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Amlodipin Jubilant

Document: Amlodipin Jubilant tablet ENG SmPC change

SUMMARY OF PRODUCT CHARACTERISTICS


1. NAME OF THE MEDICINAL PRODUCT


Amlodipin Jubilant 5 mg tablets

Amlodipin Jubilant 10 mg tablets


2. QUALITATIVE AND QUANTITATIVE COMPOSITION


Amlodipin Jubilant 5 mg tablets

Each tablet contains 5 mg amlodipine (as amlodipine besilate)


Amlodipin Jubilant 10 mg tablets

Each tablet contains 10 mg amlodipine (as amlodipine besilate)


For a full list of excipients, see section 6.1.


3. PHARMACEUTICAL form


Tablet

White, circular, biconvex, uncoated tablets plain on both sides.


4. Clinical particulars


4.1 Therapeutic indications


Hypertension.

Chronic stable angina pectoris.

Vasospastic (Prinzmetal’s) agina.


4.2 Posology and method of administration


Posology

Adults

For 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.


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


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


Special populations


Elderly

Amlodipine 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).



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.


Patients with renal impairment

Changes in amlodipine plasma concentrations are not correlated with degree of renal impairment, therefore the normal dosage is recommended (see section 5.2). Amlodipine is not dialyzable.


Paediatric population


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 Pharmacodynamic

Properties and section 5.2 Pharmacokinetic Properties).

The 2.5 mg dose cannot be obtained with Amlodipin Jubilant 5 mg tablets as these tablets are not

manufactured to break into two equal halves.


Children under 6 years old

No data are available.


Method of administration

Tablet for oral administration.


4.3 Contraindications


Amlodipine is contraindicated in patients with:


4.4 Special warnings and precautions for use


Thesafety 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 along-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 impairment.


Use in elderly patients

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


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: 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 be required.


CYP3A4 inducers: There is no data available regarding the effect of 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.


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 antihypertensive agents.


In clinical interaction studies, amlodipine did not influence the pharmacokinetics of atorvastatin, digoxin, ethanol (alcohol), warfarin or cyclosporin.


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.


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 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.


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 minor or moderate influence on the ability to drive and use machines. If patients taking amlodipin 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, oedema and fatigue.


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).


Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.


System Organ Class

Frequency

Undesirable effects

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

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 disturbances (including diplopia)

Ear and labyrinth disorders

Uncommon

Tinnitus

Cardiac disorders

common

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

Hepatobiliary disorders

Very rare

Hepatitis, jaundice, hepatic enzymes increased*

Skin and subcutaneous tissue disorders

Uncommon

Alopecia, purpura, skin discoloration, hyperhydrosis, pruritus, rash, exanthema

Very rare

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

Musculoskeletal and connective tissue 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, gynecomastia

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


Exceptional cases of extrapyramidal syndrome have been reported.


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.


Treatment:

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 the circulating fluids volume and the 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 the 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: 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 is due to a direct relaxing effect on the 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 oxygen requirements.

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 amlodipine administration.


In patients with angina, once daily administration of amlodipine increases total exercise time, time to angina onset and time to a 1 mm ST segment depression and decreases bothangina 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-center, 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 5-10 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 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 heart failure

Haemodynamic studies and exercisebased 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.


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 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 the same population amlodipine 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 2.5-10 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 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 have also not been established.


5.2 Pharmacokinetic properties


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.


Biotransformation/elimination

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 urine.


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%.


Use in 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 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.


5.3 Preclinical safety data


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 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 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 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


6. PHARMACEUTICAL PARTICULARS


6.1 List of excipients


Microcrystalline cellulose

Sodium starch glycollate

Sodium acid citrate

Magnesium stearate

Croscarmellose sodium

Crospovidone


6.2 Incompatibilities


Not applicable


6.3 Shelf life


3 years


6.4 Special precautions for storage


Do not store above 25°C.


6.5 Nature and contents of container


Blisters made of PVC/PVdC-foil and aluminium foil with VMCH coating.


Pack sizes:

Amlodipin Jubilant 5 mg: 10, 20, 28, 30, 50, 98 and 100 tablets

Amlodipin Jubilant 10 mg: 10, 20, 28, 30, 50, 90, 98 and 100 tablets


Not all pack sizes may be marketed.


6.6 Special precautions for disposal


No special requirements


7. MARKETING AUTHORISATION HOLDER

[To be completed nationally]


8. MARKETING AUTHORISATION NUMBER(S)

[To be completed nationally]


9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION


7 October 2005/7 October 2010


10. DATE OF REVISION OF THE TEXT


27 January 2014

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