Novartis Ireland Limited

Rasilez HCT 150 mg/12.5 mg film-coated tablets

Rasilez HCT 150 mg/25 mg film-coated tablets

Rasilez HCT 300 mg/12.5 mg film-coated tablets

Rasilez HCT 300 mg/25 mg film-coated tablets

Rasilez HCT 150 mg/12.5 mg film-coated tablets: Each film-coated tablet contains 150 mg aliskiren (as hemifumarate) and 12.5 mg hydrochlorothiazide.

Rasilez HCT 150 mg/25 mg film-coated tablets: Each film-coated tablet contains 150 mg aliskiren (as hemifumarate) and 25 mg hydrochlorothiazide.

Rasilez HCT 300 mg/12.5 mg film-coated tablets: Each film-coated tablet contains 300 mg aliskiren (as hemifumarate) and 12.5 mg hydrochlorothiazide.

Rasilez HCT 300 mg/25 mg film-coated tablets: Each film-coated tablet contains 300 mg aliskiren (as hemifumarate) and 25 mg hydrochlorothiazide.

Excipients:

Rasilez HCT 150 mg/12.5 mg film-coated tablets: Each tablet contains 25 mg lactose monohydrate and 24.5 mg wheat starch.

Rasilez HCT 150 mg/25 mg film-coated tablets: Each tablet contains 50 mg lactose monohydrate and 49 mg wheat starch.

Rasilez HCT 300 mg/12.5 mg film-coated tablets: Each tablet contains 25 mg lactose monohydrate and 24.5 mg wheat starch

Rasilez HCT 300 mg/25 mg film-coated tablets: Each tablet contains 50 mg lactose monohydrate and 49 mg wheat starch.

For a full list of excipients, see section 6.1.

Film-coated tablet

Rasilez HCT 150 mg/12.5 mg film-coated tablets: White, biconvex, ovaloid film-coated tablet imprinted with “LCI” on one side and “NVR” on the other.

Rasilez HCT 150 mg/25 mg film-coated tablets: Pale yellow, biconvex, ovaloid film-coated tablet imprinted with “CLL” on one side and “NVR” on the other.

Rasilez HCT 300 mg/12.5 mg film-coated tablets: Violet white, biconvex, ovaloid film-coated tablet imprinted with “CVI” on one side and “NVR” on the other.

Rasilez HCT 300 mg/25 mg film-coated tablets: Light yellow, biconvex, ovaloid film-coated tablet imprinted with “CVV” on one side and “NVR” on the other.

Treatment of essential hypertension in adults.

Rasilez HCT is indicated in patients whose blood pressure is not adequately controlled on aliskiren or hydrochlorothiazide used alone.

Rasilez HCT is indicated as substitution therapy in patients adequately controlled with aliskiren and hydrochlorothiazide, given concurrently, at the same dose level as in the combination.

The recommended dose of Rasilez HCT is one tablet per day. Rasilez HCT 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 Rasilez HCT.

The antihypertensive effect is largely manifested within 1 week and the maximum effect is generally seen within 4 weeks.

Posology in patients not adequately controlled with aliskiren or hydrochlorothiazide monotherapy

Individual dose titration with each of the two components may be recommended before changing to the fixed combination. When clinically appropriate, direct change from monotherapy to the fixed combination may be considered.

Rasilez HCT 150 mg/12.5 mg film-coated tablets: Rasilez HCT 150 mg /12.5 mg may be administered in patients whose blood pressure is not adequately controlled with aliskiren 150 mg or hydrochlorothiazide 12.5 mg alone.

Rasilez HCT 150 mg/25 mg film-coated tablets: Rasilez HCT 150 mg /25 mg may be administered in patients whose blood pressure is not adequately controlled with aliskiren 150 mg or hydrochlorothiazide 25 mg alone or by Rasilez HCT 150 mg/12.5 mg.

Rasilez HCT 300 mg/12.5 mg film-coated tablets: Rasilez HCT 300 mg /12.5 mg may be administered in patients whose blood pressure is not adequately controlled with aliskiren 300 mg or hydrochlorothiazide 12.5 mg alone or by Rasilez HCT 150 mg/12.5 mg.

Rasilez HCT 300 mg/25 mg film-coated tablets: Rasilez HCT 300 mg /25 mg may be administered in patients whose blood pressure is not adequately controlled with aliskiren 300 mg or hydrochlorothiazide 25 mg alone or by Rasilez HCT 300 mg/12.5 mg or Rasilez HCT 150 mg/25 mg

If blood pressure remains uncontrolled after 2-4 weeks of therapy, the dose may be titrated up to a maximum of Rasilez HCT 300 mg/25 mg daily. Dosing should be individualised and adjusted according to the patient's clinical response.

Posology as substitution therapy

For convenience, patients receiving aliskiren and hydrochlorothiazide from separate tablets may be switched to a fixed combination tablet of Rasilez HCT containing the same component doses.

Renal impairment

No adjustment of the initial dose is required for patients with mild to moderate renal impairment. Rasilez HCT is contraindicated for use in patients with severe renal impairment (glomerular filtration rate (GFR) < 30 ml/min/1.73 m²) and the concomitant use of Rasilez HCT 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

Thiazides should be used with caution in patients with impaired hepatic function. No adjustment of the initial dose is required for patients with mild to moderate hepatic impairment (see section 5.2). Due to the hydrochlorothiazide component, Rasilez HCT is contraindicated in patients with severe hepatic impairment (see sections 4.3 and 4.4).

Elderly patients (over 65 years)

The recommended starting dose of aliskiren in elderly 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.

Paediatric patients

Rasilez HCT is not recommended for use in children and adolescents below age 18 due to a lack of data on safety and efficacy (see section 5.2).

− Hypersensitivity to the active substances or to any of the excipients (see section 6.1), or to other sulphonamide-derived substances.

− History of angioedema with aliskiren.

− Hereditary or idiopathic angioedema.

− Second and third trimesters of pregnancy, lactation (see section 4.6).

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

− Refractory hypokalaemia, hypercalcaemia.

− 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).

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.

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).

Heart failure

Aliskiren should be used with caution in patients with serious congestive heart failure (New York Heart Association (NYHA) functional class III-IV). Rasilez HCT should be used with caution in patients with heart failure due to limited clinical efficacy and safety data.

Angioedema

As with other agents acting on the renin-angiotensin system, 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 medicines that can cause angioedema, including RAAS blockers (angiotensin converting enzyme inhibitors or angiotensin receptor blockers) (see section 4.8).

Patients with a 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 angioedema occurs, Rasilez HCT should be promptly discontinued and appropriate therapy and monitoring provided until complete and sustained resolution of signs and symptoms has occurred. 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.

Intravascular volume depletion

Symptomatic hypotension may occur in patients who are volume and/or sodium depleted as a result of vigorous diuretic therapy, dietary salt restriction, diarrhoea or vomiting. Such conditions should be corrected before the administration of Rasilez HCT.

Electrolyte imbalance

As for any patient receiving diuretic therapy, periodic determination of serum electrolytes should be performed at appropriate intervals. Thiazides, including hydrochlorothiazide, can cause fluid or electrolyte imbalance (including hypokalaemia, hyponatraemia and hypochloraemic alkalosis). Warning signs of fluid or electrolyte imbalance are dry mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pain or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea or vomiting (see section 4.8).

Although hypokalaemia may develop with the use of thiazide diuretics, concurrent therapy with aliskiren may reduce diuretic-induced hypokalaemia. The risk of hypokalaemia is greater in 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 sections 4.3, 4.5 and 4.8).

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

Thiazides may reduce urinary calcium excretion and cause an intermittent and slight elevation of serum calcium in the absence of known disorders of calcium metabolism. Marked hypercalcaemia may be evidence of hidden hyperparathyroidism. Thiazides should be discontinued before carrying out tests for parathyroid function.

Thiazides have been shown to increase the urinary excretion of magnesium, which may result in hypomagnesaemia (see also section 4.5).

Renal impairment and kidney transplantation

When Rasilez HCT is used in patients with impaired renal function, periodic monitoring of potassium, creatinine and uric acid serum levels is recommended. There is no experience regarding the administration of Rasilez HCT in patients who have recently undergone kidney transplantation. No dosage adjustment is necessary in patients with renal impairment whose GFR is 30 ml/min/1.73 m². However, in patients with mild to moderate renal impairment (GFR 30 ml/min/1.73 m² but < 90 ml/min/1.73 m²), Rasilez HCT should be administered with caution. Rasilez HCT is contraindicated in patients with severe renal impairment (GFR < 30 ml/min/1.73 m²).

As for other agents acting on the renin-angiotensin system, caution should be exercised when aliskiren 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.

Hepatic impairment

Thiazides should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma.

There is no clinical experience with Rasilez HCT in patients with hepatic impairment.

Moderate P-gp inhibitors

Co-administration of aliskiren 300 mg with ketoconazole 200 mg or verapamil 240 mg resulted in a 76% or 97% increase in aliskiren AUC, respectively. Therefore caution should be exercised when aliskiren is administered with moderate P-gp inhibitors such as ketoconazole or verapamil (see section 4.5).

Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy

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

Renal artery stenosis and renovascular hypertension

No controlled clinical data are available on the use of Rasilez HCT in patients with unilateral or bilateral renal artery stenosis, or stenosis to a solitary kidney. However, as with other agents acting on the renin-angiotensin 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.

Metabolic and endocrine effects

Thiazide therapy may impair glucose tolerance. In diabetic patients dosage adjustments of insulin or oral hypoglycaemic agents may be required. Latent diabetes mellitus may occur during thiazide therapy. To date, no data are available from clinical studies that were specifically-designed to evaluate the safety of Rasilez HCT in diabetic patients. Concomitant use of Rasilez HCT with ARBs or ACEIs is contraindicated in patients with diabetes mellitus (see section 4.3).

Increases in cholesterol and triglyceride levels have been associated with thiazide diuretic therapy. Hyperuricaemia may occur or frank gout may be precipitated in certain patients receiving thiazide therapy.

General

In the event of severe and persistent diarrhoea, Rasilez HCT therapy should be stopped.

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

Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of allergy or bronchial asthma, but are more likely in patients with such a history. Exacerbation or activation of systemic lupus erythematosus has been reported with the use of thiazide diuretics.

Excipients

Rasilez HCT contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Rasilez HCT contains wheat starch. It is suitable for people with coeliac disease. Patients with wheat allergy (different from coeliac disease) should not take this medicine.

Information on Rasilez HCT interactions

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, laxatives, amphotericin, carbenoxolone, penicillin G sodium, corticosteroids, ACTH, 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 Rasilez HCT is administered with medicinal products affected by serum potassium disturbances (e.g. digitalis glycosides, antiarrhythmics).

Other antihypertensive agents: The antihypertensive effect of Rasilez HCT may be increased with the concomitant use of other antihypertensive agents.

Additional information on aliskiren interactions

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).

Compounds that have been investigated in aliskiren clinical pharmacokinetic studies include acenocoumarol, atenolol, celecoxib, fenofibrate, pioglitazone, allopurinol, isosorbide-5-mononitrate, digoxin, metformin, amlodipine, atorvastatin, cimetidine and hydrochlorothiazide. No clinically relevant interactions have been identified. As a result no dose adjustment for aliskiren or these co-administered medicinal products is necessary.

P-glycoprotein 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.

P-gp potent inhibitors: A single dose drug interaction study in healthy subjects has shown that ciclosporin (200 and 600 mg) increases C_max 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 C_max 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).

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).

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 C_max increased by 50%.

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).

Grapefruit juice: Administration of grapefruit juice with aliskiren resulted in a decrease in AUC and C_max of aliskiren. Co-administration with aliskiren 150 mg resulted in a 61% decrease in aliskiren AUC and co-administration 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 Rasilez HCT.

Furosemide: When aliskiren was co-administered with furosemide, the AUC and C_max of furosemide were reduced by 28% and 49%, respectively. It is therefore recommended to monitor the effects when initiating and adjusting furosemide therapy to avoid possible underutilisation in clinical situations of volume overload.

Non-steroidal anti-inflammatory drugs (NSAIDs): As with other agents acting on the renin-angiotensin system, NSAIDs may reduce the anti-hypertensive effect of aliskiren. In some patients with compromised renal function (dehydrated patients or elderly patients) aliskiren given concomitantly with NSAIDs may result in further deterioration of renal function, including possible acute renal failure, which is usually reversible. Therefore the combination of aliskiren with an NSAID requires caution, especially in elderly patients.

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

Food interactions: Meals with a high fat content have been shown to reduce the absorption of aliskiren substantially.

Additional information on hydrochlorothiazide interactions

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

Lithium: Renal clearance of lithium is reduced by thiazides, therefore the risk of lithium toxicity may be increased with hydrochlorothiazide. Co-administration of lithium and hydrochlorothiazide is not recommended. If this combination proves essential, careful monitoring of serum lithium level is recommended during concomitant use.

Alcohol: Potentiation of orthostatic hypotension may occur.

Antidiabetic medicinal products (oral agents and insulins): Dosage adjustment of the antidiabetic medicinal product may be required (see section 4.4).

Cholestyramine and colestipol resins: Absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins.

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

NSAIDs: The administration of an NSAID may reduce the diuretic, natriuretic and antihypertensive effects of thiazide diuretics in some patients.

Pressor amines (e.g. noradrenaline): The effect of pressor amines may be decreased.

Antigout medicine: Dosage adjustments of antigout medications may be necessary as hydrochlorothiazide may raise the level of serum uric acid. Increase in dosage of probenecid or sulfinpyrazone may be necessary. Co-administration of thiazide diuretics may increase the incidence of hypersensitivity reactions to allopurinol.

Calcium salts: Thiazide diuretics may increase serum calcium levels due to decreased excretion. If calcium supplements or calcium-sparing medicinal products (e.g. vitamin D therapy) must be prescribed, serum calcium levels should be monitored and calcium dosage adjusted accordingly.

Curare derivatives (e.g. tubocurarine): The effect of non-depolarising skeletal muscle relaxants may be potentiated by hydrochlorothiazide.

Other interactions: The hyperglycaemic effect of beta blockers and diazoxide may be enhanced by thiazides. Anticholinergic agents (e.g. atropine, biperiden) may increase the bioavailability of thiazide-type diuretics by decreasing gastrointestinal motility and stomach-emptying rate. Thiazides may increase the risk of adverse effects caused by amantadine. Thiazides may reduce the renal excretion of cytotoxic medicinal products (e.g. cyclophosphamide, methotrexate) and potentiate their myelosuppressive effects.

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 RAAS have been associated with serious foetal malformations and neonatal death when used during second and third trimesters.

Prolonged exposure to thiazides during the third trimester of pregnancy can reduce maternal plasma volume as well as uteroplacental blood flow, which may cause a foeto-placental ischaemia and growth retardation. Moreover, rare cases of hypoglycaemia and thrombocytopenia in neonates have been reported following exposure near term.

No specific clinical studies have been performed with this combination, therefore Rasilez HCT should not be used during the first trimester of pregnancy or in women planning to become pregnant and is contraindicated during the second and third trimesters (see section 4.3). A switch to a suitable alternative treatment should be carried out in advance of a planned pregnancy. If pregnancy is detected during therapy, Rasilez HCT should be discontinued as soon as possible.

Breast-feeding

Rasilez HCT is contraindicated during lactation (see section 4.3). It is not known whether aliskiren is excreted in human milk. Aliskiren was secreted in the milk of lactating rats. Thiazides appear in human milk and may inhibit lactation. They can produce adverse biological effects including hypokalaemia, haemolysis (glucose-6-phosphate dehydrogenase (G6PD) defect) and hypersensitivity due to sulphonamide properties.

No studies on the effect on the ability to drive and use machines have been performed. Rasilez HCT is unlikely to affect the ability to drive and use machines. However, when driving vehicles or operating machinery it must be borne in mind that dizziness or drowsiness may occasionally occur when taking antihypertensive therapy.

Aliskiren/hydrochlorothiazide combination

The safety of Rasilez HCT has been evaluated in 9 clinical trials with more than 3,900 patients, including over 700 treated for over 6 months, and 190 for over 1 year. The incidence of adverse reactions showed no association with gender, age, body mass index, race or ethnicity. Treatment with Rasilez HCT had an overall incidence of adverse experiences at doses up to 300 mg/25 mg similar to placebo. Adverse reactions have generally been mild and transient in nature and have only infrequently required discontinuation of therapy. The most common adverse drug reaction observed with Rasilez HCT is diarrhoea. The adverse drug reactions previously reported with one of the individual components of Rasilez HCT (aliskiren and hydrochlorothiazide) and listed in the respective paragraphs on the individual components may occur with Rasilez HCT.

The frequency of adverse reactions listed below is defined 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) and not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Diarrhoea: Diarrhoea is a dose-related adverse drug reaction for aliskiren. In controlled clinical trials, the incidence of diarrhoea in Rasilez HCT-treated patients was 1.3% compared to 1.4% for aliskiren- or 1.9% for hydrochlorothiazide-treated patients.

Serum potassium: In a large placebo-controlled clinical trial, the opposite effects of aliskiren (150 mg or 300 mg) and hydrochlorothiazide (12.5 mg or 25 mg) on serum potassium approximately balanced each other in many patients. In other patients, one or the other effect may be dominant. Periodic determinations of serum potassium to detect possible electrolyte imbalance should be performed in patients at risk at appropriate intervals (see sections 4.4 and 4.5).

Additional information on individual components

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

Aliskiren

Treatment with Aliskiren up to 300 mg resulted in an overall incidence of adverse reactions similar to placebo. Adverse reactions have generally been mild and transient in nature and have only infrequently required discontinuation of therapy. The most common adverse drug reaction is diarrhoea.

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

Angioedema and hypersensitivity reactions 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 medicines known to cause angioedema, including RAAS blockers (ACE inhibitors or ARBs).

Hypersensitivity reactions have also been reported in post-marketing experience.

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 some cases this occurred as part of a hypersensitivity reaction.

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 agents acting on the renin-angiotensin system, such as ACEI 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).

In post-marketing experience, renal dysfunction and cases of acute renal failure have been reported in patients at risk (see section 4.4). There have also been reports of peripheral oedema, increase in blood creatinine and severe cutaneous adverse reactions (SCARs) including toxic epidermal necrolysis (TEN) and oral mucosal reactions.

Hydrochlorothiazide

Adverse events (regardless of relationship to medicinal product) reported with the use of hydrochlorothiazide alone include:

No information is available on the treatment of overdose with Rasilez HCT. The most likely manifestation of overdose would be hypotension, related to the antihypertensive effect of aliskiren.

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

Pharmacotherapeutic group: Renin inhibitor (aliskiren) combinations with diuretics (hydrochlorothiazide), ATC code: C09XA52

Rasilez HCT combines two antihypertensive compounds to control blood pressure in patients with essential hypertension: Aliskiren belongs to the class of direct renin inhibitors and hydrochlorothiazide to the class of thiazide diuretics. The combination of these substances with complementary mechanisms of action provides an additive antihypertensive effect, reducing blood pressure to a greater degree than either component alone.

Aliskiren

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 agents that inhibit the RAAS (angiotensin converting enzyme inhibitors (ACEI) and angiotension 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 agents. The clinical implications of the effects on PRA are not known at the present time.

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 blood-pressure-lowering effect was observed after 2 weeks. The blood-pressure-lowering effect was sustained during long-term treatment (12 months), and was independent of age, gender, body mass index and ethnicity.

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 efficacious and well tolerated.

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 a 8-week study in 754 hypertensive elderly ( 65 years) and very elderly patients (30% 75 years) 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 effect on pulse rate in patients treated in controlled clinical studies. 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. Preliminary study results indicated a hazard ratio for the primary endpoint of 1.09 in favour of placebo (95% Confidence Interval: 0.97, 1.22, 2-sided p=0.17). In addition, an increased incidence of serious adverse outcomes was observed with aliskiren compared to placebo for renal complications (4.7% versus 3.3%), hyperkalaemia (36.9% versus 27.1%), hypotension (18.4% versus 14.6%) and stroke (2.7% versus 2.0%). The increased incidence of non-fatal stroke was greater in patients with renal insufficiency.

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.

Aliskiren/hydrochlorothiazide

Over 3,900 hypertensive patients received Rasilez HCT once daily in clinical trials.

In hypertensive patients, once-daily administration of Rasilez HCT provided dose-dependent reductions in both systolic and diastolic blood pressure that were maintained over the entire 24-hour dose interval. The antihypertensive effect is largely manifested within 1 week and the maximum effect is generally seen within 4 weeks.The blood-pressure-lowering effect was sustained during long-term treatment, and was independent of age, gender, body mass index and ethnicity. The antihypertensive effect of a single dose of the combination persisted for 24 hours. Upon withdrawal of the aliskiren treatment (aliskiren with or without hydrochlorothiazide add-on), the return of blood pressure towards baseline was gradual (3-4 weeks) with no evidence of the rebound effect.

Rasilez HCT was studied in a placebo-controlled trial including 2,762 hypertensive patients with diastolic blood pressure 95 mmHg and < 110 mmHg (mean baseline blood pressure of 153.6/99.2 mmHg). In this study, Rasilez HCT in doses from 150 mg/12.5 mg to 300 mg/25 mg produced dose-dependent blood pressure reductions (systolic/diastolic) from 17.6/11.9 mmHg to 21.2/14.3 mmHg, respectively, compared to 7.5/6.9 mmHg with placebo. The greater blood pressure reductions with these combination doses were also significantly greater than the respective doses of aliskiren and hydrochlorothiazide when used alone. The combination of aliskiren and hydrochlorothiazide neutralised the reactive increase of PRA caused by hydrochlorothiazide.

When administered in hypertensive patients with markedly elevated blood pressure (systolic blood pressure 160 mmHg and/or diastolic blood pressure 100 mmHg), Rasilez HCT in doses from 150 mg/12.5 mg to 300 mg/25 mg administered without up-titration from monotherapy demonstrated significantly greater systolic/diastolic blood pressure control rates (< 140/90 mmHg) as compared to the respective monotherapies. In this population, Rasilez HCT 150 mg/12.5 mg to 300 mg/25 mg provided dose-dependent systolic/diastolic blood pressure reduction from 20.6/12.4 mmHg to 24.8/14.5 mmHg, which were significantly superior to the respective monotherapies. The safety of the combination therapy was similar to the respective monotherapies regardless of severity of hypertension or of the presence or absence of additional cardiovascular risk. Hypotension and related adverse events were uncommon with the combination treatment, with no increased incidence in elderly patients.

In a study in 880 randomised patients not adequately responsive to aliskiren 300 mg treatment, the combination of aliskiren/hydrochlorothiazide 300 mg/25 mg produced systolic/diastolic blood pressure reductions of 15.8/11.0 mmHg, which were significantly greater than aliskiren 300 mg monotherapy. In a study in 722 randomised patients not adequately responsive to hydrochlorothiazide 25 mg treatment, the combination of aliskiren/hydrochlorothiazide 300 mg/25 mg produced systolic/diastolic blood pressure reductions of 16.78/10.7 mmHg, which were significantly greater than hydrochlorothiazide 25 mg monotherapy.

In another clinical trial, the efficacy and safety of Rasilez HCT were also assessed in 489 obese hypertensive patients who did not respond to hydrochlorothiazide 25 mg (baseline systolic/diastolic blood pressure 149.4/96.8 mmHg). In this difficult-to-treat population, Rasilez HCT provided a blood pressure reduction (systolic/diastolic) of 15.8/11.9 mmHg compared to 15.4/11.3 mmHg for irbesartan/hydrochlorothiazide, 13.6/10.3 mmHg for amlodipine/hydrochlorothiazide and 8.6/7.9 mmHg for hydrochlorothiazide monotherapy, with similar safety to hydrochlorothiazide monotherapy.

In a study in 183 randomised patients with severe hypertension (mean sitting diastolic blood pressure 105 and < 120 mmHg), aliskiren treatment regimen with optional addition of hydrochlorothiazide 25 mg was shown to be safe and efficacious in reducing blood pressure.

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 C_max by 85% and AUC by 70%. 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.

Metabolism and elimination

The mean half-life is about 40 hours (range 34-41 hours). Aliskiren is mainly eliminated as unchanged compound in the faeces (oral radioactive dose recovery = 91%). 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, the mean plasma clearance is approximately 9 l/h.

Linearity

Exposure to aliskiren increased slightly 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 C_max, respectively. Mechanisms responsible for the deviation from dose proportionality have not been identified. A possible mechanism is saturation of transporters at the absorption site or at the hepatobiliary clearance route.

Hydrochlorothiazide

Absorption

The absorption of hydrochlorothiazide, after an oral dose, is rapid (T_max about 2 h), with similar absorption characteristics for both suspension and tablet formulations. Absolute bioavailability of hydrochlorothiazide is 60-80% after oral administration.

Concomitant administration with food has been reported to both increase and decrease the systemic availability of hydrochlorothiazide compared with the fasted state. The magnitude of these effects is small and has little clinical importance.

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.

Metabolism and elimination

After oral administration, > 95% of the absorbed dose being excreted as unchanged compound in the urine. The distribution and elimination kinetics have generally been described by a bi-exponential decay function, with a terminal half-life of 6-15 h.

Linearity

The increase in mean AUC is linear and dose proportional in the therapeutic range. There is no change in the kinetics of hydrochlorothiazide on repeated dosing, and accumulation is minimal when dosed once daily.

Aliskiren/hydrochlorothiazide

Following oral administration of Rasilez HCT tablets, the median peak plasma concentration time is within 1 hour for aliskiren and 2.5 hours for hydrochlorothiazide.

The rate and extent of absorption of Rasilez HCT are equivalent to the bioavailability of aliskiren and hydrochlorothiazide when administered as individual monotherapies. Similar food effect was observed for Rasilez HCT as for the individual monotherapies.

Characteristics in patients

Rasilez HCT has been shown to be effective as a once-a-day antihypertensive treatment in adult patients, regardless of gender, age, body mass index and ethnicity.

The pharmacokinetics of aliskiren and hydrochlorothiazide are not significantly affected in patients with mild to moderate liver disease. Consequently, no initial dose adjustment of Rasilez HCT is required in patients with mild to moderate hepatic impairment. No data are available on patients with severe hepatic impairment treated by Rasilez HCT. However, due to its hydrochlorothiazide component, Rasilez HCT is contraindicated in patients with severe hepatic impairment (see section 4.3).

No adjustment of the initial dose is required for patients with mild to moderate renal impairment (see sections 4.4 and 4.2). Rasilez HCT is contraindicated in patients with severe renal impairment (GFR < 30 ml/min/1.73 m²) and the concomitant use of Rasilez HCT with ARBs or ACEIs is contraindicated in patients with renal impairment (GFR < 60 ml/min/1.73 m²) (see section 4.3).

No initial dose adjustment of Rasilez HCT is required in elderly patients.

No pharmacokinetic data are available in the paediatric population.

Safety pharmacology studies with aliskiren 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. No carcinogenic potential for aliskiren was detected in a 2-year rat study and a 6-month transgenic mouse study. One colonic adenoma and one caecal adenocarcinoma recorded in rats at the dose of 1,500 mg/kg/day were not statistically significant. Aliskiren was devoid of any mutagenic potential, embryo-foetal toxicity or teratogenicity. Fertility, prenatal development and postnatal development were unaffected in rats.

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.

The findings observed in the 2-week and 13-week toxicity studies were consistent with those observed previously with aliskiren or hydrochlorothiazide monotherapies. There were no new or unexpected findings observed of relevance to human use. Increased cellular vacuolation of the adrenal gland zona glomerulosa was observed during the 13-week toxicity study in rats. The finding was observed in animals treated with hydrochlorothiazide but not in those animals receiving aliskiren alone or vehicle. There was no evidence that this finding was enhanced in the aliskiren/hydrochlorothiazide combination as it was only apparent at a minimal severity in all animals.

Tablet core:

Cellulose microcrystalline

Crospovidone

Lactose monohydrate

Wheat starch

Povidone

Magnesium stearate

Silica colloidal anhydrous

Talc

Coating:

Rasilez HCT 150 mg/12.5 mg film-coated tablets:

Talc

Hypromellose

Macrogol

Titanium dioxide (E171)

Rasilez HCT 150 mg/25 mg film-coated tablets:

Talc

Hypromellose

Macrogol

Titanium dioxide (E171)

Red iron oxide (E172)

Yellow iron oxide (E172)

Rasilez HCT 300 mg/12.5 mg film-coated tablets:

Talc

Hypromellose

Macrogol

Titanium dioxide (E171)

Red iron oxide (E172)

Black iron oxide (E172)

Rasilez HCT 300 mg/25 mg film-coated tablets:

Talc

Hypromellose

Macrogol

Titanium dioxide (E171)

Red iron oxide (E172)

Yellow iron oxide (E172)

Not applicable.

24 months

Do not store above 30°C.

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

PA/Alu/PVC – Alu blisters:

Single-packs containing 7, 14, 28, 30, 50 or 56 tablets.

Multi-packs containing 90, 98 or 280 tablets.

PVC/polychlorotrifluoroethylene (PCTFE) – Alu blisters:

Single-packs containing 7, 14, 28, 30, 50, 56, 90 or 98 tablets.

Single-packs (perforated unit dose blister) containing 56 x 1 tablets.

Multi-packs containing 280 tablets.

Multi-packs (perforated unit dose blister) containing 98 x 1 tablets.

Not all pack sizes or strengths may be marketed.

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

Novartis Europharm Limited

Wimblehurst Road

Horsham

West Sussex, RH12 5AB

United Kingdom

EU/1/08/491/001-020

16.01.2009

April 2012