Monday, July 13, 2009

Amdixal

Amdixal® Tablet
Amlodipine maleate


COMPOSITION:
  • Each tablet Amdixal@ 5 contains:
    Amlodipine maleate equivalent to 5 mg of Amlodipine
  • Each tablet Amdixal@ 10 contains:
    Amlodipine maleate equivalent to 10 mg of Amlodipine
DESCRIPTION:
Pharmacodynamic Properties
Amlodipine is a calcium ion antagonist that inhibits the depolarisation dependent slow Ca-channels in the cell membrane by which the influx of calcium ions into cardiac and smooth muscle is inhibited. The antihypertensive effect of Amlodipine is due to a direct relaxant effect on vascular smooth muscle. The precise mechanism by which Amlodipine relieves the symptoms of angina pectoris has not been fully determined, but Amlodipine reduces total ischaemic burden by the two actions mentioned below:
Amlodipine dilates peripheral arterioles and thus reduces the total peripheral resistance (aflerload) against which the heart works. Because the heart rate remains stable, this unloading of the heart reduces myocardial energy consumption and oxygen requirements.
Amlodipine probably dilates the main coronary arteries and coronary arterioles, both in normal and ischaemic regions. This dilation increases myocardial oxygen delivery in patients with coronary artery spasm (Prinzmetal’s angina 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-hours interval. Due to the slow onset of action, initiation of Amlodipine treatment is not associated with acute hypotension. Amlodipine has been used in combination with thiazide diuretics, alpha-adrenergic blocking agents, beta-blockers and ACE inhibitors. Patients with an inadequate hypotensive response to monotherapy with the above-mentioned drugs or other antihypertensive agents may benefit from the addition of Amlodipine.
Amlodipine may be used as monotherapy, or in combination with other antianginal drugs in patients with angina that is refractory to nitrates and/or beta-blockers.
In patients with angina pectoris, once daily administration of Amlodipine prolongs exercise time and delays the emergence of pain, as well as significantly reduces the ischaemic decrease in ST depression compared with placebo. Angina attack frequency and the need for nitroglycerin tablets are reduced.

Pharmacokinetic properties
Amlodipine is well absorbed after administration of therapeutic doses and peak concentrations are achieved after 6 to 12 hours. Absolute bioavailability has been estimated to be 64 to 80%. Food does not affect the absorption of Amlodipine.
The distribution volume of Amlodipine is approximately 21 l/kg. Plasma protein binding approximates 97%. The plasma elimination half-life of Amlodipine is 35 to 50 hours after once daily dosing. Steady state plasma concentrations are achieved after 7 to 8 days of consecutive daily ingestion. Amlodipine is extensively metabolized in the liver to inactive metabolites. Approximately 10% of the Amlodipine dose is excreted in urine unchanged and 60% as metabolites.
In elderly: The time to reach peak plasma concentrations is similar in elderly and younger patients. These clearances tend to be decreased with resulting increase in “Area Under Curve (AUC)” and terminal elimination half life. The recommended dosage regimen for the elderly is the same, although increasing the dose should take place with caution.
In patients with renal failure: Amlodipine is extensively metabolized to inactive metabolites. 10 % of the parent compound is excreted unchanged in urine. Changes in Amlodipine concentration are not correlated with the degree of renal impairment. Therefore the normal dosage is recommended. Amlodipine is not dialyzable.
Patients with hepatic impairment: The half life of Amlodipine is prolonged in patients with impaired hepatic function.

Preclinical safety data
Cardiotoxic damages in dogs after repeated administration of doses that have cumulative hypotensive effect, are of no importance for the patients, as these changes are results of the pronounced haemodynamic changes which are not seen in human beings. No animal studies showed signs of drug related embryo toxicity, foetal toxicity or teratogenicity.
In animal studies with respect to the reproduction in rats at high dose delayed parturition, difficult labour and impaired foetal and pup survival were seen.
No signs of carcinogen effect.

INDICATION:

  1. Amdixal® is indicated for the treatment of hypertension and can be used as the sole agent to control blood pressure in the majority of patients. Patients not adequately controlled in a single antihypertensive agent may benefit from the addition of Amdixal®, which has been used in combination with a thiazide diuretic, beta-adrenoseptor blocking agent, or an angiotensin converting enzyme inhibitor.
  2. Amdixal® is indicated for the first line treatment of myocardial ischemia. Whether due to fixed obstruction (stable angina) and/or vasospasm/vasoconstriction (Prinzmetal’s or variant angina) of coronary vasculature. Amdixal® may be used where the clinical presentation suggests a possible vasospastic/ vasoconstriction component but where vasospasm/vasoconstriction has not been confirmed Amdixal® may be used alone, as monotherapy or in combination with other anti-anginal drugs in patients with angina that is refractory to nitrates and/or adequate doses of beta-blocker.
DOSAGE AND ADMINISTRATION:

  • For both hypertension and angina the usual initial dose is 5 mg Amdixal® once daily, which maybe increased to a maximum dose of 10 mg depending on the individual patients response and severity.
  • Small, fragile or elderly individuals or patients with hepatic insufficiency maybe started on 2.5 mg once daily and this dose may be used when adding Amdixal® to other antihypertensive therapy.
  • Majority of hypertensive patients with 5 mg/day the dose may not necessarily be increased. For those who need higher dose, Amdixal® can be increased to 7.5 mg/day with maximum dose of 10 mg/day.
  • The recommended for chronic stable or vasospastic angina is 5-10 mg, with the lower dose suggested in the elderly and in patients with hepatic insufficiency. The dose adjustment of Amdixal® is required upon concomitant administration of thiazide diuretics, beta-blocker, and angiotensin converting enzyme inhibitor.
  • Use in children: No experience is available on use of Amdixal1® in children.

CONTRAINDICATION:

  • Amdixal® is contraindicated in patients with known sensitivity to Amlodipine
  • Severe hypotension
  • Shock
  • Hypersensitivity to dihydropyridine derivatives, Amlodipine or any of the excipients
  • Heart failure after acute myocardial infarction (during the first 28 days)
  • Obstruction of the outflow-tractor the left ventricle (e.g. high grade aortic stenosis)
  • Instable angina pectoris
ADVERSE REACTIONS:
In general, treatment with Amdixal® was well-tolerated at doses up to 10 mg daily. Most adverse reactions reported during therapy with Amlodipine were of mild or moderate severity.
The most common side effects are headache and edema.
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, neuropathy peripheral, paresthesia, tremor, vertigo.
Gastrointestinal: anorexia, constipation, dyspepsia, ** dysphagia, diarrhea, flatulence, pancreatitis, vomiting, gingival hyperplasia.
General: allergic reaction, asthesia, **back pain, hot flushes, malaise, pain, rigors, weight gain, weight decrease.
Musculoskeletal System: arthralgia, arthrosis, 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.
(**) These events occurred in less than 1 % in placebo controlled trials, but the incidence of these side effects was between 1 % and 2 % in ail multiple dose studies.

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: leukopenia, purpura, thrombocytopenia.
The following events occurred in ≤ 0.1 % of patients 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 xerophtalmia.
Other reaction occurred sporadically and cannot be distinguished from medications or concurrent disease states such as myocardial infarction and angina.
Amlodipine therapy has not been associated with clinically significant changes in routine laboratory test. No clinically relevant changes were noted in serum potassium, serum glucose, total triglycerides, total cholesterol, HDL cholesterol, uric acid, blood urea nitrogen, or creatinine.
The following post marketing event has been reported infrequently where a causal relationship is uncertain: gynecomastia. In post marketing experience, jaundice and hepatic enzyme elevations (mostly consistent with cholestatis or hepatitis) in some cases severe enough to require hospitalization have been reported in association with use of Amlodipine.
Amlodipine has been used safely in patients with chronic obstructive pulmonary disease, well-compensated congestive heart failure, peripheral vascular disease, diabetes mellitus, and abnormal lipid profiles.

SPECIAL WARNING AND SPECIAL PRECAUTIONS FOR USE:
Warnings
Increased Angina and/or Myocardial Infarction: Rarely, patients, particularly those with severe obstructive coronary artery disease, have developed documented increased frequency, duration and/or severity of angina or acute myocardial infarction on starting calcium channel blocker therapy or at the time of dosage increase. The mechanism of this effect has not been elucidated.
Amdixal® should be administered with caution to patients with low cardiac reserve.

Precautions
General: Since the vasodilation induced by Amlodipine is gradual in onset, acute hypotension has rarely been reported after oral administration of Amlodipine. Nonetheless, caution should be exercised when administering Amlodipine as with any other peripheral vasodilator particularly in patients with severe aortic stenosis.
Use in Patients with Congestive Heart Failure. In general, calcium channel blockers should be used with caution in patients with heart failure.
Beta-Blocker Withdrawal: Amlodipine is not a beta-blocker and therefore gives no protection against the dangers of abrupt beta-blockers withdrawal, any such withdrawal should be by gradual reduction of the dose of beta-blocker.
Patients with Hepatic Failure: Since Amlodipine is extensively metabolized by the liver and the plasma elimination half-life (t1/2) is 56 hours in patients with impaired hepatic function, caution should be exercised when administering Amlodipine to patients with severe hepatic impairements.
Use in children and adolescents: Amdixal® should not be given to children and adolescents due to insufficient clinical experience.

DRUG INTERACTION:
In vitro data in human plasma indicate that Amlodipine has no effect on the protein binding of drug tested (digoxin, phenytoin, warfarin and indomethacin).
Special Studies: Effect of other agents on Amlodipine
CIMETIDINE: Co-administration of Amlodipine with Cimetidine did not alter the pharmacokinetics of Amlodipine
GRAPEFRUIT JUICE: Co-administration of 240 ml of grapefruit juice with a single oral dose of Amlodipine 10 in 20 healthy volunteers had no significant effect on the pharmacokinetics of Amlodipine.
ANTACID: Co-administration of the antacid with o 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 independent 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 of atorvastatin resulted in no significant change in the steady state pharmacokinetic parameters of atorvastatin.
DIGOXIN: Co-administration of Amdixal® with digoxin did not change serum digoxin levels or digoxin renal clearance in normal volunteers.
ETHANOL (Alcohol): Single and multiple 10 mg doses of Amdixal® had no significant effect on the pharmacokinetics of ethanol.
WARFARIN: Co-administration of Amdixal® with warfarin did not change the warfarin prothrombin response time.
In clinical trials, Amlodipine has been safely administered with thiazid diuretics, beta-blocker, angiotensin-converting enzyme inhibitors, long-acting nitrates, sublingual nitroglycerin, digoxin, warfarin, non-steroidal anti-inflammatory drugs, antibiotics, and oral hypoglycemic drugs.

PREGNANCY AND LACTATION:
No evidence of teratogenicity or other embryo/foetal toxicity was found when pregnant rats or rabbits were treated orally with up to 10 mg/kg Amlodipine (respectively 8 times* and 23 times* the maximum recommended human dose of 10 mg on a mg/m basis) during their respective periods of major organogenesis.
However, little size was significantly decreased (by about 50 %) and the number of intrauterine death was significantly increased (about 5-fold) in rats administered 10 mg/kg Amlodipine for 14 days before mating and throughout mating and gestation. Amlodipine has been shown to prolong both the gestation period and me duration of labor in rats at this dose. There are no adequate and well-controlled studies in pregnant women. Amlodipine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
* Based on patient weight of 50 kg.

Nursing Mothers: It is not known whether Amlodipine is excreted in human milk. In the absence of this information, it is recommended that nursing be discontinued while Amdixal® is administered.
Pediatric Use: Safety and effectiveness of Amdixal® in children have not been established.
Geriatric Use: Clinical studies of Amlodipine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patients should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Elderly patients hove decreased clearance of Amlodipine with a resulting increase or other drug therapy. Elderly patients have decreased clearance of Amlodipine with a resulting increase of AUC of approximately 40-60%, and a lower initial dose may be required.

OVERDOSE:
Single oral dose of 40 mg/kg and 100 mg/kg in mice and rats, respectively, caused deaths. A single oral dose of 4 mg/kg or higher in dogs caused o marked peripheral vasodilation and hypotension.
Overdosage might be expected to cause excessive peripheral vasodilation with marked hypotension and possibly a reflex tachycardia. In humans, experience with intentional overdosage of Amlodipine is limited. Reports of intentional overdosage include a patients who ingested 250 mg and was asymptomatic and was not hospitalized, another (120 mg) was hospitalized, underwent gastric lavage and remained normotensive; the third (105 mg) was hospitalized and had hypotension (90/50 mmHg) which normalized following plasma expansion. A patient who took 70 mg Amlodipine and unknown quantity of Benzodiazepine in a suicide attempt developed shock which was refractory to treatment and died the following day with abnormally high Benzodiazepine plasma concentration. A case of accidental drug overdose has been documented in a 19-month old male who ingested 30 mg Amlodipine (about 2 mg/kg). During the emergency room presentation, vital signs were stable with no evidence of hypotension, but a heart rate of 180 bpm. Ipecac was administered 3.5 hours after ingestion and on subsequent observation (overnight) no sequelae were noted.
If massive overdose should occur, active cardiac and respiratory monitoring should be instituted. Frequent blood pressure measurements are essential. Should hypotension occur, cardiovascular support including elevation of the extremities and the judicious administration of fluids should be initiated. If hypotension remains unresponsive to these conservative measures, administration of vasopressors (such as phenylephrine) should be considered with attention to circulating volume and urine output. Intravenous calcium gluconate may help to reverse the effects of calcium entry blockade. As Amdixal® is highly protein bound, hemodialysis is not likely to be of benefit.

PRESENTATION:
Amdixal® 5
Box,3 Strips @ 10 Tablets
Reg.No.: DKL0631601210A1

Amdixal® 10
Box, 3 Strips @ 10 Tablets
Reg. No.: DKL0631601210B1

HARUS DENGAN RESEP DOKTER
ON DOCTOR'S PRESCRIPTION ONLY

Store at room temperature (25° - 30° C).

Manufactured by:
PT. Sandoz Indonesia
Bandung-Indonesia

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