Gerard Laboratories

Amlodipine Mylan 5 mg tablets

Amlodipine Mylan 10 mg tablets

Each tablet contains 5 mg of amlodipine (as amlodipine besilate)

Each tablet contains 10 mg of amlodipine (as amlodipine besilate)

For a full list of excipients, see section 6.1.

Tablet.

5 mg tablet

White coloured, round biconvex tablets debossd with “5” on one side and scored on other side.

10 mg tablet

White coloured, round biconvex tablets debossed with “10” on one side and scored on other side.

The tablet can be divided into equal halves.

• Essential hypertension

• Chronic stable and vasospastic angina pectoris

For oral use

The tablets should be taken with a glass of water.

Adults

For treatment of both hypertension and angina pectoris the usual initial dose is 5 mg once daily. If the desired therapeutic effect cannot be achieved within 2-4 weeks, this dose may be increased to a maximum dose of 10 mg daily (as a single dose), depending on the individual patient's response. Amlodipine may be used either as monotherapy or in combination with other antianginal drugs in patients with angina.

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

Elderly patients

Normal dosage regimens are recommended in the elderly, but caution should be exercised when increasing the dosage (see section 5.2).

Patients with renal impairment

In these patients amlodipine can be used at the normal dosage (see section 5.2). Amlodipine should be administered with particular caution in patients undergoing dialysis. Amlodipine is not dialysable.

Patients with hepatic impairment

A dosage regimen for patients with hepatic impairment has not been established and therefore amlodipine should be administered with caution (see section 4.4).

Amlodipine is contra-indicated in patients with:

• hypersensitivity to dihydropyridine derivatives, amlodipine or to any of the excipients

• 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

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, but this was not associated with worsening of the heart failure (see section 5.1).

Use in patients with impaired hepatic function:

The half life of amlodipine is prolonged in patients with impaired liver function; dosage recommendations have not been established. Amlodipine should therefore be administered with caution in these patients.

Use in elderly patients:

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

Use in patients with 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.

Effects of other medicinal products on amlodipine

CYP3A4 inhibitors: With concomitant use with the CYP3A4 inhibitor erythromycin in young patients and diltiazem in elderly patients respectively the plasma concentration of amlodipine increased by 22% and 50 % respectively. However, the clinical relevance of this finding is uncertain. It cannot be ruled out that strong inhibitors of CYP3A4 (i.e. ketoconazole, itraconazole, ritonavir) may increase the plasma concentrations of amlodipine to a greater extent than diltiazem. Amlodipine should be used with caution together with CYP3A4 inhibitors. However, no adverse events attributable to such interaction have been reported.

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.

In clinical interaction studies grapefruit juice, 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 cyclosporin.

There is no effect of amlodipine on laboratory parameters.

Pregnancy

The safety of amlodipine in human pregnancy has not been established.

Reproductive studies in rats have shown no toxicity except for delayed date of delivery and prolonged duration of labour at dosages 50 times greater than the maximum recommended dosage for humans.

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.

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.

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.

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)

Blood and the 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, paresthesia

Very rare: Hypertonia, peripheral neuropathy

Eye disorders:

Uncommon: Visual disturbance (including diplopia)

Ear and labyrinth disorders:

Uncommon: Tinnitus

Cardiac disorders:

Uncommon: 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 diarrohea and constipation), dry mouth

Very rare: Pancreatitis, gastritis, gingival hypeplasia

Hepatobiliary disorders:

Very rare: Hepatitis, jaundice, hepatic enzymes increased*

Skin and subcutaneous tissue disorders:

Uncommon: Alopecia, purpura, skin discolouration, hyperhydrosis, pruritus, rash, exanthema

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

Musculoskeletal, 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, 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

In humans experience with intentional overdose is limited

Symptoms:

Available data suggest that gross overdose 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 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.

Pharmacotherapeutic group: Calcium antagonists. Dihydropyridine derivatives, ATC code: C08 CA01

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 dilatation increases the supply of oxygen to myocardiac muscle in patients with Prinzmetal's angina.

In patients with hypertension, once daily dosing provides a clinically significant reduction of blood pressure (in both the supine and standing position) that persists for 24 hours.

In patients with angina pectoris, once daily administration of amlodipine increases total exercise time and delays the occurrence of an anginal attack and a 1-mm ST-segment depression. Amlodipine decreases both the frequency of angina attacks and glyceryl trinitrate tablet consumption.

Use in children from 6 years to 17 years of age.

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 Heart 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.

A placebo controlled study (PRAISE) designed to evaluate patients in NYHA Class III-IV heart failure receiving digoxin, diuretics and angiotensin-converting enzyme (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 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.

Absorption/Distribution

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. The absolute bioavailability of the unchanged compound is estimated to be 64-80%. Peak plasma levels are reached 6 to 12 hours post-dose. The volume of distribution is about 20 l/kg. The pKa of amlodipine is 8.6. Plasma protein binding in vitro is approximately 98%.

Metabolism/Elimination

The plasma elimination half-life varies from 35 to 50 hours.

Steady-state plasma levels are reached after 7-8 consecutive days.

Amlodipine is extensively metabolised to inactive metabolites. About 60% of the administered dose is excreted in the urine, about 10% of which in the form of unchanged amlodipine.

Use in children from 6 years to 17 years of age.

A population PK study has been conducted in 74 hypertensive children aged from 12 months 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 21.3L/hr respectively in females. Large variability in exposure between individuals was observed. Data reported in children below 6 years is limited.

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 study (See Section 4.4).

Patients with impaired renal function

Amlodipine is extensively metabolised to inactive metabolites. Ten percent of the substance is excreted unchanged in the urine. Changes in amlodipine plasma concentration are not correlated with the degree of renal impairment. In these patients, amlodipine may be administered at the normal dosage. Amlodipine is not dialysable.

Patients with hepatic impairment

The half-life of amlodipine is prolonged in patients with impaired hepatic function.

Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential. In reproduction toxicity studies in rats, delayed parturition, difficult labour and reduced fetal and pup survival were seen at high doses.

Calcium hydrogen phosphate anhydrous

Cellulose microcrystalline

Sodium starch glycolate (type A)

Magnesium stearate

Not applicable.

2 years

Store in the original package in order to protect from light.

Amlodipine tablets may be presented in:

- PVC/PVdC/Al blister packs containing 10, 14, 28, 30, 50, 56, 60, 100, 180 tablets

- HDPE bottle with HDPE screw cap containing 28, 30, 56, 100, 180, 500 tablets

Not all pack sizes may be marketed.

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

McDermott Laboratories Limited

T/a Gerard Laboratories

35/36 Baldoyle Industrial Estate

Grange Road

Dublin 13

PA 577/133/1

PA 577/133/2

Date of first authorisation: 10 September 2010