Nicardipine Hydrochloride 20mg Capsules
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Nicardipine Hydrochloride 20 mg Capsules.
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each capsule contains 20 mg of nicardipine hydrochloride For the full list of excipients, see 6.1.
3 PHARMACEUTICAL FORM
Capsule.
Hard gelatin capsule filled with a light yellow granule.
Size 3, white opaque body, pink opaque cap.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
The prophylaxis of patients with chronic stable angina, and the treatment of mild to moderate hypertension.
4.2 Posology and method of administration
Posology
Adults
Angina: Initial dose; 20 mg three times a day, titrating upwards as required. Usual effective dose; 30 mg three times a day (range of total daily dose 60 mg - 120 mg). Allow at least 3 days before increasing the dose to ensure steady-state plasma levels have been achieved.
Hypertension: Initial dose; 20 mg three times a day, titrating upwards as required. Usual effective dose; 30 mg three times a day (range of total daily dose 60 mg - 120 mg per day).
Nicardipine may be used in combination with beta-blockers, diuretics and nitrates. When used concomitantly with beta-blockers additive anti-anginal efficacy has been demonstrated (see section 4.5).
Use in elderly
Initial dose; 20 mg three times a day. Titrate upwards with care as nicardipine may lower systolic pressure more than diastolic pressure in elderly patients.
Paediatric population
Nicardipine is not recommended in patients under the age of 18 years since safety and efficacy have not been established.
Method of administration
Nicardipine Hydrochloride 20 mg Capsules are for oral administration. They should be swallowed whole with a drink of water.
4.3 Contraindications
i) Hypersensitivity to nicardipine hydrochloride, other dihydropyridines because of the theoretical risk of cross-reactivity or to any of the excipients listed in section 6.1.
ii) Pregnancy and lactation.
iii) Severe aortic stenosis (since part of the effect of nicardipine is secondary to reduced afterload). Reduction of diastolic pressure in these patients may worsen rather than improve myocardial oxygen balance.
iv) Cardiogenic shock, clinically significant aortic stenosis, unstable angina, and during or within one month of a myocardial infarction.
v) Nicardipine should not be used for acute attacks of angina.
vi) Nicardipine should not be used for secondary prevention of myocardial infarction.
vii) Acute porphyria
4.4 Special warnings and precautions for use
When nicardipine 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 the dose of nicardipine 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 nicardipine, 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 nicardipine 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 the occurrence of worsening of cardiac failure must be considered.
Use in patients with impaired hepatic or renal function
Since nicardipine 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. Nicardipine 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 nicardipine 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 suggests 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.
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.
Digoxin
Careful monitoring of serum digoxin levels is advised in patients also receiving nicardipine as levels may be increased.
Cimetidine
Cimetidine increases nicardipine plasma levels. Carefully monitor patients receiving both drugs.
Ciclosporin, tacrolimus and sirolimus
Monitor ciclosporin, tacrolimus and sirolimus plasma levels and reduce dosage accordingly in patients concomitantly receiving nicardipine as elevated ciclosporin, tacrolimus and sirolimus levels may occur.
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 m clinical trials, such hypotensive episodes should be vigorously treated with conventional therapy such as intravenous fluids.
Propranolol, dipyridamole, warfarin, quinidine, naproxen
Therapeutic concentrations of these drugs do not change the in vitro plasma protein binding of nicardipine.
Beta-blockers and other anti-hypertensive drugs
Nicardipine may be used in combination with beta-blocking and other antihypertensive drugs but possibility of an additive effect resulting in postural hypotension should be considered
4.6 Fertility, pregnancy and lactation
Pregnancy
Nicardipine is contra-indicated in pregnancy and lactation due to the lack of experience in this patient group.
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.
Breast-feeding
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
Drowsiness, nausea and dizziness can occur, which may impair the ability to perform hazardous tasks such as driving or operating machinery.
4.8 Undesirable effects
The majority of side effects are not serious and are expected consequences of the vasodilatory effects of nicardipine.
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
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. 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
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 (depression, lassitude, nervousness)
Skin and subcutaneous tissue disorders
Itching, rash, erythema, pruritis
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)
Vascular disorders
Hypotension, orthostatic hypotension
Immune system disorders
Anaphylactic reaction Frequency: Unknown
Investigations
Hepatic enzyme increased
Frequency: Unknown
Rarely, depression impotence and thrombocytopenia have also been reported. 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 (e.g. gastric lavage), including monitoring of cardiac and respiratory functions. Position the patient to avoid cerebral anoxia. Frequent blood pressure determinations are essential. Vasopressors may be clinically indicated for patients exhibiting the effects of calcium entry blockade. Intravenous calcium gluconate may help reverse the effects of calcium entry blockade.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Calcium channel blockers ATC code: C08.
Mechanism of action
Nicardipine 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. Nicardipine produces smooth muscle relaxation and marked peripheral vasodilatation.
Pharmacodynamic effects
In humans nicardipine produces a significant decrease in systemic vascular resistance, the degree of vasodilatation being more predominant in hypertensive patients than in normotensive subjects.
Clinical efficacy and safety
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 nicardipine 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
Absorption
Nicardipine is rapidly and completely absorbed with plasma levels detectable 20 minutes after an oral dose. Maximum plasma levels are observed within 30 minutes to 2 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.
The pharmacokinetics of nicardipine are non-linear due to saturable hepatic first-pass metabolism.
Steady-state plasma levels are achieved after about 3 days of dosing at 20 mg 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 mg and 40 mg tds, the terminal plasma half-life of nicardipine averaged 8.6 hours.
Distribution
Nicardipine is highly protein bound (> 99%) in human plasma over a wide concentration range.
Biotransformation
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.
Elimination
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). Linearity/non-linearity
The pharmacokinetics of nicardipine are non-linear due to saturable hepatic first pass metabolism.
5.3 Preclinical safety data
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.
Bacteriological tests have indicated that nicardipine does not demonstrate mutagenic potential. There is no information on the carcinogenic potential of nicardipine, and no evidence in the literature that there are any grounds for suspicion that would necessitate testing.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Maize starch Sodium starch glycollate Maize starch, pregelatinised Capsule:
Gelatin
Titanium dioxide (E171)
Erythrosine (E127)
6.2 Incompatibilities
Not applicable.
6.3. Shelf life
3 years.
6.4 Special precautions for storage
Do not store above 25°C. Store in the original container.
6.5 Nature and contents of container
Al/PVC blister pack, (PE-HD) tablet container and closure. Pack sizes: 200 mg: 25 and 100
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
No special requirements for disposal
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7 MARKETING AUTHORISATION HOLDER
Tillomed Laboratories Ltd
3 Howard Road
Eaton Socon
St. Neots
Cambs
PE19 3ET
United Kingdom
8 MARKETING AUTHORISATION NUMBER(S)
PL 11311/0101
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
Date of first authorisation: 03/112000 Date of latest renewal: 23/02/2006
10 DATE OF REVISION OF THE TEXT
02/08/2016