INFORMATION FOR HEALTH PROFESSIONALS
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Syscor® CC 10: 1 film-coated tablet contains 10 mg nisoldipine
Syscor® CC 20: 1 film-coated tablet contains 20 mg nisoldipine
Syscor® CC 30: 1 film-coated tablet contains 30 mg nisoldipine
Syscor® CC 40: 1 film-coated tablet contains 40 mg nisoldipine
| Syscor® CC 10 | Modified (extended) release tablets, film-coated, for oral use. |
|---|---|
| Syscor® CC 20 | Modified (extended) release tablets, film-coated, for oral use. |
| Syscor® CC 30 | Modified (extended) release tablets, film-coated, for oral use. |
| Syscor® CC 40 | Modified (extended) release tablets, film-coated, for oral use. |
The coat tablet consists of an external coat and an internal core. Both coat and
core contain nisoldipine, the coat as a slow release formulation and the core as
a fast release formulation.
Treatment of chronic stable angina pectoris
Treatment of hypertension
The recommended initial dose in hypertension is one 10 mg tablet once-daily. If necessary, the dosage can be increased usually at weekly intervals, according to individual requirements, up to a maximum of 40 mg once-daily.
In angina, the recommended dosage range is 20 mg to 40 mg once-daily. The initial recommended dose is 20 mg once-daily.
Patients controlled on nisoldipine immediate release tablets may be switched safely to Syscor® CC at the recommended initial dose of 10 mg once-daily in hypertension or 20 mg once-daily in angina pectoris. Subsequent titration to a higher dose may be initiated as clinically warranted.
For oral administration, the tablets should be swallowed with a little liquid. Syscor® CC tablets should be taken once-daily at approximately 24-hour intervals, at the same time each day, preferably during the morning before breakfast.
In order to keep the modified release matrix tablets intact and thus to ensure 24 hours-efficacy Syscor® CC tablets must be swallowed whole; under no circumstances should they be bitten, chewed or broken up. Syscor® CC tablets should not be taken with grapefruit juice.
Increased plasma concentrations of nisoldipine may be seen in the elderly. Treatment of elderly patients should start with the lowest dosage of 10 mg once-daily in both hypertension and angina.
Nisoldipine is metabolised in the liver. It is therefore recommended that patients with liver dysfunction should commence therapy at the lowest dose of 10 mg once-daily in both hypertension and angina, with careful monitoring of clinical response as the effects of the drug can be potentiated and prolonged.
Patients with renal impairment should not require adjustment of dosage.
Treatment may be continued indefinitely.
Syscor® CC must not be administered:
- in cases of hypersensitivity to any component of the tablets
- in cases of shock
- in patients taking rifampicin (rifampin) or phenytoin chronically
- in patients taking ketoconazole, itraconazole, fluconazole
- during pregnancy and breastfeeding
Syscor® CC tablets must be swallowed whole; under no circumstances should they be bitten, chewed or broken up.
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.
Although acute haemodynamic studies of nisoldipine in patients with NYHA Class II-IV heart failure have not demonstrated negative inotropic effects, safety of Syscor® CC in patients with heart failure has not been established. Caution therefore should be exercised when using Syscor® CC 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® CC 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® CC, 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.
Cimetidine
The effects of Syscor® CC may be potentiated by simultaneous administration of cimetidine. A 30 to 45 % increase in AUC and Cmax of nisoldipine was observed with concomitant administration of cimetidine 400 mg twice daily.
Phenytoin
Chronic concomitant intake of phenytoin reduces the bioavailability of nisoldipine. Therefore, Syscor® CC must not be given concomitantly.
Quinidine
Quinidine may cause a small decrease in the AUC of Syscor® CC. The clinical relevance of this interaction is probably small but it should be borne in mind when using the two drugs concomitantly, that the dose of Syscor® CC may need to be increased to achieve the desired clinical effect.
Ketoconazole
Concomitant intake of ketoconazole 200 mg increases the bioavailability of Syscor® CC 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.
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® CC.
Erythromycin
No interaction studies have been carried out between Syscor® CC 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® CC. 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® CC due to enzyme induction. Thus, efficacy of Syscor® CC could be reduced and additional therapy could become necessary.
Carbamazepine
No interaction studies have been carried out between Syscor® CC 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® CC.
Magnesium and aluminium-containing antacids
Magnesium and aluminium-containing antacids do not influence the pharmacokinetics of Syscor® CC.
Beta-blockers
Pharmacokinetic interactions between nisoldipine and beta-blockers (atenolol, propranolol) were variable and no significant trends were observed. Syscor® CC 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® CC 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® CC does not influence the pharmacokinetics of quinidine.
Digoxin
Syscor® CC does not influence the pharmacokinetics of β-acetyl-digoxin.
Concomitant intake of grapefruit juice and Syscor® CC may potentiate the effects of the drug during the first 6-8 hours.
A food interaction has been observed with Syscor® CC 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® CC in the fasting state, i.e. before breakfast.
Syscor® CC is contraindicated throughout pregnancy. The safety of Syscor® CC for use in human pregnancy has not been established. Evaluation of experimental animal studies has shown reproductive toxicity consisting of increased occurrence of phalangeal defects at maternally toxic doses.
Syscor® CC is contraindicated during the breastfeeding period as nisoldipine may be present in breast milk.
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® CC. 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: 27.2.97):
| Incidence of frequency ≥ 10% | Adverse Drug Reactions | nisoldipine (n=2254) |
placebo (n=1083) |
|---|---|---|---|
| Metabolic and nutritional disorder: | peripheral edema | 13.4 | 3.5 |
| Nervous system: | headache | 14.4 | 8.7 |
| Incidence of frequency ≥ 1% < 10% | |||
| Body as a whole: | asthenia | 2.8 | 1.8 |
| Cardiovascular system: | angina pectoris | 2.0 | 5.4 |
| chest pain | 1.7 | 1.8 | |
| palpitation | 2.3 | 1.4 | |
| vasodilatation | 3.3 | 1.4 | |
| Digestive system: | nausea | 2.3 | 0.9 |
| Nervous system: | dizziness | 4.8 | 3.9 |
| Respiratory system: | dyspnea | 1.6 | 1.7 |
| Incidence of frequency ≥ 0.1% < 1% | |||
| Cardiovascular system: | hypotension | 0.5 | 0.6 |
| tachycardia | 0.8 | 0.3 | |
| Digestive system: | abdominal pain | 0.3 | 0.4 |
| constipation | 0.8 | 0.6 | |
| diarrhea | 0.5 | 0.5 | |
| dyspepsia | 0.8 | 0.8 | |
| vomiting | 0.6 | 0.1 | |
| Musculo-skeletal system: | myalgia | 0.1 | 0 |
| Nervous system: | nervousness | 0.2 | 0.1 |
| paraesthesia | 0.4 | 0.1 | |
| tremor | 0.3 | 0 | |
| Skin and appendages: | pruritius | 0.5 | 0.5 |
| rash | 0.5 | 0.6 | |
| Special senses: | abnormal vision | 0.1 | 0 |
| Incidence of frequency ≥ 0.01% < 0.1% | |||
| Digestive system: | liver function test abnormal, | 0.04 | 0 |
| Skin and appendages: | urticaria | 0.04 | 0.1 |
The most common adverse drug reactions based on all clinical studies with Syscor® CC sorted by frequency and body system (n = 5411 patients, status: 27.2.97):
| Incidence of frequency ≥ 1% < 10% | Adverse Drug Reactions |
|---|---|
| Body as a whole: | asthenia |
| Cardiovascular system: | angina pectoris, chest pain, palpitation, tachycardia, vasodilatation, |
| Digestive system: | nausea |
| Metabolic and nutritional disorder: | peripheral edema |
| Nervous system: | dizziness, headache |
| Respiratory system: | dyspnea |
| Incidence of frequency ≥ 0.1% < 1% | |
| Cardiovascular system: | hypotension |
| Digestive system: | abdominal pain, constipation, diarrhea, dyspepsia |
| Musculo-skeletal system: | myalgia |
| Nervous system: | nervousness, paraesthesia, tremor, |
| Skin and appendages: | pruritius, rash, urticaria |
| Urogenital system: | increased urinary frequency |
| Incidence of frequency ≥ 0.01% < 0.1% | |
| Digestive system: | gum hyperplasia, liver function test abnormal, |
| Skin and appendages: | gynaecomastia |
| Special senses: | abnormal vision |
The most common adverse drug reactions based on spontaneous reports with Syscor® CC sorted by frequency and body system calculated on patient exposure (n = 72 patients, status: 28.02.97):
| Incidence of frequency ≤ 0.01% | Adverse Drug Reactions |
|---|---|
| Skin and appendages: | anaphylactic reaction, angioedema |
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-symphathomimetics; 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, vasoconstructive 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.
Syscor® CC has been used in adjuvant treatment in patients with angina pectoris, and compensated heart failure (NYHA stage II), in whom the addition of the drug was haemodynamically beneficial and well tolerated. There are no safety data for use of the drug in patients with concomitant overt or severe heart failure (NYHA stages III-IV).
There is no evidence of tolerance developing with nisoldipine during long-term therapy.
Orally administered nisoldipine is almost completely absorbed in the gastrointestinal tract. Nisoldipine undergoes a marked first-pass metabolism in the liver and gastro-intestinal tract, giving a systemic availability of approximately 4-8% after oral administration of a solution. Unmetabolised 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® CC tablet is formulated to release nisoldipine in a controlled way to enable once-daily administration.
The pharmacokinetic profile of this formulation is characterised by reduced maximum concentrations and peak-trough fluctuations as compared to the immediate release tablet. 0-24 hour plasma-concentration vs. time profiles at steady state are plateau-like, rendering the CC-tablet appropriate for once a day administration. Absolute bioavailability of the drug in the CC-formulation was found to be 5.5%.
There are age-releated changes in the pharmacokinetics of nisoldipine with Cmax and AUC of the drug being increased approximately twofold in the elderly.
There are no differences in Cmax or AUC of Nisoldipine between healthy subjects and subjects with renal impairment including anuric patients on haemodialysis. The latter indicate that dosage adjustment is not needed in these patients. Renal dysfunction does not influence the protein binding of nisoldipine.
In patients with liver cirrhosis, Cmax and AUC may be increased by a factor of approximately 3 to 4. Treatment of these patients should be started with the lowest dose of 10 mg Syscor® CC once-daily.
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 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 embryotoxic study in monkeys, a dose which was 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® CC tablets contain the following excipients:
lactose, crospovidone, magnesium stearate, maize starch, microcrystalline cellulose, sodium lauryl sulfate, polyvidone 25, hydroxipropylcellulose (low viscosity), hydroxypropylcellulose (medium viscosity), methylhydroxypropyl-cellulose, polyethylene glycol 4000, iron oxide yellow (E 172), titanium dioxide (E 171); 30 mg and 40 mg tablets contain in addition iron oxide red (E 172).
Not applicable.
48 months from date of manufacture, stored below 25°C
The tablets should be stored in the manufacturer's original container.
Thermoformed foil PP & PVC/PVDC
Soft foil (aluminium/aluminium)
30's in 3 blister strips of 10
Glass bottles 100's
The light-sensitive active ingredient of Syscor® CC 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® CC 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
1 March 1999
Original: Syscor® CC/SPC/3 - July 14, 1998