ISTIN™

Active Ingredient: amlodipine

The tablets contain amlodipine besilate (equivalent to 5mg and 10mg amlodipine)

Tablet for oral administration

5mg tablets: White emerald shaped tablets with imprint AML-5 on one side and Pfizer logo on the other.

10mg tablets: White emerald shaped tablets with imprint AML-10 on one side and Pfizer logo on the other.

Hypertension

Prophylaxis of chronic stable angina pectoris

Prinzmetal's (variant) angina when diagnosed by a cardiologist

In hypertensive patients, Istin has been used in combination with a thiazide diuretic, alpha blocker, beta-adrenoceptor blocking agent, or an angiotensin converting enzyme inhibitor. For angina, Istin may be used as monotherapy or in combination with other antianginal drugs in patients with angina that is refractory to nitrates and/or adequate doses of beta blockers.

Istin is well tolerated in patients with heart failure and a history of hypertension or ischaemic heart disease.

In adults: For both hypertension and angina the usual initial dose is 5mg Istin once daily which may be increased to a maximum dose of 10mg depending on the individual patient's response.

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

Use in children: Not recommended.

Use in the elderly: Istin, used at similar doses in elderly or younger patients, is equally well tolerated. Therefore normal dosage regimens are recommended.

Patients with hepatic impairment: See section 4.4 Special warnings and precautions for use.

Patients with renal impairment: Changes in amlodipine plasma concentrations are not correlated with degree of renal impairment, therefore the normal dosage is recommended. Amlodipine is not dialysable.

Istin is contra-indicated in patients with a known sensitivity to dihydropyridines, amlodipine or any of the excipients.

Istin should not be used in cardiogenic shock, clinically significant aortic stenosis, unstable angina (excluding Prinzmetal's angina).

Pregnancy and lactation

Use in patients with Heart Failure: In a long-term, placebo controlled study (PRAISE-2) of Istin in patients with NYHA III and IV heart failure of nonischaemic aetiology, amlodipine was associated with increased reports of pulmonary oedema despite no significant difference in the incidence of worsening heart failure as compared to placebo. See section 5.1 “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. The drug should therefore be administered with caution in these patients.

There are no data to support the use of Istin alone, during or within one month of a myocardial infarction.

The safety and efficacy of Istin in hypertensive crisis has not been established.

Istin has been safely administered with thiazide diuretics, alpha blockers, beta blockers, angiotensin-converting enzyme inhibitors, long-acting nitrates, sublingual glyceryl trinitrate, non-steroidal anti-inflammatory drugs, antibiotics, and oral hypoglycaemic drugs.

In vitro data from studies with human plasma, indicate that amlodipine has no effect on protein binding of digoxin, phenytoin, warfarin or indometacin.

Special Studies: Effect of other agents on amlodipine

Cimetidine: Co-administration of Istin with cimetidine did not alter the pharmacokinetics of Istin.

Grapefruit Juice: Co-administration of 240ml of grapefruit juice with a single oral dose of Istin 10mg in 20 healthy volunteers had no significant effect on the pharmacokinetics of Istin.

Sildenafil: When Istin and sildenafil were used in combination, each agent independently exerted its own blood pressure lowering effect.

Special Studies: Effect of amlodipine on other agents

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

Digoxin: Co-administration of Istin with digoxin did not change serum digoxin levels or digoxin renal clearance in normal volunteers.

Warfarin: In healthy male volunteers, the co-administration of Istin does not significantly alter the effect of warfarin on prothrombin response time. Co-administration of Istin with warfarin did not change the warfarin prothrombin response time.

Ciclosporin: Pharmacokinetic studies with ciclosporin have demonstrated that Istin does not significantly alter the pharmacokinetics of ciclosporin.

Drug/Laboratory test Interactions: None known.

Although some dihydropyridine compounds have been found to be teratogenic in animals, data in the rat and rabbit for amlodipine provide no evidence for a teratogenic effect. There is, however, no clinical experience with the preparation in pregnancy or lactation. Accordingly, Istin should not be administered during pregnancy, or lactation, or to women of childbearing potential unless effective contraception is used.

Clinical experience with Istin indicates that therapy is unlikely to impair a patient's ability to drive or use machinery.

Adverse events that have been reported in amlodipine trials are categorised below, according to system organ class and frequency. Frequencies are defined as: very common (>10%); common (>1%, <10%); uncommon (>0.1%, <1%); rare (>0.01%, <0.1%) and very rare (<0.01%).

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.

Administration of activated charcoal to healthy volunteers immediately or up to two hours after ingestion of amlodipine 10mg has been shown to significantly decrease amlodipine absorption. Gastric lavage may be worthwhile in some cases.Clinically significant hypotension due to Istin overdosage 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. Since Istin is highly protein-bound, dialysis is not likely to be of benefit.

Istin 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 of Istin is due to a direct relaxant effect on vascular smooth muscle. The precise mechanism by which Istin relieves angina has not been fully determined but Istin reduces total ischaemic burden by the following two actions.

1) Istin 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 Istin 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 Istin administration.

In patients with angina, once daily administration of Istin increases total exercise time, time to angina onset, and time to 1mm ST segment depression, and decreases both angina attack frequency and glyceryl trinitrate tablet consumption.

Istin 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 Heart Failure:Haemodynamic studies and exercise based controlled clinical trials in NYHA Class II-IV heart failure patients have shown that Istin 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 Istin did not lead to an increase in risk of mortality or combined mortality and morbidity with heart failure.

In a follow-up, long term, placebo controlled study (PRAISE-2) of Istin in patients with NYHA III and IV heart failure without clinical symptoms or objective findings suggestive or underlying ischaemic disease, on stable doses of ACE inhibitors, digitalis, and diuretics, Istin had no effect on total cardiovascular mortality. In this same population Istin was associated with increased reports of pulmonary oedema despite no significant difference in the incidence of worsening heart failure as compared to placebo.

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 .

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.

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.

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 the 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.

None

Microcrystalline cellulose, E460

Dibasic calcium phosphate anhydrous

Sodium starch glycollate

Magnesium stearate, E572

Not applicable

4 years

Do not store above 25^oC

Istin is available as:

Calendar packs of 28 tablets. Aluminium/PVC blister strips, 14 tablets/strip, 2 strips in a carton box.

No special requirements

Pfizer Limited

Ramsgate Road

Sandwich

Kent

CT13 9NJ

United Kingdom

Istin Tablets 5mg PL 00057/0297

Istin Tablets 10mg PL 00057/0298

30 January 1995 / 25 April 2001

July 2007

POM

Ref: IS10_0