Treatment of essential hypertension.

Gizamlo® is indicated in patients whose blood pressure is not adequately controlled on irbesartan or amlodipine monotherapy.

The usual initial and maintenance dose of Gizamlo® is one tablet per day.

Gizamlo® can be administered with or without food.

Gizamlo® should be administered in patients whose blood pressure is not adequately controlled on monotherapy with irbesartan or amlodipine or for continuation of therapy for patients receiving irbesartan and amlodipine as separate tablets. Dose should be individualized based on response to therapy with individual components and antihypertensive response required. The maximum recommended dose with Gizamlo® is 300 mg/10 mg per day.

Therapy should be adjusted according to blood pressure response.

Pediatric patients: the safety and efficacy of Irbesartan/Amlodipine combination has not been established.

Elderly patients and patients with impaired renal function: in general, no dosage reduction is necessary in elderly patients or patients with impaired renal function (regardless of degree).

Patients with impaired hepatic function: due to the presence of amlodipine, Gizamlo® should be administered with caution. For oral administration.

Warnings

Hypotension: volume-depleted patients:

Irbesartan has been rarely associated with hypotension in hypertensive patients without other co-morbid conditions. As with ACE inhibitors, symptomatic hypotension may be expected to occur in sodium / volume-depleted patients such as those treated vigorously with diuretics and /or salt restriction, or on hemodialysis. Volume and sodium-depletion should be corrected before initiating therapy with irbesartan / amlodipine combination or a lower starting dose should be considered.

Fetal / neonatal morbidity and mortality:

Although there is no experience with irbesartan in pregnant women, in utero exposure to ACE inhibitors given to pregnant women during the second and third trimesters of gestation has been reported to cause injury and death to the developing fetus. Thus, as for any drug that also acts directly on the renin –angiotensin-aldosterone system, irbesartan / amlodipine combination should not be used during pregnancy. If pregnancy is detected during therapy, irbesartan / amlodipine combination should be discontinued as soon as possible.

Patients with heart failure:

Amlodipine was associated with increase in pulmonary edema in patients with NYHA III and IV heart failure of non-ischemic etiology despite no significant difference in the incidence of worsening heart failure.

Hepatic impairment:

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

Hypertensive crises:

The safety and efficacy in Irbesartan /Amlodipine combination in hypertensive crises has not been established.

Dual blockade of the renin-angiotensin-aldosterone system (RAAS) with aliskiren- containing medicinal products: the dual blockade of the renin-angiotensin-aldosterone system induced by administration of the Irbesartan/Amlodipine + aliskiren combination is not recommended as there is an increased risk of hypotension, hyperkalemia and impairment of renal function. Use of the Irbesartan/Amlodipine + aliskiren combination is contraindicated in patients with diabetes mellitus or with renal insufficiency (glomerular filtration rate [GFR] <60 mL/min/1.73 m2).

As a consequence of blocking the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients whose renal function is dependent on renin-angiotensin-aldosterone system activity (hypertensive patients with renal artery stenosis in one or both kidneys, or patients with severe congestive heart failure), treatment with other drugs that affect this system has been associated with oliguria and/or progressive azotemia and rarely with acute renal failure and/or death. The possibility of a similar effect occurring with the use of an angiotensin II receptor antagonist, including irbesartan, cannot be ruled out.

Geriatric use: among patients who received irbesartan, no overall differences in efficacy or safety were observed between older patients (65 years or older) and younger patients.

Pediatric use: safety and efficacy in pediatric patients have not been established.

For Irbesartan and amlodipine combination:

It was found that there is no pharmacokinetic interaction between irbesartan and amlodipine if they were given alone or in combination.

No information is available on drug interactions for irbesartan amlodipine combination with other medicinal products.

Irbesartan

No interactions would be expected to occur with drugs which metabolism depends on cytochrome P450 isoenzymes CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2D6, CYP2E1 or CYP3A4.

Irbesartan is primarily metabolized by CYP2C9, however, no significant pharmacodynamic interactions were observed when irbesartan was co-administered with warfarin (metabolized by CYP2C9).

The pharmacokinetic parameters of irbesartan are not affected by co-administration with nifedipine or hydrochlorothiazide.

Irbesartan does not affect the pharmacokinetics of simvastatin (metabolized by CYP3A4) or digoxin (substrate of P-glycoprotein efflux transporter).

Based on experience with the use of other drugs that act on the renin-angiotensin system, concomitant use of potassium – sparing diuretics, potassium supplements, or salt substitutes containing potassium may increase serum potassium levels.

Use of Gizamlo® concomitantly with medicinal products containing aliskiren is contraindicated in patients with diabetes mellitus or moderate to severe renal insufficiency (glomerular filtration rate [GFR] <60mL/ min/1.73m2), and is not recommended in other patients. In elderly patients, volume-depleted patients (including those treated with diuretics), or in patients with impaired renal function, co- administration of irbesartan with NSAIDs, including selective COX-2 inhibitors, or with angiotensin II receptor antagonists, including irbesartan, can cause deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Renal function should be monitored periodically in patients receiving occasional treatment with irbesartan and NSAIDs. The antihypertensive effect of angiotensin II receptor antagonists, including irbesartan, may be attenuated by NSAIDs including selective COX-2 inhibitors.

Amlodipine:

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

It was reported that amlodipine has no effect on the protein binding of studied medicines (digoxin, phenytoin, warfarin or indomethacin).

·         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 10 mg oral dose of amlodipine had no significant effect on the pharmacokinetics of Amlodipine.

·         Aluminum / magnesium (antacids): Concomitant administration of an antacid containing aluminum / magnesium with a single dose of amlodipine had no significant effect on the pharmacokinetic profile of amlodipine.

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

·         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: it was shown that co-administration of amlodipine with digoxin did not change serum digoxin levels or digoxin renal clearance.

·         Warfarin: co-administration of amlodipine did not change warfarin prothrombin response time.

·         Cyclosporine: it was shown that amlodipine does not significantly alter the pharmacokinetics of cyclosporine.

Pregnancy and lactation:

Pregnancy:

There are no adequate data in pregnant women. Irbesartan Amlodipine combination is contraindicated during pregnancy. Gizamlo® must not be administered to women of childbearing potential unless effective contraception is used. When pregnancy is detected during therapy with Irbesartan Amlodipine, treatment shall be discontinued as soon as possible.

Lactating mothers:

Gizamlo® is contraindicated during lactation.

Based on its pharmacodynamic properties, irbesartan is unlikely to affect the ability to drive and use machines. When driving vehicles or operating machines, it should be taken into account that dizziness or weariness may occur during treatment.

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.

Because clinical trials are conducted under widely varying conditions, the incidence of adverse reaction observed in the clinical trials of one drug cannot be directly compared to that observed in the clinical trials of other drugs and may not reflect that observed in practice. Irbesartan has been evaluated for safety in clinical studies.

Adverse events in patients receiving irbesartan were generally mild and transient with no relationship to the dose. The incidence of adverse events was not related to age, gender or race.

The frequency of adverse events is defined using the following convention:

Very common ( 1/10); common ( 1/100 and < 1/10); uncommon ( 1/1,000 and < 1/100); rare ( 1/10,000 and < 1/1,000); very rare (< 1/10,000); unknown: no incidence data available.

a.       Includes all adverse events whether causal relationship to therapy is probable possible or unlikely, irrespective of incidence in the placebo-treated patients

b.      Includes all adverse events whether causal relationship to therapy is probable possible or unlikely, occurring with an incidence of 0.5% to <1% and at similar or slightly increased incidence in irbesartan treated patients compared to placebo-treated patients (no statistically significant differences between the 2 treatment groups)

For amlodipine

Adverse events that have been reported in amlodipine are categorized below according to system organ class and frequency (see table 2).

The following CIOMS frequency rating is used, when applicable:

Very common (  1/10%); common (  1 and < 10%); uncommon (  0.1 and < 1%); rare ( 0.01 and < 0.1%); very rare (< 0.01%); unknown: cannot be estimated from available data.

In clinical trials comparing the fixed-dose combination irbesartan/amlodipine to either irbesartan or amlodipine monotherapy, the types and incidences of treatment-emergent adverse events (TEAEs) possibly related to study treatment were similar to those observed earlier monotherapy clinical trials and postmarketing reports. The most frequently reported adverse event was peripheral edema, mainly associated with amlodipine (see table 3).

The following CIOMS frequency rating is used, when applicable:

Very common: ≥ 10 %; common: ≥ 1 and < 10 %; uncommon: ≥ 0.1 % and < 1%; rare;

≥ 0.01 % and < 0.1 %; very rare: < 0.01 %, unknown (cannot be estimated from available data).

To report side effects:

The National Pharmacovigilance Centre (NPC)

−      Fax: +966-11-205-7662

−      Call NPC at +966- 11-2038222, Ext 2317, 2356, 2340

−      SFDA Call Centre: 19999

−      E-mail: npc.drug@sfda.gov.sa

−      Website: www.sfda.gov.sa/npc

Experience in adults exposed to doses of up to 900 mg/day irbesartan for 8 weeks revealed no toxicity. No specific information is available on the treatment of overdose with irbesartan. Available data for amlodipine suggest that overdose could result in excessive peripheral vasodilatation and possibly reflex tachycardia, Marked and probably prolonged systemic hypotension and shock with fatal outcome have been reported.

The patient should be closely monitored and symptomatic and supportive treatment administered. Suggested measures include gastric lavage. Administration of activated charcoal to healthy subjects immediately or up to two hours after ingestion of amlodipine 10 mg has been shown to significantly decrease amlodipine absorption.

As amlodipine is highly protein bound and irbesartan is not removed from the body by hemodialysis, hemodialysis does not appear to be useful. If massive overdose should occur, active cardiac and respiratory monitoring should be initiated.

Frequent blood pressure measurement is essential.

Clinically significant hypotension due to amlodipine overdose calls for active cardiovascular support including elevation of the 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.

Angiotensin-II is a substance produced in the body which binds to receptors in blood vessels causing them to tighten. This results in an increase in blood pressure. Irbesartan prevents the binding of angiotensin-II to these receptors, causing the blood vessels to relax and the blood pressure to lower.

Amlodipine is a calcium antagonist belonging to the dihydropyridine group which acts on the calcium channel binding sites. It causes prolonged inhibition of the entry of calcium via slow calcium channels into smooth muscles and myocardial cells.

Pharmacodynamic properties of Irbesartan

Pharmacotherapeutic group: Angiotensin-II antagonists, plain. ATC code: C09C A04.

Mechanism of action: Irbesartan is a potent, orally active, selective angiotensin-II receptor (type AT1) antagonist. It is expected to block all actions of angiotensin-II mediated by the AT1 receptor, regardless of the source or route of synthesis of

angiotensin-II. The selective antagonism of the angiotensin-II (AT1) receptors results in increases in plasma renin levels and angiotensin-II levels, and a decrease in plasma aldosterone concentration. Serum potassium levels are not significantly affected by irbesartan alone at the recommended doses. Irbesartan does not inhibit ACE (kininase- II), an enzyme which generates angiotensin-II and also degrades bradykinin into inactive metabolites.

Irbesartan does not require metabolic activation for its activity. Clinical efficacy

Hypertension

Irbesartan lowers blood pressure with minimal change in heart rate. The decrease in blood pressure is dose-related for once a day doses with a tendency towards plateau at doses above 300 mg. Doses of 150-300 mg once daily lower supine or seated blood pressures at trough (i.e. 24 hours after dosing) by an average of 8-13/5-8 mm Hg (systolic/diastolic) greater than those associated with placebo.

Peak reduction of blood pressure is achieved within 3-6 hours after administration and the blood pressure lowering effect is maintained for at least 24 hours. At 24 hours the reduction of blood pressure was 60-70% of the corresponding peak diastolic and systolic responses at the recommended doses. Once daily dosing with 150 mg produced trough and mean 24 hour responses similar to twice daily dosing on the same total dose.

The blood pressure lowering effect of Irbesartan is evident within 1-2 weeks, with the maximal effect occurring by 4-6 weeks after start of therapy. The antihypertensive effects are maintained during long term therapy. After withdrawal of therapy, blood pressure gradually returns toward baseline. Rebound hypertension has not been observed.

The blood pressure lowering effects of irbesartan and thiazide-type diuretics are additive. In patients not adequately controlled by irbesartan alone, the addition of a low dose of hydrochlorothiazide (12.5 mg) to irbesartan once daily results in a further placebo-adjusted blood pressure reduction at trough of 7-10/3-6 mm Hg (systolic/diastolic).

The efficacy of Irbesartan is not influenced by age or gender. As is the case with other medicinal products that affect the renin-angiotensin system, black hypertensive patients have notably less response to irbesartan monotherapy. When irbesartan is administered concomitantly with a low dose of hydrochlorothiazide (e.g. 12.5 mg daily), the antihypertensive response in black patients approaches that of white patients.

There is no clinically important effect on serum uric acid or urinary uric acid secretion.

Paediatric population

Reduction of blood pressure with 0.5 mg/kg (low), 1.5 mg/kg (medium) and 4.5 mg/kg (high) target titrated doses of irbesartan was evaluated in 318 hypertensive or at risk (diabetic, family history of hypertension) children and adolescents aged 6 to 16 years over a three week period. At the end of the three weeks the mean reduction from baseline in the primary efficacy variable, trough seated systolic blood pressure (SeSBP) was 11.7 mmHg (low dose), 9.3 mmHg (medium dose), 13.2 mmHg (high dose). No significant difference was apparent between these doses. Adjusted mean change of trough seated diastolic blood pressure (SeDBP) was as follows: 3.8 mmHg (low dose), 3.2 mmHg (medium dose), 5.6 mmHg (high dose). Over a subsequent two week period where patients were re-randomized to either active medicinal product or placebo, patients on placebo had increases of 2.4 and 2.0 mmHg in SeSBP and SeDBP compared to +0.1 and -0.3 mmHg changes respectively in those on all doses of irbesartan (see section 4.2).

Hypertension and type 2 diabetes with renal disease

The “Irbesartan Diabetic Nephropathy Trial (IDNT)” shows that irbesartan decreases the progression of renal disease in patients with chronic renal insufficiency and overt proteinuria. IDNT was a double blind, controlled, morbidity and mortality trial comparing Irbesartan, amlodipine and placebo. In 1,715 hypertensive patients with type 2 diabetes, proteinuria ≥ 900 mg/day and serum creatinine ranging from 1.0-3.0 mg/dl, the long-term effects (mean 2.6 years) of Irbesartan on the progression of renal disease and all-cause mortality were examined. Patients were titrated from 75 mg to a maintenance dose of 300 mg Irbesartan, from 2.5 mg to 10 mg amlodipine, or placebo as tolerated.

Patients in all treatment groups typically received between 2 and 4 antihypertensive agents (e.g., diuretics, beta blockers, alpha blockers) to reach a predefined blood pressure goal of ≤ 135/85 mmHg or a 10 mmHg reduction in systolic pressure if baseline was > 160 mmHg. Sixty per cent (60%) of patients in the placebo group reached this target blood pressure whereas this figure was 76% and 78% in the irbesartan and amlodipine groups respectively. Irbesartan significantly reduced the relative risk in the primary combined endpoint of doubling serum creatinine, end-stage renal disease (ESRD) or allcause mortality. Approximately 33% of patients in the irbesartan group reached the primary renal composite endpoint compared to 39% and 41% in the placebo and amlodipine groups [20% relative risk reduction versus placebo (p = 0.024) and 23% relative risk reduction compared to amlodipine (p = 0.006)]. When the individual components of the primary endpoint were analysed, no effect in all cause mortality was observed, while a positive trend in the reduction in ESRD and a significant reduction in doubling of serum creatinine were observed.

Subgroups consisting of gender, race, age, duration of diabetes, baseline blood pressure, serum creatinine, and albumin excretion rate were assessed for treatment effect. In the female and black subgroups which represented 32% and 26% of the overall study population respectively, a renal benefit was not evident, although the confidence intervals do not exclude it. As for the secondary endpoint of fatal and non-fatal cardiovascular events, there was no difference among the three groups in the overall population, although an increased incidence of non-fatal MI was seen for women and a decreased incidence of non-fatal MI was seen in males in the irbesartan group versus the placebo-based regimen. An increased incidence of non-fatal MI and stroke was seen in females in the irbesartan-based regimen versus the amlodipine-based regimen, while hospitalization due to heart failure was reduced in the overall population. However, no proper explanation for these findings in women has been identified.

The study of the “Effects of Irbesartan on Microalbuminuria in Hypertensive Patients with type 2 Diabetes Mellitus (IRMA 2)” shows that irbesartan 300 mg delays progression to overt proteinuria in patients with microalbuminuria. IRMA 2 was a placebo-controlled double blind morbidity study in 590 patients with type 2 diabetes, microalbuminuria (30-300 mg/day) and normal renal function (serum creatinine ≤ 1.5 mg/dl in males and < 1.1 mg/dl in females). The study examined the long-term effects (2 years) of Irbesartan on the progression to clinical (overt) proteinuria (urinary albumin excretion rate (UAER) > 300 mg/day, and an increase in UAER of at least 30% from baseline). The predefined blood pressure goal was ≤ 135/85 mmHg. Additional antihypertensive agents (excluding ACE inhibitors, angiotensin II receptor antagonists and dihydropyridine calcium blockers) were added as needed to help achieve the blood pressure goal. While similar blood pressure was achieved in all treatment groups, fewer subjects in the irbesartan 300 mg group (5.2%) than in the placebo (14.9%) or in the irbesartan 150 mg group (9.7%) reached the endpoint of overt proteinuria, demonstrating a 70% relative risk reduction versus placebo (p = 0.0004) for the higher dose. An accompanying improvement in the glomerular filtration rate (GFR) was not observed during the first three months of treatment. The slowing in the progression to clinical proteinuria was evident as early as three months and continued over the 2 year period. Regression to normoalbuminuria (< 30 mg/day) was more frequent in the Irbesartan 300 mg group (34%) than in the placebo group (21%).

Dual blockade of the renin-angiotensin-aldosterone system (RAAS)

Two large randomised, controlled trials (ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs Nephropathy in Diabetes)) have examined the use of the combination of an ACE-inhibitor with an angiotensin II receptor blocker. ONTARGET was a study conducted in patients with a history of cardiovascular or cerebrovascular disease, or type 2 diabetes mellitus accompanied by evidence of end-organ damage. VA NEPHRON-D was a study in patients with type 2 diabetes mellitus and diabetic nephropathy.

These studies have shown no significant beneficial effect on renal and/or cardiovascular outcomes and mortality, while an increased risk of hyperkalaemia, acute kidney injury and/or hypotension as compared to monotherapy was observed. Given their similar pharmacodynamic properties, these results are also relevant for other ACE-inhibitors and angiotensin II receptor blockers. ACE-inhibitors and angiotensin II receptor blockers should therefore not be used concomitantly in patients with diabetic nephropathy.

ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was a study designed to test the benefit of adding aliskiren to a standard therapy of an ACE-inhibitor or an angiotensin II receptor blocker in patients with type 2 diabetes mellitus and chronic kidney disease, cardiovascular disease, or both. The study was terminated early because of an increased risk of adverse outcomes. Cardiovascular death and stroke were both numerically more frequent in the aliskiren group than in the placebo group and adverse events and serious adverse events of interest (hyperkalaemia, hypotension and renal dysfunction) were more frequently reported in the aliskiren group than in the placebo group.

Pharmacodynamic properties of Amlodipine

Pharmacotherapeutic group: calcium channel blockers – Dihydropyridine derivatives. ATC code: C08CA01.

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

•     Amlodipine 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.

•  The mechanism of action of amlodipine 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 amlodipine administration.

In patients with angina, once daily administration of amlodipine 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.

Amlodipine 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 coronary artery disease (CAD)

The effectiveness of amlodipine in preventing clinical events in patients with coronary artery disease (CAD) has been evaluated in an independent, multicente, randomized, double-blind, placebo-controlled study of 1997 patients; Comparison of Amlodipine vs. Enalapril to Limit Occurrences of Thrombosis (CAMELOT). Of these patients, 663 were treated with amlodipine 5-10 mg, 673 patients were treated with enalapril 10-20 mg, and 655 patients were treated with placebo, in addition to standard care of statins, betablockers, diuretics and aspirin, for 2 years. The key efficacy results are presented in Table 1. The results indicate that amlodipine treatment was associated with fewer hospitalizations for angina and revascularization procedures in patients with CAD.

Abbreviations: CHF, congestive heart failure; CI, confidence interval; MI, myocardial infarction; TIA, transient ischemic attack.

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 ACE inhibitors has shown that amlodipine 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 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 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.

Treatment to prevent heart attack trial (ALLHAT):

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.

Use in children (aged 6 years and older):

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.

Pharmacokinetic properties of Irbesartan Absorption

After oral administration, irbesartan is well absorbed: studies of absolute bioavailability

gave values of approximately 60-80%. Concomitant food intake does not significantly influence the bioavailability of irbesartan.

Distribution

Plasma protein binding is approximately 96%, with negligible binding to cellular blood components. The volume of distribution is 53 - 93 litres.

Biotransformation

Following oral or intravenous administration of 14C irbesartan, 80-85% of the circulating plasma radioactivity is attributable to unchanged irbesartan. Irbesartan is metabolised by the liver via glucuronide conjugation and oxidation. The major circulating metabolite is irbesartan glucuronide (approximately 6%). In vitro studies indicate that irbesartan is primarily oxidised by the cytochrome P450 enzyme CYP2C9; isoenzyme CYP3A4 has negligible effect.

Linearity/non-linearity

Irbesartan exhibits linear and dose proportional pharmacokinetics over the dose range of 10 to 600 mg. A less than proportional increase in oral absorption at doses beyond 600 mg (twice the maximal recommended dose) was observed; the mechanism for this is unknown. Peak plasma concentrations are attained at 1.5 - 2 hours after oral administration. The total body and renal clearance are 157 - 176 and 3 - 3.5 ml/min, respectively. The terminal elimination half-life of irbesartan is 11 - 15 hours.

Steady-state plasma concentrations are attained within 3 days after initiation of a once- daily dosing regimen. Limited accumulation of irbesartan (< 20%) is observed in plasma upon repeated once-daily dosing. In a study, somewhat higher plasma concentrations of irbesartan were observed in female hypertensive patients. However, there was no difference in the half-life and accumulation of irbesartan. No dosage adjustment is necessary in female patients. Irbesartan AUC and Cmax values were also somewhat greater in older subjects (≥ 65 years) than those of young subjects (18 - 40 years).

However the terminal half-life was not significantly altered. No dosage adjustment is necessary in older people.

Elimination

Irbesartan and its metabolites are eliminated by both biliary and renal pathways. After either oral or IV administration of 14C irbesartan, about 20% of the radioactivity is recovered in the urine, and the remainder in the faeces. Less than 2% of the dose is excreted in the urine as unchanged irbesartan.

Paediatric population

The pharmacokinetics of irbesartan were evaluated in 23 hypertensive children after the administration of single and multiple daily doses of irbesartan (2 mg/kg) up to a maximum daily dose of 150 mg for four weeks. Of those 23 children, 21 were evaluable for comparison of pharmacokinetics with adults (twelve children over 12 years, nine children between 6 and 12 years). Results showed that Cmax, AUC and clearance rates were comparable to those observed in adult patients receiving 150 mg irbesartan daily. A limited accumulation of irbesartan (18%) in plasma was observed upon repeated once daily dosing.

Renal impairment

In patients with renal impairment or those undergoing haemodialysis, the pharmacokinetic parameters of irbesartan are not significantly altered. Irbesartan is not removed by haemodialysis.

Hepatic impairment

In patients with mild to moderate cirrhosis, the pharmacokinetic parameters of irbesartan are not significantly altered.

Studies have not been performed in patients with severe hepatic impairment.

Pharmacokinetic properties of Amlodipine

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.

The bioavailability of amlodipine is not affected by food intake.

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.

Hepatic impairment

Very limited clinical data are available regarding amlodipine administration in patients with hepatic impairment. Patients with hepatic insufficiency have decreased clearance of amlodipine resulting in a longer half-life and an increase in AUC of approximately 40-60%.

Paediatric population

A population PK study has been conducted in 74 hypertensive children aged from 1 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 21.3 L/hr respectively in females. Large variability in exposure between individuals was observed. Data reported in children below 6 years is limited.

Elderly population

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. Increase in AUC and elimination half-life in patients with congestive heart failure were as expected for the patient age group studied.

1.1    Irbesartan:

No carcinogenic evidence was observed with administration of irbesartan at doses of up to 500/1000 mg/kg/day in rats (male/female, respectively) and 1000 mg/kg/day in mice for 2 years. These doses provided a systemic exposure 4-25 times (rats) and 4-6 times (mice) the exposure in humans receiving 300 mg/day. Irbesartan was not mutagenic in a battery of in vitro tests (Ames microbial test, rat hepatocyte DNA repair test, V79 mammalian-cell forward gene-mutation assay). Irbesartan was negative in several tests for induction of chromosomal aberrations (in vitro human lymphocyte assay; in vivo mouse micronucleus study). Fertility and reproductive performance were not affected in studies of male and female rats, even at doses causing some parental toxicity (up to 650 mg/kg/day).

No significant effects on the number of corpora lutea, implants, or live fetuses were observed. Irbesartan had no effect on survival, development, or reproduction of offspring.

Transient toxic effects (increased renal pelvic cavitation, hydroureter or subcutaneous edema) were observed in rat fetuses at doses of 50 mg/kg/day or higher, which resolved after birth. In rabbits, maternal mortality, abortion and early resorption were observed at doses of 30 mg/kg/day.

No other teratogenic effects were observed in rats or rabbits.

Amlodipine:

Carcinogenesis: Rats and mice treated with amlodipine in the diet for two years, at concentrations calculated to provide daily dosage levels of 0.5, 1.25 and 2.5 mg/kg/day showed no evidence of carcinogenicity, The highest dose (similar to the maximum recommended human dose of 10 mg on a mg/m2 basis for mice, and about twice* this maximum dose for rats) was close to the maximum tolerated dose for mice but not for rats.

Mutagenesis: Mutagenesis studies revealed no amlodipine - related effects at either the gene or chromosome levels.

Infertility: There was no effect on fertility in rats treated with amlodipine at doses up to 10 mg/kg/day (8 times* the maximum recommended human dose of 10 mg on a mg/m2 basis).

* (based on a 50 kg patient)

The inactive ingredients are: Croscarmellose sodium, microcrystalline cellulose, hypromellose, colloidal anhydrous Silica, magnesium stearate, polyethylene glycol and titanium dioxide. Gizamlo® 150mg/10mg contains red iron oxide (E172). Gizamlo® 300mg/5mg contains yellow iron oxide (E172).

Not applicable.

Do not store above 30°C.

Packs of 30 film coated tablets.

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