Amlodipine Besilate 10mg Tabs 28s UK

UGX19,100.00

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Name of the medicinal product

Amlodipine 10 mg tablets

2. Qualitative and quantitative composition

Active Ingredient: amlodipine.

One tablet contains amlodipine besilate equivalent to 10 mg amlodipine.

For a full list of excipients, see section 6.1.

3. Pharmaceutical form

Tablet.

The tablets are white, circular, biconvex and plain on both sides.

4. Clinical particulars
4.1 Therapeutic indications

– Essential hypertension

– Chronic stable and vasospastic anginal 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 amlodipine once daily which may be increased to a maximum dose of 10 mg depending on the individual patient’s response. For angina, Amlodipine 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.

In hypertensive patients, Amlodipine has been used in combination with a thiazide diuretic, Alpha-blocker, beta-blockers, or angiotensin-converting enzyme inhibitors.

No dose adjustment of Amlodipine is required upon concomitant administration of thiazide diuretics, beta-blockers, and angiotensin-converting enzyme inhibitors.

Special populations

Pediatric population:

Children with hypertension from 6 years to 17 years of age.

The recommended antihypertensive oral dose in pediatric 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 pediatric patients (see section 5.1 Pharmacodynamic Properties and section 5.2 Pharmacokinetic Properties).

The 2.5 mg dose cannot be obtained with Amlodipine tablets 5 mg and 10mg as these tablets are not manufactured to break into two equal halves.

Children under 6 years old:

The effect of amlodipine on blood pressure in patients less than 6 years of age is not known.

Use in the elderly

Amlodipine, used at similar doses in elderly or younger patients, is equally well tolerated. Therefore normal dosage regimens are recommended, but an increase of the dosage should take place with care (see sections 4.4 and 5.2).

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 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.

See section 4.4 “Special warnings and special precautions for use”.

Patients with renal impairment

Changes in amlodipine plasma concentrations are not correlated with the degree of renal impairment, therefore the normal dosage is recommended. Amlodipine is not dialysable.

Method of administration

Tablet for oral administration.

4.3 Contraindications

Amlodipine is contraindicated in patients with:

Hypersensitivity to dihydropyridines derivatives, amlodipine or to any of the excipients listed in section 6.1. Amlodipine should not be used in cardiogenic shock, obstruction of the outflow tract of the left ventricle (e.g., high-grade aortic stenosis). unstable angina (excluding Prinzmetal’s angina), severe hypotension, hemodynamically unstable heart failure after acute myocardial infarction.

4.4 Special warnings and precautions for use

The safety and efficacy of amlodipine in hypertensive crises have not been established.

Use in patients with heart 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 edema 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 function

As with all calcium antagonists, amlodipine’s half-life is prolonged and AUC values are higher in patients with impaired liver function and dosage recommendations have not been established. The drug should, therefore, be administered with caution in these patients.

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.

There are no data to support the use of amlodipine alone, during or within one month of myocardial infarction.

Elderly patients

In the elderly increase of the dosage should take place with care (see sections 4.2 and 5.2).

Patients with renal impairment

Amlodipine may be used in such patients at normal doses. Changes in amlodipine plasma concentrations are not correlated with the degree of renal impairment. Amlodipine is not dialysable.

There are no data to support the use of amlodipine alone, during or within one month of myocardial infarction.

4.5 Interaction with other medicinal products and other forms of interaction

In vitro data from studies with human plasma, indicate that amlodipine has no effect on protein binding of digoxin, phenytoin, warfarin or indomethacin.

Consumption of grapefruit/grapefruit juice should be avoided while taking amlodipine. The intake of grapefruit juice may result in increased plasma amlodipine concentrations, which may enhance the blood pressure lowering effects of amlodipine. This interaction has been observed with other dihydropyridine calcium antagonists and represents a class effect

Effects of other medicinal products on amlodipine:

CYP3A4 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 a significant increase in amlodipine exposure resulting in an increased risk of hypotension. 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

Upon co-administration of known inducers of the CYP3A4, the plasma concentration of amlodipine may vary. Therefore, blood pressure should be monitored and dose regulation considered both during and after concomitant medication particularly with strong CYP3A4 inducers (e.g. rifampicin, Hypericum perforatum).

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 the 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 products

The blood pressure lowering effects of amlodipine adds to the blood pressure – lowering effects of other medicinal products with antihypertensive properties.

Tacrolimus

There is a risk of increased tacrolimus blood levels when co-administered with amlodipine but the pharmacokinetic mechanism of this interaction is not fully understood. In order to avoid the 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.

Cimetidine: Co-administration of amlodipine with cimetidine did not alter the pharmacokinetics of amlodipine.

Sildenafil: When amlodipine and sildenafil were used in combination, each agent independently exerted its own blood pressure-lowering effect.

Special Studies: Effect of amlodipine on other agents

Atorvastatin: Co-administration of multiple 10 mg doses of amlodipine with 80mg of atorvastatin resulted in no significant change in the steady-state pharmacokinetic parameters of atorvastatin.

Digoxin: Co-administration of amlodipine with digoxin did not change serum digoxin levels or digoxin renal clearance in normal volunteers.

Warfarin: In healthy male volunteers, the co-administration of amlodipine does not significantly alter the effect of warfarin on prothrombin response time. Co-administration of amlodipine with warfarin did not change the warfarin prothrombin response time.

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.

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 fetus.

Breast-feeding

Amlodipine is excreted in human milk. The proportion of the maternal dose received by the infant has been estimated with an interquartile range of 3 – 7%, with a maximum of 15%. The effect of amlodipine on infants is unknown. A decision on whether to continue/discontinue breastfeeding or to continue/discontinue therapy with amlodipine should be made taking into account the benefit of breastfeeding 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 a 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. Caution is recommended especially at the start of treatment.

4.8 Undesirable effects

Summary of the safety profile

The most commonly reported adverse reactions during treatment are somnolence, dizziness, headache, palpitations, flushing, abdominal pain, nausea, ankle swelling, edema, and fatigue.

Tabulated list of adverse reactions

The 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 the 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
Rare Confusion
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
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 diarrhea 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 discoloration, hyperhidrosis, pruritus, rash, exanthema, urticaria
Very rare Angioedema, erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, Quincke edema, photosensitivity
Unknown Toxic Epidermal Necrolysis
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 Edema
Common Fatigue, asthenia
Uncommon Chest pain, pain, malaise
Investigations Uncommon Weight increased, weight decreased

*mostly consistent with cholestasis

Exceptional cases of extrapyramidal syndrome have been reported.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product are 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 or search for MHRA Yellow Card in the Google Play or Apple App Store.

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 a reflex tachycardia. Marked and probably prolonged systemic hypotension up to and including shock with fatal outcome have been reported.

Treatment

Administration of activated charcoal to healthy volunteers immediately or up to two hours after ingestion of amlodipine 10mg has been shown to significantly decrease amlodipine absorption.

Gastric lavage may be worthwhile in some cases. Clinically significant hypotension due to amlodipine overdosage calls for active cardiovascular support including frequent monitoring of cardiac and respiratory function, the 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. Since amlodipine is highly protein-bound, dialysis is not likely to be of benefit.

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