1. Name Of The Medicinal Product
Amlodipine 10mg tablets
2. Qualitative And Quantitative Composition
Each tablet contains 10 mg amlodipine (as amlodipine mesilate monohydrate).
For excipients, see 6.1.
3. Pharmaceutical Form
Tablet
The tablets are white to off-white, round biconvex and scored and embossed with “10” on one side.
4. Clinical Particulars
4.1 Therapeutic Indications
Essential hypertension.
Chronic stable and vasospastic angina pectoris.
4.2 Posology And Method Of Administration
In adults
For treatment of both hypertension and angina pectoris the usual initial dose is 5 mg once daily. If the desired therapeutic effect cannot be achieved within 2-4 weeks this dose may be increased to a maximum dose of 10 mg daily (as single dose) depending on the individual patient's response.
Children with hypertension from 6 years to 17 years of age.
The recommended antihypertensive oral dose in pediatric patients ages 6-17 years is 2.5 mg once daily as a starting dose, up-titrated to 5 mg once daily if blood pressure goal is not achieved after 4 weeks. Doses in excess of 5 mg daily have not been studied in pediatric patients (see section 5.1 Pharmacodynamic Properties and section 5.2 Pharmacokinetic Properties). The effect of amlodipine on blood pressure in patients less than 6 years of age is not known.
The 2.5 mg dose cannot be obtained with Amlodipine tablets 5 mg as these tablets are not manufactured to break into two equal halves
In the elderly
Normal dosage regimens are recommended in the elderly, however, increase of the dosage should take place with care (see Section 5.2 Pharmacokinetic properties).
In patients with renal impairment
Amlodipine is not dialysable. In these patients amlodipine can be used in the normal dosage (see Section 5.2 Pharmacokinetic properties)
In patients with hepatic impairment
A dosage regimen for patients with hepatic impairment has not been established , therefore amlodipine should be administered with caution (see Section 4.4 Special warnings and precautions for use).
The tablets should be taken with a glass of water independently from meals.
4.3 Contraindications
Amlodipine is contra-indicated in patients with:
• severe hypotension
• shock, including cardiogenic shock
• hypersensitivity to dihydropyridine derivatives, amlodipine or any of the excipients.
• heart failure after acute myocardial infarction (during the first 28 days)
• obstruction of the outflow-tract of the left ventricle (e.g. high grade aortic stenosis)
• unstable angina pectoris
4.4 Special Warnings And Precautions For Use
Amlodipine should be administered with caution to patients with low cardiac reserve. There are no data to support the use of amlodipine alone, during or within one month of myocardial infarction. The safety and efficacy of amlodipine in hypertensive crisis has not been established.
Patients with cardiac failure
Patients with cardiac failure should be treated with caution In a long-term study including patients suffering from severe heart failure (NYHA grade III and IV) the reported incidence of pulmonary oedema was higher in the amlodipine treated group than in the placebo group, but this was not indicating an aggravation of the heart failure (see Section 5.1 Pharmacodynamic properties).
Use in patients with impaired hepatic function
Amlodipine's half-life is prolonged in patients with impaired liver function; dosage recommendations have not been established. Amlodipine should therefore be administered with caution in these patients.
Use in elderly patients
In the elderly, increase of the dosage should take place with care (see Section 5.2 Pharmacokinetic properties).
Use in children (under 18 years of age)
Amlodipine should not be given to children due to insufficient clinical experience.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Effects of other medicinal products on amlodipine
CYP3A4 inhibitors: A study of elderly patients has shown that diltiazem inhibits metabolism of amlodipine, probably via CYP3A4, since plasma concentration increases by approx. 50% and the effect of amlodipine is increased. It cannot be excluded that stronger inhibitors of CYP3A4 (i.e. ketoconazole, itraconazole, ritonavir) increase the plasma concentration of amlodipine to a greater extent than diltiazem. Caution should be exercised in combination of amlodipine and CYP3A4 inhibitors.
CYP3A4 inducers: There is no information available on the effect of CYP3A4 inducers (i.e. rifampicin, St. John's wort) on amlodipine. Co-administration may lead to reduced plasma concentration of amlodipine. Caution should be exercised in combination of amlodipine and CYP3A4 inducers.
In clinical interaction studies grapefruit juice, cimetidine, aluminium/magnesium (antacid) and sildenafil did not affect the pharmacokinetics of amlodipine.
Effects of amlodipine on other medicinal products
Amlodipine may potentiate the effect of other antihypertensive agents, such as beta-adrenoceptor blocking agents, ACE-inhibitors, alpha-1-blockers and diuretics. In patients with an increased risk (for example after myocardial infarction) the combination of a calcium channel blocker with a beta-adrenoceptor blocking agent may lead to heart failure, to hypotension and to a (new) myocardial infarction.
In clinical interaction studies, amlodipine did not affect the pharmacokinetics of atorvastatin, digoxin, warfarin or ciclosporin.
There is no effect of amlodipine on laboratory parameters.
4.6 Pregnancy And Lactation
There are no adequate data from the use of amlodipine in pregnant women. Animal studies have shown reproductive toxicity at high doses (see Section 5.3 Preclinical safety data). The potential risk for humans is unknown. Amlodipine should not be used during pregnancy unless clearly necessary.
It is not known whether amlodipine is excreted in breast milk. It is advised to stop breastfeeding during treatment with amlodipine.
4.7 Effects On Ability To Drive And Use Machines
In patients suffering from dizziness, headache, fatigue or nausea the ability to react may be impaired.
4.8 Undesirable Effects
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4.9 Overdose
In humans, experience with intentional overdose is limited. Available data suggest that large overdoses (> 100mg) could result in excessive peripheral vasodilatation with subsequent marked and probably prolonged systemic hypotension. Clinically significant hypotension due to amlodipine 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 2 hours after administration of amlodipine 10mg has been shown to reduce the absorption rate of amlodipine. Since amlodipine is highly protein-bound, dialysis is not likely to be of benefit.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: Dihydropyridine derivatives
ATC code: C08CA01
Amlodipine is a calcium antagonist and inhibits the influx of calcium ions into cardiac and vascular smooth muscle. The mechanism of the antihypertensive action is due to a direct relaxant effect on vascular smooth muscle. The precise mechanism by which amlodipine relieves angina has not been fully determined but the following two actions play a role:
1. Amlodipine dilates peripheral arterioles and thus, reduces the total peripheral resistance (afterload) against which the heart works. This unloading of the heart reduces myocardial energy consumption and oxygen requirements.
2. The mechanism of action also probably involves dilatation of the main coronary arteries and coronary arterioles. This dilation increases the supply in oxygen to myocardiac muscle in patients with Prinzmetal anginal attack.
In patients with hypertension, once daily dosing provides clinically significant reductions of blood pressure (in both supine and standing positions) throughout the 24 hour interval.
In patients with angina, once daily administration of amlodipine increases total exercise time, the delay of occurrence of anginal attack and the delay of the occurrence of a 1-mm ST interval. Amlodipine decreases both angina attack frequency and glyceryl trinitrate tablet consumption.
Patients with cardiac failure
Haemodynamic studies and exercise based clinical trials in NYHA Class II-IV heart failure patients have shown that amlodipine 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 patients receiving digoxin, diuretics and ACE inhibitors has shown that amlodipine did not lead to an increase in risk of mortality or a combined risk of mortality and morbidity with heart failure.
A follow-up study (PRAISE 2) showed that amlodipine did not have an affect on the total or cardiovascular mortality of decompensatio Cordis class III-IV patients without ischaemic origin. In this study treatment with amlodipine was associated with an increase in pulmonary oedema, although this could not be related to an increase in symptoms.
In a study involving 268 children aged 6-17 years with predominantly secondary hypertension, comparison of a 2.5mg dose, and 5.0mg dose of amlodipine 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 on growth, puberty and general development have not been studied. The long-term efficacy of amlodipine on therapy in childhood to reduce cardiovascular morbidity and mortality in adulthood have also not been established.
5.2 Pharmacokinetic Properties
Absorption/Distribution
After oral administration of therapeutic doses, amlodipine is slowly absorbed. Absorption of amlodipine is not influenced by concomitant food intake. Absolute bioavailability of the unchanged active substance is estimated to be 64-80%. Peak plasma levels are reached 6-12 hours after administration. The volume of distribution is approximately 21 l/kg. The pKa of amlodipine is 8.6. In vitro studies have shown that amlodipine is bound to plasmatic proteins up to 97.5%.
Metabolism/Elimination
The plasma elimination half-life is about 35-50 hours. Steady-state plasma levels are reached after 7-8 consecutive days. Amlodipine is extensively metabolised to inactive metabolites. About 60% of the administered dose is excreted in the urine, of which 10% is as unchanged amlodipine.
In the elderly
The time to reach peak plasma concentrations is similar in elderly and younger patients. The clearance tends to be decreased with resulting increases in “area under the curve” (AUC) and terminal elimination half-life. The recommended dosage regimen for the elderly is the same, although increasing the dose should take place with caution.
In patients with renal failure
Amlodipine is extensively metabolised to inactive metabolites. 10% of the parent compound is excreted unchanged in urine. Changes in amlodipine concentration are not correlated with degree of renal impairment. Therefore the normal dosage is recommended. Amlodipine is not dialysable.
Patients with hepatic impairment:
The half-life of amlodipine is prolonged in patients with impaired hepatic function.
Children
A population PK study has been conducted in 74 hypertensive children aged from 12 month to 17 years (with 34 patients aged 6 to 12 years and 28 patients aged 13 to 17 years) receiving amlodipine 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 21.3L/hr respectively in females. Large variability in exposure between individuals was observed. Data reported in children below 6 years is limited.
5.3 Preclinical Safety Data
Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential. In animal studies with respect to reproduction in rats at high doses delayed parturition, difficult labour and impaired foetal and pup survival were seen.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Microcrystalline cellulose,
Anhydrous calcium hydrogen phosphate
Sodium starch glycollate type A
Magnesium stearate
6.2 Incompatibilities
Not applicable.
6.3 Shelf Life
3 years.
6.4 Special Precautions For Storage
Do not store above 30°C. Store in the original package.
6.5 Nature And Contents Of Container
PVC/PE/PVdC-aluminium blister.
Pack sizes:
10, 14, 20, 28, 30, 50, 98, 100 and 200 tablets
Not all pack sizes may be marketed.
6.6 Special Precautions For Disposal And Other Handling
No special requirements.
7. Marketing Authorisation Holder
Actavis UK Limited
(Trading style: Actavis)
Whiddon Valley
BARNSTAPLE
N Devon EX32 8NS
United Kingdom
8. Marketing Authorisation Number(S)
PL 00142/0615
9. Date Of First Authorisation/Renewal Of The Authorisation
11th October 2004
10. Date Of Revision Of The Text
10.08.2010
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