Sprimeo HCT - summary of medicine characteristics

4.2 Posology and method of administration

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

Sprimeo 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 Sprimeo HCT 150 mg/12.5 mg.

If blood pressure remains uncontrolled after 2–4 weeks of therapy, the dose may be titrated up to a maximum of Sprimeo 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 Sprimeo HCT containing the same component doses.

Renal impairment

No adjustment of the initial dose is required for patients with mild to moderate renal impairment (see sections 4.4 and 5.2). Due to the hydrochlorothiazide component, Sprimeo HCT is contraindicated for use in patients with anuria and in patients with severe renal impairment (glomerular filtration rate (GFR) < 30 ml/min/1.73 m2). The concomitant use of Sprimeo 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

No adjustment of the initial dose is required for patients with mild to moderate hepatic impairment (see section 5.2). Sprimeo 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

Sprimeo 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).

4.3

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 (see section 4.6).

Anuria.

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

Refractory hypokalaemia, hyponatraemia, hypercalcaemia and symptomatic hyperuricaemia.

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).

4.4 Special warnings and precautions for use

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). Sprimeo 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, Sprimeo 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.

Sodium- and/or volume-depleted patients

In sodium-depleted and/or volume-depleted patients, such as those receiving high doses of diuretics, symptomatic hypotension may occur after initiation of treatment with Sprimeo HCT. Sprimeo HCT should be used only after correction of any pre-existing sodium and/or volume depletion.

Electrolyte imbalance

Treatment with Sprimeo HCT 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 Sprimeo HCT should be discontinued until stable correction of the potassium balance. 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).

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 correction of pre-existing hyponatraemia. In case severe or rapid hyponatraemia develops during Sprimeo HCT therapy, the treatment should be discontinued until normalisation of natraemia.

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

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. Sprimeo HCT is contraindicated in patients with hypercalcaemia and should only be used after correction of any preexisting hypercalcaemia. Sprimeo HCT 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 impairment and kidney transplantation

Thiazide diuretics may precipitate azotaemia in patients with chronic kidney disease. When Sprimeo HCT is used in patients with renal impairment, periodic monitoring of serum electrolytes including potassium, creatinine and uric acid serum levels is recommended. Sprimeo HCT is contraindicated in patients with severe renal impairment or anuria (see section 4.3).

No dosage adjustment is necessary in patients with mild to moderate renal impairment (GFR > 30 ml/min/1.73 m2).

There is no experience regarding the administration of Sprimeo HCT in patients who have recently undergone kidney transplantation.

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       K

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. No adjustment of the initial dose is required for patients with mild to moderate hepatic impairment. No data are available for the use of Sprimeo HCT in patients with severe hepatic impairment. Due to the hydrochlorothiazide component, Sprimeo HCT is contraindicated in patients with severe hepatic impairment (see sections 4.3 and 5.2).

There is no clinical experience with Sprimeo 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 Sprimeo 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.

Systemic lupus erythematosus

Thiazide diuretics, including hydrochlorothi­azide, have been reported to exacerbate or activate systemic lupus erythematosus.

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 dosage adjustments of insulin or oral hypoglycaemic agents may be required. Concomitant use of Sprimeo HCT with ARBs or ACEIs is contraindicated in patients with diabetes mellitus (see section 4.3).

Due to the hydrochlorothiazide component, Sprimeo HCT 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. Sprimeo HCT is contraindicated in patients with hypercalcaemia and should only be used after correction of any preexisting hypercalcaemia. Sprimeo HCT 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.

Photosensitivity

Cases of photosensitivity reactions have been reported with thiazide diuretics (see section 4.8). If photosensitivity reaction occurs during treatment with Sprimeo HCT, 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 glauco ma^S

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.

General

In the event of severe and persistent diarrhoea, Sprimeo 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, but are more likely in patients with allergy and asthma.

Excipients

Sprimeo 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.

Sprimeo 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.

4.5 Interaction with other medicinal products and other forms of interaction

Information on Sprimeo 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, corticosteroids, laxatives, adrenocorticotropic 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 Sprimeo HCT is administered with medicinal products affected by serum potassium disturbances (e.g. digitalis glycosides, antiarrhythmics).

Non-steroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase-2 inhibitors (COX-2 inhibitors), acetylsalicylic acid and non-selective NSAIDs: As with other agents acting on the renin-angiotensin system, NSAIDs may reduce the anti-hypertensive effect of aliskiren. NSAIDs may also weaken the diuretic and antihypertensive activity of hydrochlorothi­azide.

In some patients with compromised renal function (dehydrated patients or elderly patients) aliskiren and hydrochlorothiazide given concomitantly with NSAIDs may result in further deterioration of renal function, including possible acute renal failure, which is usually reversible. Therefore the use of Sprimeo HCT with an NSAID requires caution, especially in elderly patients.

Other antihypertensive agents: The antihypertensive effect of Sprimeo 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 coadministered 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 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).

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 Cmax 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 Cmax 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 Sprimeo HCT.

Furosemide: When aliskiren was co-administered with furosemide, the AUC and Cmax 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.

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.

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.

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.

Digoxine or other digitalis glycosides: Thiazide-induced hypokalaemia or hypomagnesaemia may occur as undesirable effects, favouring the onset of digitalis-induced cardiac arrhythmias.

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.

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.

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.

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.

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 thiazidetype diuretics.

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

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.

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

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

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.

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.

4.6 Fertility, pregnancy and lactation

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. 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.

No specific clinical studies have been performed with this combination, therefore Sprimeo 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, Sprimeo HCT should be discontinued as soon as possible.

Breast-feeding

It is not known whether aliskiren is 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 Sprimeo HCT during breast-feeding is not recommended. If Sprimeo HCT is used during breast-feeding, doses should be kept as low as possible.

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. Sprimeo 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.

4.8 Undesirable effects

Aliskiren/hydrochlo­rothiazide combination

The safety of Sprimeo HCT has been evaluated in 9 clinical trials with including over 700 treated for over 6 months, and 190 for over 1 year.

reactions showed no association with gender, age, body mass index, race or ethnicity. Treatment with Sprimeo 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 Sprimeo HCT is diarrhoea. The adverse drug reactions previously reported with one of the individual components of Sprimeo HCT (aliskiren and hydrochlorothi­azide) and listed in the respective paragraphs on the individual components may occur with Sprimeo 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.

Common:          Diarrhoea

Diarrhoea : Diarrhoea is a dose-related adverse drug reaction for aliskiren. In controlled clinical trials, the incidence of diarrhoea in Sprimeo 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 Sprimeo 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.

Common:          Dizziness

Vascular disorders

Uncommon:        Hypotension

Gastrointestinal disorders

Common:          Diarrhoea

Immune system disorders

Rare:                H­ypersensitivi­ty reactions

Skin and subcutaneous tissue disorders

Uncommon:         Rash, severe cutaneous adverse reactions (SCARs) including toxic

epidermal necrolysis (TEN) and oral mucosal reactions

Rare:              An­gioedema

Musculoskeletal and connective tissue disorders

Common:           Arthral­gia

Renal and urinary disorders

Uncommon:         Acute renal failure, renal impairment

General disorders and administration site conditions

Uncommon:        Oedema peripheral

Investigations

Common:          Hyper­kalaemia

Rare:               ­Haemoglobin decreased, haematocrit decreased

Rare:                B­lood creatinine increased

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 reninangiotensin 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

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

4.9 Overdose

No information is available on the treatment of overdose with Sprimeo 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.

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 asren over-exposure.

5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties

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

Sprimeo 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 bloodpressure-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 (3o% > 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 Sprimeo HCT once daily in clinical trials.

In hypertensive patients, once-daily administration of Sprimeo 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.

Sprimeo 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, Sprimeo 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), Sprimeo 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, Sprimeo 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 Sprimeo 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, Sprimeo 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.

5.2 Pharmacokinetic properties

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%. 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.

X.CT