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Amlodipine 5mg tablets

Last Updated on eMC 17-Oct-2016 View changes  | Concordia International- formerly Focus Pharmaceuticals Ltd Contact details

1. Name of the medicinal product

Amlodipine 5 mg tablets

2. Qualitative and quantitative composition

Amlodipine 5 mg tablets:

Each tablet contains 5 mg of amlodipine (as amlodipine maleate).

Excipients with known effect

Lactose monohydrate: contains 151.600 mg of lactose monohydrate per tablet

For the full list of excipients, see Section 6.1

3. Pharmaceutical form

5 mg tablets:

White round tablets.

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

Posology

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.

Paediatric population (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.

(under 6 years old)

No data are available.

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.

Method of administration: Oral

The tablets should be taken with a glass of water independently from meals.

4.3 Contraindications

Amlodipine is contra-indicated in patients with:

• hypersensitivity to the active substance or to any of the excipients listed in section 6.1

• 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 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 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 (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 pressure-lowering effects of other antihypertensive 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 higher 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 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 has 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)

Not known: cannot be estimated from available data

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

Not known

Extrapyramidal disorder

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 mediastinal disorders

Uncommon

Dyspnoea, rhinitis

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.

Management

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; Comparision of Amlodipine vs. Enalapril to Limit Occurences of Thrombosis (CAMELOT). Of these patients, 663 were treated with amlodipine 5-10 mg, 673 patients were treated with analapril 10-20 mg, and 655 patients were treated with placebo, in addition to standard care of stains, 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 significant 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 (0.54-0.88)

.003

Individual Components

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 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 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 (0.90-1.07) 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.

5.2 Pharmacokinetic properties

Absorption

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.

Distribution

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%.

Biotransformation

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.

Elimination

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 in AUC of approximately 40-60%.

Paediatric population

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.

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

24 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 5 mg tablets: Al/Al blister packs with 10, 20, 28, 30, 50, 98,100, 300 (10 x 30) tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements for disposal.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements

7. Marketing authorisation holder

Focus Pharmaceuticals Ltd

Capital House,

85 King William Street,

London EC4N 7BL,

United Kingdom.

8. Marketing authorisation number(s)

PL 20046/0020

9. Date of first authorisation/renewal of the authorisation

30/11/2008

10. Date of revision of the text

12/10/2016

Company contact details

Concordia International- formerly Focus Pharmaceuticals Ltd

Company image
Address

Capital House, 1st Floor, 85 King William Street, London, EC4N 7BL, UK

Fax

+44 (0)208 588 9217

Medical Information e-mail
Medical Information Fax

+44 (0)208 588 9200

Stock Availability
Telephone

+44 (0)208 588 9100

Medical Information Direct Line

+44 (0)208 588 9207

Customer Care direct line

+44 (0)208 588 9202

Stock Availability

+44 (0)208 588 9202

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Active ingredients

amlodipine maleate

Legal categories

POM - Prescription Only Medicine

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