Amlodipine 5mg Tablets
Out of date information, search anotherSUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Amlodipine 5 mg tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains Amlodipine Besilate equivalent to 5 mg of amlodipine. For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Tablet
White to off white coloured elongated octagon shaped flat faced bevelled edged tablets debossed with “S-481” on one side and plain on the other side.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Essential hypertension.
Chronic stable and vasospastic angina pectoris.
4.2 Posology and method of administration
For oral administration. The tablets should be taken with a glass of water with or without food.
Adults
For treatment of both hypertension and angina pectoris, the usual initial dose is 5 mg once daily. If the desired therapeutic effect cannot be achieved within 24 weeks, this dose can be increased up to a maximum of 10 mg daily (as a single dose), depending on the individual patient’s response. Amlodipine may be used either as monotherapy or in combination with other antianginal drugs in patients with angina.
Children 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 section 5.1 and 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 Amlodipine tablets 5 mg as these tablets are not manufactured to break into two equal halves.
Elderly patients
Normal dosage regimens are recommended in elderly patients, but caution should be exercised when increasing the dosage (see section 5.2).
Patients with renal impairment
In these patients, amlodipine can be used at the normal dosage (see section
5.2). Amlodipine should be administered with particular caution in patients undergoing dialysis. Amlodipine is not dialysable.
Patients with hepatic impairment
A dosage regimen for patients with hepatic impairment has not been established and therefore amlodipine should be administered with caution (see section 4.4).
4.3 Contraindications
Amlodipine is contraindicated in patients with:
• hypersensitivity to dihydropyridine derivatives, amlodipine or any of the excipients
• 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 myocardial infarction
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 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, but this was not associated with worsening of the heart failure (see section 5.1).
Use in patients with impaired hepatic function
The half-life of amlodipine is prolonged in patients with impaired liver function; dosage recommendations have not been established. Amlodipine should therefore be administered with caution in these patients.
Use in elderly patients
In the elderly increase of the dosage should take place with care (see section
5.2).
Use in children
Amlodipine is not indicated in children under the age of 6 years (see section
4.2).
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 dialyzable.
4.5 Interaction with other medicinal products and other forms of interaction
Effects of other medicinal products on amlodipine
CYP3A4 inhibitors: With concomitant use with the CYP3A4 inhibitor erythromycin in young patients and diltiazem in elderly patients respectively the plasma concentration of amlodipine increased by 22% and 50 % respectively.
However, the clinical relevance of this finding is uncertain. It cannot be ruled out that strong inhibitors of CYP3A4 (i.e. ketoconazole, itraconazole, ritonavir) may increase the plasma concentrations of amlodipine to a greater extent than diltiazem. Amlodipine should be used with caution together with CYP3A4 inhibitors. However, no adverse events attributable to such interaction have been reported.
CYP3A4 inducers: There is no data available regarding the effect 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.
In clinical interaction studies, grapefruit juice, 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 antihypertensive agents.
In clinical interaction studies, amlodipine did not affect the pharmacokinetics of atorvastatin, digoxin, ethanol (alcohol), warfarin or ciclosporin.
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.
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 dosage 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.
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.
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 to <1/10); uncommon (>1/1,000 to <1/100); rare (>1/10,000 to <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 |
|
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, paresthesia | |
|
Very Rare |
Hypertonia, peripheral neuropathy | |
|
Eye disorders |
Uncommon |
Visual disturbance (including diplopia) |
|
Ear and labyrinth disorders |
Uncommon |
Tinnitus |
|
Cardiac disorders |
Uncommon |
Palpitations |
|
Very Rare |
Myocardial infarction, arrhythmia (including bradycardia, ventricular tachycardia and atrial fibrillation) | |
|
Vascular disorders |
Common |
Flushing |
|
Uncommon |
Hypotension | |
|
Very Rare |
Vasculitis | |
|
Respiratory, thoracic and mediastinal disorders |
Uncommon |
Dyspnoea, rhinitis |
|
Very Rare |
Cough | |
|
Gastrointestinal disorders |
Common |
Abdominal pain, nausea |
|
Uncommon |
Vomiting, dyspepsia, altered bowel habits (including diarrhoea and |
|
constipation), dry mouth | ||
|
Very Rare |
Pancreatitis, gastritis, gingival hyperplasia | |
|
Hepato-biliary disorders |
Very Rare |
Hepatitis, jaundice, hepatic enzymes increased* |
|
Skin and subcutaneous tissue disorders |
Uncommon |
Alopecia, purpura, skin discolouration, hyperhidrosis, pruritus, rash, exanthema |
|
Very Rare |
Angioedema, erythema multiforme, urticaria, exfoliative dermatitis, Stevens-Johnson syndrome, Quincke oedema, photosensitivity | |
|
Musculoskeletal, connective tissue and bone 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, 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 cholestasis
4.9 Overdose
In humans, experience with intentional overdose is limited.
Symptoms:
Available data suggest that gross overdose 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 active cardiovascular support, including frequent monitoring of cardiac and respiratory function, elevation of the 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 2h 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: C08CA01
Amlodipine is a calcium antagonist and inhibits the influx of calcium ions into cardiac and smooth muscle cells. The mechanism of its 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 mechanism of action. This dilatation increases the supply of oxygen to myocardiac muscle in patients with Prinzmetal’s angina.
In patients with hypertension, once daily dosing provides a clinically significant reduction of blood pressure (in both the supine and standing position), that persists for 24 hours.
In patients with angina pectoris, once daily administration of amlodipine increases total exercise time and delays the occurrence of an anginal attack and a 1-mm ST-segment depression. Amlodipine decreases both the frequency of angina attacks and glyceryl trinitrate tablet consumption.
In haemodynamic studies in patients with heart failure and in clinical studies based on exercise tests in patients with NYHA class II-IV heart failure, amlodipine was found not to cause any clinical deterioration, as measured by exercise tolerance, left ventricular ejection fraction and clinical signs and symptoms.
In a placebo-controlled study (PRAISE), designed to evaluate patients with NYHA class III-IV heart failure treated with digoxin, diuretics and ACE inhibitors, amlodipine was shown not to cause any increase in the risk of death or in the combined risk of mortality and morbidity risk in patients 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 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.
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 have also not been established.
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 to be 64 - 80%. Peak plasma levels are reached 6-12 hours post-dose. The volume of distribution is approximately 20 l/kg. The pKa of amlodipine is 8.6. Plasma protein binding in vitro is approximately 98%.
Metabolism/ elimination
The plasma elimination half-life varies from 35 to 50 hours.
Steady-state plasma levels are reached after 7-8 consecutive days.
Amlodipine is extensively metabolised to inactive metabolites. About 60% of the administered dose is excreted in the urine, about 10% of which in the form of unchanged amlodipine.
Paediatric patients
A population pharmacokinetic study has been conducted in 74 hypertensive children aged from 1 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.
Elderly patients
The time to reach peak plasma concentrations is the same in elderly and younger patients. Clearance may be reduced in elderly patients, so that the area under the curve (AUC) and the terminal elimination half-life are increased. Increases in AUC and elimination half life in patients with congestive heart failure were as expected for the patient age group in one study (See Section 4.4).
Patients with impaired renal function
Amlodipine is extensively metabolised to inactive metabolites. Ten percent of the substance is excreted unchanged in the urine. Changes in amlodipine plasma concentration are not correlated with the degree of renal impairment. In these patients, amlodipine may be administered at the normal dosage. Amlodipine is not dialysable.
Patients with hepatic impairment
The half-life of amlodipine is prolonged in patients with impaired hepatic function.
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. In reproduction toxicity studies in rats, delayed parturition, difficult labour and impaired foetal and pup survival were seen at high doses.
6 PHARMACEUTICAL PARTICULARS
List of excipients
6.1
Cellulose microcrystalline (E460),
Calcium hydrogen phosphate anhydrous (E341), Sodium starch glycolate (Type A)
Magnesium stearate (E572).
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
2 years
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
Amlodipine 5mg tablets are packed in the following packs:
Alu/Alu blister pack: 10s, 14s - 1 blister packed in a carton along with a PIL.
20s, 28s - 2 blisters packed in a carton along with
a PIL.
30s - 3 blisters packed in a carton along with
a PIL.
40s, 56s - 4 blisters packed in a carton along with
a PIL.
100s - 10 blisters packed in a carton along
with a PIL.
6.6 Special precautions for disposal
No special requirements.
MARKETING AUTHORISATION HOLDER
7
Dawa Limited 5 Sandridge Close Harrow, Middlesex HA1 1XD
8 MARKETING AUTHORISATION NUMBER(S)
PL 30684/0223
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
19/12/2012
10 DATE OF REVISION OF THE TEXT
19/12/2012