APITIM

Description

APITIM 5

For prescription only.

Read all of this leaflet carefully before you start taking this medicine.

Do not exceed the prescribed dosage. 

Inform your doctor of all undesirable effects upon drug administration.

Consult your doctor for further information.

Do not use the expired medicine.

Keep out of reach of children.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Active ingredient: Amlodipine besilate, calculated on Amlodipine ........................ 5 mg

Excipients: Avicel, dicalcium phosphate dihydrate, PVP K30, sodium laurilsulfate, sodium starch glycolate, aerosil, magnesium stearate

PHARMACEUTICAL FORM: Hard capsule

Product description: A yellow/white to off-white hard capsule imprinted with the pattern          on capsule body containing homogeneous drug powder inside.

THERAPEUTIC INDICATIONS

- Hypertension.

- Chronic stable angina.

- Vasospastic angina (Prinzmetal's angina).

POSOLOGY AND METHOD OF ADMINISTRATION

Posology

Adults:

For hypertension and angina, the usual starting dose is 5 mg amlodipine once per day, which may be increased up to a maximum of 10 mg once per day, depending on the patient's individual response.

In hypertensive patients, amlodipine has been used concomitantly with thiazide diuretics, alpha-blockers, beta-blockers or angiotensin converting enzyme inhibitors. For angina, amlodipine may be used in monotherapy or concomitantly with other anti-angina drugs in patients with angina refractory to nitrate derivatives and/or to appropriate beta-blocker doses.

No dose adjustment is necessary when using amlodipine concomitantly with thiazide diuretics, alpha-blockers, beta-blockers, or angiotensin converting enzyme inhibitors.

Special populations

Elderly

Amlodipine, used in similar doses in elderly or younger patients, has the same tolerance profile. Normal doses are recommended in the elderly, and dose increase should be undertaken with caution (see section Special warnings and precautions for use and section Pharmacokinetic properties).

Patients with hepatic impairment

Dose recommendations have not been established in patients with mild to moderate liver failure; therefore, the dose should be chosen with caution and treatment initiated with the lowest efficient dose (see section Special warnings and precautions for use and section Pharmacokinetic properties). Amlodipine pharmacokinetic properties have not been studied for cases of severe liver failure. Amlodipine should be initiated at the lowest dose and increased slowly in patients with severe liver failure.

Patients with renal impairment

Changes in amlodipine plasma concentrations are not correlated with the degree of renal failure; therefore, the usual dose is recommended. Amlodipine is not dialysable.

Children and adolescents

Hypertensive children and adolescents from 6 to 17 years old:

The recommended oral anti-hypertensive dose in children aged 6 to 17 years old is 2.5 mg once per day as initial dose, which may be increased up to 5 mg once per day if the expected blood pressure has not been reached after four weeks. Doses greater than 5 mg once per day have not been studied in paediatric patients (see section Pharmacodynamic properties and section Pharmacokinetic properties).

An amlodipine dose of 2.5 mg is not possible with this dosage form, suggest to use amlodipine 5 mg tablet instead. Amlodipine 5 mg tablets can be divided into halves to provide a 2.5 mg dose.

Children less than 6 years old:

There are no available data.

Method of administration: Hard capsule for oral administration.

CONTRAINDICATIONS

Amlodipine is contraindicated in patients with:

- sensitivity to dihydropyridine derivatives, amlodipine or any of the excipients.

- severe hypotension

- shock (including cardiogenic shock)

- obstruction of ejection route of left ventricle (e.g. high degree of aortic stenosis)

- cardiac failure hemodynamically unstable following acute myocardial infarction.

SPECIAL WARNINGS AND PRECAUTIONS FOR USE

Use in patients with heart failure

In a long-term placebo-controlled study (PRAISE-2) of amlodipine in patients with New York Heart Association (NYHA) class III and IV heart failure of nonischemic etiology, amlodipine was associated with increased reports of pulmonary edema despite no significant differences in the incidence of worsening heart failure compared to placebo (see section Pharmacodynamic properties).

Use in patients with impaired hepatic function

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

USE IN PREGNANCY AND LACTATION

The safety of amlodipine in human pregnancy or lactation has not been established. Amlodipine does not demonstrate toxicity in animal reproductive studies other than delay in parturition and prolongation of labor in rats at a dose level 50 times the maximum recommended dose in humans. Accordingly, 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. There was no effect on the fertility of rats treated with amlodipine (see section Preclinical safety data).

Experience in humans indicates that amlodipine is transferred into human breast milk. The median amlodipine concentration ratio of milk/plasma in 31 lactating women with pregnancy-induced hypertension was 0.85 following amlodipine administration at an initial dose of 5 mg once daily which was adjusted as needed (mean daily dose and body weight adjusted daily dose: 6 mg and 98.7 mcg/kg, respectively). The estimated daily dose of amlodipine in the infant via breast milk was 4.17 mcg/kg.

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.

INTERACTIONS

Drug interaction

Amlodipine has been safely administered with thiazide diuretics, alpha-blockers, beta-blockers, ACE inhibitors, long-acting nitrates, sublingual nitroglycerine, non-steroidal anti-inflammatory drugs, antibiotics, and oral hypoglycemic drugs.

In vitro data from studies in human plasma indicate that amlodipine has no effect on protein binding of the drugs tested (digoxin, phenytoin, warfarin, or indomethacin).

Simvastatin

Co-administration of multiple doses of 10 mg 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.

Grapefruit juice

Co-administration of 240 ml grapefruit juice with a single oral dose of 10 mg amlodipine in 20 healthy volunteers had no significant effect on the pharmacokinetics of amlodipine. The study did not allow examination of the effect of genetic polymorphism in CYP3A4, the primary enzyme responsible for metabolism of amlodipine; therefore, 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.

CYP3A4 Inhibitors

Co-administration of a 180 mg daily dose of diltiazem with 5 mg amlodipine in elderly hypertensive patients (69 to 87 years of age) resulted in a 57% increase in amlodipine systemic exposure. Co-administration of erythromycin in healthy volunteers (18 to 43 years of age) did not significantly change amlodipine systemic exposure (22% increase in area under the concentration versus time curve [AUC]). Although the clinical relevance of these findings is uncertain, pharmacokinetic variations may be more pronounced in the elderly.

Strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, ritonavir) may increase the plasma concentrations of amlodipine to a greater extent than diltiazem. Amlodipine should be used with caution when administered with CYP3A4 inhibitors.

Clarithromycin

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

There is no data available regarding the effect of CYP3A4 inducers on amlodipine. Concomitant use of CYP3A4 inducers (e.g., rifampicin, Hypericum perforatum) may decrease the plasma concentrations of amlodipine. Amlodipine should be used with caution when administered with CYP3A4 inducers.

In the following studies, there were no significant changes in the pharmacokinetics of either amlodipine or another drug within the study, when co-administered.

Special studies: Effects of other agents on amlodipine

Cimetidine

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

Aluminum/ Magnesium (Antacid)

Co-administration of aluminum/magnesium (antacid) with a single dose of amlodipine had no significant effect on the pharmacokinetics of amlodipine.

Sildenafil

A single 100 mg dose of sildenafil in subjects with essential hypertension had no effect on the pharmacokinetic parameters of amlodipine. When amlodipine and sildenafil were used in combination, each agent independently exerted its own blood pressure lowering effect.

Special studies: Effects of amlodipine on other agents

Atorvastatin

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

Digoxin

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

Ethanol (Alcohol)

Single and multiple 10 mg doses of amlodipine had no significant effect on the pharmacokinetics of ethanol.

Warfarin

Co-administration of amlodipine with warfarin did not change the warfarin prothrombin response time.

Cyclosporin

No drug interaction studies have been conducted with cyclosporin and amlodipine in healthy volunteers or other populations, with the exception of renal transplant patients. Various studies in renal transplant patients report that co-administration of amlodipine with cyclosporin affects the trough concentrations of cyclosporin, from no change up to an average increase of 40%. Consideration should be given for monitoring cyclosporin levels in renal transplant patients on amlodipine.

Tacrolimus

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.

Mechanistic target of rapamycin (mTOR) inhibitors

mTOR inhibitors such as sirolimus, temsirolimus and everolimus are CYP3A substrates. Amlodipine is a weak CYP3A inhibitor. With concomitant use of mTOR inhibitors, amlodipine may increase exposure of mTOR inhibitors.

Drug/Laboratory test interactions: None known.

Incompatibilities: Not relevant.

UNDESIRABLE EFFECTS

Amlodipine is well tolerated. In placebo controlled clinical trials involving patients with hypertension or angina, the most commonly observed side effects were:

MedDRA System Organ Class	Undesirable Effects
Nervous system disorders	Headache, dizziness, somnolence
Cardiac disorders	Palpitations
Vascular disorders	Flushing
Gastrointestinal disorders	Abdominal pain, nausea
General disorders and administration site conditions	Oedema, fatigue

In these clinical trials no pattern of clinically significant laboratory test abnormalities related to amlodipine has been observed.

Less commonly observed side effects in marketing experience include:

MedDRA system organ class	Undesirable effects
Blood and lymphatic system disorders	Leucopenia, thrombocytopenia
Metabolism and nutrition disorders	Hyperglycaemia
Psychiatric disorders	Insomnia, mood altered
Nervous system disorders	Hypertonia, hypoaesthesia/paraesthesia, neuropathy peripheral, syncope, dysgeusia, tremor, extrapyramidal disorder
Eye disorders	Visual impairment
Ear and labyrinth disorders	Tinnitus
Vascular disorders	Hypotension, vasculitis
Respiratory, thoracic, and mediastinal disorders	Cough, dyspnoea, rhinitis
Gastrointestinal disorders	Change in bowel habits, dry mouth, dyspepsia (including gastritis), gingival hyperplasia, pancreatitis, vomiting
Skin and subcutaneous tissue disorders	Alopecia, hyperhidrosis, purpura, skin discolouration, urticarial
Musculoskeletal and connective tissue disorders	Arthralgia, back pain, muscle spasms, myalgia
Renal and urinary disorders	Pollakiuria, micturition disorder, nocturia
Reproductive system and breast disorders	Gynaecomastia, erectile dysfunction
General disorders and administration site conditions	Asthenia, malaise, pain
Investigations	Weight increased/decreased

Rarely reported events were allergic reaction including pruritus, rash, angioedema, and erythema multiforme.

Hepatitis, jaundice and hepatic enzyme elevations have also been reported very infrequently (mostly consistent with cholestasis). Some cases severe enough to require hospitalization have been reported in association with use of amlodipine. In many instances, causual association is uncertain.

As with other calcium channel blockers the following adverse events have been rarely reported and cannot be distinguished from the natural history of the underlying disease: myocardial infarction, arrhythmia (including bradycardia, ventricular tachycardia and atrial fibrillation) and chest pain.

Pediatric patients (aged 6 – 17 years)

Amlodipine is well tolerated in children. Adverse events were similar to those seen in adults. In a study of 268 children, the most frequently reported adverse events were:

MedDRA system organ class	Undesirable effects
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