- Hypertension.

- Chronic stable angina pectoris.

- Vasospastic (Prinzmetal's) angina.

Posology

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.

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

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

Pediatric population

- Children and adolescents 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).

- Children under 6 years old: No data are available.

Elderly patients

Amlodipine used at similar doses in elderly or younger patients is equally well tolerated. Normal dosage regimens are recommended in the elderly, but increase of the dosage should take place with care (see sections 4.4 and 5.2).

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 dialyzable.

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 (see sections 4.4 and 5.2). The pharmacokinetics of Amlodipine have not been studied in severe hepatic impairment. Amlodipine should be initiated at the lowest dose and titrated slowly in patients with severe hepatic impairment.

Method of administration

Tablet for oral administration.

Amloben® is contraindicated in patients with: - hypersensitivity to dihydropyridine derivatives, Amlodipine or any of the excipients - severe hypotension - shock (including cardiogenic shock) - obstruction of the outflow tract of the left ventricle (e.g. high grade aortic stenosis) - hemodynamically unstable heart failure after acute myocardial infarction. Concomitant use of angiotensin receptor antagonists (ARBs) - including valsartan - or of angiotensin converting enzyme inhibitors (ACE) inhibitors with aliskiren is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 mL/min/1.73m2).

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

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) the reported incidence of pulmonary edema was higher in the Amlodipine treated group than in the placebo group (see section 5.1). Calcium channel blockers, including Amlodipine, 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 impaired hepatic function:

The half-life of Amlodipine is prolonged and AUC values are higher in patients with impaired liver function; dosage recommendations have not been established. Amlodipine 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.

Use in elderly patients:

In the elderly increase of the dosage should take place with care (see sections 4.2 and 5.2).

Use in renal failure:

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

Dual blockade of the renin-angiotensin-aldosterone system (RAAS)

There is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual blockade of RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended.

If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure.

ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.

Other conditions with stimulation of the renin-angiotensin-aldosterone system

In patients whose vascular tone and renal function depend predominantly on the activity of the renin-angiotensin-aldosterone system (e.g. patients with severe congestive heart failure or underlying renal disease, including renal artery stenosis), treatment with medicinal products that affect this system has been associated with acute hypotension, hyperazotaemia, oliguria, or rarely acute renal failure.

Effects of other medicinal products on Amlodipine

CYP3A4 inhibitors:

Concomitant use of Amlodipine with strong or moderate CYP3A4 inhibitors (protease inhibitors, azole antifungals, macrolides like erythromycin or clarithromycin, verapamil or diltiazem) may give rise to significant increase in Amlodipine exposure. The clinical translation of these PK variations may be more pronounced in the elderly. Clinical monitoring and dose adjustment may thus be required.

CYP3A4 inducers:

There is no data available regarding the effect of CYP3A4 inducers on Amlodipine. The concomitant use of CYP3A4 inducers (e.g., rifampicin, hypericum perforatum) may give a lower plasma concentration of Amlodipine. Amlodipine should be used with caution together with CYP3A4 inducers.

Administration of Amlodipine with grapefruit or grapefruit juice is not recommended as bioavailability may be increased in some patients resulting in increased blood pressure lowering effects.

Dantrolene (infusion): In animals, lethal ventricular fibrillation and cardiovascular collapse are observed in association with hyperkalemia after administration of verapamil and dantrolene I.V. Due to risk of hyperkalemia, it is recommended that the coadministration of calcium channel blockers such as Amlodipine be avoided in patients susceptible to malignant hyperthermia and in the management of malignant hyperthermia.

Effects of Amlodipine on other medicinal products

The blood pressure lowering effects of Amlodipine adds to the blood pressure-lowering effects of other medicinal products with antihypertensive properties.

In clinical interaction studies, Amlodipine did not affect the pharmacokinetics of atorvastatin, digoxin, warfarin or cyclosporin.

Simvastatin: Co-administration of multiple doses of 10 mg of Amlodipine with 80 mg simvastatin resulted in a 77% increase in exposure to simvastatin compared to simvastatin alone. Limit the dose of simvastatin in patients on Amlodipine to 20 mg daily.

Pregnancy

The safety of Amlodipine in human pregnancy has not been established.

In animal studies, reproductive toxicity was observed at high doses (see section 5.3).

Use in pregnancy is only recommended when there is no safer alternative and when the disease itself carries greater risk for the mother and fetus.

Lactation

It is not known whether Amlodipine is excreted in breast milk. A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with Amlodipine should be made taking into account the benefit of breast-feeding to the child and the benefit of Amlodipine therapy to the mother.

Fertility

Reversible biochemical changes in the head of spermatozoa have been reported in some patients treated by calcium channel blockers. Clinical data are insufficient regarding the potential effect of Amlodipine on fertility. In one rat study, adverse effects were found on male fertility (see section 5.3).

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

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

The following undesirable effects have been observed and reported during treatment with Amlodipine 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).

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

Blood and lymphatic system disorders

Very Rare: Leukocytopenia, thrombocytopenia.

Immune system disorders

Very Rare: Allergic reactions.

Metabolism and nutrition disorders

Very Rare: Hyperglycemia.

Psychiatric disorders

Uncommon: Insomnia, mood changes (including anxiety), depression.

Rare: Confusion.

Nervous system disorders

Common: Somnolence, dizziness, headache (especially at the beginning of the treatment).

Uncommon: Tremor, dysgeusia, syncope, hypoesthesia, paresthesia.

Very Rare: Hypertonia, peripheral neuropathy.

Eye disorders

Uncommon: Visual disturbance (including diplopia).

Ear and labyrinth disorders

Uncommon: Tinnitus.

Cardiac disorders

Common: Palpitations.

Very Rare: Myocardial infarction, arrhythmia (including bradycardia, ventricular tachycardia and atrial fibrillation).

Vascular disorders

Common: Flushing.

Uncommon: Hypotension.

Very Rare: Vasculitis.

Respiratory, thoracic and medicinal disorders

Uncommon: Dyspnea, rhinitis.

Very Rare: Cough.

Gastrointestinal disorders

Common: Abdominal pain, nausea.

Uncommon: Vomiting, dyspepsia, altered bowel habits (including diarrhea and constipation), dry mouth.

Very Rare: Pancreatitis, gastritis, gingival hyperplasia.

Hepato-biliary disorders

Very Rare: Hepatitis, jaundice, hepatic enzymes increased (mostly consistent with cholestasis).

Skin and subcutaneous tissue disorders

Uncommon: Alopecia, purpura, skin discoloration, hyperhydrosis, pruritus, rash, exanthema.

Very Rare: Angioedema, erythema multiforme, urticaria, exfoliative dermatitis, Stevens-Johnson syndrome, Quincke edema, photosensitivity.

Musculoskeletal, connective tissue and bone disorders

Common: Ankle swelling.

Uncommon: Arthralgia, myalgia, muscle cramps, back pain.

Renal and urinary disorders

Uncommon: Micturition disorder, nocturia, increased urinary frequency.

Reproductive system and breast disorders

Uncommon: Impotence, gynecomastia.

General disorders and administration site conditions

Common: Edema, fatigue.

Uncommon: Chest pain, asthenia, pain, malaise.

Investigations

Uncommon: Weight increase, weight decrease.

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 at:

·        Saudi Arabia:

-  National Pharmacovigilance and Drug Safety Center (NPC)

o   Fax +966-11-205-7662

o   Call NPC at +966-11-2038222, Exts: 2317-2356-2353-2354-2334-2340

o   Toll free phone: 8002490000

o   Email: npc.drug@sfda.gov.sa

o   Website: www.sfda.gov.sa/npc

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 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 10 mg has been shown to reduce the absorption rate of Amlodipine.

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

Pharmacotherapeutic group: Calcium channel blockers, ATC code: C08CA01.

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 ischemic 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 ischemic 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 1 mm 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.

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.

The bioavailability of Amlodipine is not affected by food intake.

Biotransformation and elimination

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

Use in children

A population PK study has been conducted in 74 hypertensive children aged from 12 months 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 21.3 L/hr respectively in females. Large variability in exposure between individuals was observed. Data reported in children below 6 years is limited.

Use in 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.

Patients with impaired hepatic function

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

Reproductive toxicology

Reproductive studies in rats and mice have shown delayed date of delivery, prolonged duration of labor 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 (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 Besylate 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 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.

Amloben^® tablets:

Microcrystalline Cellulose PH 102

Colloidal Silicone Dioxide 200

Magnesium Stearate

Not applicable.

3 years.

Store below 30°C.

Keep in original pack in intact conditions.

Amloben^® tablets: 1 carton contains 30 tablets (in PVC-PVdC/Alu blisters packs of 15).

Keep the blister in the outer carton in order to protect from light.