- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
AdultsFor both hypertension and angina the usual initial dose is 5 mg Istin once daily which may be increased to a maximum dose of 10 mg depending on the individual patient's response.In hypertensive patients, Istin has been used in combination with a thiazide diuretic, alpha blocker, beta blocker, or an angiotensin converting enzyme inhibitor. For angina, Istin 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 Istin is required upon concomitant administration of thiazide diuretics, beta blockers, and angiotensin-converting enzyme inhibitors.
ElderlyIstin 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 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.
Patients with renal impairmentChanges in amlodipine plasma concentrations are not correlated with degree of renal impairment, therefore the normal dosage is recommended. Amlodipine is not dialysable.
Paediatric populationChildren and adolescents with hypertension from 6 years to 17 years of age.The recommended antihypertensive oral dose in paediatric 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 paediatric patients (see sections 5.1 and 5.2).
Children under 6 years oldNo data are available.
Method of administrationTablet for oral administration.
Patients with cardiac failurePatients 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.
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 patients with 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 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 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 or warfarin.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.
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-feedingIt 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.
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).
Summary of the safety profileThe 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 reactionsThe 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).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||Depression, mood changes (including anxiety), insomnia|
|Nervous system disorders||Common||Somnolence, dizziness, headache (especially at the beginning of the treatment)|
|Uncommon||Tremor, dysgeusia, syncope, hypoaesthesia, paraesthesia|
|Very rare||Hypertonia, peripheral neuropathy|
|Eye disorders||Common||Visual disturbance (including diplopia)|
|Ear and labyrinth disorders||Uncommon||Tinnitus|
|Uncommon||Arrhythmia (including bradycardia, ventricular tachycardia and atrial fibrillation)|
|Very rare||Myocardial infarction|
|Respiratory, thoracic and mediastinal disorders||Common||Dyspnoea|
|Gastrointestinal disorders||Common||Abdominal pain, nausea, dyspepsia, altered bowel habits (including diarrhoea and constipation)|
|Uncommon||Vomiting, dry mouth|
|Very rare||Pancreatitis, gastritis, gingival hyperplasia|
|Hepatobiliary disorders||Very rare||Hepatitis, jaundice, hepatic enzyme 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|
|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, gynaecomastia|
|General disorders and administration site conditions||Very common||Oedema|
|Uncommon||Chest pain, pain, malaise|
|Investigations||Uncommon||Weight increased, weight decreased|
Reporting of suspected adverse reactionsReporting 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 the Yellow Card Scheme at www.mhra.gov.uk/yellowcard.
SymptomsAvailable 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.
TreatmentClinically 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.
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-centre, randomized, double- blind, placebo-controlled study of 1997 patients; Comparison of Amlodipine vs. Enalapril to Limit Occurrences of Thrombosis (CAMELOT). Of these patients, 663 were treated with amlodipine 5-10 mg, 673 patients 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. (%)||Amlopidine vs. Placebo|
|Outcomes||Amlopidine||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|
|Abbreviations: CHF, congestive heart failure; CI, confidence interval; MI, myocardial infarction; TIA, transient ischemic attack.|
Use in patients with heart failureHaemodynamic studies and exercise based controlled clinical trials in NYHA Class II-IV heart failure patients have shown that Istin 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 Istin 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 Istin 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, Istin had no effect on total cardiovascular mortality. In this same population Istin was associated with 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 2.5 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 has also not been established.
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 the urine.
Use in hepatic impairmentVery 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 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 1 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.
Reproductive toxicologyReproductive studies in rats and mice have shown delayed date of delivery, prolonged duration of labour and decreased pup survival at dosages approximately 50 times greater than the maximum recommended dosage for humans based on mg/kg.
Impairment of fertilityThere 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 besilate 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, mutagenesisRats 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
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