Cardene SR 30 and 45mg

1. Name Of The Medicinal Product

Cardene SR 30

Cardene SR 45

2. Qualitative And Quantitative Composition

Nicardipine hydrochloride 30 mg

Nicardipine hydrochloride 45 mg

3. Pharmaceutical Form

Sustained release capsules

4. Clinical Particulars

4.1 Therapeutic Indications

Treatment of mild to moderate hypertension.

4.2 Posology And Method Of Administration

Adults

Starting dose: 30 mg every 12 hours titrating upwards as required.

Usual effective dose: 45 mg every 12 hours (range 30 mg to 60 mg every 12 hours).

Individually adjust the dose for each patient. Where appropriate Cardene SR may also be used in combination with beta-blockers and/or diuretics.

Use in the elderly:

Starting dose: 30 mg every 12 hours. Titrate upwards with care as nicardipine may lower systolic pressure more than diastolic pressure in these patients.

Children:

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

4.3 Contraindications

i) Use in pregnancy and lactation.

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

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

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

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

4.4 Special Warnings And Precautions For Use

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

If switching from beta-blockers to Cardene SR, 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 SR 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 SR 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.

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

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Digoxin

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

Propranolol, 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.

Ciclosporin:

Monitor ciclosporin plasma levels and reduce dosage accordingly in patients concomitantly receiving nicardipine as elevated ciclosporin 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.

4.6 Pregnancy And Lactation

See contra-indications.

4.7 Effects On Ability To Drive And Use Machines

None known.

4.8 Undesirable Effects

Most are expected consequences of the vasodilator effects of Cardene SR.

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 sustained release dihydropyridines in patients with ischaemic heart disease, exacerbation of angina pectoris may occur rarely at the start of treatment with Cardene SR. 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.

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

4.9 Overdose

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.

Use routine measures (eg gastric lavage) including monitoring of cardiac and respiratory functions. Position the patient to avoid cerebral anoxia. Frequent blood pressure determinations are essential. Vasopressors are clinically indicated for patients exhibiting the effects of calcium entry blockade.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Mode of action

Cardene is a potent calcium channel blocker. Pharmacological studies suggest it is highly selective for the peripheral vasculature over the myocardium accounting for its minimal negative inotropic effects and marked peripheral vasodilatation when used clinically.

In mild to moderate hypertensive patients Cardene SR has been shown to reduce blood pressure and maintain control over 24 hours, only if the doses are regularly administered exactly 12 hours apart.

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.

5.2 Pharmacokinetic Properties

Cardene Capsules are completely absorbed with plasma levels detectable 20 minutes following an oral dose. Maximal plasma levels are generally achieved between one and four hours. Cardene SR is subject to saturable first pass metabolism with somewhat lower bioavailability than the standard capsule formulation of nicardipine (about 35% following a 30mg oral standard capsule at steady state) except at the 60mg dose. Minimum plasma levels produced by equivalent daily doses are similar. Cardene SR thus exhibits significantly reduced fluctuation in plasma levels in comparison to standard nicardipine capsules.

When Cardene SR is taken with a high fat meal, fluctuation in plasma levels are reduced.

Cardene is extensively metabolised by the liver; none of the metabolites possess significant biological activity.

5.3 Preclinical Safety Data

Please refer to section 4.6 Pregnancy and Lactation.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Starch, Pregelatinised

Magnesium Stearate

Microcrystalline cellulose

Maize Starch

Lactose

Methacrylic acid co-polymer

Cardene SR 30mg

Capsule shell body

Titanium Dioxide E171

Gelatin

Cardene SR 45mg

Capsule shell body

Titanium Dioxide E171

Gelatin

Indigotine E132

Cardene SR 30mg

Capsule shell cap

Titanium Dioxide E171

Gelatin

Cardene SR 45mg

Capsule shell cap

Titanium Dioxide E171

Gelatin

Indigotine E132

Cardene SR 30mg and Cardene SR 45mg

Printing ink: Opacode Red S-1-25082

Shellac

Iron oxide, red (E172)

n-Butyl alcohol NF

Propylene glycol (E1520)

Purified water

Ammonia solution

Industrial methylated spirit

Isopropyl alcohol

Printing Ink: TekPrint SW-1102 Red Ink

Shellac

Dehydrated alcohol

Isopropyl alcohol

Butyl alcohol

Propylene glycol

Strong ammonia solution

Iron oxide, red (E172)

Potassium hydroxide

Purified water

6.2 Incompatibilities

None known.

6.3 Shelf Life

60 months.

6.4 Special Precautions For Storage

Protect from light and excessive humidity. Do not store above 25°C.

6.5 Nature And Contents Of Container

Blister packs of 56

Blister packs of 14

Securitainers of 100

6.6 Special Precautions For Disposal And Other Handling

No special instructions required.

ADMINISTRATIVE DATA

7. Marketing Authorisation Holder

Astellas Pharma Limited

Lovett House

Lovett Road

Staines

TW18 3AZ

United Kingdom

8. Marketing Authorisation Number(S)

Cardene SR 30mg - PL 00166/0183

Cardene SR 45mg - PL 00166/0184

9. Date Of First Authorisation/Renewal Of The Authorisation

1 July 1998/ 15 July 2002

10. Date Of Revision Of The Text

8^th March 2010

11. LEGAL CATEGORY

POM