Amlodipine 10mg Tablets
Out of date information, search anotherSUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Amlodipine 10mg Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Amlodipine 10 mg tablets:
Each tablet contains 10 mg of amlodipine (as amlodipine maleate).
For a full list of excipients, see Section 6.1
3 PHARMACEUTICAL FORM
10 mg tablets:
White round tablets with a break score on both sides. Breaking along the score line allows for dosing at a level of 5mg.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Hypertension.
Prophylaxis of chronic stable angina pectoris.
Prinzmetal's (variant) angina when diagnosed by a cardiologist.
4.2 Posology and method of administration
The tablets should be taken with a glass of water independently from meals.
In adults
For treatment of both hypertension and angina the usual initial dose is 5 mg once daily which may be increased to a maximum dose of 10 mg depending on the individual patient’s response.
No dose adjustment of amlodipine is required upon concomitant administration of thiazide diuretics, beta blockers, and angiotensin-converting enzyme inhibitors.
In children (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 Section 5.1 and Section 5.2). 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 5mg tablets as these tablets are not manufactured to break into two equal halves.
In children under 6 years old No data are available.
In the elderly
Amlodipine, used at similar doses in elderly or younger patients, is equally well tolerated. Therefore, normal dosage regimens are recommended but increase of the dosage should take place with care (see sections 4.4 and 5.2).
In patients with 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.
In patients with 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 Section 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.
In patients with hypertension
In hypertensive patients, amlodipine has been used in combination with a thiazide diuretic, alpha blocker, beta-adrenoceptor blocking agent, or an angiotensin converting enzyme inhibitor. For angina, amlodipine may be used as monotherapy or in combination with other antianginal drugs in patients with angina that is refractory to nitrates and/or adequate doses of beta blockers.
4.3 Contraindications
Amlodipine is contra-indicated in patients with:
• hypersensitivity to amlodipine, dihydropyridine derivatives or to any of the excipients
• severe hypotension
• shock, including cardiogenic shock
• haemodynamically unstable heart failure after acute myocardial infarction (during the first 28 days)
• obstruction of the outflow tract of the left ventricle (e.g. high grade aortic stenosis)
• unstable angina pectoris
4.4 Special warnings and precautions for use
The safety and efficacy of amlodipine in hypertensive crisis has not been established.
Patients with cardiac failure
Patients with cardiac failure should be treated with caution. In a long-term, placebo controlled study 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, but this was not associated with worsening of the heart failure (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 function
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.
Use in renal failure
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 dialysable.
Use in elderly patients
In the elderly, increase of the dosage should take place with care (see Section 5.2).
This product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this product.
4.5 Interaction with other medicinal products and other forms of interaction
Effects of other medicinal products on amlodipine
CYP3A4 inhibitors: Concomitant use with strong or moderate CYP3A4 inhibitors (protease inhibitors, azole antifungals, macrolides like erythromycin or clarithromycin, verapamil or diltizem) 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 (i.e. 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.
In clinical interaction studies, cimetidine, aluminium/magnesium (antacid) and sildenafil did not affect the pharmacokinetics of amlodipine.
Effects of amlodipine on other medicinal products
The blood pressure lowering effects of amlodipine adds to the blood pressurelowering effects of other antihypertensives agents.
In clinical interaction studies, amlodipine did not affect the pharmacokinetics of atorvastatin, digoxin, ethanol (alcohol), warfarin or ciclosporin.
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.
There is no effect of amlodipine on laboratory parameters.
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).
Reproductive studies in rats have shown no toxicity except for delayed date of delivery and prolonged duration of labour at dosages 50 times greater than the maximum recommended for humans.
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.
Lactation
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 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, diplopia, headache, fatigue or nausea the ability to react may be impaired. Caution is recommended especially at the start of treatment.
4.8 Undesirable effects
The following undesirable effects have been observed and reported during treatment with amlodipine with the following frequencies:
Very common: >1/10 Common: >1/100 and <1/10 Uncommon: >1/1,000 and <1/100 Rare: >1/10,000 and <1/1,000 Very rare: <1/10,000
|
System Organ Class |
Frequency |
Undesirable Effects |
|
Blood and the lymphatic system disorders |
Very rare |
Leukocytopenia, thrombocytopenia |
|
Immune system disorders |
Very rare |
Allergic reactions |
|
Metabolism and nutrition disorders |
Very rare |
Hyperglycaemia |
|
Nervous system disorders |
Common |
Somnolence, headache (especially in the beginning of the treatment), dizziness |
|
Uncommon |
Tremor, dysgeusia, syncope, hypoesthesia, paraesthesia | |
|
Very rare |
Hypertonia, peripheral neuropathy | |
|
Eye disorders |
Uncommon |
Visual disturbances (including diplopia) |
|
Psychiatric disorders |
Uncommon |
Insomnia, mood changes (including anxiety), depression |
|
Rare |
Confusion | |
|
Ear and labyrinth disorders |
Uncommon |
Tinnitus |
|
Cardiac disorders |
Common |
Palpitations |
|
Very rare |
Myocardial infarction, arrhythmia (including ventricular tachycardia, bradycardia and atrial fibrillation) | |
|
Vascular disorders |
Common |
Flushing |
|
Uncommon |
Hypotension | |
|
Very rare |
Vasculitis | |
|
Respiratory, thoracic and |
Uncommon |
Dyspnoea, rhinitis |
|
System Organ Class |
Frequency |
Undesirable Effects |
|
mediastinal disorders |
Very rare |
Cough |
|
Gastrointestinal disorders |
Common |
Nausea, abdominal pain |
|
Uncommon |
Vomiting, dyspepsia, altered bowel habits (including diarrhoea and constipation), dry mouth | |
|
Very rare |
Gastritis, pancreatitis, gingival hyperplasia | |
|
Hepato-biliary disorders |
Very rare |
Hepatic enzymes increased*, jaundice, hepatitis |
|
Skin and subcutaneous tissue disorders |
Uncommon |
Exanthema, pruritus, alopecia, purpura, skin discolouration, hyperhydrosis, rash |
|
Very rare |
Angioedema, erythema multiforme, urticaria, exfoliative dermatitis, Stevens-Johnson syndrome, Quincke oedema, photosensitivity | |
|
Musculoskeletal, connective tissue and bone disorders |
Common |
Ankle swelling |
|
Uncommon |
Muscle cramps, back pain, myalgia, arthralgia | |
|
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 |
Common |
Oedema, fatigue |
|
Uncommon |
Chest pain, asthenia, pain, malaise | |
|
Investigations |
Uncommon |
Weight increase, weight decrease |
* mostly consistent with cholestatis
Exceptional cases of extrapyramidal syndrome have been reported.
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 the 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.
Treatment
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.
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.
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 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:
1. Amlodipine dilates peripheral arterioles and thus reduces the peripheral resistance (afterload) against which the heart pumps. This unloading of the heart reduces myocardial energy consumption and oxygen requirements.
2. Dilatation of the main coronary arteries and the coronary arterioles also probably plays a role in its action. This dilation increases the supply in oxygen to myocardiac muscle in patients with Prinzmetal anginal attack.
In patients with hypertension, once daily dosing provides clinically significant reductions of blood pressure (in both supine and standing positions) that persist for 24 hours. 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, the delay of occurrence of anginal attack and the delay of the occurrence of a 1-mm ST interval. Amlodipine decreases both 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.
In a study involving 268 children aged 6-17 years with predominantly secondary hypertension, comparison of a 2.5mg dose, and 5.0mg 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.
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 independant, 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 asprin, 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 si |
gnificant clinical outcomes for CAMELOT | ||||
|
Cardiovascular event rates, No. |
Amlopidine vs. | ||||
|
(%) |
Placebo | ||||
|
Outcomes |
Amlopidine |
Placebo |
Enalapril |
Hazard Ratio (95% CI) |
P Value |
|
Primary Endpoint | |||||
|
Adverse cardiovascular events |
110 (16.6) |
151 (23.1) |
136 (20.2) |
0.69 (0.540.88) |
.003 |
|
Individual Components | |||||
|
Coronary revascularization |
78 (11.8) |
103 (15.7) |
95 (14.1) |
0.73 (0.540.98) |
.03 |
|
Hospitalization for angina |
51 (7.7) |
84 (12.8) |
86 (12.8) |
0.58 (0.410.82) |
.002 |
|
Nonfatal MI |
14 (2.1) |
19 (2.9) |
11 (16) |
0.73 (0.371.46) |
.37 |
|
Stroke or TIA |
6 (0.9) |
12 (1.8) |
8 (1.2) |
0.50 (0.191.32) |
.15 |
|
Cardiovascular death |
5 (0.8) |
2 (0.3) |
5 (0.7) |
2.46 (0.4812.7) |
.27 |
|
Hospitalization for CHF |
3 (0.5) |
5 (0.8) |
4 (0.6) |
0.59 (0.142.47) |
.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 (0.5013.4) |
.24 |
|
Abbreviations: CHF, congestive heart : myocardial infarction; TIA, transient is |
ailure; CI, confidence interval; MI, chemic attack. | ||||
Use in patients with cardiac failure
Haemodynamic 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.
In a placebo-controlled study (PRAISE) designed to evaluate patients with NYHA class III-IV heart failure receiving digoxin, diuretics and angiotensin-converting enzyme (ACE) inhibitors has been shown that amlodipine did not lead to an increase in the risk of mortality or combined mortality and morbidity in patients with heart failure.
In a follow-up, long-term, placebo controlled study (PRAISE-2) of amlodipine in patients with NYHA class III and IV heart failure without clinical symptoms or objective findings suggestive of underlying ischaemic disease, on stable doses of ACE inhibitors, digitalis and diuretics, amlodipine had no effect on total or 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.
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 enrolment) 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 (0.901.07) 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.
5.2 Pharmacokinetic properties
Absorption/Distribution
After oral administration of therapeutic doses amlodipine is slowly absorbed from the gastrointestinal tract. The absorption of amlodipine is unaffected by the concomitant intake of food. The absolute bioavailability of the unchanged compound is estimated as 64-80%. Peak plasma levels are reached 6 to 12 hours post-dose. The volume of distribution is about 21 l/kg. The pKa of amlodipine is 8.6. Plasma protein binding in vitro is approximately 97.5%.
Metabolism/Elimination
The plasma elimination half-life is about 35 to 50 hours.
Steady state plasma levels are reached after 7-8 consecutive days.
Amlodipine is predominantly metabolised by the liver to inactive metabolites. About 60% of the administered dose is excreted in the urine, about 10% of which is in the form of unchanged amlodipine.
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 AUC of approximately 40-60%.
Use in Children
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.
In the elderly
The 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 study (see Section 4.4).
5.3 Preclinical safety data
Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential.
Reproductive toxicology
Reproductive 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 Fertility
There 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 of 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, mutagenesis
Rats 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 10mg on a mg/m2 basis) was close to the maximum tolerated dose for mice but not for rats.
*Based on patient weight of 50kg.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Lactose monohydrate povidone K 30 povidone K 90 microcrystalline cellulose crospovidone sodium stearyl fumarate
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
36 months.
6.4 Special precautions for storage
Do not store above 25°C.
Store in the original package.
6.5 Nature and contents of container
Amlodipine 10mg Tablets: Al/Al blister packs with 10, 20, 28, 30, 50, 98 or 100 tablets
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7 MARKETING AUTHORISATION HOLDER
Focus Pharmaceuticals Ltd Capital House, 1st Floor,
85 King William Street,
London EC4N 7BL,
United Kingdom.
8 MARKETING AUTHORISATION NUMBER(S)
PL 20046/0021
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
30/11/2008
10 DATE OF REVISION OF THE TEXT
25/06/2015