breast milk and there are no data available to estimate the pharmacodynamic effects of nisoldipine in infants.
In single cases of in-vitro fertilization, similar calcium antagonists (nifedipine) have been associated with reversible biochemical changes in the spermatozoa's head section that may result in impaired sperm function. In men who are repeatedly unsuccessful in fathering a child by in-vitro fertilization and if no other explanation can be found, nisoldipine should be considered a possible reason.
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.
Most side-effects are consequences of the vasodilatory effects of Syscor. Side effects occur predominantly at the onset of therapy or on increasing dosage. They are mostly mild and transient in nature.
In placebo controlled clinical studies the following adverse drug reactions sorted by frequency and body system have been reported (status: 10.03.97):
| Incidence of frequency ≥1% < 10% | Adverse Drug Reactions | nisoldipine (n = 1388) |
placebo (n = 991) |
|---|---|---|---|
| Body as a whole: | asthenia | 2.8 | 1.6 |
| Cardiovascular system: | chest pain | 1.2 | 0.3 |
| palpitation | 1.9 | 0.2 | |
| vasodilatation | 4.0 | 1.0 | |
| Metabolic and nutritional disorder: | peripheral edema | 1.5 | 0.4 |
| Nervous system: | dizziness | 3.6 | 2.2 |
| headache | 5.1 | 3.0 | |
| nervousness | 1.0 | 0.7 | |
| Respiratory system: | dyspnea | 1.2 | 0.8 |
Incidence of frequency ≥0,1% < 1% |
|||
| Cardiovascular system: | angina pectoris | 0.6 | 0.3 |
| hypotension | 0.4 | 0.1 | |
| tachycardia | 0.6 | 0.1 | |
| Digestive system: | abdominal pain | 0.7 | 0.2 |
| constipation | 0.4 | 0.2 | |
| diarrhea | 0.3 | 0.1 | |
| dyspepsia | 0.4 | 0.6 | |
| liver function test abnormal | 0.1 | 0 | |
| nausea | 0.8 | 1.0 | |
| vomiting | 0.2 | 0.1 | |
| Musculo-skeletal system: | myalgia | 0.1 | 0.1 |
| Nervous system: | paraesthesia | 0.4 | 0 |
| tremor | 0.4 | 0.2 | |
| Skin and appendages: | gynaecomastia | 0.1 | 0.1 |
| pruritus | 0.1 | 0.1 | |
| rash | 0.2 | 0.2 | |
| Special senses: | abnormal vision | 0.1 | 0 |
| Urogenital system: | increased urinary frequency | 0.1 | 0 |
The most common adverse drug reactions based on all clinical studies sorted by frequency and body system (n = 8452 patients, status: 27.02.1997):
| Incidence of frequency: ≥10% | ||
|---|---|---|
| Nervous system: | headache | |
| Metabolic and nutritional disorder: | peripheral edema | |
| Incidence of frequency: ≥1% < 10% | ||
| Body as a whole: | asthenia | |
| Cardiovascular system: | palpitation, tachycardia, vasodilatation | |
| Digestive system: | nausea | |
| Nervous system: | dizziness | |
| Incidence of frequency: ≥0,1% < 1% | ||
| Cardiovascular system: | angina pectoris, chest pain, hypotension | |
| Digestive system: | abdominal pain, constipation, diarrhea, dyspepsia, liver function test abnormal, vomiting | |
| Musculo-skeletal system: | myalgia, | |
| Nervous system: | nervousness,paraesthesia, tremor | |
| Respiratory system: | dyspnea | |
| Skin and appendages: | pruritus, rash, urticaria | |
| Incidence of frequency: ≥0,01% < 0,1% | ||
| Skin and appendages: | gynaecomastia | |
| Special senses: | abnormal vision | |
| Urogenital system: | increased urinary frequency | |
Adverse Drug Reactions
The most common adverse drug reactions based on spontaneous reports sorted by frequency and body system calculated on patient exposure (n = 236 patients, status: 28.02.97):
| Incidence of frequency: ≤0,01% | |
|---|---|
| Digestive system: | gum hyperplasia |
| Skin and appendages: | anaphylactic reaction, angioedema, photosensitive dermatitis |
Symptoms of nisoldipine overdosage may include a fall in blood pressure, shock and disturbances of cardiac rhythm (tachycardia and bradycardia).
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 (administration of oxygen, possibly mechanical ventilation, 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 vasodilation may be treated with calcium, as 10-20 ml of a 10 % calcium gluconate solution administered slowly by the intravenous route and repeated, if necessary. 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 might 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.
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 demonstrates selectivity for vascular smooth muscle dilating both coronary and peripheral arteries. Experimental data demonstrate a more potent action of nisoldipine on coronary vessels than peripheral arterial vessels. However, this observation has not been confirmed in clinical trials. Consequently, when nisoldipine is used to treat coronary heart disease, there is an improvement in myocardial oxygen supply as a result of the reduction of afterload.
In hypertension, the main effect of nisoldipine is to dilate the peripheral arterial vessels and thus reduce peripheral resistance.
At therapeutic doses, nisoldipine has no significant negative inotropic effect and does not modify impulse generation or conducting in the heart.
There is no evidence of tolerance developing with nisoldipine during long-term therapy.
Orally administered nisoldipine is almost completely absorbed through the mucosae in the gastrointestinal tract. Nisoldipine undergoes a marked first-pass metabolism in the liver and gastro-intestinal tract, giving a systemic availability of 4-8% after oral administration of a solution. Unmetabolised nisoldipine can be detected in the plasma 15-30 minutes after administration of a solution. Peak plasma concentrations are reached after 0.5-2 h. After administration of the 5 mg film-coated tablet they are approximately 0.9 ng/ml (0.5-1.7 ng/ml), rising dose-proportionally to 1.9 ng/ml (1.3-2.6 ng/ml) after the 10 mg tablet. Nisoldipine is eliminated through metabolism, 70-80% of ist 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.
There are age-related changes in the pharmacokinetics of nisoldipine with Cmax and AUC of the drug being increased approximately twofold in elderly subjects (mean age 69 years) when compared to young subjects (mean age 24 years).
There were no changes in Cmax or AUC of the drug between healthy subjects and subjects with renal impairment including anuric patients requiring maintenance haemodialysis indicating that renal impairment does not necessitate a change of dose. Renal dysfunction also did not influence the protein-binding of nisoldipine.
The bioavailability of the drug was increased 4-fold in patients with liver-cirrhosis indicating the need for dose-reduction in these patients.
In acute oral administration nisoldipine is only slightly toxic.
In subacute and subchronic studies in rats, nisoldipine was tolerated without damage at doses of up to 100 mg/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 3 mg/kg p.o.
In studies of fertility, embryotoxicity, and perinatal and postnatal development in rats, doses of up to 10 mg/kg p.o. were tolerated without damage.
Studies in rabbits have not revealed any general embryotoxic or specific teratogenic effects after doses of up to 10 mg/kg p.o.
In an embryotoxicity study in monkeys, a dose which was clearly maternally toxic (100 mg/kg p.o.) induced phalangeal defects.
In in-vitro and in-vivo tests, nisoldipine has not been associated with mutagenic properties.
Syscor and Syscor 10 contain the following excipients:
maize starch, microcrystalline cellulose, lactose, povidone (polyvinylpyrrolidone), sodium lauryl sulfate, magnesium stearate, methylhydroxypropylcellulose, polyethylene glycol 4000 (macrogol 4000), titanium dioxide (E 171/C.I. 77891), iron oxide red (E 172/C.I. 77491)
36 months, stored below 25°C.
The tablets should be protected from light.
Glass bottle or Red PVC thermoformed foil
The light-sensitive active ingredient of Syscor and Syscor 10 film-coated tablets is protected from light inside its packaging; hence it is advisable not to remove the tablets from the pack until immediately before use.
Syscor must not be used after the expiry date.
Keep out of the reach of children.
Prescription Medicine
Name and Address:
Bayer New Zealand Limited
Argus Place
Glenfield
Auckland
New Zealand
4 February, 1999
Original: Syscor®/SPC/5 - July 14, 1998