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AMLODIPINE THAME 10MG/5ML ORAL SOLUTION
Active substance(s): AMLODIPINE BESILATE
NAME OF THE MEDICINAL PRODUCT
Amlodipine Thame 10mg/5ml Oral Solution
QUALITATIVE AND QUANTITATIVE COMPOSITION
Amlodipine Thame Oral Solution contains the active ingredient, amlodipine
(as amlodipine besilate).
Each 5ml of oral solution contains 10mg amlodipine.
Each ml of oral solution contains 2mg amlodipine.
Excipients with known effect:
Each 5ml of oral solution contains 3mg methyl parahydroxybenzoate (E218)
and 5.5g of glycerol (E422).
For the full list of excipients, see section 6.1.
A clear, greenish yellow coloured solution
Chronic stable angina pectoris
Vasospastic (Prinzmetal's) angina
Posology and method of administration
Method of administration
For oral use.
Measure the prescribed dose from the 2.5-5ml double ended spoon provided in the
For both hypertension and angina the usual initial dose is 5mg (2.5ml). Amlodipine
Thame once daily which may be increased to a maximum dose of 10mg (5ml)
depending on the individual patient's response.
The higher strength Amlodipine Thame 10mg/5ml Oral Solution is recommended for
use in adults, or when higher doses are prescribed.
In hypertensive patients, Amlodipine Thame has been used in combination with a
thiazide diuretic, alpha blocker, beta blocker, or an angiotensin converting enzyme
inhibitor. For angina, Amlodipine Thame 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 Amlodipine Thame is required upon concomitant
administration of thiazide diuretics, beta blockers, and angiotensin-converting
Amlodipine Thame used at similar doses in elderly or younger patients is equally well
tolerated. Normal dosage regimens are recommended in the elderly, but increase of
the dosage should take place with care (see sections 4.4 and 5.2).
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
Changes in amlodipine plasma concentrations are not correlated with degree of renal
impairment, therefore the normal dosage is recommended. Amlodipine is not
Children and adolescents with hypertension from 6 years to 17 years of age.
The recommended antihypertensive oral dose in paediatric patients ages 6-17 years is
2.5mg (2.5ml of Amlodipine Thame 5mg/5ml) once daily as a starting dose. This
dose is not attainable with the higher 10mg/5ml strength because the measuring spoon
supplied does not have the required 1.25ml graduation mark. Treatment may be
up-titrated to 5mg (5ml of Amlodipine Thame 5mg/5ml) once daily if blood pressure
goal is not achieved after 4 weeks. The lower strength Amlodipine Thame 5mg/5ml is
recommended for use in children, or when lower doses are prescribed.
Doses in excess of 5mg daily have not been studied in paediatric patients (see
sections 5.1 and 5.2).
Children under 6 years old
The safety and efficacy of amlodipine in children under the age of 6 has not yet been
Amlodipine is contraindicated in patients with:
Hypersensitivity to dihydropyridine derivatives, amlodipine or to any of the
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 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 (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 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
Use in elderly patients
In the elderly, increase of the dosage should take place with care (see sections 4.2 and
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.
This product also contains:
Methyl parahydroxybenzoate (E218) which may cause allergic reactions (possibly
Glycerol (E422), which may cause headache, stomach upset and diarrhoea.
Interaction with other medicinal products and other forms of interaction
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 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
Clarithromycin is an inhibitor of CYP3A4. There is an increased risk of hypotension
in patients receiving clarithromycin with amlodipine. Close observation of patients is
recommended when amlodipine is co administered with clarithromycin.
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
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 medicinal products
The blood pressure lowering effects of amlodipine adds to the blood pressure
lowering effects of other medicinal products with antihypertensive properties.
In clinical interaction studies, amlodipine did not affect the pharmacokinetics of
atorvastatin, digoxin, warfarin or cyclosporin.
Simvastatin: Co-administration of multiple doses of 10mg of amlodipine with 80mg
simvastatin resulted in a 77% increase in exposure to simvastatin compared to
simvastatin alone. Limit the dose of simvastatin to 20mg daily in patients on
There is a risk of increased tacrolimus blood levels when co administered with
amlodipine. 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.
Fertility, pregnancy and lactation
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.
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 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.
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).
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. Caution is recommended especially at the
start of treatment.
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.
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); not known (cannot be estimated from the available data).
Within each frequency grouping, adverse reactions are presented in order of
System organ class
Blood and lymphatic
Insomnia, mood changes (including
Ear and labyrinth
Myocardial infarction, arrhythmia,
(including bradycardia, ventricular
tachycardia and atrial fibrillation)
Abdominal pain, nausea
Vomiting, dyspepsia, altered bowel
habits (including diarrhoea and
constipation), dry mouth
Pancreatitis, gastritis, gingival
Hepatitis, jaundice, hepatic enzymes
Alopecia, purpura, skin discolouration,
hyperhidrosis, pruritus, rash,
Angioedema, erythema multiforme,
urticaria, exfoliative dermatitis,
Stevens-Johnson syndrome, Quincke
Toxic Epidermal Necrolysis
Arthralgia, myalgia, muscle cramps,
Visual disturbance (including diplopia)
Somnolence, dizziness, headache
(especially at the beginning of the
Tremor, dysgeusia, syncope, hypoesthesia,
Hypertonia peripheral neuropathy
Renal and urinary
system and breast
Micturition disorder, nocturia,
increased urinary frequency
Chest pain, asthenia, pain, malaise
*mostly consistent with cholestasis
Weight increase, weight decrease
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 at: www.mhra.gov.uk/yellowcard or search for
MHRA Yellow Card in the Google Play or Apple App Store.
In humans experience with intentional overdose is limited.
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
Clinically significant hypotension due to amlodipine 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
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 10mg has been shown to
reduce the absorption rate of amlodipine.
Since amlodipine is highly protein-bound, dialysis is not likely to be of benefit.
Pharmacotherapeutic group: Calcium channel blockers, selective calcium channel
blockers with mainly vascular effects. ATC Code: C08CA01.
Amlodipine 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 amlodipine is due to a direct
relaxant effect on vascular smooth muscle. The precise mechanism by which
amlodipine relieves angina has not been fully determined but amlodipine reduces
total ischaemic burden by the following two actions.
1) Amlodipine 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
2) The mechanism of action of amlodipine 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
In patients with angina, once daily administration of amlodipine increases total
exercise time, time to angina onset, time to 1mm ST segment depression, and
decreases both angina 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.
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-centre,
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 5-10mg, 673 patients were treated
with enalapril 10-20mg, 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.
Table 1. Incidence of significant clinical outcomes for CAMELOT
Cardiovascular event rates,
Amlodipine vs. Placebo
Enalapril Hazard Ratio
95 (14.1) 0.73 (0.54-0.98)
86 (12.8) 0.58 (0.41-0.82)
Stroke or TIA
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 amlodipine 5mg did not lead to clinical
deterioration as measured by exercise tolerance, left ventricular ejection fraction and
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 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) of amlodipine in
patients with NYHA III and IV heart failure without clinical symptoms or objective
findings suggestive or 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 5mg 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 2.5-10mg/d (calcium
channel blocker) or lisinopril 10-40mg/d (ACE-inhibitor) as first-line therapies to that
of the thiazide-diuretic, chlorthalidone 12.5-25mg/d in mild to moderate
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
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 5.0mg 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 has also not been
Absorption, distribution, plasma protein binding:
After oral administration of therapeutic doses, amlodipine 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
amlodipine is bound to plasma proteins.
The bioavailability of amlodipine is not affected by food intake.
The terminal plasma elimination half life is about 35-50 hours and is consistent with
once daily dosing. Amlodipine is extensively metabolised by the liver to inactive
metabolites with 10% of the parent compound and 60% of metabolites excreted in the
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
Use in the 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 studied.
Use in children
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 amlodipine between 1.25 and 20mg 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.
Preclinical safety data
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 10mg/kg/day (8 times* the
maximum recommended human dose of 10mg 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.
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 2.5mg/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.
Mutagenicity studies revealed no drug related effects at either the gene or
*Based on patient weight of 50 kg
List of excipients
Methyl parahydroxybenzoate (E218)
Propylene glycol (E1520)
Disodium phosphate, anhydrous (E339)
Sodium dihydrogen phosphate dihydrate
In the absence of compatibility studies, this medicinal product must not be mixed
with other medicinal products.
For 100ml and 150ml: Discard after 30 days of first opening.
For 300ml: Discard after 60 days of first opening.
Special precautions for storage
Store in a refrigerator (2°C to 8°C).
Nature and contents of container
Bottle: Amber (Ph. Eur.Type III) glass
Closure: Tamper evident, child resistant plastic polypropylene/ polyethylene
cap with an EPE liner.
Dosing device: Double ended white polypropylene plastic spoon with 2.5ml
and 5ml measuring ends.
Pack size: 100ml, 150ml and 300ml
Not all pack sizes may be marketed.
Special precautions for disposal
Any unused medicinal product or waste material should be disposed of in
accordance with local requirements.
MARKETING AUTHORISATION HOLDER
Syri Limited t/a Thame Laboratories
Unit 4, Bradfield Road,
HA4 0NU, UK
MARKETING AUTHORISATION NUMBER(S)
DATE OF FIRST AUTHORISATION/RENEWAL OF THE
DATE OF REVISION OF THE TEXT