AMBES Tablet

1. Hypertension

Amlodipine is used alone or in combination with other classes of antihypertensive drugs for the treatment of hypertension. Data from clinical outcome trials indicate that lowering blood pressure with any of several classes of drugs, including thiazides, beta-blockers, calcium-channel blockers, ACE inhibitors, or angiotensinⅡreceptor antagonists will reduce the complication of hypertension.

2. Coronary Artery Diseases

Angina

Amlodipine is used alone or in combination with other antianginal agents for the management of Prinzmetal’s variant angina and chronic stable angina pectoris.

Angiographically Documented Coronary Artery Disease (CAD)

Amlodipine is used in patients with recently documented coronary artery disease by angiography (without heart failure or an ejection fraction less than 40%) to reduce the risk of coronary revascularization procedure and hospitalization due to angina.

Notes:

Data from a multicenter randomized controlled trial indicated that amlodipine-based regimen (amlodipine adding perindopril) reduced the risk of non-fatal myocardial infarction, fatal coronary heart disease, and stroke.

Dosage

Adults and Geriatric Patients

Hypertension

The usual initial adult dosage is 2.5-5mg once daily.

In geriatric patients, an initial dosage of 2.5mg once daily is recommended.

This reduced initial dosage also can be used in adults when amlodipine is added to an existing antihypertensive drug regimen.

Subsequent dosage should be adjusted according to the patient’s blood pressure response and tolerance and usually should not exceed 10mg once daily.

Generally, dosage is increased gradually at 7-14 day intervals until optimum control of blood pressure is maintained. The usual maintenance dosage in adults is 5-10mg once daily.

Prinzmetal’s variant angina or chronic stable angina

The usual adult dosage is 5-10mg once daily. In geriatric patients, the lower dosage of 5mg once daily is recommended.

Adequate control of angina usually requires a maintenance dosage of 10mg daily.

Angiographically Documented Coronary Artery Disease (CAD)

The recommended adult dosage is 5-10mg once daily. In clinical studies the majority of patients required a dosage of 10mg daily.

Children 6-17 years of age:

Hypertension: The usual dosage is 2.5-5mg once daily. The safety and efficacy of dosages exceeding 5mg daily have not been established.

Dosage in Hepatic impairment

Hypertension: An initial dosage of 2.5mg daily is recommended. Subsequent dosage should be adjusted according to patient response and tolerance but usually should not exceed 10mg once daily.

Prinzmetal’s variant angina or chronic stable angina: The dosage of 5mg is recommended. Adequate control of angina usually requires a maintenance dosage of 10mg daily.

Mode of administration

Orally. Amlodipine generally can be given without regard to meals.

In patients known hypersensitivity to amlodipine and drugs under dihydropyridine group or any component of the formulation.

The most common side effects are headache and edema.

Doses related side effects from amlodipine are edema, dizziness, flushing and palpitation whereas unclear doses related side effects are headache, fatigue, nausea, abdominal pain and somnolence.

Rare side effects that a causal relationship is uncertain are as follows:

 Cardiovascular: arrhythmia (including ventricular tachycardia and atrial fibrillation), bradycardia, chest pain, hypotension, peripheral ischemia, syncope, tachycardia, postural dizziness, postural hypotension, vasculitis.

 Central and peripheral nervous system: hypoesthesia, peripheral neuropathy, paresthesia, tremor, vertigo.

 Gastrointestinal: anorexia, constipation, dyspepsia, dysphagia, diarrhea, flatulence, pancreatitis, vomiting, gingival hyperplasia.

 General: allergic reaction, asthenia, back pain, hot flushes, malaise, pain, rigors, weight gain, weight decrease.

 Musculoskeletal system: arthralgia, arthroses, muscle cramps, myalgia.

 Psychiatric: sexual dysfunction (male and female), insomnia, nervousness, depression, abnormal dreams anxiety, depersonalization.

 Respiratory system: dyspnea, epistaxis.

 Skin and appendages: angioedema, erythema multiforme, pruritus, rash, rash erythematous, rash maculopapular.

 Special senses: abnormal vision, conjunctivitis, diplopia, eye pain, tinnitus,

 Urinary system: micturition frequency, micturition disorder, nocturia.

 Autonomic nervous system: dry mouth, sweating increased.

 Metabolic and nutritional: hyperglycemia, thirst.

 Hemopoietic: leucopenia, purpura, thrombocytopenia.

Very rare side effects are cardiac failure, pulse irregularity, extra systoles, skin discoloration, urticaria, skin dryness, alopecia, dermatitis, muscle weakness, twitching, ataxia, hypertonia, migraine, cold and clammy skin, apathy, agitation, amnesia, gastritis, increased appetite, loose stools, coughing, rhinitis, dysuria, polyuria, parosmia, taste perversion, abnormal visual accommodation, and xerophthalmia.

See the package insert about the details below.

- alpha1-blockers, antifungal agents (azole derivatives), calcium channel blockers (nondihydropyridine), cyclosporine, moderate inhibitors of CYP3A4, strong inhibitors of CYP3A4, dasatinib, diazoxide, fluconazole, grapefruit juice, herbs (hypotensive properties), macrolide antibiotics, magnesium salts, monoamine oxidase inhibitors, pentoxifylline, phosphodiesterase 5 inhibitors, prostacyclin analogues, protease inhibitors, quinupristin.

- amifostine, antihypertensives, CYP1A2 substrates, neuromuscular-blocking agents (non-depolarizing), nitroprusside, phenytoin, rituximab, tacrolimus.

- barbiturates, calcium salts, carbamazepine, deferasirox, herbs (CYP3A4 inducers), methylphenidate, nafcillin, rifamycin derivatives, yohimbine.

- clopidogrel, quinidine.

- lithium

- St John’s wort

- ephedra, yohimbe, ginseng

- garlic

Pregnancy

Pregnancy category C

Embryotoxic effects have been demonstrated in small animals. No well-controlled studies have been conducted in pregnant women. Use in pregnancy only when clearly needed and when the benefits outweigh the potential hazard to the fetus.

Lactation

It is not known whether amlodipine is excreted in breast milk. Use in breastfeeding is not recommended.

- Increased angina and/or myocardial infarction has occurred with initiation or dosage titration of calcium blockers.

- Because amlodipine is extensively metabolized by the liver and the plasma elimination half- life will be prolonged in patients with impaired hepatic function, the dose should be slowly adjusted in such patients.

- Elderly patients and patients with hepatic impairment have decreased clearance of amlodipine with the resulting increase in AUC and half-life of the drug. These patients may be more sensitive to the hypotensive effects of amlodipine and may require a lower initial dose.

- Symptomatic hypotension with or without syncope can rarely occur; blood pressure must be lowered at a rate appropriate for the patient’s clinical condition. However, there is a possibility for hypotension incidence in patients with severe aortic stenosis and/or hypertropic cardiomyopathy.

- The safety and efficacy of amlodipine in children less than 6 years of age have not been established.

Amlodipine is classified as calcium ion influx inhibitor (slow channel blocker or calcium ion antagonist). It inhibits an influx of calcium ions across cell membrane into cardiac and vascular smooth muscles.

Amlodipine produces arteriolar vasodilation by acting directly on vascular smooth muscle. This mechanism results in a reduction of blood pressure. The precise mechanisms by which amlodipine relieves angina have not been fully delineated, but are thought to include the two categories as follows:

1. Amlodipine is a peripheral arteriolar vasodilator; thus it reduces total peripheral resistance (afterload) against which the heart works. Due to static heart rate, reduction in heart work causes reduction in myocardial energy and oxygen demand.

2. Mechanism of action of amlodipine may be related to blocking constriction and restoring blood flow in coronary arteries and arterioles. This inhibition of coronary spasm is responsible for the effectiveness in vasospastic (Prinzmetal’s variant angina).