Amlodipine

Registered South African indications:

• Hypertension - mild to moderate
• Angina pectoris
• Chronic stable angina
  - As monotherapy or in combination with other antianginal agents for the first line treatment of myocardial ischaemia, whether due to fixed obstruction (stable angina) and/or vasospasm/vasoconstriction (Prinzmetal's or variant angina) of coronary vasculature
• Coronary artery disease (CAD)
  - To reduce the risk of coronary revascularisation and the need for hospitalisation due to angina in patients with coronary artery disease
  - To reduce the risk of fatal coronary heart disease and non-fatal myocardial infarction, and to reduce the risk of stroke

Contraindications

South African recommendations

• Hypersensitivity to the active ingredient or any of its excipients
• Hypersensitivity to dihydropyridines
• 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
• Coadministration with grapefruit juice

Recommendations in other jurisdictions

• Hypersensitivity to the active ingredient or any of its excipients
• Hypersensitivity to dihydropyridine derivatives
• 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

Cautions

South African recommendations

• Pregnancy
• Breastfeeding
• Severe renal impairment
• Hepatic impairment
• Elderly
• Heart failure
  - NYHA class III and IV of non-ischaemic etiology
  - Congestive heart failure
• Renal transplant patients on ciclosporin
• May impair ability to drive and operate machinery

Recommendations in other jurisdictions

• Pregnancy
• Breastfeeding
• Males of reproductive potential
• Hepatic impairment
• Elderly
• Hypertensive crisis
• Heart failure
  - Severe heart failure (NYHA class III and IV)
  - Congestive heart failure
• Patients susceptible to malignant hyperthermia
• Renal transplant patients on ciclosporin (See additional prescribing points)
• Males of reproductive potential
• May impair ability to drive and operate machinery

Forms avail. in SA and covered in this monograph: tab

Dosages below include:

• South African registered indications and dosages
• Indications and dosages registered in other jurisdictions

South African registered indications and dosages

Hypertension - mild to moderate
Angina pectoris

• Oral (tab): Initial: 5mg, dly; Titrate up to 10mg, dly after 10-14 days depending on the individual patient's response; Max: 10mg/24hrs

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No dose reduction is required when adding amlodipine to thiazide diuretics, beta-blockers, or angiotensin-converting enzyme inhibitors

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Coronary artery disease (CAD)
- To reduce the risk of coronary revascularisation and the need for hospitalisation due to angina in patients with coronary artery disease
- To reduce the risk of fatal coronary heart disease and non-fatal myocardial infarction, and to reduce the risk of stroke
Chronic stable angina
- As monotherapy or in combination with other antianginal agents for the first line treatment of myocardial ischaemia, whether due to fixed obstruction (stable angina) and/or vasospasm/vasoconstriction (Prinzmetal's or variant angina) of coronary vasculature

• Oral (tab): 5-10mg, dly

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In clinical studies, the majority of patients required 10mg

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Indications and dosages registered in other jurisdictions

Hypertension
Chronic stable angina pectoris
Vasospastic (Prinzmetal's) angina

• Oral (tab): Initial: 5mg, dly; Titrate up to 10mg, dly, depending on the individual patient's response; Max: 10mg/24hrs

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In hypertensive patients, amlodipine has been used in combination with a thiazide diuretic, alpha-blocker, beta-blocker, or an angiotensin-converting enzyme inhibitor

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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

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

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See additional prescribing points for additional notes

Forms avail. in SA and covered in this monograph: tab

Paed. dosages below include:

• South African registered indications and dosages
• Indications and dosages registered in other jurisdictions

South African registered indications and dosages

Hypertension - mild to moderate

Younger than 6 years

• Not established for use

Between 6-17 years

• Oral (tab): 2.5-5mg, dly

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Doses in excess of 5mg daily have not been studied in paediatric patients

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Indications and dosages registered in other jurisdictions

Hypertension

Younger than 6 years

• Not established for use

Between 6-17 years

• Oral (tab): Initial: 2.5mg, dly; Titrate to 5mg, dly if blood pressure goal is not achieved after 4 weeks

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Doses in excess of 5mg daily have not been studied in paediatric patients

Pregnancy

South African recommendations

• Caution
• Safety of amlodipine in pregnancy has not been established

Recommendations in other jurisdictions

• Caution; positive evidence of risk in animal studies
• The safety of amlodipine in human pregnancy has not been established. In animal studies, reproductive toxicity was observed at high doses. Use in pregnancy is only recommended when there is no safer alternative and when the disease itself carries a greater risk for the mother and foetus

Breastfeeding

South African recommendations

• Caution
• Safety of amlodipine in breastfeeding women has not been established

Recommendations in other jurisdictions

• Caution; not recommended
• 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 breastfeeding or to continue/discontinue therapy with amlodipine should be made taking into account the benefit of breastfeeding to the child and the benefit of amlodipine therapy to the mother

Fertility

South African recommendations

• No information available

Recommendations in other jurisdictions

• 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

Renal Impairment

South African recommendations

• Mild to moderate: No dose adjustment recommended
• Severe: Caution; no dose adjustment recommended
  Amlodipine dose may need to be reduced
  Amlodipine is not dialysable

Recommendations in other jurisdictions

• No dose adjustment recommended 
  Amlodipine is not dialysable

Hepatic Impairment

South African recommendations

• Caution; no dose adjustment recommended
  Amlodipine should be administered at a lower initial dose in these patients

Recommendations in other jurisdictions

• Mild to moderate: Caution; no dose adjustment recommended
  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
• Severe: Caution; no information available
  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

Elderly

• Caution; no dose adjustment recommended
  Elderly patients should start amlodipine therapy at a lower dose
  Increase of the dosage should take place with care

Porphyria Information

• Probably not porphyrinogenic (PNP)

Drugs in Sport

•  Permitted - No warnings

Central Nervous System Disorders

• Somnolence
• Dizziness
• Headache
• Tremor
• Syncope
• Hypoaesthesia
• Paraesthesia
• Hypertonia
• Peripheral neuropathy
• Extrapyramidal syndrome
• Depression
• Mood changes
  - Anxiety
• Insomnia
• Confusion
• Fatigue

Cardiovascular Disorders

• Palpitations
• Arrhythmia
  - Bradycardia
  - Ventricular tachycardia
  - Atrial fibrillation
• Myocardial infarction
• Flushing
• Hypotension
• Vasculitis
• Chest pain
• Vasodilation (Paediatric patients)
• Uncontrolled hypertension (Paediatric patients)

Respiratory Disorders

• Dyspnoea
• Cough
• Rhinitis
• Epistaxis (Paediatric patients)

Gastrointestinal Disorders

• Abdominal pain
• Nausea and vomiting
• Dyspepsia
• Altered bowel habits
  - Diarrhoea
  - Constipation
• Dry mouth
• Pancreatitis
• Gastritis
• Gingival hyperplasia

Hepatobiliary Disorders

• Hepatitis
• Jaundice
• Increased hepatic enzymes
  - Cholestasis

Genitourinary Disorders

• Impotence
• Micturition disorder
• Nocturia
• Increased urinary frequency

Endocrine and Metabolic Disorders

• Increased weight
• Decreased weight
• Hyperglycaemia
• Gynaecomastia

Musculoskeletal Disorders

• Ankle swelling
• Muscle cramps
• Arthralgia
• Myalgia
• Back pain

Skin and Subcutaneous Tissue Disorders

• Alopecia
• Purpura
• Skin discolouration
• Hyperhidrosis
• Pruritus
• Rash
• Exanthema
• Urticaria
• Angioedema
• Erythema multiforme
• Exfoliative dermatitis
• Stevens-Johnson syndrome
• Quincke oedema
• Photosensitivity
• Toxic epidermal necrolysis

Immune, Blood and Lymphatic System Disorders

• Leukopenia
• Thrombocytopenia
• Allergic reactions
• Oedema

Sensory Disorders

• Tinnitus
• Visual disturbance
  - Diplopia
• Dysgeusia

Others

• Pain

• Moderate to strong CYP3A4 inhibitors
• Protease inhibitors
• Azole antifungals
• Macrolides
• Erythromycin
• Clarithromycin
• Verapamil
• Diltiazem
• Other anti-hypertensives
• CYP3A4 inducers
• Rifampicin
• Dantrolene
• Tacrolimus
• Ciclosporin (See additional prescribing points)
• Simvastatin

Other interactions

• St John's wort (Hypericum perforatum)
• Grapefruit/grapefruit juice

• Heart rate
• Blood pressure

Specific cases may require

• Hepatic function

Additional notes

• 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

Ciclosporin

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

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 two actions. Firstly, 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. Secondly, 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).

Tablet 5mg

• Adco Norpene (Adcock Ingram)
• Almadin (Pharmacare)
• Amlate (Dr Reddy's)
• Amloc (Pharma Dynamics)
• Amlodac 5 (Zydus)
• Amlodipine Ascendis (Dezzo)
• Amlodipine 5 Biotech (Biotech Laboratories)
• Amlodipine 5 Oethmaan (Oethmaan)
• Amlodipine Unicorn (Accord)
• Amlodipine 5 Kiara (Unichem)
• Amlosyn (Litha)
• Amtas (Accord)
• Aprate (Aurobindo)
• Austell-Amlodipine (Austell)
• Calbloc (Be-Tabs)
• Ciplavasc (Cipla Medpro)
• Gulf Amlodipine (Gulf Drug)
• Indo Amlodopine (Dezzo)
• Keysal (Novagen)
• Klodip-5 (Teva Pharmaceuticals)
• Lomanor (Pfizer)
• Norcard (Pharma-Q)
• Norvasc (Pfizer) originator
• Pendine (Unichem)
• Pharma Dynamics Amlodipine (Pharma Dynamics)
• Sandoz Amlodipine (Sandoz)

Tablet 10mg

• Adco Norpene (Adcock Ingram)
• Almadin (Pharmacare)
• Amlate (Dr Reddy's)
• Amloc (Pharma Dynamics)
• Amlodac 10 (Zydus)
• Amlodipine 10 Biotech (Biotech Laboratories)
• Amlodipine 10 Oethmaan (Oethmaan)
• Amlodipine Unicorn (Accord)
• Amlodipine 10 Kiara (Unichem)
• Amlosyn (Litha)
• Amtas (Accord)
• Aprate (Aurobindo)
• Austell-Amlodipine (Austell)
• Calbloc (Be-Tabs)
• Ciplavasc (Cipla Medpro)
• Gulf Amlodipine (Gulf Drug)
• Keysal (Novagen)
• Lomanor (Pfizer)
• Norcard (Pharma-Q)
• Norvasc (UpJohn) originator
• Pendine (Unichem)
• Pharma Dynamics Amlodipine (Pharma Dynamics)
• Sandoz Amlodipine (Sandoz)