Amlodipin Accord
Summary of product characteristics
1. NAME OF THE MEDICINAL PRODUCT
Amlodipin Accord 5 mg tablets
Amlodipin Accord 10 mg tablets
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Amlodipin Accord 5 mg tablets
Each tablet contains amlodipine besilate equivalent to 5 mg amlodipine.
Amlodipin Accord 10 mg tablets
Each tablet contains amlodipine besilate equivalent to 10 mg amlodipine.
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Tablet.
5 mg: White, approximately 6.6 mm round, biconvex tablets
10 mg: White, approximately 8.5 mm round, biconvex tablets
4. CLINICAL PARTICULARS
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 once dailywhichmay be increased to a maximum doseof 10 mg depending on the individual patient'sresponse.
Inhypertensivepatients,Amlodipine hasbeenusedincombinationwithathiazidediuretic,alphablocker, betablocker,oranangiotensinconvertingenzymeinhibitor.Forangina,Amlodipine may be used as monotherapy or in combination with other antianginalmedicinalproductsin patients with angina thatis refractorytonitratesand/ortoadequatedosesofbetablockers.
No dose adjustment of Amlodipin Accord tablets is required upon concomitant administration of thiazide diuretics, beta blockers, and angiotensin-converting enzyme inhibitors.
Specialpopulations
Elderly patients
Amlodipineusedatsimilardosesinelderlyoryoungerpatientsisequallywelltolerated.Normaldosage regimensarerecommendedintheelderly,butincreaseofthedosageshouldtakeplacewithcare(see sections4.4and5.2).
Patients with hepaticimpairment
Dosagerecommendationshavenotbeenestablishedinpatientswithmildto moderatehepatic impairment;thereforedoseselectionshouldbecautiousandshouldstartatthelowerendofthedosing range(seesections4.4and5.2).Thepharmacokineticsofamlodipinehavenotbeenstudiedinsevere hepaticimpairment.Amlodipineshouldbeinitiatedatthelowestdoseandtitratedslowlyinpatients withseverehepaticimpairment.
Patients with renal impairment
Changesinamlodipineplasmaconcentrationsarenotcorrelatedwithdegreeofrenalimpairment, thereforethenormaldosageisrecommended.Amlodipine is not dialysable.
Paediatricpopulation
Children andadolescentswith hypertension from 6 years to 17 years of age
The recommended antihypertensive oral dose in paediatricpatients 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 4weeks.Dosesinexcessof5mgdailyhavenotbeenstudiedinpaediatricpatients (see sections5.1 and5.2).
Dosesofamlodipine2.5mgarenotpossiblewiththismedicinalproduct.
Childrenunder6yearsold
Nodataareavailable.
Method of administration
Tabletfororaladministration.
4.3 Contraindications
Amlodipine is contraindicated in patients with:
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Hypersensitivity to the active substance or to any of the excipients listed in section 6.1
-
Severe hypotension.
-
Shock (including cardiogenic shock).
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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 hasnot been established.
Patients with cardiacfailure
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.
Patients with hepatic impairment
The halflife of amlodipine is prolongedandAUCvaluesarehigherin patients with impaired liver function; dosage recommendations have not been established. Amlodipine should therefore be initiatedatthelowerendofthedosingrangeandcautionshouldbeused,both on initial treatment and when increasing the dose. Slow dose titration and careful monitoring may be required in patients with severe hepatic impairment.
Elderlypatients
Intheelderlyincreaseofthedosageshouldtakeplacewithcare(seesections4.2and5.2).
Patients with 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 dialysable.
4.5 Interaction with other medicinal products and other forms of interaction
Effects of other medicinalproductson amlodipine
CYP3A4 inhibitors: concomitant use ofamlodipinewith strongormoderateCYP3A4 inhibitors (proteaseinhibitors,azoleantifungals,macrolideslikeerythromycin orclarithromycin,verapamilor diltiazem)maygiverisetosignificantincreaseinamlodipineexposure resulting in an increased risk of hypotension.The clinical translationof thesePKvariationsmaybe morepronouncedintheelderly.Clinicalmonitoringanddoseadjustment maythusbe required.
CYP3A4 inducers:
There is no dataavailable regardingthe 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.Amlodipineshould be used withcautiontogetherwith 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 medicinalproducts
Thebloodpressureloweringeffectsofamlodipineaddstothe bloodpressure-loweringeffectsof other medicinalproductswithantihypertensive properties.
Tacrolimus
There is a risk of increased tacrolimus blood levels when coadministered 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.
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.
Inanimalstudies,reproductivetoxicitywasobservedathighdoses(seesection5.3).
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 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.Cautionisrecommendedespeciallyatthestartoftreatment.
4.8 Undesirable effects
Summaryofthesafetyprofile
Themostcommonlyreportedadversereactionsduringtreatmentaresomnolence,dizziness,headache, palpitations,flushing,abdominalpain,nausea,ankleswelling,oedemaandfatigue.
The following adversereactionshavebeen observed and reported duringtreatment with amlodipinewiththefollowingfrequencies: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.
Blood and lymphatic system disorders
Very rare: leucocytopenia, 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, paraesthesia
Very rare: Hypertonia, peripheral neuropathy
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 diarrohea and constipation)
Uncommon: vomiting, 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,hyperhydrosis, pruritis, rash, exanthema
Very rare:angioedema, erythema multiforme, urticaria, exfoliative dermatitis, Stevens-Johnson syndrome, Quincke oedema, photosensitivity
Musculoskeletal and connective tissue disorders
Common: Ankle swelling, muscle cramps
Uncommon: myalgia, arthralgia, 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
Very Common: Oedema
Common : fatigue, asthenia
Uncommon: Chest pain, pain, malaise
Investigations
Uncommon: Weight increase, weight decrease
*mostly consistent with cholestasis
Exceptional casesof 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 national reporting system (To be completed nationally).
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 overdosage calls for activecardiovascular 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 administrationof amlodipine 10mghas been shown to reduce the absorption rateof amlodipine.
Since amlodipine is highly protein-bound, dialysis is not likely to be of benefit.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Calciumchannelblockers,selectivecalciumchannelblockerswith mainlyvasculareffects.ATC code: C08CA01.
Amlodipine is a calcium ioninfluxinhibitorofthedihydropyridinegroup(slowchannelblockeror calciumionantagonist)and inhibits the transmembraneinflux of calcium ions into cardiac and vascular smooth muscle.
Themechanismofthe antihypertensive actionofamlodipineis due to a direct relaxant effect on vascular smooth muscle. The precise mechanism by which amlodipine relieves angina has not been fullydeterminedbutamlodipinereducestotalischaemicburdenbythefollowingtwoactions:
1)Amlodipine dilates peripheral arterioles and thus,reduces the total peripheral resistance (afterload) against which the heart works. Sincetheheartrateremainsstable,this unloading of the heart reduces myocardialenergy consumption and oxygen requirements.
2)The mechanism of action ofamlodipinealso probably involves dilatation of the maincoronaryarteries and coronaryarterioles,bothinnormalandischaemicregions.This dilatation increases myocardialoxygen deliveryin patients with coronaryarteryspasm(Prinzmetal's orvariantangina).
In patients with hypertension, once daily dosing providesclinically significant reductionsofblood pressure in both the supine and standing positionsthroughoutthe24 hourinterval. 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 anginaonset,andtimeto1mmST segment depression,anddecreases both angina attack frequency and glyceryltrinitratetabletconsumption.
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.
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 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.
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Table 1. Incidence of significant clinical outcomes for CAMELOT |
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Cardiovascular event rates, No. (%) |
Amlopidine vs. Placebo |
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|
Outcomes |
Amlopidine |
Placebo |
Enalapril |
Hazard Ratio (95% CI) |
P Value |
|
|
Primary Endpoint |
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|
Adverse cardiovascular events |
110 (16.6) |
151 (23.1) |
136 (20.2) |
0.69 (0.54-0.88) |
.003 |
|
|
Individual Components |
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|
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. |
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Use in Patients with Heart Failure
Haemodynamic studies and exercise based controlled clinical trials in NYHA Class II-IV heart failure patients have shown that amlodipine does 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 does not lead to an increased 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 of 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 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 2.5mg dose, and 5.0 mgdose of amlodipine with placebo, showed that both doses reduced Systolic Blood Pressuresignificantly 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 havealso not been established.
5.2 Pharmacokinetic properties
Absorption,distribution,plasmaproteinbinding:After oral administration of therapeutic doses, amlodipine is wellabsorbed withpeakbloodlevelsbetween6-12hourspostdose.Absolute bioavailability has been estimated to be between 64 and 80%. The volume of distribution is approximately 21 l/kg. In vitrostudies 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/elimination
The terminalplasma eliminationhalf life is about35-50 hoursandis consistentwithoncedailydosing.Amlodipine is extensivelymetabolised bytheliverto inactive metaboliteswith10%oftheparent compoundand60% of metabolitesexcreted in the urine.
Hepaticimpairment
Verylimitedclinicaldataareavailableregardingamlodipineadministrationinpatientswithhepatic impairment.Patientswithhepaticinsufficiencyhavedecreasedclearanceofamlodipineresultingina
longerhalf-lifeandanincreaseinAUCofapproximately40-60%.
Elderly population
The time to reachpeak plasma concentrations of amlodipine is similar in elderly and younger subjects. Amlodipine clearance tends to bedecreasedwith resulting increasesin AUC and eliminationhalf-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.
Paediatric population
A 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 adolescents13-17 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.
5.3 Preclinical safety data
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 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, 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 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
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Microcrystalline cellulose
Sodium starch glycolate
Magnesium stearate
Disodium hydrogen citrate
Crospovidone
Croscarmellose sodium
6.2 Incompatibilities
Not relevant.
6.3 Shelf life
3 years.
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
Blister packs of PVC/PVdC foil and aluminium foil.
5mg - 10, 14, 20, 28, 30, 50, 60, 90, 98, 100 tablets.
10mg - 10, 14, 20, 28, 30, 50, 60, 90, 98, 100 tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
No special requirements for disposal.
7. MARKETING AUTHORISATION HOLDER
To be completed nationally
8. MARKETING AUTHORISATION NUMBERS
To be completed nationally
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation: 2008-10-10
Date of latest renewal: 2013-10-10
10. DATE OF REVISION OF THE TEXT
2016-05-11