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SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Amlodipine 5 mg Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 6.94 mg amlodipine besilate equivalent to 5 mg amlodipine. For a full list of excipients, see section 6.1

3 PHARMACEUTICAL FORM

Tablet

Amlodipine 5 mg tablets are white to off white, round, tablets with “5” debossed on one side and plain on the other side.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Hypertension

Prophylaxis of chronic stable angina pectoris Prinzmetal's (variant) angina when diagnosed by a cardiologist In hypertensive patients, Amlodipine has been used in combination with a thiazide diuretic, alpha blocker, beta-adrenoceptor blocking agent, or an angiotensin converting enzyme inhibitor. For angina, Amlodipine may be used as monotherapy or in combination with other antianginal drugs in patients with angina that is refractory to nitrates and/or adequate doses of beta blockers. Amlodipine is well tolerated in patients with heart failure and a history of hypertension or ischaemic heart disease.

4.2 Posology and method of administration

For oral use

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

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

Use in children: Amlodipine is not recommended in children and adolescents below the age of 18 years due to a lack of data on safety and efficacy. (see section 5.1)

Use in the elderly: Amlodipine, used at similar doses in elderly or younger patients, is equally well tolerated. Therefore normal dosage regimens are recommended.

Patients with hepatic impairment: See section 4.4

Patients with renal impairment: Changes in amlodipine plasma concentrations are not correlated with degree of renal impairment, therefore the normal dosage is recommended. amlodipine is not dialysable.

4.3 Contraindications

1.    Amlodipine is contra-indicated in patients with a known sensitivity to dihydropyridines, amlodipine or any of the excipients.

2.    Amlodipine should not be used in cardiogenic shock, clinically significant aortic stenosis, unstable angina (excluding Prinzmetal's angina).

3.    Pregnancy and lactation.

4.4 Special warnings and precautions for use

Use in patients with Heart Failure: In a long-term, placebo controlled study (PRAISE-2) of amlodipine in patients with NYHA III and IV heart failure of nonischaemic aetiology, amlodipine was associated with increased reports of pulmonary oedema despite no significant difference in the incidence of worsening heart failure as compared to placebo. See section 5.1.

Use in patients with impaired hepatic function: As with all calcium antagonists, amlodipine's half-life is prolonged in patients with impaired liver function and dosage recommendations have not been established. The drug should therefore be administered with caution in these patients.

There are no data to support the use of Amlodipine alone, during or within one month of a myocardial infarction.

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

4.5 Interaction with other medicinal products and other forms of interaction

Amlodipine has been safely administered with thiazide diuretics, alpha blockers, beta blockers, angiotensin-converting enzyme inhibitors, long-acting nitrates, sublingual glyceryl trinitrate, non-steroidal anti-inflammatory drugs, antibiotics, and oral hypoglycaemic drugs.

In vitro data from studies with human plasma, indicate that amlodipine has no effect on protein binding of digoxin, phenytoin, warfarin or indometacin.

Special Studies: Effect of other agents on amlodipine

Cimetidine: Co-administration of Amlodipine with cimetidine did not alter the pharmacokinetics of Amlodipine.

Grapefruit Juice: Co-administration of 240 ml of grapefruit juice with a single oral dose of Amlodipine 10 mg in 20 healthy volunteers had no significant effect on the pharmacokinetics of Amlodipine.

Sildenafil: When Amlodipine and sildenafil were used in combination, each agent independently exerted its own blood pressure lowering effect.

Special Studies: Effect of amlodipine on other agents

Atorvastatin: Co-administration of multiple 10 mg doses of Amlodipine with 80 mg of atorvastatin resulted in no significant change in the steady state pharmacokinetic parameters of atorvastatin.

Digoxin: Co-administration of Amlodipine with digoxin did not change serum digoxin levels or digoxin renal clearance in normal volunteers.

Warfarin: In healthy male volunteers, the co-administration of Amlodipine does not significantly alter the effect of warfarin on prothrombin response time. Co-administration of Amlodipine with warfarin did not change the warfarin prothrombin response time.

Ciclosporin: Pharmacokinetic studies with ciclosporin have demonstrated that Amlodipine does not significantly alter the pharmacokinetics of ciclosporin. Drug/Laboratory test Interactions: None known.

4.6 Fertility, pregnancy and lactation

Although some dihydropyridine compounds have been found to be teratogenic in animals, data in the rat and rabbit for amlodipine provide no evidence for a teratogenic effect. There is, however, no clinical experience with the preparation in pregnancy or lactation. Accordingly, amlodipine should not be administered during pregnancy, or lactation, or to women of childbearing potential unless effective contraception is used.

4.7 Effects on ability to drive and use machines

Clinical experience with amlodipine indicates that therapy is unlikely to impair a patient's ability to drive or use machinery.

4.8 Undesirable effects

Adverse events that have been reported in amlodipine trials are categorised below

VFrequency Organ. System	Very Com mon (>1/10 )	Common (>1/100 to <1/10)	Uncommon (>1/1,000 to <1/100)	Rare (>1/10,00 0 to <1/1,000)	Very rare (<1/10,000), not known (cannot be estimated from the available data)
Blood and the Lymphatic System Disorders					Thrombo cytopenia
Immune System Disorders					allergic reaction
Metabolism and nutrition Disorders					hyperglycaemia
Psychiatric Disorders			insomnia, mood changes
Nervous system disorders		somno lence, dizziness, headache.	tremor, taste perversion, syncope, hypoaesthesia, paraesthesia		peripheral neuropathy
Frequency Organ System \	Very Com mon (>1/10 )	Common (>1/100 to <1/10)	Uncommon (>1/1,000 to <1/100)	Rare (>1/10,00 0 to <1/1,000)	Very rare (<1/10,000), not known (cannot be estimated from the available data)
Eye Disorders			visual disturbances
Ear and Labyrinth Disorders			tinnitus

Cardiac Disorders		palpita tions			myocardial infarction, arrhythmia, ventricular tachycardia and atrial fibrillation)
Vascular disorder		flushing	hypotension		vasculitis
Respiratory, Thoracic and Mediastinal Disorders			dyspnoea, rhinitis		coughing
Gastro intestinal disorders		abdominal pain, nausea	vomiting, dyspepsia, altered bowel habits, dry mouth		pancreatitis, gastritis, gingival hyperplasia
Hepatobiliar y disorders					hepatitis, jaundice and hepatic enzyme elevations (mostly consistent with cholestasis)
Skin and subcutaneou s tissue disorders			alopecia, purpura, skin discolouration, increased sweating, pruritus, rash		angioedema, erythema multiforme, urticaria
Musculoskel etal, connective tissue and bone			arthralgia, myalgia, muscle cramps, back pain
Frequency Organ \ System \	Very Com mon (>1/10 )	Common (>1/100 to <1/10)	Uncommon (>1/1,000 to <1/100)	Rare (>1/10,00 0 to <1/1,000)	Very rare (<1/10,000), not known (cannot be estimated from the available data)
Renal and Urinary Disorders			micturition disorder, nocturia, increased urinary frequency

Reproductive System and Breast Disorders			impotence, gynaecomastia
General disorders		oedema, fatigue	chest pain, asthenia, pain, malaise
Investigation s			weight increase, weight decrease

4.9 Overdose

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.

Administration of activated charcoal to healthy volunteers immediately or up to two hours after ingestion of amlodipine 10 mg has been shown to significantly decrease amlodipine absorption. Gastric lavage may be worthwhile in some cases. 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. Since amlodipine is highly protein-bound, dialysis is not likely to be of benefit.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties ATC code: C08CA01

Pharmacotherapeutic group: Selective calcium channel blockers with mainly vascular effects; Dihydropyridine derivatives .

Amlodipine 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 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 Amlodipine reduces total ischaemic burden by the following two actions.

1)    Amlodipine 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 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 administration.

In patients with angina, once daily administration of Amlodipine 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 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 Heart Failure: Haemodynamic studies and exercise based controlled 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 receiving digoxin, diuretics and ACE inhibitors has shown that amlodipine 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) of Amlodipine in patients with NYHA III and IV heart failure without clinical symptoms or objective findings suggestive or underlying ischaemic disease, on stable doses of ACE inhibitors, digitalis, and diuretics, amlodipine had no effect on total cardiovascular mortality. In this same population amlodipine was associated with increased reports of pulmonary oedema despite no significant difference in the incidence of worsening heart failure as compared to placebo.

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 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-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 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-based therapy and chlorthalidone-based therapy. RR 0.96 95% CI [0.89-1.02] p=0.20.

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, plasma protein binding: After oral administration of therapeutic doses, amlodipine 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 is bound to plasma proteins.

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

Use in the elderly: The time to reach peak plasma concentrations of amlodipine is similar in elderly and younger subjects. Amlodipine 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.

5.3 Preclinical safety data

None

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Microcrystalline cellulose

Calcium hydrogen phosphate dihydrate Sodium Starch Glycolate Type A Colloidal Anhydrous Silica Magnesium Stearate

6.2    Incompatibilities

Not applicable.

6.3 Shelf life

3 years

Special precautions for storage

Store below 30°C. Keep the blister in the outer carton in order to protect from light.

15/11/2012