This information is intended for use by health professionals

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

Nicardipine should be taken with liquids and swallowed whole.

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:

The safety and efficacy in low birth weight infants, newborns, nursing infants, infants, and children has not been established. Cardene SR is not recommended for use in patients under the age of 18.

4.3 Contraindications

(1) Use in pregnancy and lactation.

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

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

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

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

4.4 Special warnings and precautions for use

When Cardene SR is used as monotherapy, caution is advised to avoid an excessive decrease in blood pressure. If used in combination with diuretics or beta-blockers, careful titration of Cardene SR is advised.

Caution should be exercised when using nicardipine in combination with a beta-blocker in patients with decreased cardiac function.

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.

Ischemic heart disease:

Short-acting dihydropyridines are associated with an increased risk of ischemic cardiovascular events.

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

Inhibitors and inducers of cytochrome P450 3A4

Nicardipine is metabolized by cytochrome P450 3A4. Concomitant administration of nicardipine with inducers (e.g. carbamazepine and rifampicin) or inhibitors (e.g cimetidine and grapefruit juice) of cytochrome P450 3A4 may alter the plasma levels of nicardipine.

Clinical monitoring during treatment with an enzyme inducing or inhibiting agent, and after its discontinuation, is required.

Cyclosporine, tacrolimus and sirolimus:

Concomitant administration of nicardipine and cyclosporine, tacrolimus or sirolimus results in elevated plasma cyclosporine, tacrolimus or sirolimus levels. Cyclosporine, tacrolimus or sirolimus level should be monitored and dosage of immunosuppressant and/or nicardipine should be reduced, if required.

Digoxin

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

Beta-blockers and other anti-hypertensive drugs

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.

Propranolol, Dipyridamole, Warfarin, Quinidine, Naproxen:

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

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.

4.6 Pregnancy and lactation

Pregnancy

See contra-indications (section 4.3).

Acute pulmonary oedema has been observed when nicardipine has been used as tocolytic during pregnancy (see section 4.8), especially in cases of multiple pregnancy (twins or more), with the intravenous route and/or concomitant use of beta-2 agonists.

Lactation

Because nicardipine was found in maternal milk, breast feeding must be discontinued during nicardipine treatment (see section 5.3).

4.7 Effects on ability to drive and use machines

Caution should be exercised because the hypotensive effects of this drug may cause dizziness.

4.8 Undesirable effects

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

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

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

Cardiac disorders

Tachycardia

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.

Gastro-intestinal disorders

Gastro-intestinal upset

Gingival hyperplasia

Vomiting

General disorders and administration site conditions

Asthenia

Hepatobiliary disorders

Hepatic function abnormal

Renal and urinary disorders

Renal function abnormal

Frequency of micturition

Nervous system disorders

Drowsiness

Insomnia

Tinnitus

Paraesthesia

Functional disorders

Respiratory, thoracic and mediastinal disorders

Dyspnoea

Frequency: unknown

Pulmonary oedema*

*cases have been also reported when used as tocolytic during pregnancy (see section 4.6)

Skin and subcutaneous tissue disorders

Erythema

Pruritis

Rash

Vascular disorders

Hypotension

Orthostatic hypotension

Immune system disorders

Anaphylactic reaction

Frequency: Unknown

Investigations

Hepatic enzyme increased

Frequency: Unknown

Rarely, depression, impotence and thrombocytopenia have been reported.

The above mentioned listed adverse reactions have been observed during clinical studies and/or during marketed use.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

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. Nicardipine is metabolized by cytochrome P450 3A4. Studies involving either a single dose, or administration 3 times daily for 3 days, have shown that less than 0.03% of unchanged nicardipine is recovered in the urine in humans after oral or intravenous administration. The most abundant metabolite in human urine is the glucuronide of the hydroxy form, which is formed by the oxidative cleaving of the N-methylbenzyl moiety and the oxidation of the pyridine.

Following a radioactive oral solution dose, 60% of the radioactivity was recovered in the urine and 35% in faeces. Most of the dose (> 90%) was recovered within 48 hours of dosing.

Renal impairment

The pharmacokinetics of orally administered nicardipine SR capsule 45 mg were studied in subjects with severe renal dysfunction requiring hemodialysis (creatinine clearance < 10 ml/min), mild/moderate renal dysfunction (creatinine clearance 10 - 50 mi/min) and normal renal dysfunction (creatinine clearance >50 ml/min). At steady state, Cmax and AUC were significantly higher and clearance significantly lower in subjects with mild/moderate renal dysfunction compared with in subjects with normal renal function. There were no significant differences in the principal pharmacokinetic parameters between severe renal dysfunction and normal renal dysfunction. These results are similar to those seen with other oral formulations (see section 4.4).

5.3 Preclinical safety data

Please refer to section 4.6 Pregnancy and Lactation. Nicardipine has been shown to pass into the milk of lactating animals. It has been reported in animal experiments that the drug is excreted into breast milk.

In animal experiments where this drug was administered at a high dose during the terminal stage of pregnancy, an increase in fetal deaths, delivery disturbances, decrease in the body weight of offsprings, and suppression of post-natal body weight gain were reported.

However, the toxicity to reproduction has not been reported.

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:

Shellac (E904)

Red Iron oxide (E172)

Propylene glycol

Ammonia solution

Potassium hydroxide

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 Ltd.

2000 Hillswood Drive

Chertsey

Surrey

KT16 0RS

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

25 January 2017

11. Legal category

POM