Rasitrio - summary of medicine characteristics

1. NAME OF THE MEDICINAL PRODUCT

Rasitrio 150 mg/5 mg/12.5 mg film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 150 mg aliskiren (as hemifumarate), 5 mg amlodipine (as besylate) and 12.5 mg hydrochlorothi­azide.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Film-coated tablet.

Violet white, ovaloid convex film-coated tablet with bevelled edges, with “YIY” debossed on one side and “NVR” on the other.

CLINICAL PARTICULARS

Therapeutic indications

Rasitrio is indicated for the treatment of essential hypertension as substitution therapy in adult patients whose blood pressure is adequately controlled on the combination of aliskiren, amlodipine and hydrochlorothiazide given concurrently at the same dose level as in the combination.

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4. 2 Posology and method of administration

Posology

The recommended dose of Rasitrio is one tablet per day.

Patients receiving aliskiren, amlodipine and hydrochlorothiazide from separate tablets given concurrently at the same time of the day may be switched to a fixed combination tablet of Rasitrio containing the same component doses.

The fixed dose combination should only be used after a stable effect on the monocomponents, given concurrently, has been established after dose titration. Dose should be individualised and adjusted according to the patient’s clinical response.

Special populations

Elderly patients aged 65 years and over

There is evidence of an increased risk of adverse events related to hypotension in patients aged 65 years or older treated with Rasitrio. Therefore, particular caution should be exercised when administering Rasitrio in patients aged 65 years or over.

The recommended starting dose of aliskiren in this group of patients is 150 mg. No clinically meaningful additional blood pressure reduction is observed by increasing the dose to 300 mg in the majority of elderly patients.

Elderly patients aged 75 years and over

Very limited data are available on the use of Rasitrio in patients aged 75 years or older (see section 5.2). The use of Rasitrio in patients aged 75 years or older should be restricted to patients for whom blood pressure control has been established for the free combination of aliskiren, amlodipine and hydrochlorothiazide given concurrently without accompanying safety concerns, in particular hypotension. Extreme caution, including more frequent monitoring of blood pressure, is recommended (see sections 4.4, 4.8, 5.1 and 5.2).

Renal impairment

No adjustment of the initial dose is required for patients with mild to moderate renal impairment (estimated glomerular filtration rate (GFR) 89–60 ml/min/1.73 m2 and 59–30 ml/min/1.73 m2, respectively) (see sections 4.4 and 5.2). Due to the hydrochlorothiazide component, Rasitrio is contraindicated for use in patients with anuria and in patients with severe renal impairment (GFR <30 ml/min/1.73 m2). The concomitant use of Rasitrio with angiotensin II receptor blockers (ARB) or angiotensin converting enzyme inhibitors (ACEI) is contraindicated in patients with renal impairment (GFR <60 ml/min/1.73 m2) (see sections 4.3, 4.4 and 5.2).

Hepatic impairment

Rasitrio is contraindicated in patients with severe hepatic impairment. Caution should be exercised when administering Rasitrio in patients with mild to moderate hepatic impairment or patients with progressive liver disease. No dosage recommendations have been established for amlodipine in patients with mild to moderate hepatic impairment (see sections 4.3 and 4.4).

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Method of administration

Oral use. The tablets should be swallowed whole with some water. Rasitrio should be taken with a light meal once a day, preferably at the same time each day. Grapefruit juice should not be taken together with Rasitrio (see section 4.5).

Contraindications

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1, to other dihydropyridine derivatives, or to other sulphonamide-derived substances.

History of angioedema with aliskiren.

athic angioedema.

mesters of pregnancy (see section 4.6).

Anuria.

Severe renal impairment (GFR <30 ml/min/1.73 m2).

Hyponatraemia, hypercalcaemia, symptomatic hyperuricaemia and refractory hypokalaemia.

Severe hepatic impairment.

The concomitant use of aliskiren with ciclosporin and itraconazole, two highly potent P-glycoprotein (P-gp) inhibitors, and other potent P-gp inhibitors (e.g. quinidine), is contraindicated (see section 4.5).

The concomitant use of aliskiren with ARBs or ACEIs is contraindicated in patients with diabetes mellitus or renal impairment (GFR <60 ml/min/1.73 m2) (see sections 4.2, 4.4, 4.5 and 5.1).

Severe hypotension.

Shock (including cardiogenic shock).

Obstruction of the outflow tract of the left ventricle (e.g. high grade aortic stenosis).

Haemodynamically unstable heart failure after acute myocardial infarction.

4.4 Special warnings and precautions for use

General

In the event of severe and persistent diarrhoea, Rasitrio therapy should be stopped (see section 4.8).

As with any antihypertensive medicinal product, excessive reduction of blood pressure in patients with ischaemic cardiopathy or ischaemic cardiovascular disease could result in a myocardial infarction or stroke.

Symptomatic hypotension occurred with higher frequency in patients with non-complicated hypertension treated with Rasitrio than in patients treated with dual combinations of aliskiren/amlo­dipine, aliskiren/hydrochlo­rothiazide or amlodipine/hy­drochlorothia­zide.

Hypersensitivity reactions to hydrochlorothiazide may occur in patients, but are more likely in patients with allergy and asthma.

Systemic lupus erythematosus

Thiazide diuretics, including hydrochlorothi­azide, have been reported to exacer systemic lupus erythematosus.

The safety and efficacy of amlodipine in hypertensive crisis have not been established.

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

Hypotension, syncope, stroke, hyperkalaemia, and changes in renal function (including acute renal failure) have been reported in susceptible individuals, especially if combining medicinal products that affect this system (see section 5.1). Dual blockade of the renin-angiotensin-aldosterone system by combining aliskiren with an angiotensin converting enzyme inhibitor (ACEI) or an angiotensin II receptor blocker (ARB) is therefore not recommended. Close monitoring of blood pressure, renal function and electrolytes should be exercised if co-administration is considered absolutely necessary.

The use of aliskiren in combination with ARBs or ACEIs is contraindicated in patients with diabetes mellitus or renal impairment (GFR <60 ml/min/1.73 m2) (see section 4.3).

Geriatric patients aged 65 years and over

Particular caution should be exercised when administering Rasitrio in patients aged 65 years or older. Symptomatic hypotension occurred with higher frequency in patients with non-complicated hypertension treated with Rasitrio than in patients treated with dual combinations of aliskiren/amlo­dipine, aliskiren/hydrochlo­rothiazide or amlodipine/hy­drochlorothia­zide. Patients aged 65 years old or over, are more susceptible to hypotension-related adverse reactions following treatment with Rasitrio (see sections 4.2, 4.8, 5.1 and 5.2).

Geriatric patients aged 75 years and over

Very limited efficacy and safety data are available on the use of Rasitrio in patients aged 75 years or older. Extreme caution, including more frequent monitoring of blood pressure, is recommended (see sections 4.2, 4.8, 5.1 and 5.2).

Heart failure

Calcium channel blockers, including amlodipine, should be used with caution in patients with congestive heart failure, as they may increase the risk of future cardiovascular events and mortality.

No data on cardiovascular mortality and morbidity are available for Rasitrio in patients with heart failure (see section 5.1).

Aliskiren should be used with caution in patients with heart failure treated with furosemide or torasemide (see section 4.5).

Risk of symptomatic hypotension

Symptomatic hypotension could occur after initiation of treatment with Rasitrio in the following cases:

• • Patients with marked volume depletion or patients with salt depletion (e.g. those receiving high

doses of diuretics) or

• • Combined use of aliskiren with other agents acting on the RAAS.

The volume or salt depletion should be corrected prior to administration of Rasitrio, or the treatment should start under close medical supervision.

Electrolyte imbalance

Treatment with Rasitrio should only start after correction of hypokalaemia and any coexisting hypomagnesaemia. Thiazide diuretics can precipitate new onset hypokalaemia or exacerbate preexisting hypokalaemia. Thiazide diuretics should be administered with caution in patients with conditions involving enhanced potassium loss, for example salt-losing nephropathies and prerenal (cardiogenic) impairment of kidney function. If hypokalaemia develops during hydrochlorothiazide therapy Rasitrio should be discontinued until stable correction of the potassium balance.

Hypokalaemia may develop with the use of thiazide diuretics. The risk of hypo patients with cirrhosis of the liver, patients experiencing brisk diuresis, patients with inadequate oral electrolyte intake and patients receiving concomitant therapy with corticosteroids or adrenocorticotropic hormone (ACTH) (see sections 4.5 and 4.8).

Conversely, increases in serum potassium have been observed with aliskiren in post-marketing experience and these may be exacerbated by concomitant use of other agents acting on the RAAS or by non-steroidal anti-inflammatory drugs (NSAIDs). Consistent with standard medical practice, periodic determination of renal function including serum electrolytes is advised if co-administration is considered necessary. The concomitant use of aliskiren and ACEIs or ARBs is contraindicated in patients with diabetes mellitus or renal impairment (GFR <60 ml/min/1.73 m2) (see section 4.3, 4.5 and 4.8).

Thiazide diuretics can precipitate new onset hyponatraemia and hypochloroaemic alkalosis or exacerbate pre-existing hyponatraemia. Hyponatraemia, accompanied by neurological symptoms (nausea, progressive disorientation, apathy) has been observed. Treatment with hydrochlorothiazide should only be started after co ion of pre-existing hyponatraemia. In case severe or rapid hyponatraemia develops durin sitrio therapy, the treatment should be discontinued until normalisation of natraemia.

All patients receiving thiazide diuretics should be periodically monitored for imbalances in electrolytes, particularly potassium, sodium and magnesium.

Thiazides reduce urinary calcium excretion and may cause an intermittent and slight elevation of serum calcium in the absence of known disorders of calcium metabolism. Rasitrio is contraindicated in patients with hypercalcaemia and should only be used after correction of any pre-existing hypercalcaemia. Rasitrio should be discontinued if hypercalcaemia develops during treatment. Serum levels of calcium should be periodically monitored during treatment with thiazides. Marked hypercalcaemia may be evidence of hidden hyperparathyro­idism. Thiazides should be discontinued before carrying out tests for parathyroid function.

There is no evidence that Rasitrio would reduce or prevent diuretic-induced hyponatraemia. Chloride deficit is generally mild and usually does not require treatment.

Renal impairment and kidney transplantation

Thiazide diuretics may precipitate azotaemia in patients with chronic kidney disease. When Rasitrio is used in patients with renal impairment, periodic monitoring of serum electrolytes including potassium, creatinine and uric acid serum levels is recommended. No data is available in hypertensive patients with severe renal impairment (serum creatinine >150 gmol/l or 1.70 mg/dl in women and >177 gmol/l or 2.00 mg/dl in men and/or estimated glomerular filtration rate (GFR)

<30 ml/min/1.73 m2), history of dialysis, nephrotic syndrome or renovascular hypertension. Rasitrio is contraindicated in hypertensive patients with severe renal impairment (GFR <30 ml/min/1.73 m2) or anuria (see sections 4.2. and 4.3). No dose adjustment is necessary in patients with mild to moderate renal impairment.

As for other medicinal products acting on the RAAS, caution should be exercised when Rasitrio is given in the presence of conditions pre-disposing to kidney dysfunction such as hypovolaemia (e.g. due to blood loss, severe or prolonged diarrhoea, prolonged vomiting, etc.), heart disease, liver disease, diabetes mellitus or kidney disease. The concomitant use of aliskiren and ACEIs or ARBs is contraindicated in patients with renal impairment (GFR < 60 ml/min/1.73 m2). Acute renal failure, reversible upon discontinuation of treatment, has been reported in at-risk patients receiving aliskiren in post-marketing experience. In the event that any signs of renal failure occur, aliskiren should be promptly discontinued.

There is no experience regarding the administration of Rasitrio in patients who have recently undergone kidney transplantation, therefore caution should be exercised in these patients.

Hepatic impairment

Rasitrio is contraindicated in hypertensive patients with severe hepatic impairment (see sections 4.3 and 5.2). Caution should be exercised when administering Rasitrio to patients with mild to moderate hepatic impairment or progressive liver disease (see sections 4.2 and 5.2).

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The half life of amlodipine is prolonged and AUC values are higher in patients with impaired liver function; dosage recommendations have not been established.

Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy

As with all other vasodilators, special caution is indicated when using amlodipine in patients suffering from aortic or mitral stenosis, or obstructive hypertrophic cardiomyopathy.

Metabolic and endocrine effects

Thiazide diuretics, including hydrochlorothi­azide, may alter glucose tolerance and raise serum levels of cholesterol and triglycerides, and uric acid. In diabetic patients dose adjustments of insulin or oral hypoglycaemic medicinal products may be required during Rasitrio therapy. Concomitant use of Rasitrio with ARBs or ACEIs is contraindicated in patients with diabetes mellitus (see section 4.3).

Due to the hydrochlorothiazide component, Rasitrio is contraindicated in symptomatic hyperuricaemia (see section 4.3). Hydrochlorothiazide may raise the serum uric acid level due to reduced clearance of uric acid and may cause or exacerbate hyperuricaemia as well as precipitate gout in susceptible patients.

Thiazides reduce urinary calcium excretion and may cause an intermittent and slight elevation of serum calcium in the absence of known disorders of calcium metabolism. Rasitrio is contraindicated in patients with hypercalcaemia and should only be used after correction of any pre-existing hypercalcaemia. Rasitrio should be discontinued if hypercalcaemia develops during treatment. Serum levels of calcium should be periodically monitored during treatment with thiazides. Marked hypercalcaemia may be evidence of hidden hyperparathyro­idism. Thiazides should be discontinued before carrying out tests for parathyroid function.

Renal artery stenosis

No controlled clinical data are available on the use of Rasitrio in patients with unilateral or bilateral renal artery stenosis, or stenosis to a solitary kidney. However, as with other medicinal products acting on the renin-angiotensin-aldosterone system, there is an increased risk of renal insufficiency, including acute renal failure, when patients with renal artery stenosis are treated with aliskiren. Therefore caution should be exercised in these patients. If renal failure occurs, treatment should be discontinued.

Anaphylactic reactions and angioedema

Anaphylactic reactions have been observed during treatment with aliskiren from post-marketing experience (see section 4.8). As with other medicinal products acting on the renin-angiotensin-aldosterone system (RAAS), angioedema or symptoms suggestive of angioedema (swelling of the face, lips, throat and/or tongue) have been reported in patients treated with aliskiren.

A number of these patients had a history of angioedema or symptoms suggestive of angioedema, which in some cases followed use of other medicinal products that can cause angioedema, including RAAS blockers (angiotensin converting enzyme inhibitors or angiotensin receptor blockers) (see section 4.8).

In post-marketing experience, angioedema or angioedema-like reactions have been reported when aliskiren was co-administered with ACEIs and/or ARBs (see section 4.8).

Special caution is necessary in patients with a hypersensitivity predisposition.

Patients with history of angioedema may be at increased risk of experiencing angioedema during treatment with aliskiren (see sections 4.3 and 4.8). Caution should therefore be exercised when prescribing aliskiren to patients with a history of angioedema, and such patients should be closely monitored during treatment (see section 4.8) especially at the beginning of the treatment.

If anaphylactic reactions or angioedema occur, Rasitrio should be promptly discontinued and appropriate therapy and monitoring provided until complete and sustained resolution of signs and symptoms has occurred. Patients should be informed to report to the physician any signs suggestive of allergic reactions, in particular difficulties in breathing or swallowing, swelling of face, extremities, eyes, lips or tongue. Where there is involvement of the tongue, glottis or larynx adrenaline should be administered. In addition, measures necessary to maintain patent airways should be provided.

Photosensitivity       &

Cases of photosensitivity reactions have been reported with thiazide diuretics (see section 4.8). If photosensitivity reaction occurs during treatment with Rasitrio, it is recommended to stop the treatment. If a re-administration of the diuretic is deemed necessary, it is recommended to protect exposed areas to the sun or to artificial UVA.

Acute angle-closure glaucoma

Hydrochlorothi­azide, a sulphonamide, has been associated with an idiosyncratic reaction resulting in acute transient myopia and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of treatment initiation.

Untreated acute angle-closure glaucoma can lead to permanent vision loss. The primary treatment is to discontinue hydrochlorothiazide as rapidly as possible. Prompt medical or surgical treatment may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulphonamide or penicillin allergy.

4.5 Interaction with other medicinal products and other forms of interaction

Information on Rasitrio interactions

A population pharmacokinetic analysis in patients with hypertension did not indicate any clinically relevant changes in the steady-state exposure (AUC) and Cmax of aliskiren, amlodipine and hydrochlorothiazide compared to the corresponding dual therapies.

Medicinal products affecting serum potassium levels : The potassium-depleting effect of hydrochlorothiazide is attenuated by the potassium-sparing effect of aliskiren. However, this effect of hydrochlorothiazide on serum potassium would be expected to be potentiated by other medicinal products associated with potassium loss and hypokalaemia (e.g. other kaliuretic diuretics, corticosteroids, laxatives, adrenocoricotropic hormone (ACTH), amphotericin, carbenoxolone, penicillin G, salicylic acid derivatives). Conversely, concomitant use of other agents affecting the RAAS, of NSAIDs or of agents that increase serum potassium levels (e.g. potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium, heparin) may lead to increases in serum potassium. If co-medication with an agent affecting the level of serum potassium is considered necessary, caution is advisable. The combination of aliskiren with ARBs or ACEIs is contraindicated in patients with diabetes mellitus or renal impairment (GFR <60 ml/min/1.73 m2) and is not recommended in other patients (see sections 4.3, 4.4 and 5.1).

Medicinal products affected by serum potassium disturbances : Periodic monitoring of serum potassium is recommended when Rasitrio is administered with medicinal products affected by serum potassium disturbances (e.g. digitalis glycosides, antiarrhythmics).

Non-steroidal anti-inflammatory drugs (NSAIDs), includin (COX-2 inhibitors), acetylsalicylic acid and non-selective

renin-angiotensin system, NSAIDs may reduce the anti-also weaken the diuretic and antihypertensive activity o

In some patients with compromised renal fu

and hydrochlorothiazide given concomit function, including possible acute renal f

Rasitrio with an NSAID requires caution, especially in elderly patients.

Information on aliskiren inter ns

Contraindicated (see section

• - Dual RAAS blockade

The combination of aliskiren with ARBs or ACEIs is contraindicated in patients with diabetes

ent (GFR <60 ml/min/1.73 m2) and is not recommended in other patients (see sections 4.3, 4.4 and 5.1).

• - P-glycoprotein (P-gp) potent inhibitors

A single dose drug interaction study in healthy subjects has shown that ciclosporin (200 and 600 mg) increases Cmax of aliskiren 75 mg approximately 2.5-fold and AUC approximately 5-fold. The increase may be higher with higher aliskiren doses. In healthy subjects, itraconazole (100 mg) increases AUC and Cmax of aliskiren (150 mg) by 6.5-fold and 5.8-fold, respectively. Therefore, concomitant use of aliskiren and P-gp potent inhibitors is contraindicated (see section 4.3).

Not recommended (see section 4.2)

• - Grapefruit juice

Administration of grapefruit juice with aliskiren resulted in a decrease in AUC and Cmax of aliskiren. Co-administration with aliskiren 150 mg resulted in a 61% decrease in aliskiren AUC and coadministration with aliskiren 300 mg resulted in a 38% decrease in aliskiren AUC. This decrease is likely due to an inhibition of organic anion transporting polypeptide-mediated uptake of aliskiren by grapefruit juice in the gastrointestinal tract. Therefore, because of the risk of therapeutic failure, grapefruit juice should not be taken together with Rasitrio.

Caution required with concomitant use

• - P-gp interactions

MDR1/Mdr1a/1b (P-gp) was found to be the major efflux system involved in intestinal absorption and biliary excretion of aliskiren in preclinical studies. Rifampicin, which is an inducer of P-gp, reduced aliskiren bioavailability by approximately 50% in a clinical study. Other inducers of P-gp (St. John’s wort) might decrease the bioavailability of aliskiren. Although this has not been investigated for aliskiren, it is known that P-gp also controls tissue uptake of a variety of substrates and P-gp inhibitors can increase the tissue-to-plasma concentration ratios. Therefore, P-gp inhibitors may increase tissue levels more than plasma levels. The potential for drug interactions at the P-gp site will likely depend on the degree of inhibition of this transporter.

• - Moderate P-gp inhibitors

Co-administration of ketoconazole (200 mg) or verapamil (240 mg) with aliskiren (300 mg) resulted in a 76% or 97% increase in aliskiren AUC, respectively. The change in plasma levels of aliskiren in the presence of ketoconazole or verapamil is expected to be within the range that would be achieved if the dose of aliskiren were doubled; aliskiren doses of up to 600 mg, or twice the highest recommended therapeutic dose, have been found to be well tolerated in controlled clinical trials. Preclinical studies indicate that aliskiren and ketoconazole co-administration enhances aliskiren gastrointestinal absorption and decreases biliary excretion. Therefore, caution should be exercised when aliskiren is administered with ketoconazole, verapamil or other moderate P-gp inhibitors (clarithromycin, telithromycin, erythromycin, amiodarone).

• - Medicinal products affecting serum potassium levels

Concomitant use of other agents affecting the RAAS, of NSAIDs or of agents that increase serum potassium levels (e.g. potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium, heparin) may lead to increases in serum potassium. If co-administration with an agent affecting the level of serum potassium is conside     ecessary, caution is advisable. The combination

of aliskiren with ARBs or ACEIs is contraindica      patients with diabetes mellitus or renal

impairment (GFR <60 ml/min/1.73 m2) and is not recommended in other patients (see sections 4.3, 4.4 and 5.1).

• - Furosemide and torasemide

Oral co-administration of aliskiren and furosemide had no effect on the pharmacokinetics of aliskiren but reduced exposure to furosemide by 20–30% (the effect of aliskiren on furosemide administered intramuscularly or intravenously has not been investigated). After multiple doses of furosemide (60 mg/day) co-administered with aliskiren (300 mg/day) to patients with heart failure the urinary sodium excretion and the urine volume were reduced during the first 4 hours by 31% and 24%, respectively, as compared to furosemide alone. The mean weight of patients concomitantly treated with furosemide and 300 mg aliskiren (84.6 kg) was higher than the weight of patients treated with furosemide alone (83.4 kg). Smaller changes in furosemide pharmacokinetics and efficacy were observed with aliskiren 150 mg/day.

The available clinical data did not indicate that higher doses of torasemide were used after coadministration with aliskiren. Torasemide renal excretion is known to be mediated by organic anion transporters (OATs). Aliskiren is minimally excreted via the renal route, and only 0.6% of the aliskiren dose is recovered in urine following oral administration (see section 5.2). However, since aliskiren has been shown to be a substrate for the organic anion-transporting polypeptide 1A2 (OATP1A2) (see interaction with organic anion transporting polypeptide (OATP) inhibitors), there is a potential for aliskiren to reduce plasma torasemide exposure by an interference with the absorption process.

In patients treated with both aliskiren and oral furosemide or torasemide, it is therefore recommended that the effects of furosemide or torasemide be monitored when initiating and adjusting furosemide, torasemide or aliskiren therapy to avoid changes in extracellular fluid volume and possible situations of volume overload (see section 4.4).

• - Warfarin

The effects of aliskiren on warfarin pharmacokinetics have not been evaluated.

• - Food interactions

Meals (low or high fat content) have been shown to reduce the absorption of aliskiren substantially (see section 4.2).

No interactions

• – Compounds that have been investigated in aliskiren clinical pharmacokinetic studies include

acenocoumarol, atenolol, celecoxib, pioglitazone, allopurinol, isosorbide-5-mononitrate and hydrochlorothi­azide. No interactions have been identified.

Co-administration of aliskiren with either metformin (¿28%), amlodipine (¿29%) or cimetidine (¿19%) resulted in between 20% and 30% change in Cmax or AUC of aliskiren. When

administered with atorvastatin, steady-state aliskiren AUC and Cmax increased by 50%. Co-

administration of aliskiren had no significant impact on atorvastatin, metformin or amlodipine pharmacokinetics. As a result no dose adjustment for aliskiren or these co-administered medicinal products is necessary.

Digoxin and verapamil bioavailability may be slightly decreased by aliskiren.

• - CYP450 interactions

Aliskiren does not inhibit the CYP450 isoenzymes (CYP1A2, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A).

Aliskiren does not induce CYP3A4. Therefore aliskiren is not expected to affect the systemic exposure of substances that inhibit, induce or are metabolised by these enzymes. Aliskiren is metabolised minimally by the cytochrome P450 enzymes. Hence, interactions due to inhibition or induction of CYP450 isoenzymes are not expected. However, CYP3A4 inhibitors often also affect Pgp. Increased aliskiren exposure during co-administration of CYP3A4 inhibitors that also inhibit P-gp can therefore be expected (see other P-gp references in section 4.5).

• - P-gp substrates or weak inhibitors

No relevant interactions with atenolol, digoxin, amlodipine or cimetidine have been observed. When administered with atorvastatin (80 mg), steady-state aliskiren (300 mg) AUC and Cmax increased by 50%. In experimental animals, it has been shown that P-gp is a major determinant of aliskiren bioavailability. Inducers of P-gp (St. John’s wort, rifampicin) might therefore decrease the bioavailability of aliskiren.

• - Organic anion transporting polypeptide (OATP) inhibitors

Preclinical studies indicate that aliskiren might be a substrate of organic anion transporting polypeptides. Therefore, the potential exists for interactions between OATP inhibitors and aliskiren when administered concomitantly (see interaction with Grapefruit juice).

Information on amlodipine interactions

Effects of other medicinal products on amlodipine

Caution required with concomitant use

• - CYP3A4 inhibitors

Concomitant use of amlodipine with strong or moderate CYP3A4 inhibitors (protease inhibitors, azole antifungals, macrolides like erythromycin or clarithromycin, verapamil or diltiazem) may give rise to significant increase in amlodipine exposure. The clinical translation of these pharmacokinetic variations may be more pronounced in the elderly. Clinical monitoring and dose adjustment may thus be required.

• - CYP3A4 inducers

There is no data available regarding the effect of CYP3A4 inducers on amlodipine. The concomitant use of CYP3A4 inducers (e.g. rifampicin, hypericum perforatum ) may give a lower plasma concentration of amlodipine. Amlodipine should be used with caution together with CYP3A4 inducers.

• - Grapefruit juice

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.

• - Dantrolene (infusion)

In animals, lethal ventricular fibrillation and cardiovascular collapse are observed in association with hyperkalaemia after administration of verapamil and intravenous dantrolene. Due to risk of hyperkalaemia, it is recommended that the co-administration of calcium channel blockers such as amlodipine be avoided in patients susceptible to malignant hyperthermia and in the management of malignant hyperthermia.

Effects of amlodipine on other medicinal products /-Qs

• – The blood pressure lowering effects of amlodipine add to the blood pressure lowering effects of

other antihypertensive medicinal products.

Co-administration of multiple doses of 10 mg of amlodipine with 80 mg simvastatin resulted in a 77% increase in exposure to simvastatin compared to simvastatin alone. It is recommended to limit the dose of simvastatin to 20 mg daily in patients on amlodipine.

No interactions

• – In clinical interaction studies, amlodipine did not affect the pharmacokinetics of atorvastatin,

digoxin, warfarin or ciclosporin.

Information on hydrochlorothiazide interactions

When administered concurrently, the following medicinal products may interact with thiazide

diuretics:

Caution required with concomitant use

• - Alcohol , barbiturates or narcotics

Concomitant administration of thiazide diuretics with subtances that also have a blood pressure lowering effect (e.g. by reducing sympathetic central nervous system activity or direct vasodilatation) may potentiate orthostatic hypotension.

• - Amantadine

Thiazides, including hydrochlorothi­azide, may increase the risk of adverse reactions caused by amantadine.

• - Antidiabetic agents (e.g. insulin and oral antidiabetic agents)

Thiazides may alter glucose tolerance. Dose adjustment of the antidiabetic medicinal product may be necessary (see section 4.4). Metformin should be used with caution because of the risk of lactic acidosis induced by possible functional renal failure linked to hydrochlorothi­azide.

• - Anticholinergic agents and other medicinal products affecting gastric motility

The bioavailability of thiazide-type diuretics may be increased by anticholinergic agents (e.g. atropine, biperiden), apparently due to a decrease in gastrointestinal motility and the stomach emptying rate. Conversely, it is anticipated that prokinetic substances such as cisapride may decrease the bioavailability of thiazide-type diuretics.

• - Medicinal products used in the treatment of gout

Dose adjustment of uricosuric medicinal products may be necessary as hydrochlorothiazide may raise the level of serum uric acid. Increase of dose of probenecid or sulfinpyrazone may be necessary. Co administration of thiazide diuretics, including hydrochlorothi­azide, may increase the incidence of hypersensitivity reactions to allopurinol.

• - Medicinal products that could induce torsades de pointes

Due to the risk of hypokalaemia, hydrochlorothiazide should be administered with caution when associated with medicinal products that could induce torsades de pointes , in particular Class Ia and Class III antiarrhythmics and some antipsychotics.

• - Medicinal products affecting serum sodium level

The hyponatraemic effect of diuretics may be intensified by concomitant administration of medicinal products such as antidepressants, antipsychotics, antiepileptics, etc. Caution is indicated in long-term administration of these medicinal products.

• - Beta blockers and diazoxide

Concomitant use of thiazide diuretics, including hydrochlorothi­azide, with beta blockers may increase the risk of hyperglycaemia. Thiazide diuretics, including hydrochlorothi­azide, may enhance the hyperglycaemic effect of diazoxide.

I h

• - Ion exchange resins

Absorption of thiazide diuretics, including hydrochlorothi­azide, is decreased by cholestyramine or colestipol. This could result in sub-therapeutic effects of thiazide diuretics. However, staggering the dosage of hydrochlorothiazide and resin such that hydrochlorothiazide is administered at least 4 hours before or 4–6 hours after the administration of resins would potentially minimise the interaction.

• - Vitamin D and calcium salts

Administration of thiazide diuretics, including hydrochlorothi­azide, with vitamin D or with calcium salts may potentiate the rise in serum calcium. Concomitant use of thiazide type diuretics may lead to hypercalcaemia in patients pre-disposed for hypercalcaemia (e.g. hyperparathyro­idism, malignancy, or vitamin-D-mediated conditions) by increasing tubular calcium reabsorption.

• - Non-depolarising skeletal muscle relaxants

Thiazides, including hydrochlorothi­azide, potentiate the action of skeletal muscle relaxants such as curare derivatives.

• - Cytotoxic agents

Thiazides, including hydrochlorothi­azide, may reduce the renal excretion of cytotoxic agents (e.g. cyclophosphamide, methotrexate) and potentiate their myelosuppressive effects.

• - Digoxine or digitalis glycosides

Thiazide-induced hypokalaemia or hypomagnesaemia favour the onset of digitalis-induced cardiac arrhythmias (see section 4.4).

• - Methyldopa

There have been isolated reports of haemolytic anaemia occurring with concomitant use of hydrochlorothiazide and methyldopa.

• - Iodine contrasting agents

In case of diuretic-induced dehydration, there is an increased risk of acute renal failure, especially with high doses of iodine products. Patients should be rehydrated before administration.

• - Pressor amines (e.g. noradrenaline, adrenaline)

Hydrochlorothiazide may reduce the response to pressor amines such as noradrenaline. The clinical significance of this effect is uncertain and not sufficient to preclude their use.

4.6 Fertility, pregnancy and lactation

Women of childbearing potential/con­traception in males and females

Healthcare professionals prescribing Rasitrio should counsel women of childbearing potential about the potential risk during pregnancy. A switch to a suitable alternative antihypertensive treatment should be carried out in advance of a planned pregnancy since Rasitrio should not be used in women planning to become pregnant.

Pregnancy

There are no data on the use of aliskiren in pregnant women. Aliskiren was not teratogenic in rats or rabbits (see section 5.3). Other substances that act directly on the renin-angiotensin-aldosterone system have been associated with serious foetal malformations and neonatal death. As for any medicinal product that acts directly on the renin-angiotensin-aldosterone system, aliskiren should not be used during the first trimester of pregnancy and is contraindicated during the second and third trimesters (see section 4.3).

The safety of amlodipine in human pregnancy has not been established. Reproductive studies in rats have shown no toxicity except for delayed date of delivery and prolonged duration of labour at dosages 50 times greater than the maximum recommended dosage for humans (see section 5.3). Use in pregnancy is only recommended when there is no safer alternative and when the disease itself carries greater risk for the mother and foetus.

There is limited experience with hydrochlorothiazide during pregnancy, especially during the first trimester. Animal studies are insufficient.

Hydrochlorothiazide crosses the placenta. Based on the pharmacological mechanism of action of hydrochlorothi­azide, its use during the second and third trimester may compromise foeto-placental perfusion and may cause foetal and neonatal effects like icterus, disturbance of electrolyte balance and thrombocytopenia.

Hydrochlorothiazide should not be used for gestational oedema, gestational hypertension or pre-eclampsia due to the risk of decreased plasma volume and placental hypoperfusion, without a beneficial effect on the course of the disease.

Hydrochlorothiazide should not be used for essential hypertension in pregnant women except in rare situations where no other treatment could be used.

Rasitrio should not be used during the first trimester of pregnancy. Rasitrio is contraindicated during the second and third trimesters (see section 4.3).

If pregnancy is detected during therapy, Rasitrio should be discontinued accordingly as soon as possible.

Breast-feeding

It is not known whether aliskiren and/or amlodipine are excreted in human milk. Aliskiren was secreted in the milk of lactating rats.

Hydrochlorothiazide is excreted in human milk in small amounts. Thiazides in high doses causing intense diuresis can inhibit milk production.

The use of Rasitrio during breast-feeding is not recommended. If Rasitrio is used during breastfeeding, doses should be kept as low as possible.

Fertility

There are no clinical data on fertility with the use of Rasitrio.

Reversible biochemical changes in the head of spermatozoa have been reported in some patients treated by calcium channel blockers. Clinical data are insufficient regarding the potential effect of amlodipine on fertility. In one rat study, adverse effects were found on male fertility (see section 5.3). The fertility of rats was unaffected at doses of up to aliskiren 250 mg/kg/day and hydrochlorothiazide 4 mg/kg/day (see section 5.3).

4.7 Effects on ability to drive and use machines

No studies on the effect on the ability to drive and use machines have been performed. However, when driving vehicles or using machines it must be borne in mind that dizziness or drowsiness may occasionally occur when taking Rasitrio.

Amlodipine can have minor or moderate influence on the ability to drive and use machines. If patients taking amlodipine suffer from dizziness, drowsiness, headache, fatigue or nausea, the ability to react may be impaired.

4.8 Undesirable effects

.         fth ft fl

Summary of the safety profile

xgr

Aliskiren/amlo­dipine/hydrochlo­rothiazide combination

The safety profile of Rasitrio presented below is based on clinical studies performed with Rasitrio and the known safety profile of the individual components aliskiren, amlodipine and hydrochlorothi­azide. Safety information for Rasitrio in patients aged 75 years and older is limited.

The most frequent adverse reactions observed with Rasitrio are hypotension and dizziness. The adverse reactions previously reported with one of the individual components of Rasitrio (aliskiren, amlodipine and hydrochlorothi­azide) and listed in the respective paragraphs on the individual components may occur with Rasitrio.

Tabulated list of adverse reactions:

The adverse reactions for aliskiren, amlodipine and hydrochlorothiazide are ranked under heading of frequency, the most frequent first, using the following convention: very common (>1/10); common (>1/100 to <1/10); uncommon (>1/1,000 to <1/100); rare (>1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Information on Rasitrio

Nervous system disorders

Common          Dizziness

Vascular disorders

Common          Hypo­tension

General disorders and administration site conditions

Common Peripheral oedema

Peripheral oedema is a known, dose-dependent adverse reaction of amlodipine and has also been reported with aliskiren therapy in post-marketing experience. The incidence of peripheral oedema for Rasitrio in a short-term double active-controlled study was 7.1% compared to 8.0% for aliskiren/amlo­dipine, 4.1% for amlodipine/hy­drochlorothia­zide and 2.0% for aliskiren/hydrochlo­rothiazide dual combinations.

The incidence of any adverse reactions potentially related to hypotension in a short-term active controlled study was 4.9% with Rasitrio versus up to 3.7% with dual combinations. In patients >65 years the incidence was 10.2% with Rasitrio versus up to 5.4% with dual combinations.

Additional information on individual components

Other adverse reactions previously reported with one of the individual components may occur with Rasitrio even if not observed in clinical trials.

Aliskiren

Serious adverse reactions include anaphylactic reaction and angioedema which have been reported in post-marketing experience and may occur rarely (less than 1 case per 1,000 patients). The most common adverse reaction is diarrhoea.

Tabulated list of adverse reactions:

The known aliskiren adverse reactions are presented in the table below using the same convention as described previously for the fixed combination.

_____________­______________________!_­________________________­________________________­________________________­________________________­________________________­___________________

Immune system disorders

Rare                 ­Anaphylactic reactions, hypersensitivity reactions

Cardiac disorders                               ­O)

Common          Dizziness           gp

Uncommon         Palpi­tations, oedemaperipheral

Vascular disorders

Uncommon        Hypotension    '

Respiratory, thoracic and mediastinaldi­sorders

Uncommon        Cough.

Gastrointestinal disorders

Common          Diarrhoea

Hepatobiliary disorders ,

Not known        -Quiver disorder*, j aundice, hepatitis, liver failure

Skin and subcutaneous2issue disorders

Uncommon pO> Severe cutaneous adverse reactions (SCARs) including Stevens

Johnson syndrome, toxic epidermal necrolysis (TEN), oral mucosal reactions, rash, pruritus, urticaria

Rare              An­gioedema, erythema

Musculoskeletal and connective tissue disorders

Common           Arthral­gia

Renal and urinary disorders

Uncommon         Acute renal failure, renal impairment

Investigations

Common          Hyper­kalaemia

Uncommon         Liver enzyme increased

Rare                H­aemoglobin decreased, haematocrit decreased, blood creatinine

_____________­________________in­creased _____________­________________________­_______________________ *Isolated cases of liver disorder with clinical symptoms and laboratory evidence of more marked hepatic dysfunction.

Including one case of ‘liver failure fulminant’ reported in the post-marketing experience, for which a causal relationship with aliskiren cannot be excluded.

Description of selected adverse events:

Hypersensitivity reactions including anaphylactic reactions and angioedema have occurred during treatment with aliskiren.

In controlled clinical trials, angioedema and hypersensitivity reactions occurred rarely during treatment with aliskiren with rates comparable to treatment with placebo or comparators.

Cases of angioedema or symptoms suggestive of angioedema (swelling of the face, lips, throat and/or tongue) have also been reported in post-marketing experience. A number of these patients had a history of angioedema or symptoms suggestive of angioedema which in some cases was associated with the administration of other medicinal products known to cause angioedema, including RAAS blockers (ACEIs or ARBs).

In post-marketing experience, cases of angioedema or angioedema-like reactions have been reported when aliskiren was co-administered with ACEIs and/or ARBs.

Hypersensitivity reactions including anaphylactic reactions have also been reported in post-marketing experience (see section 4.4).

In the event of any signs suggesting a hypersensitivity reaction/angioedema (in particular difficulties in breathing, or swallowing, rash, itching, hives or swelling of the face, extremities, eyes, lips and/or tongue, dizziness) patients should discontinue treatment and contact the physician (see section 4.4).

Arthralgia has been reported in post-marketing experience. In hypersensitivity reaction.

In post-marketing experience, renal dysfunction and cases of acute renal failure have been reported in patients at risk (see section 4.4).

Investigations: In controlled clinical trials, clinically relevant changes in standard laboratory parameters were uncommonly associated with the administration of aliskiren. In clinical studies in hypertensive patients, aliskiren had no clinically important effects on total cholesterol, high density lipoprotein cholesterol (HDL-C), fasting triglycerides, fasting glucose or uric acid.

Haemoglobin and haematocrit : Small decreases in haemoglobin and haematocrit (mean decreases of approximately 0.05 mmol/l and 0.16 volume percent, respectively) were observed. No patients discontinued therapy due to anaemia. This effect is also seen with other medicinal products acting on the RAAS, such as ACEIs and ARBs.

Serum potassium : Increases in serum potassium have been observed with aliskiren and these may be exacerbated by concomitant use of other agents acting on the RAAS or by NSAIDs. Consistent with standard medical practice, periodic determination of renal function including serum electrolytes is advised if co-administration is considered necessary. The combination of aliskiren with ARBs or ACEIs is contraindicated in patients with diabetes mellitus or renal impairment (GFR <60 ml/min/1.73 m2) and is not recommended in other patients (see sections 4.3, 4.4 and 5.1).

Paediatric population: Based on the limited amount of safety data available from a pharmacokinetic study of aliskiren treatment in 39 hypertensive children 6–17 years of age, the frequency, type and severity of adverse reactions in children are expected to be similar to that seen in hypertensive adults. As for other RAAS blockers, headache is a common adverse event in children treated with aliskiren.

Amlodipine

Blood and lymphatic system disorders
Very rare	Leukopenia, thrombocytopenia
Immune system disorders
Very rare	Allergic reactions
Metabolism and nutrition disorders
Very rare	Hyperglycaemia
Psychiatric disorders
Uncommon	Insomnia, mood changes (including anxiety), depression
Rare	Confusion
Nervous system disorders
Common	Somnolence, headache (especially at the beginning of treatment)
Uncommon	Tremor, dysgeusia, syncope, hypoesthesia, paraesthesia
Very rare	Hypertonia, peripheral neuropathy
Eye disorders
Uncommon	Visual disturbance (including diplopia)       x
Ear and labyrinth disorders
Uncommon	Tinnitus                               _ Çj
Cardiac disorders                                             ­r.f'S
Common	Palpitations
Very rare	Myocardial infarction, arrhythmiOOin­cluding bradycardia, ventricular tachycardia and atriafibrillation)
Vascular disorders
Common	Flushing
Very rare	Vasculitis
Respiratory, thoracic and mediastinal disorders.C^
Uncommon	Dyspnoea, rhinitis
Very rare	Cough
Gastrointestinal disorders           _
Common	Abdominal pain, nausea
Uncommon	Vomiting, dyspepsia, altered bowel habits (including diarrhoea and zCOnstipation), dry mouth
Very rare                  ,	^Pancreatitis, gastritis, gingival hyperplasia
Hepatobiliary disorders
Very rare            >52/ ($>	Hepatitis, jaundice, hepatic enzymes increased (mostly consistent with cholestasis)
Skin and subcutaneous tissue d	isorders
Uncommon	Alopecia, purpura, skin decolouration, hyperhidrosis, pruritus, rash, exanthema
Very rare	Angioedema, erythema multiforme, urticaria, exfoliative dermatitis, Stevens-Johnson syndrome, Quincke oedema, photosensitivity
Musculoskeletal and connective tissue disorders
Common	Ankle swelling
Uncommon	Arthralgia, myalgia, muscle cramps, back pain
Renal and urinary disorders
Uncommon	Micturition disorder, nocturia, increased urinary frequency
Reproductive system and breast disorders
Uncommon	Impotence, gynaecomastia
General disorders and administration site conditions
Common	Oedema, fatigue
Uncommon	Chest pain, asthenia, pain, malaise
Investigations
Uncommon	Weight increase, weight decrease

Exceptional cases of extrapyramidal syndrome have been reported.

Hydrochlorothi­azide

Hydrochlorothiazide has been extensively prescribed for many years, frequently in higher doses than those contained in Rasitrio. The following adverse reactions have been reported in patients treated with thiazide diuretics alone, including hydrochlorothi­azide:

Blood and lymphatic system disorders

Rare Very rare	Thrombocytopenia sometimes with purpura Agranulocytosis, bone marrow depression, haemolytic anaemia, leucopenia
Not known Immune system disorders Very rare	Aplastic anaemia Hypersensitivity

Metabolism and nutrition disorders

Very common Common Rare	Hypokalaemia Hyperuricaemia, hypomagnesaemia, hyponatraemia Hypercalcaemia, hyperglycaemia, worsening of diabetic metabolic state
Very rare Psychiatric disorders Rare Nervous system disorders Rare Eye disorders Rare Not known Cardiac disorders Rare Vascular disorders Common	Hypochloraemic alkalosis Depression, sleep disturbances Dizziness, headache, paraesthesia Visual impairment Acute angle-closure glaucoma. Cardiac arrhythmias Orthostatic hypotension

Respiratory, thoracic and mediastinal disorders

Very rare           Res­piratory distress (including pneumonitis and pulmonary oedema)

Gastrointestinal disorders

Common Rare Very rare Hepatobiliary disorders Rare

Decreased appetite, mild nausea and vomiting Abdominal discomfort, constipation, diarrhoea Pancreatitis Intrahepatic cholestasis, jaundice

Skin and subcutaneous tissue disorders

Common Rare Very rare	Urticaria and other forms of rash Photosensitivity reactions Cutaneous lupus erythematosus-like reactions, reactivation of cutaneous lupus erythematosus, vasculitis necrotising and toxic epidermal necrolysis
Not known	Erythema multiforme

Musculoskeletal and connective tissue disorders

Not known

Muscle spasm

Renal and urinary disorders

Not known

Renal dysfunction, acute renal failure

Reproductive system and breast disorders

Common

Impotence

General disorders and administration site conditions

Not known	Asthenia, pyrexia
Investigations Very common Rare	Increases in cholesterol and triglycerides Glycosuria

4.9 Overdose

Symptoms

The most likely manifestation of overdose for Rasitrio would be hypotension, related to the antihypertensive effect of the combination of aliskiren, amlodipine and hydrochlorothi­azide.

With aliskiren, the most likely manifestation of overdose would be hypotension, related to the antihypertensive effect of aliskiren.

With amlodipine, available data suggest that gross overdose 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 with amlodipine.

Overdose with hydrochlorothiazide is associated with electrolyte depletion (hypokalaemia, hypochloraemia, hyponatraemia) and dehydration resulting from excessive diuresis. The most common signs and symptoms of overdose are nausea and somnolence. Hypokalaemia may result in muscle spasms and/or accentuate cardiac arrhythmias associated with the concomitant use of digitalis glycosides or certain antiarrhythmic medicinal products.

Treatment                                  (­£■

If symptomatic hypotension should occur with Rasitrio, supportive treatment should be initiated.

• .. • ' , ,...........

Clinically significant hypotension due to amlodipine overdose 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.

Gastric lavage may be worthwhile in some cases. In healthy volunteers the use of charcoal up to 2 hours after administration of amlodipine 10 mg has been shown to reduce the absorption rate of amlodipine.

Since amlodipine is highly protein-bound, dialysis is not likely to be of benefit.

In a study conducted in patients with end stage renal disease (ESRD) receiving haemodialysis, dialysis clearance of aliskiren was low (<2% of oral clearance). Therefore dialysis is not adequate to treat aliskiren over-exposure.

5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Agents acting on the renin-angiotensin system, renin-inhibitors; ATC code C09XA54

Rasitrio combines three antihypertensive active substances with complementary mechanisms to control blood pressure in patients with essential hypertension: aliskiren belongs to the direct renin inhibitor class, amlodipine to the calcium channel blocker class and hydrochlorothiazide to the thiazide diuretics class. When combined, the consolidated effects of inhibition of the renin-angiotensin-aldosterone system, calcium channel-mediated vasodilatation and sodium chloride excretion result in a reduction of blood pressure to a greater degree than the corresponding dual combinations.

Aliskiren/amlo­dipine/hydrochlo­rothiazide combination

In hypertensive patients, once-daily administration of Rasitrio provided clinically meaningful reductions in both systolic and diastolic blood pressure that were maintained over the entire 24-hour dose interval. The greater blood pressure reduction for Rasitrio over each dual combination was seen at every hour including the early morning hours with the 24-hour ambulatory blood pressure monitoring.

Rasitrio was studied in a double-blind, randomised, active-controlled study in 1,181 patients of which 773 were classified as moderately hypertensive (msSBP 160–180 mmHg) and 408 as severely hypertensive (msSBP >180 mmHg) at baseline. A large number of patients were obese (49%) and over 14% of the total population had diabetes. During the first 4 weeks of double-blind treatment, patients received triple combination aliskiren/amlo­dipine/hydrochlo­rothiazide (HCTZ) 150/5/12.5 mg (N=308), or dual combinations of aliskiren/HCTZ 150/12.5 mg (N=295), aliskiren/amlo­dipine 150/5 mg (N=282) and amlodipine/HCTZ 5/12.5 mg (N=295). Patients were force-titrated to higher doses after 4 weeks for an additional 4 weeks of double-blind treatment to aliskiren/amlo­dipine/HCTZ 300/10/25 mg, aliskiren/HCTZ 300/25 mg, aliskiren/amlo­dipine 300/10 mg and amlodipine/HCTZ 10/25 mg.

.............

In this study, Rasitrio at a dose of 300/10/25 mg produced statistically significant mean blood pressure reductions (systolic/dias­tolic) from baseline of 37.9/20.6 mmHg compared to 31.4/18.0 mmHg with aliskiren/amlo­dipine combination (300/10 mg), 28.0/14.3 mmHg with aliskiren/hydrochlo­rothiazide (300/25 mg) and 30.8/17.0 mmHg with amlodipine/hy­drochlorothia­zide (10/25 mg) in patients with moderate to severe hypertension. In patients with severe hypertension (SBP >180 mmHg), the reduction in blood pressure from baseline for Rasitrio and the dual combinations respectively was 49.5/22.5 mmHg compared to 38.1/17.6 mmHg with aliskiren/amlo­dipine combination (300/10 mg), 33.2/14.3 mmHg with aliskiren/hydrochlo­rothiazide (300/25 mg) and 39.9/17.8 mmHg with amlodipine/hy­drochlorothia­zide (10/25 mg). In a subset of 588 patients in which patients >65 years were scarcely represented and those aged >75 years were very scarcely represented, the combination of aliskiren/amlo­dipine/hydrochlo­rothiazide (300/10/25 mg) produced a systolic/diastolic mean blood pressure reduction of 39.7/21.1 mmHg from baseline, compared to 31.3/18.74 mmHg for aliskiren/amlo­dipine (300/10 mg), 25.5/12.5 mmHg for aliskiren/hydrochlo­rothiazide (300/25 mg) and 29.2/16.4 mmHg for amlodipine/hy­drochlorothia­zide (10/25 mg) (the subset constitutes patients without aberrant readings, defined as a difference between systolic blood pressure (SBP) readings >10 mmHg at baseline or endpoint). The effect of Rasitrio was observed as early as one week after initiation of therapy. The blood-pressure-lowering effect in patients with moderate to severe hypertension was independent of age, gender, race, body mass index and overweight-associated disorders (metabolic syndrome and diabetes).

Rasitrio was associated with a significant reduction in plasma renin activity (PRA) (-34%) from baseline while the dual combination of amlodipine with hydrochlorothiazide increased PRA (+170%). The clinical implications of the differences in effect on PRA are not known at the present time.

In a 28 to 54 week open label safety study, efficacy was measured as secondary endpoint and Rasitrio at a dose of 300/10/25 mg produced mean blood pressure reductions (systolic/dias­tolic) of

37.3/21.8 mmHg over 28 to 54 weeks of treatment. Efficacy of Rasitrio was maintained over one year of treatment, with no evidence of loss of effect.

In a randomised, double blind, active controlled, 36-week study in elderly patients whose blood pressure was not controlled with aliskiren/HCTZ 300/25 mg (SBP >140 mmHg), clinically meaningful further BP reduction was seen at week 36 endpoint for patients who received Rasitrio at a dose of 300/10/25 mg (from reductions in msSBP/msDBP of 15.0/8.6 mmHg at week 22 to reductions of 30.8/14.1 mmHg at week 36 endpoint).

Rasitrio has been administered to more than 1,155 patients in completed clinical trials, including 182 patients for one year or more. Treatment with Rasitrio was well tolerated at doses up to 300 mg/10 mg/25 mg with an overall incidence of adverse events similar to the corresponding dual combinations, except for symptomatic hypotension. The incidence of any adverse reactions potentially related to hypotension in a short-term controlled study was 4.9% with Rasitrio versus up to 3.7% with dual combinations. In patients >65 years the incidence was 10.2% with Rasitrio versus up to 5.4% with dual combinations.

The incidence of adverse events did not show any association with gender, age (with the exception of symptomatic hypotension), body mass index, race or ethnicity. Adverse events have generally been mild and transient in nature. Very limited safety data are available for patients aged >75 years or patients with major cardiovascular co-morbidities. Discontinuation of therapy due to a clinical adverse event occurred in 3.6% of patients treated with Rasitrio versus 2.4% in aliskiren/amlo­dipine, 0.7% in aliskiren/hydrochlo­rothiazide and 2.7% in amlodipine/hy­drochlorothia­zide.

Aliskiren                                  -O)

Aliskiren is an orally active, non-peptide, potent and selective direct inhibitor of human renin.

By inhibiting the enzyme renin, aliskiren inhibits the RAAS at the point of activation, blocking the conversion of angiotensinogen to angiotensin I and decreasing levels of angiotensin I and angiotensin II. Whereas other medicinal products that inhibit the RAAS (ACEI and angiotensin II receptor blockers (ARB)) cause a compensatory rise in plasma renin activity (PRA), treatment with aliskiren decreases PRA in hypertensive patients by approximately 50 to 80%. Similar reductions were found when aliskiren was combined with other antihypertensive medicinal products. The clinical implications of the differences in effect on PRA are not known at the present time.

Hypertension

In hypertensive patients, once-daily administration of aliskiren at doses of 150 mg and 300 mg provided dose-dependent reductions in both systolic and diastolic blood pressure that were maintained over the entire 24-hour dose interval (maintaining benefit in the early morning) with a mean peak to trough ratio for diastolic response of up to 98% for the 300 mg dose. 85 to 90% of the maximal bloodpressure-lowering effect was observed after 2 weeks. The blood-pressure-lowering effect was sustained during long-term treatment, and was independent of age, gender, body mass index and ethnicity. Aliskiren has been studied in 1,864 patients aged 65 years or older, and in 426 patients aged 75 years or older.

Aliskiren monotherapy studies have shown blood-pressure-lowering effects comparable to other classes of antihypertensive medicinal products including selected ACEI and ARB. Compared to a diuretic (hydrochlorot­hiazide, HCTZ), aliskiren 300 mg lowered systolic/diastolic blood pressure by 17.0/12.3 mmHg, compared to 14.4/10.5 mmHg for HCTZ 25 mg after 12 weeks of treatment.

Combination therapy studies are available for aliskiren added to the diuretic hydrochlorothi­azide, the calcium channel blocker amlodipine and the beta blocker atenolol. These combinations were well tolerated. Aliskiren induced an additive blood-pressure-lowering effect when added to hydrochlorothi­azide.

The efficacy and safety of aliskiren-based therapy were compared to ramipril-based therapy in a 9-month non-inferiority study in 901 elderly patients (>65 years) with essential systolic hypertension. Aliskiren 150 mg or 300 mg per day or ramipril 5 mg or 10 mg per day were administered for 36 weeks with optional add-on therapy of hydrochlorothiazide (12.5 mg or 25 mg) at week 12, and amlodipine (5 mg or 10 mg) at week 22. Over the 12-week period, aliskiren monotherapy lowered systolic/diastolic blood pressure by 14.0/5.1 mmHg, compared to 11.6/3.6 mmHg for ramipril, consistent with aliskiren being non-inferior to ramipril at the dosages chosen and the differences in systolic and diastolic blood pressure were statistically significant. Tolerability was comparable in both treatment arms, however cough was more often reported with the ramipril regimen than the aliskiren regimen (14.2% vs. 4.4%), whilst diarrhoea was more common with the aliskiren regimen than for the ramipril regimen (6.6% vs. 5.0%).

In an 8-week study in 754 hypertensive geriatric patients aged 65 years or older and geriatric patients aged 75 years or older (30%) aliskiren at doses of 75 mg, 150 mg and 300 mg provided statistically significant superior reduction in blood pressure (both systolic and diastolic) when compared to placebo. No additional blood pressure lowering effect was detected with 300 mg aliskiren compared to 150 mg aliskiren. All three doses were well tolerated in both elderly and very elderly patients.

There has been no evidence of first-dose hypotension and no controlled clinical studies. Excessive hypotension was uncommonly (0.1%) seen in patients with uncomplicated hypertension treated with aliskiren alone. Hypotension was also uncommon (<1%) during combination therapy with other antihypertensive medicinal products. With cessation of treatment, blood pressure gradually returned towards baseline levels over a period of several weeks, with no evidence of a rebound effect for blood pressure or PRA.

In a 36-week study involving 820 patients with ischaemic left ventricular dysfunction, no changes in ventricular remodelling as assessed by left ventricular end systolic volume were detected with aliskiren compared to placebo on top of background therapy.

The combined rates of cardiovascular death, hospitalisation for heart failure, recurrent heart attack, stroke and resuscitated sudden death were similar in the aliskiren group and the placebo group. However, in patients receiving aliskiren there was a significantly higher rate of hyperkalaemia, hypotension and kidney dysfunction when compared to the placebo group.

Aliskiren was evaluated for cardiovascular and/or renal benefit in a double blind placebo controlled randomised trial in 8,606 patients with type 2 diabetes and chronic kidney disease (evidenced by proteinuria and/or GFR <60 ml/min/1.73 m2) with or without cardiovascular disease. In most patients arterial blood pressure was well controlled at baseline. The primary endpoint was a composite of cardiovascular and renal complications.

In this study, aliskiren 300 mg was compared to placebo when added to standard of care which included either an angiotensin converting enzyme inhibitor or an angiotensin receptor blocker. The study was discontinued prematurely because the participants were unlikely to benefit from aliskiren. Study results indicated a hazard ratio for the primary endpoint of 1.11 in favour of placebo (95% Confidence Interval: 1.00, 1.23, 2-sided p=0.05). In addition, an increased incidence of adverse events was observed with aliskiren compared to placebo (37.9% versus 30.2%). In particular there was an increased incidence of renal dysfunction (14.0% versus 12.1%), hyperkalaemia (38.9% versus 28.8%), hypotension-related events (19.7% versus 16.2%) and adjudicated stroke endpoints (3.4% versus 2.6%). The increased incidence of stroke was greater in patients with renal insufficiency.

Effects of aliskiren on mortality and cardiovascular morbidity are currently unknown.

No long-term efficacy data for aliskiren in patients with heart failure are currently available (see section 4.4).

Cardiac electrophysiology

No effect on QT interval was reported in a randomised, double-blind, placebo, and active-controlled study using standard and Holter electrocardio­graphy.

Amlodipine

The amlodipine component of Rasitrio inhibits the transmembrane entry 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, causing reductions in peripheral vascular resistance and in blood pressure. Experimental data suggest that amlodipine binds to both dihydropyridine and non-dihydropyridine binding sites.

The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels.

Following administration of therapeutic doses to patients with hypertension, amlodipine produces vasodilatation resulting in a reduction of supine and standing blood pressures. These decreases in blood pressure are not accompanied by a significant change in heart rate or plasma catecholamine levels with chronic dosing.

Plasma concentrations correlate with effect in both young and elderly patients.

In hypertensive patients with normal renal function, therapeutic doses of amlodipine resulted in a

As with other calcium channel blockers, haemodynamic measurements of cardiac function at rest and during exercise (or pacing) in patients with normal ventricular function treated with amlodipine have generally demonstrated a small increase in cardiac index without significant influence on dP/dt or on left ventricular end diastolic pressure or volume. In haemodynamic studies, amlodipine has not been associated with a negative inotropic effect when administered in the therapeutic dose range to intact animals and humans, even when co-administered with beta blockers to humans.

Amlodipine does not change sinoatrial nodal function or atrioventricular conduction in intact animals or humans. In clinical studies in which amlodipine was administered in combination with beta blockers to patients with either hypertension or angina, no adverse effects on electrocardio­graphic parameters were observed.

Amlodipine has demonstrated beneficial clinical effects in patients with chronic stable angina, vasospastic angina and angiographically documented coronary artery disease.

Use in patients with heart failure

Calcium channel blockers, including amlodipine, should be used with caution in patients with congestive heart failure, as they may increase the risk of future cardiovascular events and mortality.

Use in patients with hypertension

A randomised double-blind morbidity-mortality study called the Antihypertensive and LipidLowering treatment to prevent Heart Attack Trial (ALLHAT) was performed to compare newer therapies: amlodipine 2.5–10 mg/day (calcium channel blocker) or lisinopril 10–40 mg/day (ACEinhibitor) as first-line therapies to that of the thiazide-diuretic, chlorthalidone 12.5–25 mg/day in mild to moderate hypertension.

A total of 33,357 hypertensive patients aged 55 or older were randomised and followed for a mean of 4.9 years. The patients had at least one additional coronary heart disease risk factor, including: previous myocardial infarction or stroke (>6 months prior to enrollment) or documentation of other atherosclerotic cardiovascular disease (overall 51.5%), type 2 diabetes (36.1%), high density lipoprotein – cholesterol <35 mg/dl or <0.906 mmol/l (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 coronary heart disease or non-fatal myocardial infarction. There was no significant difference in the primary endpoint between amlodipine-based therapy and chlorthalidone-based therapy: risk ratio (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 chlorthalidonebased therapy RR 0.96 95% CI [0.89–1.02] p=0.20.

Hydrochlorothi­azide

The site of action of thiazide diuretics is primarily in the renal distal convoluted tubule. It has been shown that there is a high-affinity receptor in the renal cortex as the primary binding site for the thiazide diuretic action and inhibition of NaCl transport in the distal convoluted tubule. The mode of action of thiazides is through inhibition of the Na+Cl- symporter by competing for the Cl- site, thereby affecting electrolyte reabsorption mechanisms: directly increasing sodium and chloride excretion to an approximately equal extent, and indirectly by this diuretic action reducing plasma volume, with consequent increases in plasma renin activity, aldosterone secretion and urinary potassium loss, and a decrease in serum potassium.

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with Rasitrio in all subsets of the paediatric population in essential hypertension (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

Aliskiren/amlo­dipine/hydrochlo­rothiazide combination

Following oral administration of a fixed combination tablet of aliskiren, amlodipine and hydrochlorothi­azide, peak concentrations were achieved for aliskiren within 1–2 hours, for amlodipine within 8 hours and for hydrochlorothiazide within 2–3 hours. The rate and extent of absorption of d hydrochlorothiazide following administration of a fixed combination tablet inistered as individual dosage forms.

The results from a food effect study using a standard high-fat meal with the 300/10/25 mg fixed combination tablet showed that food reduced the rate and extent of absorption of aliskiren in the fixed combination tablet with a similar magnitude of effect as for aliskiren monotherapy. Food had no effect on the pharmacokinetics of amlodipine or hydrochlorothiazide in the fixed combination tablet.

Aliskiren

Absorption

Following oral absorption, peak plasma concentrations of aliskiren are reached after 1–3 hours. The absolute bioavailability of aliskiren is approximately 2–3%. Meals with a high fat content reduce Cmax by 85% and AUC by 70%. At steady state meals with low fat content reduce Cmax by 76% and AUC 0-tau by 67% in hypertensive patients. Steady-state plasma concentrations are reached within 5–7 days following once-daily administration and steady-state levels are approximately 2-fold greater than with the initial dose.

Distribution

Following intravenous administration, the mean volume of distribution at steady state is approximately 135 litres, indicating that aliskiren distributes extensively into the extravascular space. Aliskiren plasma protein binding is moderate (47–51%) and independent of the concentration.

Biotransformation and elimination

The mean half-life is about 40 hours (range 34–41 hours). Aliskiren is mainly eliminated as unchanged compound in the faeces (78%). Approximately 1.4% of the total oral dose is metabolised. The enzyme responsible for this metabolism is CYP3A4. Approximately 0.6% of the dose is recovered in urine following oral administration. Following intravenous administration, mean plasma clearance is approximately 9 l/h.

Linearity

Exposure to aliskiren increased more than in proportion to the increase in dose. After single dose administration in the dose range of 75 to 600 mg, a 2-fold increase in dose results in a ~2.3 and 2.6-fold increase in AUC and Cmax, respectively. At steady state the non-linearity may be more pronounced. Mechanisms responsible for deviation from linearity have not been identified. A possible mechanism is saturation of transporters at the absorption site or at the hepatobiliary clearance route.

Paediatric population

In a pharmacokinetic study of aliskiren treatment in 39 paediatric hypertensive patients (aged 6–17 years) given daily doses of 2 mg/kg or 6 mg/kg aliskiren administered as granules

(3.125 mg/tablet), pharmacokinetic parameters were similar to those in adults. The available data did

not suggest that age, body weight or gender have any signific (see section 4.2).

Amlodipine

Absorption

After oral administration of therapeutic doses of amlodipine alone, peak plasma concentrations of amlodipine are reached in 6–12 hours. Absolute bioavailability has been estimated as between 64%

and 80%. Amlodipine bioavailability is

Distribution

The volume of distribution is approximately 21 l/kg. In vitro studies with amlodipine have shown that approximately 97.5% of circulating amlodipine is bound to plasma proteins.

ination

(approximately 90%) metabolised in the liver to inactive metabolites, with

ound and 60% of the metabolites excreted in the urine.

Amlodipine elimination from plasma is biphasic with a terminal elimination half-life of approximately 30 to 50 hours. Steady-state plasma levels are reached after continuous administration for 7–8 days.

Linearity

Amlodipine exhibits linear pharmacokinetics between the therapeutic dose range of 5 mg and 10 mg.

Hydrochlorothi­azide

Absorption

The absorption of hydrochlorothi­azide, after an oral dose, is rapid (Tmax about 2 h.

The effect of food on hydrochlorothiazide absorption, if any, has little clinical significance. Absolute bioavailability of hydrochlorothiazide is 70% after oral administration.

Distribution

The apparent volume of distribution is 4–8 l/kg. Circulating hydrochlorothiazide is bound to serum proteins (40–70%), mainly serum albumin. Hydrochlorothiazide also accumulates in erythrocytes at approximately 3 times the level in plasma.

Biotransformation and elimination

Hydrochlorothiazide is eliminated predominantly as unchanged compound. Hydrochlorothiazide is eliminated from plasma with a half-life averaging 6 to 15 hours in the terminal elimination phase. There is no change in the kinetics of hydrochlorothiazide on repeated dosing, and accumulation is minimal when dosed once daily. There is more than 95% of the absorbed dose being excreted as unchanged compound in the urine. The renal clearance is composed of passive filtration and active secretion into the renal tubule.

Linearity

The increase in mean AUC is linear and dose proportional in the therapeutic range.

Special populations

Rasitrio is an effective once-a-day antihypertensive treatment in adult patients, regardless of gender, age, body mass index and ethnicity.

Renal impairment

Due to its hydrochlorothiazide component, Rasitrio is contraindicated in patients with anuria or severe renal impairment (GFR <30 ml/min/1.73 m2) (see section 4.3). No adjustment of the initial dose is required in patients with mild to moderate renal impairment (see sections 4.4 and 4.2).

atients with varying degrees of renal

ubjects with renal impairment ranged between single dose administration and at steady state.

elate with the severity of renal impairment. No uired in patients with mild to moderate renal impairment (see sections 4.2 and 4.4). Aliskiren is not recommended in patients with severe renal impairment (glomerular filtration rate (GFR) <30 ml/min/1.73 m2). Concomitant use of aliskiren with ARBs or ACEIs is contraindicated in patients with renal impairment (GFR <60 ml/min/1.73 m2) (see section 4.3).

The pharmacokinetics of aliskiren were evaluated in patients with end stage renal disease receiving haemodialysis. Administration of a single oral dose of 300 mg aliskiren was associated with very minor changes in the pharmacokinetics of aliskiren (change in Cmax of less than 1.2 fold; increase in AUC of up to 1.6 fold) compared to matched healthy subjects. Timing of haemodialysis did not significantly alter the pharmacokinetics of aliskiren in ESRD patients. Therefore, if administration of aliskiren in ESRD patients receiving haemodialysis is considered necessary, no dose adjustment is warranted in these patients. However, the use of aliskiren is not recommended in patients with severe renal impairment (see section 4.4).

The pharmacokinetics of amlodipine are not significantly influenced by renal impairment.

As expected for a compound which is cleared almost exclusively via the kidneys, renal function has a marked effect on the kinetics of hydrochlorothi­azide. In the presence of renal impairment, mean peak plasma levels and AUC values of hydrochlorothiazide are increased and the urinary excretion rate is reduced. In patients with mild to moderate renal impairment, a 3-fold increase in hydrochlorothiazide AUC has been observed. In patients with severe renal impairment an 8-fold increase in AUC has been observed.

Hepatic impairment

Rasitrio is contraindicated in patients with severe hepatic impairment (see section 4.3).

The pharmacokinetics of aliskiren were not significantly affected in patients with mild to severe liver disease. Consequently, no adjustment of the initial dose of aliskiren is required in patients with mild to moderate 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 with resulting increase in AUC of approximately 40–60%. Therefore caution should be exercised in patients with hepatic impairment.

Geriatric patients

No data are available on systemic exposure after administration of Rasitrio in geriatric patients. When administered alone, the AUC of aliskiren in geriatric subjects (>65 years) is 50% higher than in young subjects. 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 geriatric patients. Therefore particular caution is recom administering Rasitrio to patients aged 65 years and over, and extreme caution 75 years or older (see sections 4.2, 4.4, 4.8 and 5.1).

Limited data suggest that the systemic clearance of hydrochlorothiazide is reduced in both healthy and hypertensive elderly subjects compared to young healthy volunteers. There are no specific data regarding the effect of hydrochlorothiazide in elderly patients.

Paediatric population (age below 18 years)

The pharmacokinetics of Rasitrio have not been investigated. A population pharmacokinetic 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 are limited.

5.3

Aliskiren/hydrochlo­rothiazide and aliskiren/amlo­dipine

Non-clinical studies of the toxicology of Rasitrio alone have not been conducted as these studies have been conducted for the individual components.

The toxicity profiles of the combination of aliskiren/hydrochlo­rothiazide and aliskiren/amlo­dipine have been well characterised in preclinical studies. Both combinations were generally well tolerated by rats. The findings from 2– and 13-week oral toxicity studies were consistent with those for the individual components.

Aliskiren

Carcinogenic potential was assessed in a 2-year rat study and a 6-month transgenic mouse study. No carcinogenic potential was detected. One colonic adenoma and one caecal adenocarcinoma recorded in rats at the dose of 1,500 mg/kg/day were not statistically significant. Although aliskiren has known irritation potential, safety margins obtained in humans at the dose of 300 mg during a study in healthy volunteers were considered to be appropriate at 9–11-fold based on faecal concentrations or 6-fold based on mucosa concentrations in comparison with 250 mg/kg/day in the rat carcinogenici­ty study.

Aliskiren was devoid of any mutagenic potential in the in vitro and in vivo mutagenicity studies. The assays included in vitro assays in bacterial and mammalian cells and in vivo assessments in rats.

Reproductive toxicity studies with aliskiren did not reveal any evidence of embryofoetal toxicity or teratogenicity at doses up to 600 mg/kg/day in rats or 100 mg/kg/day in rabbits. Fertility, pre-natal development and post-natal development were unaffected in rats at doses up to 250 mg/kg/day. The doses in rats and rabbits provided systemic exposures of 1 to 4 and 5 times higher, respectively, than the maximum recommended human dose (300 mg).

Safety pharmacology studies did not reveal any adverse effects on central nervous, respiratory or cardiovascular function. Findings during repeat-dose toxicity studies in animals were consistent with the known local irritation potential or the expected pharmacological effects of aliskiren.

Amlodipine

Safety data for amlodipine are well established both clinically and non-clinically.

Reproductive toxicology

Reproductive studies in rats and mice have shown delayed date of delivery, prolonged duration of labour and decreased pup survival at dosages approximately 50 times greater than the maximum recommended dosage for humans based on mg/kg.

Impairment of fertility

There was no effect on the fertility of rats treated with amlodipine (males for 64 days and females 14 days prior to mating) at doses up to 10 mg/kg/day (8 times* the maximum recommended human dose of 10 mg on a mg/m2 basis). In another rat study in which male rats were treated with amlodipine besilate for 30 days at a dose comparable with the human dose based on mg/kg, decreased plasma follicle-stimulating hormone and testosterone were found as the number of mature spermatids and Sertoli cells.

Carcinogenesis, mutagenesis

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 (for mice, similar to, and for rats twice* the maximum recommended clinical dose of 10 mg on a mg/m2 basis) was close to thimum tolerated dose for mice but not for rats.

Mutagenicity studies revealed no effects related to the medicinal product at either the gene or chromosome levels.

*Based on patient weight o

Hydrochlorothi­azide —Q)

Preclinical evaluations to support the administration of hydrochlorothiazide in humans included in vitro genotoxicity assays and reproductive toxicity and carcinogenicity studies in rodents. Extensive clinical data are available for hydrochlorothiazide and these are reflected in the relevant sections.

Hydrochlorothiazide had no adverse effects on the fertility of mice and rats of either sex in studies wherein these species were exposed, via their diet, to doses of up to 100 and 4 mg/kg,/day respectively, prior to mating and throughout gestation. These doses of hydrochlorothiazide in mice and rats represent 19 and 1.5 times, respectively, the maximum recommended human dose on a mg/m2 basis. (Calculations assume an oral dose of 25 mg/day and a 60-kg patient.)

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

Tablet core

Cellulose microcrystalline

Crospovidone

Povidone

Magnesium stearate Silica colloidal anhydrous

Coating

Hypromellose

Titanium dioxide (E171)

Macrogol

Talc

Iron oxide red (E172)

Iron oxide black (E172)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

PVC/polychloro­trifluoroethy­lene (PCTFE) – Alu calendar blisters:

• 2 years

PVC/polychloro­trifluoroethy­lene (PCTFE) – Alu blisters:

• 2 years

PA/Alu/PVC – Alu calendar blisters: 18 months

Do not store above 30°C.

Store in the original package in order to protect from moisture and light.

6.5 Nature and contents of container

PVC/polychloro­trifluoroethy­lene (PCTFE) – Alu calendar blisters:

Single pack containing 14, 28, 56, 98 tablets

PVC/polychloro­trifluoroethy­lene (PCTFE) – Alu blisters:

Single pack containing 30, 90 tablets

Unit dose pack (perforated unit dose blister) containing 56×1 tablet

Multipacks of unit dose (perforated unit dose blister) containing 98×1 tablet (2 packs of 49×1)

PA/Alu/PVC – Alu calendar blisters:

Single pack containing 14, 28, 56 tablets

Multipacks containing 98 tablets (2 packs of 49)

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

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

7. MARKETING AUTHORISATION HOLDER

Novartis Europharm Limited

Wimblehurst Road

Horsham

West Sussex, RH12 5AB

United Kingdom

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/11/730/001–012

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE

Date of first authorisation: 22 November 2011

Date of latest renewal: