Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: Astellas Pharma Ltd., SPACE, 68 Chertsey Road, Woking, Surrey, GU21 5BJ, United Kingdom
Pharmacotherapeutic group: Selective calcium channel blocker (dihydropyridine derivative) with mainly vascular effects
ATC code: C08CA04
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.
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 Tmax = 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.
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 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. Nicardipine does not induce its own metabolism and does not induce hepatic microsomal enzymes.
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.
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).
The pharmacokinetics of Cardene are non-linear due to saturable hepatic first pass metabolism.
Please refer to section 4.6 Fertility, 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.
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