4.1. Therapeutic indications

Hypertension

Chronic stable angina pectoris.

Vasospastic (Prinzmetal's) angina

4.2. Posology and method of administration

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 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 is required upon concomitant administration of thiazide diuretics, beta blockers, and angiotensin-converting enzyme inhibitors.

Special populations

Elderly

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).

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.

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.

Paediatric population

Children and adolescents with hypertension from 6 years to 17 years of age.

The recommended antihypertensive oral dose in paediatric patient's 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. Amlodipine 2.5 mg is not currently available and 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. Doses in excess of 5 mg daily have not been studied in paediatric patients (see sections 5.1 and 5.2).

Children under 6 years old

No data are available.

Method of administration

Tablet for oral administration.

4.3. Contraindications

Amlodipine is contraindicated in patients with:

- hypersensitivity to dihydropyridine derivatives, amlodipine or to any of the excipients listed in section 6.1.

- 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

4.4. Special warnings and precautions for use

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

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 oedema 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.

Hepatic impairment:

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.

Elderly

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

Renal impairment:

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.

Amlodipine contains sodium

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free.'

4.5. Interaction with other medicinal products and other forms of interaction

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 resulting in an increased risk of hypotension.. 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:

Upon co-administration of known inducers of the CYP3A4, the plasma concentration of amlodipine may vary. Therefore, blood pressure should be monitored and dose regulation considered both during and after concomitant medication particularly with strong CYP3A4 inducers (e.g. rifampicin, hypericum perforatum).

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 intravenous dantrolene. Due to risk of hyperkalemia, it is recommended that the co-administration 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.

Tacrolimus:

There is a risk of increased tacrolimus blood levels when co- administered with amlodipine but the pharmacokinetic mechanism of this interaction is not fully understood. In order to avoid toxicity of tacrolimus, administration of amlodipine in a patient treated with tacrolimus requires monitoring of tacrolimus blood levels and dose adjustment of tacrolimus when appropriate.

Mechanistic Target of Rapamycin (mTOR) Inhibitors:

mTOR inhibitors such as sirolimus, temsirolimus, and everolimus are CYP3A substrates. Amlodipine is a weak CYP3A inhibitor. With concomitant use of mTOR inhibitors, amlodipine may increase exposure of mTOR inhibitors.

Cyclosporine:

No drug interaction studies have been conducted with cyclosporine and amlodipine in healthy volunteers or other populations with the exception of renal transplant patients, where variable trough concentration increases (average 0% - 40%) of cyclosporine were observed. Consideration should be given for monitoring cyclosporine levels in renal transplant patients on amlodipine, and cyclosporine dose reductions should be made as necessary.

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.

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

4.6. Fertility, pregnancy and lactation

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 foetus.

Breast-feeding

Amlodipine is excreted in human milk. The proportion of the maternal dose received by the infant has been estimated with an interquartile range of 3 - 7%, with a maximum of 15%. The effect of amlodipine on infants is unknown.. 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).

4.7. Effects on ability to drive and use machines

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.

4.8. Undesirable effects

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.

Tabulated list of adverse reactions

The following adverse reactions 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) not known (cannot be estimated from the available data).

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

System Organ Class

Frequency

Adverse reactions

Blood and lymphatic system disorders

Very Rare

Leukocytopenia, thrombocytopenia

Immune system disorders

Very Rare

Allergic reactions

Metabolism and nutrition disorders

Very Rare

Hyperglycaemia

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

Not known

Extrapyramidal disorder

Eye disorders

Common

Visual disturbance (including diplopia)

Ear and labyrinth disorders

Uncommon

Tinnitus

Cardiac disorders

Common

Palpitations

Uncommon

Arrhythmia (including bradycardia, ventricular tachycardia and atrial fibrillation)

Very Rare

Myocardial infarction

Vascular disorders

Common

Flushing

Uncommon

Hypotension

Very Rare

Vasculitis

Respiratory, thoracic and mediastinal disorders

Common

Dyspnoea

Uncommon

Cough, rhinitis

Gastrointestinal disorders

Common

Abdominal pain, nausea , dyspepsia, altered bowel habits (including diarrhoea and constipation)

Uncommon

Vomiting, dry mouth

Very Rare

Pancreatitis, gastritis, gingival hyperplasia

Hepato-biliary disorders

Very Rare

Hepatitis, jaundice, hepatic enzymes increased*

Skin and subcutaneous tissue disorders

Uncommon

Alopecia, purpura, skin discolouration, hyperhidrosis, pruritus, rash, exanthema, urticaria

Very Rare

Angioedema, erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, Quincke oedema, photosensitivity

Not Known

Toxic Epidermal Necrolysis

Musculoskeletal and connective tissue disorders

Common

Ankle swelling, muscle cramps

Uncommon

Arthralgia, myalgia, 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

Oedema

Common

Fatigue, asthenia

Uncommon

Chest pain, pain, malaise

Investigations

Uncommon

Weight increased, weight decreased

*mostly consistent with cholestasis

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 Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard

4.9. Overdose

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.

Non-cardiogenic pulmonary oedema has rarely been reported as a consequence of amlodipine overdose that may manifest with a delayed onset (24-48 hours post-ingestion) and require ventilatory support. Early resuscitative measures (including fluid overload) to maintain perfusion and cardiac output may be precipitating factors.

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.