Document: document 9 change

• document 0
• document 1
• document 2
• document 3
• document 4
• document 5
• document 6
• document 7
• document 8
• document 9
• document 10
• document 11

---

SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Amlodipine 5 mg Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

The tablets contain 5 mg of amlodipine (as amlodipine besilate). Excipients:

Each 5 mg tablet contains 140.292 mg of lactose.

For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Tablet.

White, round, flat notched on one-side tablets.

The score line is only to facilitate breaking for ease of swallowing and not to divide into equal doses.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

•    Essential hypertension.

•    Chronic stable and vasospastic angina pectoris.

4.2 Posology and method of administration

Posology

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.

Amlodipine can be used as a monotherapy or in combination with the anti-anginous medication in patients suffering from angina pectoris.

In the elderly

Normal dosage regimens are recommended in the elderly, but caution should be exercised when increasing the dosage.

Paediatric population

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 5 mg Tablets as these tablets are not manufactured to break into two equal halves.

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).

In patients with renal impairment

In these patients amlodipine can be used in the normal dosage (see section 5.2.). Amlodipine should be administered with particular caution in patients undergoing dialysis. Amlodipine is not dialysable.

Method of administration

The tablets should be taken with a glass of water with or without food.

4.3 Contraindications

Amlodipine is contra-indicated in patients with:

•    Known hypersensitivity to amlodipine, dihydropyridine derivatives or to any of the excipients

•    Severe hypotension

•    Shock, including cardiogenic shock

•    Heart failure after acute myocardial infarction (during the first 28 days)

•    Unstable angina pectoris

•    Obstruction to the left ventricular outflow tract (e.g. high-grade aortic stenosis)

4.4 Special warnings and precautions for use

Amlodipine should be administered with care in patients with lower cardiac reserves. 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.

Use in patients with heart failure

Patients with heart failure should be treated with caution. In a placebo-controlled 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, this was not associated with worsening heart failure (see Section 5.1 “Pharmacodynamic properties”).

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.

Use in elderly patients

In the elderly, caution should be exercised when increasing the dosage (see section 4.2 and 5.2)

This medicine contains lactose. It is not recommended for patients with rare hereditary problems of galactose intolerance, lactase deficiency or glucose-galactose malabsorption.

4.5 Interaction with other medicinal products and other forms of interaction

Effects of other medicinal products on amlodipine:

Cimetidine, Aluminum/magnesium (anti-acid) and Sildenafil had no significant effect on the pharmacokinetic of amlodipine.

CYP3A4 inhibitors: A study of elderly patients has shown that diltiazem inhibits the metabolism of amlodipine, probably via CYP3A4, since the plasma concentration increases by approximately 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 and CYP3A4 inhibitors.

CYP3A4-inducing agents: There is no information available on the effect of CYP3A4 inducers (i.e. rifampicin, St John’s wort) on amlodipine. Co-administration may reduce plasma concentration of amlodipine. Caution should be exercised in combination of amlodipine and CYP3A4 inducers.

Effects of amlodipine on other medicinal products:

Amlodipine may potentiate the effect of other antihypertensive drugs such as beta-adrenoreceptor blocking agents, ACE-inhibitors, alpha-1-blockers and diuretics. In patients with increased risk (for example after myocardial infarction), the combination of a calcium channel blocker with a beta-adrenoreceptor blocking agent may lead to heart failure, hypotension and a (new) myocardial infarction.

In clinical interaction studies, amlodipine did not influence the pharmacokinetic properties of atorvastatin, digoxin, warfarin or ciclosporin.

Amlodipine does not influence lab tests.

Ethanol (alcohol)

Multiple and single 10 mg doses of amlodipine resulted in no significant change in ethanol’s pharmacokinetics.

Amlodipine had no significant effect on the pharmacokinetic parameter of atorvastatin, digoxin, warfarin or ciclosporin.

4.6 Fertility, pregnancy and lactation

There are no adequate data from the use of amlodipine in pregnant women. In animal studies, effects on reproduction were found at high dosages (see section 5.3). The potential risk for humans is unknown. Accordingly, amlodipine should not be used during pregnancy unless clearly needed.

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

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Amlodipine is well tolerated. In placebo-controlled clinical trials that involved patients with hypertension or angina, the adverse events reported categorised below, according to frequency:

Blood and lymphatic system disorders Very rare: leukopenia, thrombocytopenia

Endocrine Disorders Uncommon: gynaecomastia

Metabolism and nutrition disorders Very rare: hyperglycaemia

Psychiatric disorders

Uncommon: sleep disorder, irritability and depression Rare: confusion, mood changes including anxiety

Nervous system disorders

Common: headache especially at the start of the treatment, fatigue, dizziness and asthenia.

Uncommon: malaise, tremor, hypoaesthesia, paraesthesia, increased sweating Rare: taste changes

Very rare: hypertonia, peripheral neuropathy Eye Disorders

Uncommon: visual disturbances

Ear and Labyrinth Disorders Uncommon: tinnitus

Cardiac disorders Common: palpitations

Uncommon: syncope, tachycardia, chest pain, aggravation of angina pectoris (may occur at the start of treatment).

Very Rare: isolated cases of myocardial infarction and arrhythmias) and angina pectoris have been reported in patients with coronary artery disease, but a clear association with amlodipine has not been established.

Vascular Disorders Uncommon: hypotension Very rare: vasculitis

Respiratory, Thoracic and Mediastinal Disorders Uncommon: dyspnoea, rhinitis Very rare: cough

Gastrointestinal Disorders

Common: abdominal pain, nausea, dyspepsia

Uncommon: vomiting, diarrhoea, constipation, gingival hyperplasia and dry mouth. Very rare: gastritis

Hepatobiliary Disorders

Rare: elevated liver enzymes, hepatitis and jaundice Very rare: pancreatitis

Skin and Subcutaneous Tissue Disorders

Uncommon: alopecia, purpura, skin discolouration, pruritus, rash, exanthema, urticaria

Very rare: angioedema, isolated cases of allergic reactions including pruritus, rash, angioedema and erythema exsudativum multiform, exfoliative dermatitis, Stevens Johnson syndrome and Quinke oedema have been reported.

Common: facial flushing whit heat sensation, especially at the start of treatment. Very common: ankle swelling

Musculoskeletal and Connective Tissue Disorders Uncommon: arthralgia, myalgia, muscle cramps, back pain

Renal and Urinary Disorders

Uncommon: nocturia, increased micturition frequency

Reproductive System and Breast Disorders Uncommon: impotence

General Disorders and Administration Site Conditions Common: oedema, fatigue

Uncommon: asthenia, pain, malaise, increase or decrease in weight.

In clinical trials with amlodipine, no clinical significant abnormalities were observed in laboratory parameters.

4.9 Overdose

In humans, experience with intentional overdose is limited. Gastric lavage may be    worthwhile in some cases. Available data suggest that overdose (>100

mg) could result in excessive peripheral vasodilatation with subsequent marked and probably prolonged systemic hypotension. Clinically significant hypotension due to amlodipine overdose 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.

In healthy volunteers, the use of activated charcoal up to 2h after administration of amlodipine 10 mg has been shown to reduce the absorption rate of amlodipine

The administration of insulin while maintaining normal blood glucose levels (hyperinsulinemia-euglycemia therapy) can also be a first-line therapy in amlodipine overdose. Close monitoring of blood glucose must continue throughout treatment.

Terlipressin or other vasopressin analogous, like argipressin, can be an option to treat the hypotension in addition to the usual measures. With terlipressin it might be possible to reduce the needed volume in patients with a reduced cardiac ejection fraction to prevent complications like pulmonary edema.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Dihydropyridine derivatives ATC code: C08C A01

Amlodipine is a calcium antagonist and inhibits the influx of calcium ions into cardiac and smooth muscle cells. The mechanism of the antihypertensive action for amlodipine is due to the direct spasmolytic effect on vascular smooth muscle cells. The precise mechanism by which amlodipine relieves angina pectoris has not been fully determined, but the following two actions play a role:

Amlodipine dilates peripheral arterioles and reduces the peripheral resistance (afterload) against which the heart pumps. This unloading of the heart reduces myocardial energy consumption and oxygen requirements.

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.

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.

In haemodynamic studies in patients with heart failure and in clinical studies based on exercise tests in patients with NYHA class II-IV heart failure, amlodipine was found not to cause any clinical deterioration, as measured by exercise tolerance, left ventricular ejection fraction and clinical signs and symptoms

Use in Patients with Heart Failure

In haemodynamic studies in patients with heart failure and in clinical studies based on exercise tests in patients with NYHA class II-IV cardiac decompensation, amlodipine was found not to cause any clinical deterioration, as measured by exercise tolerance, left ventricular ejection fraction and clinical signs and symptoms.

In a placebo-controlled study (PRAISE) designed to evaluate patients with NYHA class III-IV cardiac decompensation treated with digoxin, diuretics and ACE inhibitors, amlodipine was shown not to cause any increase in the risk of death or in the combined risk of mortality and morbidity in patients with cardiac decompensation.

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.

Paediatric population

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 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 and distribution

After oral intake of therapeutic doses, amlodipine is slowly absorbed through the gastrointestinal channel. The bioavailability of amlodipine is not influenced by concomitant intake of food. The absolute bioavailability of the unchanged active substance is approximately 64 - 80%. Peak plasma concentrations are reached within 6 -12 hours after the administration. The volume of distribution is approximately 20 l/kg. The pKa of amlodipine is 8,6. In vitro plasma protein binding is approximately

98%.

Metabolism/Elimination

The plasma elimination half-life varies between 35 and 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 urine, about 10% of which in the form of unchanged amlodipine.

Elderly patients

The time necessary to reach peak plasma concentration is the same as in younger patients. The clearance tends to be decreased with resulting increases in “area under the curve (AUC)” and terminal elimination half-life. However, the recommended dose for elderly patients remains the same, but caution is needed when a dose increase is required.

In patients with impaired renal function

Amlodipine is extensively metabolised into inactive metabolites. 10% of the substance is excreted unchanged in the urine. The changes in the plasma concentration of amlodipine are not correlated with the degree of renal impairment. These patients can be treated with a normal dosage of amlodipine. Amlodipine can not be dialysed.

Patients suffering from hepatic impairment

The half-life of amlodipine is prolonged in patients with an impaired hepatic function. Paediatric population

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 21.3 L/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 repeated dose toxicity, genotoxicity and carcinogenic potential. In reproductive

6 PHARMACEUTICAL PARTICULARS

6.1    List of excipients

-    Microcrystalline cellulose

-    Lactose monohydrate

-    Sodium starch glycolate

-    Magnesium stearate

6.2    Incompatibilities

Not applicable.

6.3    Shelf life

4 years.

6.4    Special precautions    for    storage

Do not store above 25°C.

6.5    Nature and contents of    container

Tablets are packed in opaque PVC+PVdC / Aluminium blister. Packs of 10 / 20 / 28 / 30 / 60 / 100 / 500 Not all pack sizes may be marketed.

6.6    Special precautions    for    disposal

No special requirements.