Summary of Product Characteristics Updated 05-May-2016 | Kent Pharmaceuticals Ltd
AdultsFor 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.
ElderlyAmlodipine 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).
Renal impairmentChanges in amlodipine plasma concentrations are not correlated with degree of renal impairment, therefore the normal dosage is recommended. Amlodipine is not dialysable.
Hepatic impairmentDosage 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.
Paediatric populationChildren and adolescents with hypertension from 6 years to 17 years of age.The recommended antihypertensive oral dose in paediatric patients aged 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 paediatric patients (see sections 5.1 and 5.2). Doses of amlodipine 2.5 mg are not possible with this medicinal product.
Children under 6 years oldNo data are available.
Method of administrationTablet for oral administration.
Patients with cardiac failurePatients with cardiac 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.
Use in patients with impaired hepatic functionThe 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 patientsIn the elderly, increase of the dosage should take place with care (see sections 4.2 and 5.2).
Use in renal failureAmlodipine 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 dialysable.
Effects of other medicinal products on amlodipineCYP3A4 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 hyperkalaemia after administration of verapamil and intravenous dantrolene. Due to risk of hyperkalaemia, 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 productsThe 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.
PregnancyThe 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 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 woman.FertilityReversible 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).
|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|
|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|
|Very rare||Myocardial infarction, arrhythmia (including bradycardia, ventricular tachycardia and atrial fibrillation)|
|Respiratory, thoracic and mediastinal disorders||Uncommon||Dyspnoea, rhinitis|
|Gastrointestinal disorders||Common||Abdominal pain, nausea|
|Uncommon||Vomiting, dyspepsia, altered bowel habits (including diarrhoea and constipation), dry mouth|
|Very rare||Pancreatitis, gastritis, gingival hyperplasia|
|Hepatobiliary disorders||Very rare||Hepatitis, jaundice, hepatic enzymes increased*|
|Skin and subcutaneous tissue disorders||Uncommon||Alopecia, purpura, skin discolouration, hyperhidrosis, pruritus, rash, exanthema|
|Very rare||Angiodema, erythema, multiforme, urticaria, exfoliative dermatitis, Stevens-Johnson syndrome, Quincke oedema, photosensitivity|
|Musculoskeletal and connective tissue 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||Oedema, fatigue|
|Uncommon||Chest pain, asthenia, pain, malaise|
|Investigations||Uncommon||Weight increase, weight decrease|
Use in patients with coronary artery disease (CAD)The effectiveness of amlodipine in preventing clinical events in patients with coronary artery disease (CAD) has been evaluated in an independent, multi-center, randomized, double-blind, placebo-controlled study of 1997 patients; Comparison of Amlodipine vs. Enalapril to Limit Occurrences of Trombosis (CAMELOT). Of these patients, 663 were treated with amlodipine 5-10mg, 673 were treated with enalapril 10-20 mg, and 655 patients were treated with placebo, in addition to standard care of statins, beta blockers, diuretics and aspirin, for 2 years. The key efficacy results are presented in table 1. The results indicate that amlodipine treatment was associated with fewer hospitalizations for angina and revascularization procedures in patients with CAD.
|Table 1. Incidence of significant clinical outcomes for CAMELOT|
|Cardiovascular event rates, No. (%)||Amlodipine vs. Placebo|
|Outcomes||Amlodipine||Placebo||Enalapril||Hazard Ratio (95% CI)||P Value|
|Adverse cardiovascular events||110 (16.6)||151 (23.1)||136 (20.2)||0.69 (0.54-0.88)||.003|
|Coronary revascularization||78 (11.8)||103 (15.7)||95 (14.1)||0.73 (0.54-0.98)||.03|
|Hospitalization for angina||51 (7.7)||84 (12.8)||86 (12.8)||0.58 (0.41-0.82)||.002|
|Nonfatal MI||14 (2.1)||19 (2.9)||11 (1.6)||0.73 (0.37-1.46)||.37|
|Stroke or TIA||6 (0.9)||12 (1.8)||8 (1.2)||0.50 (0.19-1.32)||.15|
|Cardiovascular death||5 (0.8)||2 (0.3)||5 (0.7)||2.46 (0.48-12.7)||.27|
|Hospitalization for CHF||3 (0.5)||5 (0.8)||4 (0.6)||0.59 (0.14-2.47)||.46|
|Resuscitated cardiac arrest||0||4 (0.6)||1 (0.1)||NA||.04|
|New-onset peripheral vascular disease||5 (0.8)||2 (0.3)||8 (1.2)||2.6 (0.50-13.4)||.24|
Use in patients with heart failureHaemodynamic 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 increased reports of pulmonary oedema.
Treatment to prevent heart attack trial (ALLHAT)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.
Use in Children (aged 6 years and older)In a study involving 268 children aged 6-17 years with predominantly secondary hypertension, comparison of a 2.5mg 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.
Absorption, distribution, plasma protein bindingAfter 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/eliminationThe 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 urine.
Use in hepatic impairment: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%.
Use in the elderlyThe 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 area under the curve (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.
Use in childrenA population PK study has been conducted in 74 hypertensive children aged from 1to 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.
In patients with renal failureAmlodipine is extensively metabolised to inactive metabolites. 10% of the parent compound is excreted unchanged in urine. Changes in amlodipine concentration are not correlated with degree of renal impairment. Therefore the normal dosage is recommended. Amlodipine is not dialysable.
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