Amlodipine Besilate Norma

- Hypertension

- Chronic stable angina pectoris

- Vasospastic (Prinzmetal's) angina

Posology

Adults

For both hypertension and angina the usual initial dose is 5 mg Amlodipine Besilate Norma once daily which may be increased to a maximum dose of 10 mg depending on the individual patient's response.

In hypertensive patients, Amlodipine Besilate Norma has been used in combination with a thiazide diuretic, alpha blocker, beta blocker, or an angiotensin converting enzyme inhibitor. For angina, Amlodipine Besilate Norma may be used as monotherapy or in combination with other antianginal medicinal products in patients with angina that is refractory to nitrates and/or to adequate doses of beta blockers.

No dose adjustment of Amlodipine Besilate Norma is required upon concomitant administration of thiazide diuretics, beta blockers, and angiotensin-converting enzyme inhibitors.

Paediatric population

Use in children and adolescents (less than 18 years of age)

Not recommended.

Special populations

Use in the elderly

Amlodipine Besilate Norma, used at similar doses in elderly or younger patients, is equally well tolerated. Therefore normal dosage regimens are recommended in the elderly, but increase of the dosage should take palce with care.

Patients with hepatic impairment

Dosage recommendations have not been established in patients with mild to moderate hepatic impairment; therefore dose selection should be cautious and should start at the lower end of the dosing range. The pharmacokinetics of Amlodipine Besilate Norma have not been studied in severe hepatic impairment. Amlodipine Besilate Norma should be initiated at the lowest dose and titrated slowly in patients with severe hepatic impairment.

Patients with renal impairment

Changes in Amlodipine Besilate Norma plasma concentrations are not correlated with degree of renal impairment, therefore the normal dosage is recommended. Amlodipine Besilate Norma is not dialysable.

Method of administration

Tablet for oral administration.

Amlodipine Besilate Norma is contraindicated in patients with:

-

- severe hypotension.

- shock (including cardiogenic shock).

- obstruction of the outflow tract of the left ventricle (e.g., high grade aortic stenosis).

- haemodynamically unstable heart failure after acute myocardial infarction.

The safety and efficacy of Amlodipine Besilate Norma in hypertensive crisis has not been established.

Use in patients with cardiac failure

Patients with heart failure should be treated with caution. In a long term, placebo controlled study, in patients with severe heart failure (NYHA class III and IV) Amlodipine Besilate Norma was associated with increased reports of pulmonary oedema despite no significant difference in the incidence of worsening heart failure as compared to placebo. Calcium channel blockers, including Amlodipine Besilate Norma, should be used with caution in patients with congestive heart failure, as they may increase the risk of future cardiovascular events and mortality.

Use in patients with hepatic impairment

As with all calcium antagonists, Amlodipine Besilate Norma's half-life is prolonged and AUC values are higher in patients with impaired liver function; dosage recommendations have not been established. The drug should therefore be initiated at the lower end of the dosing range and caution should be used, both on initial treatment and when increasing the dose. Slow dose titration and careful monitoring may be required in patients with severe hepatic impairment.

Elderly patients

In the elderly increase of the dosage should take place with care.

Patients with renal impairment

Amlodipine Besilate Norma may be used in such patients at normal doses. Changes in Amlodipine Besilate Norma plasma concentrations are not correlated with degree of renal impairment. Amlodipine Besilate Norma is not dialysable.

Amlodipine Besilate Norma can have minor or moderate influence on the ability to drive and use machines. In patients suffering from dizziness, headache, fatigue or nausea the ability to react may be impaired. Caution is recommended especially at the start of treatment.

a) Summary of the safety profile

The most commonly reported adverse reactions during treatment are somnolence, dizziness, headache, palpitations, flushing, abdominal pain, nausea, ankle swelling, oedema and fatigue.

b) Tabulated list of adverse reactions

The following adverse reactions have been observed and reported during treatment with Amlodipine Besilate Norma with the following frequencies: Very common (>1/10); common (>1/100 to <1/10); uncommon (>1/1,000 to <1/100); rare (>1/10,000 to <1/1,000); very rare (<1/10,000); Not known (cannot be estimated from the available data).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

*mostly consistent with cholestasis

Exceptional cases of extrapyramidal syndrome have 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 or search for MHRA Yellow Card in the Google Play or Apple App Store.

In humans, experience with intentional overdose is limited.

Symptoms

Available data suggest that gross overdosage could result in excessive peripheral vasodilatation and possibly reflex tachycardia. Marked and probably prolonged systemic hypotension up to and including shock with fatal outcome have been reported.

Treatment

Clinically significant hypotension due to Amlodipine Besilate Norma overdosage calls for active cardiovascular support including frequent monitoring of cardiac and respiratory function, elevation of extremities, and attention to circulating fluid volume and urine output.

A vasoconstrictor may be helpful in restoring vascular tone and blood pressure, provided that there is no contraindication to its use. Intravenous calcium gluconate may be beneficial in reversing the effects of calcium channel blockade.

Gastric lavage may be worthwhile in some cases. In healthy volunteers, the use of charcoal up to 2h after administration of Amlodipine Besilate Norma 10 mg has been shown to reduce the absorption rate of Amlodipine Besilate Norma.

Since Amlodipine Besilate Norma is highly protein-bound, dialysis is not likely to be of benefit.

Pharmacotherapeutic group: calcium channel blockers - Dihydropyridine derivatives.

ATC code: C08CA01.

Amlodipine Besilate Norma is a calcium ion influx inhibitor of the dihydropyridine group (slow channel blocker or calcium ion antagonist) and inhibits the transmembrane influx of calcium ions into cardiac and vascular smooth muscle.

The mechanism of the antihypertensive action of Amlodipine Besilate Norma is due to a direct relaxant effect on vascular smooth muscle. The precise mechanism by which Amlodipine Besilate Norma relieves angina has not been fully determined but Amlodipine Besilate Norma reduces total ischaemic burden by the following two actions:

1) Amlodipine Besilate Norma dilates peripheral arterioles and thus, reduces the total peripheral resistance (afterload) against which the heart works. Since the heart rate remains stable, this unloading of the heart reduces myocardial energy consumption and oxygen requirements.

2) The mechanism of action of Amlodipine Besilate Norma also probably involves dilatation of the main coronary arteries and coronary arterioles, both in normal and ischaemic regions. This dilatation increases myocardial oxygen delivery in patients with coronary artery spasm (Prinzmetal's or variant angina).

In patients with hypertension, once daily dosing provides clinically significant reductions of blood pressure in both the supine and standing positions throughout the 24 hour interval. Due to the slow onset of action, acute hypotension is not a feature of Amlodipine Besilate Norma administration.

In patients with angina, once daily administration of Amlodipine Besilate Norma increases total exercise time, time to angina onset, and time to 1mm ST segment depression, and decreases both angina attack frequency and glyceryl trinitrate tablet consumption.

Amlodipine Besilate Norma has not been associated with any adverse metabolic effects or changes in plasma lipids and is suitable for use in patients with asthma, diabetes, and gout.

Use in patients with coronary artery disease (CAD)

The effectiveness of Amlodipine Besilate Norma in preventing clinical events in patients with coronary artery disease (CAD) has been evaluated in an independent, multi-centre, randomized, double-blind, placebo-controlled study of 1997 patients; Comparison of Amlodipine Besilate Norma vs. Enalapril to Limit Occurrences of Thrombosis (CAMELOT). Of these patients, 663 were treated with Amlodipine Besilate Norma 5-10 mg, 673 patients were treated with enalapril 10-20 mg, and 655 patients were treated with placebo, in addition to standard care of statins, beta-blockers, diuretics and aspirin, for 2 years. The key efficacy results are presented in Table 1. The results indicate that Amlodipine Besilate Norma treatment was associated with fewer hospitalizations for angina and revascularization procedures in patients with CAD.

Abbreviations: CHF, congestive heart failure; CI, confidence interval; MI, myocardial infarction; TIA, transient ischemic attack.

Use in patients with heart failure

Haemodynamic studies and exercise based controlled clinical trials in NYHA Class II-IV heart failure patients have shown that Amlodipine Besilate Norma did not lead to clinical deterioration as measured by exercise tolerance, left ventricular ejection fraction and clinical symptomatology.

A placebo controlled study (PRAISE) designed to evaluate patients in NYHA Class III-IV heart failure receiving digoxin, diuretics and ACE inhibitors has shown that Amlodipine Besilate Norma did not lead to an increase in risk of mortality or combined mortality and morbidity with heart failure.

In a follow-up, long term, placebo-controlled study (PRAISE-2) in patients with NYHA III and IV heart failure without clinical symptoms or objective findings suggestive of underlying ischaemic disease, on stable doses of ACE inhibitors, digitalis, and diuretics, Amlodipine Besilate Norma had no effect on total cardiovascular mortality. In this same population Amlodipine Besilate Norma was associated with increased reports of pulmonary oedema despite no significant difference in the incidence of worsening heart failure as compared to placebo.

Treatment to prevent heart attack trial (ALLHAT)

A randomized double-blind morbidity-mortality study called the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) was performed to compare newer drug therapies: Amlodipine Besilate Norma 2.5-10 mg/d (calcium channel blocker) or lisinopril 10-40 mg/d (ACE-inhibitor) as first-line therapies to that of the thiazide-diuretic, chlorthalidone 12.5-25 mg/d in mild to moderate hypertension.

A total of 33,357 hypertensive patients aged 55 or older were randomized and followed for a mean of 4.9 years. The patients had at least one additional CHD risk factor, including: previous myocardial infarction or stroke (> 6 months prior to enrollment) or documentation of other atherosclerotic CVD (overall 51.5%), type 2 diabetes (36.1%), HDL-C < 35 mg/dL (11.6%), left ventricular hypertrophy diagnosed by electrocardiogram or echocardiography (20.9%), current cigarette smoking (21.9%).

The primary endpoint was a composite of fatal CHD or non-fatal myocardial infarction. There was no significant difference in the primary endpoint between Amlodipine Besilate Norma-based therapy and chlorthalidone-based therapy: RR 0.98 95% CI (0.90-1.07) p=0.65. Among secondary endpoints, the incidence of heart failure (component of a composite combined cardiovascular endpoint) was significantly higher in the Amlodipine Besilate Norma group as compared to the chlorthalidone group (10.2% vs. 7.7%, RR 1.38, 95% CI [1.25-1.52] p<0.001). However, there was no significant difference in all-cause mortality between Amlodipine Besilate Norma-based therapy and chlorthalidone-based therapy. RR 0.96 95% CI [0.89-1.02] p=0.20.

Use in children (aged 6 years and older)

In a study involving 268 children aged 6-17 years with predominantly secondary hypertension, comparison of a 2.5 mg dose, and 5.0 mg dose of Amlodipine Besilate Norma with placebo, showed that both doses reduced systolic blood pressure significantly more than placebo. The difference between the two doses was not statistically significant.

The long-term effects of Amlodipine Besilate Norma on growth, puberty and general development have not been studied. The long-term efficacy of Amlodipine Besilate Norma on therapy in childhood to reduce cardiovascular morbidity and mortality in adulthood has also not been established.

Absorption, distribution, plasma protein binding

After oral administration of therapeutic doses, Amlodipine Besilate Norma is well absorbed with peak blood levels between 6-12 hours post dose. Absolute bioavailability has been estimated to be between 64 and 80%. The volume of distribution is approximately 21 l/kg. In vitro studies have shown that approximately 97.5% of circulating Amlodipine Besilate Norma is bound to plasma proteins.

The bioavailability of Amlodipine Besilate Norma is not affected by food intake.

Biotransformation/elimination

The terminal plasma elimination half life is about 35-50 hours and is consistent with once daily dosing. Amlodipine Besilate Norma is extensively metabolised by the liver to inactive metabolites with 10% of the parent compound and 60% of metabolites excreted in the urine.

Hepatic impairment

Very limited clinical data are available regarding Amlodipine Besilate Norma administration in patients with hepatic impairment. Patients with hepatic insufficiency have decreased clearance of Amlodipine Besilate Norma resulting in a longer half-life and an increase in AUC of approximately 40-60%.

Paediatric population

A population PK study has been conducted in 74 hypertensive children aged from 1 to 17 years (with 34 patients aged 6 to 12 years and 28 patients aged 13 to 17 years) receiving Amlodipine Besilate Norma between 1.25 and 20 mg given either once or twice daily. In children 6 to 12 years and in adolescents 13-17 years of age the typical oral clearance (CL/F) was 22.5 and 27.4 L/hr respectively in males and 16.4 and 21.3 L/hr respectively in females. Large variability in exposure between individuals was observed. Data reported in children below 6 years is limited.

Use in the elderly

The time to reach peak plasma concentrations of Amlodipine Besilate Norma is similar in elderly and younger subjects. Amlodipine Besilate Norma clearance tends to be decreased with resulting increases in AUC and elimination half-life in elderly patients. Increases in AUC and elimination half-life in patients with congestive heart failure were as expected for the patient age group studied.

Reproductive toxicology

Reproductive studies in rats and mice have shown delayed date of delivery, prolonged duration of labour and decreased pup survival at dosages approximately 50 times greater than the maximum recommended dosage for humans based on mg/kg.

Impairment of fertility

There was no effect on the fertility of rats treated with Amlodipine Besilate Norma (males for 64 days and females 14 days prior to mating) at doses up to 10 mg/kg/day (8 times* the maximum recommended human dose of 10 mg on a mg/m² basis). In another rat study in which male rats were treated with Amlodipine Besilate Norma besilate for 30 days at a dose comparable with the human dose based on mg/kg, decreased plasma follicle-stimulating hormone and testosterone were found as well as decreases in sperm density and in the number of mature spermatids and Sertoli cells.

Carcinogenesis, mutagenesis

Rats and mice treated with Amlodipine Besilate Norma in the diet for two years, at concentrations calculated to provide daily dosage levels of 0.5, 1.25, and 2.5 mg/kg/day showed no evidence of carcinogenicity. The highest dose (for mice, similar to, and for rats twice* the maximum recommended clinical dose of 10 mg on a mg/m² basis) was close to the maximum tolerated dose for mice but not for rats.

Mutagenicity studies revealed no drug related effects at either the gene or chromosome levels.

*Based on patient weight of 50 kg

None stated.

No special requirements.