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Components:
Amlodipine
Method of action:
Antianginal, Antihypertensive, Antispasmodic, Hypotensive, Vasodilator
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Medically reviewed by Oliinyk Elizabeth Ivanovna, Pharmacy. Last updated on 2019.12.07

Name of the medicinal product

Keysal

Qualitative and quantitative composition

Amlodipine

Therapeutic indications

The information provided in Therapeutic indications of Keysal is based on data of another medicine with exactly the same composition as the Keysal of the medicine (Amlodipine). Be careful and be sure to specify the information on the section Therapeutic indications in the instructions to the drug Keysal directly from the package or from the pharmacist at the pharmacy.
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- Hypertension

- Chronic stable angina pectoris

- Vasospastic (Prinzmetal's) angina

Dosage (Posology) and method of administration

The information provided in Dosage (Posology) and method of administration of Keysal is based on data of another medicine with exactly the same composition as the Keysal of the medicine (Amlodipine). Be careful and be sure to specify the information on the section Dosage (Posology) and method of administration in the instructions to the drug Keysal directly from the package or from the pharmacist at the pharmacy.
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Posology

Adults

For both hypertension and angina the usual initial dose is 5 mg Keysal once daily which may be increased to a maximum dose of 10 mg depending on the individual patient's response.

In hypertensive patients, Keysal has been used in combination with a thiazide diuretic, alpha blocker, beta blocker, or an angiotensin converting enzyme inhibitor. For angina, Keysal 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.

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

Paediatric population

Use in children and adolescents (less than 18 years of age)

Not recommended.

Special populations

Use in the elderly

Keysal, used at similar doses in elderly or younger patients, is equally well tolerated. Therefore normal dosage regimens are recommended in the elderly, but increase of the dosage should take palce with care.

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. The pharmacokinetics of Keysal have not been studied in severe hepatic impairment. Keysal should be initiated at the lowest dose and titrated slowly in patients with severe hepatic impairment.

Patients with renal impairment

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

Method of administration

Tablet for oral administration.

Contraindications

The information provided in Contraindications of Keysal is based on data of another medicine with exactly the same composition as the Keysal of the medicine (Amlodipine). Be careful and be sure to specify the information on the section Contraindications in the instructions to the drug Keysal directly from the package or from the pharmacist at the pharmacy.
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Keysal is contraindicated in patients with:

-

- 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 acute myocardial infarction.

Special warnings and precautions for use

The information provided in Special warnings and precautions for use of Keysal is based on data of another medicine with exactly the same composition as the Keysal of the medicine (Amlodipine). Be careful and be sure to specify the information on the section Special warnings and precautions for use in the instructions to the drug Keysal directly from the package or from the pharmacist at the pharmacy.
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The safety and efficacy of Keysal in hypertensive crisis has not been established.

Use in 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) Keysal was associated with increased reports of pulmonary oedema despite no significant difference in the incidence of worsening heart failure as compared to placebo. Calcium channel blockers, including Keysal, 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 hepatic impairment

As with all calcium antagonists, Keysal's half-life is prolonged and AUC values are higher in patients with impaired liver function; dosage recommendations have not been established. The drug 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.

Elderly patients

In the elderly increase of the dosage should take place with care.

Patients with renal impairment

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

Effects on ability to drive and use machines

The information provided in Effects on ability to drive and use machines of Keysal is based on data of another medicine with exactly the same composition as the Keysal of the medicine (Amlodipine). Be careful and be sure to specify the information on the section Effects on ability to drive and use machines in the instructions to the drug Keysal directly from the package or from the pharmacist at the pharmacy.
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Keysal can have minor or moderate influence on the ability to drive and use machines. In patients suffering from dizziness, headache, fatigue or nausea the ability to react may be impaired. Caution is recommended especially at the start of treatment.

Undesirable effects

The information provided in Undesirable effects of Keysal is based on data of another medicine with exactly the same composition as the Keysal of the medicine (Amlodipine). Be careful and be sure to specify the information on the section Undesirable effects in the instructions to the drug Keysal directly from the package or from the pharmacist at the pharmacy.
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a) Summary of the safety profile

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

b) Tabulated list of adverse reactions

The following adverse reactions have been observed and reported during treatment with Keysal 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); Not known (cannot be estimated from the available data).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

System organ class

Frequency

Adverse reactions

Blood and lymphatic system disorders

Very rare

Leukopenia , 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

Uncommon

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

Uncommon

Dyspnoea

Very rare

Cough, rhinitis

Gastrointestinal disorders

Common

Abdominal pain, nausea, dyspepsia, altered bowel habits (including diarrhoea 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, hyperhidrosis, pruritus, rash, exanthema, urticaria

Very rare

Angioedema, erythema multiforme, urticaria, exfoliative dermatitis, Stevens-Johnson syndrome, Quincke oedema, photosensitivity

Not known

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

Oedema

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 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 at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Overdose

The information provided in Overdose of Keysal is based on data of another medicine with exactly the same composition as the Keysal of the medicine (Amlodipine). Be careful and be sure to specify the information on the section Overdose in the instructions to the drug Keysal directly from the package or from the pharmacist at the pharmacy.
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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 Keysal overdosage 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 2h after administration of Keysal 10 mg has been shown to reduce the absorption rate of Keysal.

Since Keysal is highly protein-bound, dialysis is not likely to be of benefit.

Pharmacodynamic properties

The information provided in Pharmacodynamic properties of Keysal is based on data of another medicine with exactly the same composition as the Keysal of the medicine (Amlodipine). Be careful and be sure to specify the information on the section Pharmacodynamic properties in the instructions to the drug Keysal directly from the package or from the pharmacist at the pharmacy.
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Pharmacotherapeutic group: calcium channel blockers - Dihydropyridine derivatives.

ATC code: C08CA01.

Keysal is a calcium ion influx inhibitor of the dihydropyridine group (slow channel blocker or calcium ion antagonist) and inhibits the transmembrane influx of calcium ions into cardiac and vascular smooth muscle.

The mechanism of the antihypertensive action of Keysal is due to a direct relaxant effect on vascular smooth muscle. The precise mechanism by which Keysal relieves angina has not been fully determined but Keysal reduces total ischaemic burden by the following two actions:

1) Keysal dilates peripheral arterioles and thus, reduces the total peripheral resistance (afterload) against which the heart works. Since the heart rate remains stable, this unloading of the heart reduces myocardial energy consumption and oxygen requirements.

2) The mechanism of action of Keysal also probably involves dilatation of the main coronary arteries and coronary arterioles, both in normal and ischaemic regions. This dilatation increases myocardial oxygen delivery in patients with coronary artery spasm (Prinzmetal's or variant angina).

In patients with hypertension, once daily dosing provides clinically significant reductions of blood pressure in both the supine and standing positions throughout the 24 hour interval. Due to the slow onset of action, acute hypotension is not a feature of Keysal administration.

In patients with angina, once daily administration of Keysal increases total exercise time, time to angina onset, and time to 1mm ST segment depression, and decreases both angina attack frequency and glyceryl trinitrate tablet consumption.

Keysal 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 Keysal in preventing clinical events in patients with coronary artery disease (CAD) has been evaluated in an independent, multi-centre, randomized, double-blind, placebo-controlled study of 1997 patients; Comparison of Keysal vs. Enalapril to Limit Occurrences of Thrombosis (CAMELOT). Of these patients, 663 were treated with Keysal 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 Keysal 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 heart failure

Haemodynamic studies and exercise based controlled clinical trials in NYHA Class II-IV heart failure patients have shown that Keysal did 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 Keysal did not lead to an increase in risk of mortality or combined mortality and morbidity with heart failure.

In a follow-up, long term, placebo-controlled study (PRAISE-2) 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, Keysal had no effect on total cardiovascular mortality. In this same population Keysal was associated with increased reports of pulmonary oedema despite no significant difference in the incidence of worsening heart failure as compared to placebo.

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: Keysal 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 Keysal-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 Keysal 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 Keysal-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 2.5 mg dose, and 5.0 mg dose of Keysal 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 Keysal on growth, puberty and general development have not been studied. The long-term efficacy of Keysal on therapy in childhood to reduce cardiovascular morbidity and mortality in adulthood has also not been established.

Pharmacokinetic properties

The information provided in Pharmacokinetic properties of Keysal is based on data of another medicine with exactly the same composition as the Keysal of the medicine (Amlodipine). Be careful and be sure to specify the information on the section Pharmacokinetic properties in the instructions to the drug Keysal directly from the package or from the pharmacist at the pharmacy.
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Absorption, distribution, plasma protein binding

After oral administration of therapeutic doses, Keysal is well absorbed with peak blood levels between 6-12 hours post dose. Absolute bioavailability has been estimated to be between 64 and 80%. The volume of distribution is approximately 21 l/kg. In vitro studies have shown that approximately 97.5% of circulating Keysal is bound to plasma proteins.

The bioavailability of Keysal is not affected by food intake.

Biotransformation/elimination

The terminal plasma elimination half life is about 35-50 hours and is consistent with once daily dosing. Keysal is extensively metabolised by the liver to inactive metabolites with 10% of the parent compound and 60% of metabolites excreted in the urine.

Hepatic impairment

Very limited clinical data are available regarding Keysal administration in patients with hepatic impairment. Patients with hepatic insufficiency have decreased clearance of Keysal 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 1 to 17 years (with 34 patients aged 6 to 12 years and 28 patients aged 13 to 17 years) receiving Keysal 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.

Use in the elderly

The time to reach peak plasma concentrations of Keysal is similar in elderly and younger subjects. Keysal 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 studied.

Preclinical safety data

The information provided in Preclinical safety data of Keysal is based on data of another medicine with exactly the same composition as the Keysal of the medicine (Amlodipine). Be careful and be sure to specify the information on the section Preclinical safety data in the instructions to the drug Keysal directly from the package or from the pharmacist at the pharmacy.
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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 Keysal (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 Keysal 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 Keysal 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

Incompatibilities

The information provided in Incompatibilities of Keysal is based on data of another medicine with exactly the same composition as the Keysal of the medicine (Amlodipine). Be careful and be sure to specify the information on the section Incompatibilities in the instructions to the drug Keysal directly from the package or from the pharmacist at the pharmacy.
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None stated.

Special precautions for disposal and other handling

The information provided in Special precautions for disposal and other handling of Keysal is based on data of another medicine with exactly the same composition as the Keysal of the medicine (Amlodipine). Be careful and be sure to specify the information on the section Special precautions for disposal and other handling in the instructions to the drug Keysal directly from the package or from the pharmacist at the pharmacy.
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