Cardene 20 mg

Cardene 30 mg

Nicardipine hydrochloride 20 mg

Nicardipine hydrochloride 30 mg

Capsules

Cardene is indicated for the prophylaxis of patients with chronic stable angina. For the treatment of hypertension considered to be mild to moderate in severity.

Nicardipine should be taken with a little water.

Prophylaxis of chronic stable angina:

Starting dose: 20 mg every 8 hours titrating upwards as required.

Usual effective dose: 30 mg every 8 hours (range of total dose 60 mg - 120 mg per day).

Allow at least 3 days before increasing the dose of Cardene to ensure steady state plasma levels have been achieved.

Hypertension:

Starting dose: 20 mg every 8 hours titrating upwards as required.

Usual effective dose: 30 mg every 8 hours (range of total dose 60 mg - 120 mg per day).

Use in elderly:

Starting dose is 20 mg 3 times a day. Titrate upwards with care as nicardipine may lower systolic pressure more than diastolic pressure in these patients.

Children:

Cardene is not recommended in patients under the age of 18.

Cardene capsules are for oral administration.

(1) Pregnancy and lactation.

(2) Hypersensitivity to nicardipine hydrochloride or other dihydropyridines because of the theoretical risk of cross reactivity.

(3) Because part of the effect of nicardipine is secondary to reduced afterload, the drug should not be given to patients with advanced aortic stenosis. Reduction of diastolic pressure in these patients may worsen rather than improve myocardial infarction.

(4) Cardene should not be used in cardiogenic shock, clinically significant aortic stenosis, unstable angina, and during or within one month of a myocardial infarction.

(5) Cardene should not be used for acute attacks of angina.

(6) Cardene should not be used for secondary prevention of myocardial infarction.

If used in combination with diuretics or beta-blockers, careful titration of Cardene is advised to avoid excessive reduction in blood pressure.

If switching from beta-blockers to Cardene, gradually reduce the beta-blocker dose (preferably over 8 - 10 days) since nicardipine gives no protection against the dangers of abrupt beta-blocker withdrawal.

Stop Cardene in patients experiencing ischaemic pain within 30 minutes of starting therapy or after increasing the dose.

Use in patients with congestive heart failure or poor cardiac reserve:

Haemodynamic studies in patients with heart failure have shown that nicardipine reduces afterload and improves overall haemodynamics. In one study, intravenous nicardipine reduced myocardial contractility in patients with severe heart failure despite increases in cardiac index and ejection fraction noted in the same patients.

Since nicardipine has not been extensively studied in patients with severe left ventricular dysfunction and cardiac failure one must consider that worsening of cardiac failure may occur.

Use in patients with impaired hepatic or renal function:

Since Cardene is subject to first-pass metabolism, use with caution in patients with impaired liver function or reduced hepatic blood flow. Patients with severe liver disease showed elevated blood levels and the half-life of nicardipine was prolonged. Cardene blood levels may also be elevated in some renally impaired patients. Therefore the lowest starting dose and extending the dosing interval should be individually considered in these patients.

Use in patients following a stroke (infarction or haemorrhage):

Avoid inducing systemic hypotension when administering Cardene to these patients.

Laboratory tests:

Transient elevations of alkaline phosphatase, serum bilirubin, SGPT, SGOT and glucose, have been observed. BUN and creatinine may also become elevated. While out-of-range values were seen in T₃, T₄ and TSH, the lack of consistent alterations suggest that any changes were not drug-related.

Treatment with short acting nicardipine may induce an exaggerated fall in blood pressure and reflex tachycardia which can cause cardiovascular complications such as myocardial and cerebrovascular ischaemia.

There has been some concern about increased mortality and morbidity in the treatment of ischaemic heart disease using higher than recommended doses of some other short-acting dihydropyridines.

Digoxin

Careful monitoring of serum digoxin levels is advised in patients also receiving Cardene as levels may be increased.

Propanolol, Dipyridamole, Warfarin, Quinidine, Naproxen:

Therapeutic concentrations of these drugs does not change the in vitro plasma protein binding of nicardipine.

Cimetidine:

Cimetidine increases nicardipine plasma levels. Carefully monitor patients receiving both drugs.

Fentanyl Anaesthesia:

Severe hypotension has been reported during fentanyl anaesthesia with concomitant use of a beta-blocker and calcium blockade. Even though such interactions have not been seen in clinical trials, such hypotensive episodes should be vigorously treated with conventional therapy such as intravenous fluids.

Cyclosporin:

Monitor cyclosporin plasma levels and reduce dosage accordingly in patients concomitantly receiving nicardipine as elevated cyclosporin levels have been reported.

Rifampicin:

Rifampicin can interact with other dihydropyridines to substantially reduce their plasma levels and so rifampicin and nicardipine should be used together with caution.

As with other dihydropyridines, nicardipine should not be taken with grapefruit juice because bioavailability may be increased.

Cardene may be used in combination with beta-blocking and other anti-hypertensive drugs but the possibility of an additive effect resulting in postural hypotension should be considered.

See contra-indications.

None known.

Majority are not serious and are expected consequences of the vasodilator effects of Cardene.

The most frequent side-effects reported are headache, pedal oedema, heat sensation and/or flushing, palpitations, nausea and dizziness.

Other side-effects noted in clinical trials include the following:

Cardiovascular System: As with the use of other short-acting dihydropyridines in patients with ischaemic heart disease, exacerbation of angina pectoris may occur frequently at the start of treatment with nicardipine capsules. The occurrence of myocardial infarction has been reported although it is not possible to distinguish such an event from the natural course of ischaemic heart disease.

Central nervous system: Drowsiness, insomnia, tinnitus, paraesthesia, functional disorders.

Skin: Itching, rashes.

Hepato-Renal: Impairment, frequency of micturition.

Dyspnoea, gastro-intestinal upset and, rarely, depression, impotence and thrombocytopenia, have also been reported.

Symptoms may include marked hypotension, bradycardia, palpitations, flushing, drowsiness, confusion and slurred speech. In laboratory animals, overdosage also resulted in reversible hepatic function abnormalities, sporadic focal hepatic necrosis and progressive atrioventricular conduction block.

For treatment of overdose, standard measures including monitoring of cardiac and respiratory functions should be implemented. The patient should be positioned so as to avoid cerebral anoxia. Frequent blood pressure determinations are essential. Vasopressors are clinically indicated for patients exhibiting profound hypotension. Intravenous calcium gluconate may help reverse the effects of calcium entry blockade.

Cardene is a potent calcium antagonist. Pharmacological studies demonstrate its preferential high selectivity for the peripheral vasculature over the myocardium which accounts for its minimal negative inotropic effects. Cardene produces smooth muscle relaxation and marked peripheral vasodilatation.

In man Cardene produces a significant decrease in systemic vascular resistance, the degree of vasodilatation being more predominant in hypertensive patients than in normotensive subjects. Haemodynamic studies in patients with coronary artery disease and normal left ventricular function have shown significant increases in cardiac index and coronary blood flow, with little if any increase in left ventricular end-diastolic pressure.

Electrophysiologic effects: Electrophysiological studies in man show that Cardene does not depress sinus node function or atrial or ventricular conduction in patients with either normal or decreased electrical conduction systems. Refractory periods of the His-Purkinje system were actually shortened slightly by nicardipine and SA conduction time was improved.

Pharmacokinetics and metabolism: Nicardipine is rapidly and completely absorbed with plasma levels detectable 20 minutes following an oral dose. Maximal plasma levels are observed within 30 minutes to two hours (mean T_max = 1 hour). When given with a high fat meal peak plasma levels are reduced by 30%. Nicardipine is subject to saturable first-pass metabolism and the bioavailability is about 35% following a 30 mg oral dose at steady state.

The pharmacokinetics of Cardene are non-linear due to saturable hepatic first pass metabolism.

Steady state plasma levels are achieved after about 3 days of dosing at 20 and 30 mg tds and remain relatively constant over 28 days of dosing at 30 mg tds. Considerable intersubject variability in plasma levels is observed. Following dosing to steady state using doses of 30 and 40 mg (tds), the terminal plasma half-life of nicardipine averaged 8.6 hours. Nicardipine is highly protein-bound (>99%) in human plasma over a wide concentration range.

Nicardipine does not induce its own metabolism and does not induce hepatic microsomal enzymes.

Please refer to section 4.6 Pregnancy and Lactation.

Starch, Pregelatinised

Magnesium Stearate

Cardene 20mg

Capsule shell body

Titanium Dioxide E171

Gelatin

Cardene 30mg

Capsule shell body

Indigotine E132

Titanium Dioxide E171

Gelatin

Cardene 20mg and 30mg

Capsule shell cap

Indigotine E132

Titanium Dioxide E171

Gelatin

None known.

Cardene 20mg

Securitainer: 60 months.

Blister packs of 21, 100 and 200 capsules: 60 months.

Blister packs of 56 and 84 capsules: 36 months.

Cardene 30mg

Securitainer: 60 months

Blister packs of 21, 56, 60, 100 and 200 capsules: 60 months.

Blister packs of 84 capsules: 36 months.

Do not store above 25°C.

Cardene 20mg

Securitainer packs of 50 and 100.

PVC/aluminium foil blister strips of 21, 56, 84,100 and 200 capsules.

Cardene 30mg

Securitainer packs of 50 and 100.

PVC/aluminium foil blister strips of 21, 56, 60, 84,100 and 200 capsules.

Not applicable.

Astellas Pharma Limited

Lovett House

Lovett Road

Staines

TW18 3AZ

United Kingdom

Cardene 20mg - PL 00166/0181

Cardene 30mg - PL 00166/0182

15 May 1998/ 15 July 2002

4 November 2005

POM