RASILEZ - PACKAGE LEAFLET - LEAFLETS

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Rasilez - Package Leaflet

Indications Contraindications Precautions for use Interactions Warnings Dosage and method of use Overdose Undesirable Effects Shelf Life and Storage

Active ingredients: Aliskiren

Rasilez 150 mg film-coated tablets
Rasilez 300 mg film-coated tablets

Why is Rasilez used? What is it for?

This medicine contains an active substance called aliskiren. Aliskiren belongs to a class of medicines called renin inhibitors. Renin inhibitors reduce the amount of angiotensin II produced by the body. Angiotensin II causes blood vessels to narrow, thereby increasing blood pressure. Reducing the amount of angiotensin II allows blood vessels to relax, resulting in lower blood pressure.

This helps reduce high blood pressure in adult patients. High blood pressure increases the workload of the heart and arteries. If it continues for a long time, this condition can damage the blood vessels of the brain, heart, and kidneys and can cause stroke, heart failure, heart attack, or kidney failure. Reducing blood pressure to normal levels reduces the risk of developing these conditions.

Contraindications When Rasilez should not be used

Do not take Rasilez

if you are allergic to aliskiren or any of the other ingredients of this medicine. If you think you may be allergic, ask your doctor for advice.
if you have experienced the following forms of angioedema (difficulty in breathing or swallowing or swelling of the face, hands and feet, eyes, lips and / or tongue):
- angioedema when taking aliskiren.
- hereditary angioedema.
- angioedema with no known cause.
during the last 6 months of pregnancy or if you are breast-feeding, see section "Pregnancy and breast-feeding".
if you are taking cyclosporine (a medicine used in transplantation to prevent organ rejection or for other conditions such as rheumatoid arthritis or atopic dermatitis), itraconazole (a medicine used to treat fungal infections) or quinidine (a medicine used to correct the heart rhythm).
if you have diabetes or impaired kidney function and you are being treated with the following classes of medicines used to treat high blood pressure:
- an angiotensin converting enzyme inhibitor such as enalapril, lisinopril, ramipril or
- an angiotensin II receptor blocker such as valsartan, telmisartan, irbesartan.
if the patient is less than 2 years of age.

Precautions for use What you need to know before taking Rasilez

Talk to your doctor before taking Rasilez:

if you are taking a diuretic (a type of medicine that increases the amount of urine produced).
if you are taking the following classes of medicines used to treat high blood pressure:
- an angiotensin converting enzyme inhibitor such as enalapril, lisinopril, ramipril or
- an angiotensin II receptor blocker such as valsartan, telmisartan, irbesartan.
if your kidney function is impaired, your doctor will carefully consider whether this medicine is suitable for you and may wish to monitor you closely.
if you have already experienced angioedema (difficulty in breathing or swallowing or swelling of the face, hands and feet, eyes, lips and / or tongue). If this happens, stop taking this medicine and contact your doctor.
if you suffer from renal artery stenosis (narrowing of the blood vessels of one or both kidneys).
if you have severe congestive heart failure (a type of heart disease in which the heart cannot pump enough blood around the body).

If you have severe and persistent diarrhea you should stop taking Rasilez.

Your doctor may check your kidney function, blood pressure and the amount of electrolytes (for example potassium) in your blood at regular intervals.

See also information under the heading "Do not take Rasilez".

Children and adolescents

This medicine should not be used in children from birth to less than 2 years of age. It should not be used in children 2 to less than 6 years of age and is not recommended for use in children and adolescents 6 to less than 18 years of age.

Senior citizens

In most patients 65 years of age and older, the Rasilez 300 mg dose has no additional blood pressure lowering benefit over the 150 mg dose.

Interactions Which drugs or foods may change the effect of Rasilez

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.

If you are taking any of the following medicines your doctor may need to change your dose and / or take other precautions:

medicines that increase the amount of potassium in the blood. These include potassium-sparing diuretics and potassium supplements.
Furosemide or torasemide, medicines belonging to the class of diuretics, used to increase the amount of urine produced.
an angiotensin II receptor blocker or an angiotensin converting enzyme inhibitor.
ketoconazole, a medicine used to treat fungal infections.
verapamil, a medicine used to lower blood pressure, to correct heart rhythm or to treat angina pectoris.
some types of pain relievers known as non-steroidal anti-inflammatory drugs (NSAIDs).

Rasilez with food and drink

You should take this medicine either with a light meal or no meal once a day, preferably at the same time each day. You should avoid taking this medicine together with fruit juice and / or drinks containing plant extracts (including herbal infusions).

Warnings It is important to know that:

Pregnancy and breastfeeding

Pregnancy: do not take this medicine if you are pregnant (see section Do not take Rasilez). If you discover that you are pregnant while taking this medicine, stop taking it immediately and consult your doctor. If you suspect that you are pregnant or are planning to become pregnant, ask your doctor or pharmacist for advice before taking this medicine. Your doctor will usually advise you to stop taking this medicine before becoming pregnant and will advise you to take another medicine instead of this medicine. Rasilez is not recommended in early pregnancy, and should not be taken when you have been pregnant for more than 3 months, as it can cause serious harm to your baby if used after the third month of pregnancy.

Breastfeeding: Tell your doctor if you are breastfeeding or about to start breastfeeding. This medicine is not recommended for women who are breastfeeding and your doctor may choose another treatment for you if you wish to breastfeed.

Driving and using machines

This medicine can make you feel dizzy and this can affect your ability to concentrate. Before you drive a vehicle, operate machinery or perform other activities that require concentration, you should know your reaction to the effects of this medicine.

Dose, Method and Time of Administration How to use Rasilez: Posology

Always take this medicine exactly as your doctor has told you. If in doubt, consult your doctor or pharmacist.

Those with high blood pressure often don't notice any signs of this problem. Many feel quite normal. For best results and to reduce the risk of side effects it is very important that you take this medicine exactly as directed by your doctor. Keep your appointments with your doctor even if you feel well.

Normally the starting dosage is one 150 mg tablet once a day. The blood pressure lowering effect occurs within two weeks of starting therapy.

Based on your response to treatment, your doctor may prescribe a higher dose of one 300 mg tablet once a day. Your doctor may prescribe this medicine together with other medicines used to treat high blood pressure.

Method of administration

Take the tablet whole with some water. You must take this medicine once a day, always with or always without food, preferably at the same time each day. He must establish a comfortable daily schedule to take the medicine the same way every day, respecting the timing of his meals. You should avoid taking this medicine together with fruit juice and / or drinks containing plant extracts (including herbal infusions). During treatment, your doctor may adjust the dose according to your blood pressure response.

If you forget to take Rasilez

If you forget to take a dose of this medicine, take it as soon as you remember and then take your next dose at the usual time. However, if it is almost time for your next dose, you can simply take the next tablet at the usual time. Do not take a double dose to make up for a forgotten dose.

Overdose What to do if you have taken too much Rasilez

If you have accidentally taken too many tablets of this medicine, contact your doctor immediately. He may need medical attention.

Side Effects What are the side effects of Rasilez

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Some side effects can be serious (frequency not known):

some patients have reported serious side effects. Tell your doctor immediately if you experience any of the following:

severe allergic reaction with symptoms such as rash, itching, swelling of the face or lips or tongue, difficulty breathing, dizziness.

Possible side effects

Common (may affect up to 1 in 10 people): diarrhea, pain in the joints (arthralgia), high levels of potassium in the blood, dizziness.

Uncommon (may affect up to 1 in 100 people): skin rash (may also be a sign of allergic reactions or angioedema - see side effects below after "Rare"), kidney problems including acute kidney failure (severe decrease in amount of urine), swelling of the hands, ankles or feet (peripheral edema), severe skin reactions (toxic epidermal necrolysis and / or oral mucosal reactions - skin redness, blistering of the lips, eyes or mouth, skin peeling, fever ), low blood pressure, palpitations, cough, itching, itchy rash (hives), increased liver (liver) enzymes.

Rare (may affect up to 1 in 1,000 people): increase in blood creatinine levels, decrease in blood hemoglobin levels (anemia), decrease in red blood cell levels, redness of the skin (erythema).

Not known (frequency cannot be estimated from the available data): spinning sensation, low sodium levels in the blood, shortness of breath, nausea, vomiting, signs of liver problems (nausea, loss of appetite, dark urine or yellowing of the skin and eyes).

If any of these effects occur severely, consult your doctor.You may need to stop Rasilez.

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system. By reporting side effects you can help provide more information on the safety of this medicine.

Expiry and Retention

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton and blister. The expiry date refers to the last day of that month.

Do not store above 30 ° C.

Store in the original package to protect from moisture.

Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.

Other Information

What Rasilez contains

The active substance is aliskiren (as hemifumarate). Rasilez 150 mg film-coated tablets contain 150 mg of aliskiren and Rasilez 300 mg film-coated tablets contain 300 mg of aliskiren.
The other ingredients are crospovidone, hypromellose, magnesium stearate, macrogol, microcrystalline cellulose, povidone, anhydrous colloidal silica, talc, titanium dioxide (E 171), black iron oxide (E 172), red iron oxide (E 172).

What Rasilez looks like and contents of the pack

Rasilez 150 mg film-coated tablets are light pink, biconvex, round tablets debossed with "IL" on one side and "NVR" on the other.

Rasilez 300 mg film-coated tablets are light red, biconvex, ovaloid tablets, debossed with the letters "IU" on one side and "NVR" on the other.

Rasilez 150 mg film-coated tablets are available in the following pack sizes:

Single packs containing 7, 14, 28, 30, 50, 56, 90 or 98 tablets
Single packs containing 56x1 tablets in perforated unit dose blisters
Multipacks containing 84 (3x28), 98 (2x49) or 280 (20x14) tablets
Packs containing 98 (2x49x1) tablets in perforated unit dose blisters

Rasilez 300 mg film-coated tablets are available in the following pack sizes:

Single packs containing 7, 14, 28, 30, 50, 56, 90 or 98 tablets
Single packs containing 56x1 tablets in perforated unit dose blisters
Multipacks containing 84 (3x28), 90 (3x30), 98 (2x49) or 280 (20x14) tablets
Packs containing 98 (2x49x1) tablets in perforated unit dose blisters.

Not all packs may be available in your country.

Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.

Further information on Rasilez can be found in the "Summary of Characteristics" tab. 01.0 NAME OF THE MEDICINAL PRODUCT 02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION 03.0 PHARMACEUTICAL FORM 04.0 CLINICAL PARTICULARS 04.1 Therapeutic indications 04.2 Posology and method of administration 04.3 Contraindications 04.4 Special warnings and appropriate precautions for use 04.5 Interactions with other medicinal products and other forms of interaction04.6 Pregnancy and lactation04.7 Effects on ability to drive and use machines04.8 Undesirable effects04.9 Overdose05.0 PHARMACOLOGICAL PROPERTIES05.1 Pharmacodynamic properties05.2 Pharmacokinetic properties05.3 Preclinical safety data06.0 INFORMATION PHARMACEUTICALS 06.1 Excipients 06.2 Incompatibilities 06.3 Shelf life 06.4 Special precautions for storage 06.5 Nature of the immediate packaging and contents of the package 06.6 Instructions for use and handling 07.0 MARKETING AUTHORIZATION HOLDER08 .0 MARKETING AUTHORIZATION NUMBER 09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION 10.0 DATE OF REVISION OF THE TEXT 11.0 FOR RADIOPharmaceuticals, FULL DATA ON INTERNAL RADIATION DOSIMETRY 12.0 FOR RADIO DRUGS, ADDITIONAL DETAILED INSTRUCTIONS ON ESTEMPORANEA PREPARATION AND CONTROL

01.0 NAME OF THE MEDICINAL PRODUCT

RASILEZ HCT 150 MG / 12.5 MG TABLETS COATED WITH FILM

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 150 mg of aliskiren (as hemifumarate) and 12.5 mg of hydrochlorothiazide.

Excipients with known effects:

Each tablet contains 25 mg of lactose (as monohydrate) and 24.5 mg of wheat starch.

For the full list of excipients, see section 6.1.

03.0 PHARMACEUTICAL FORM

Film-coated tablet

White, biconvex, ovaloid film-coated tablet debossed with "LCI" on one side and "NVR" on the other.

04.0 CLINICAL INFORMATION

04.1 Therapeutic indications

Treatment of essential hypertension in adults.

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

Rasilez HCT is indicated as replacement therapy in patients adequately controlled with aliskiren and hydrochlorothiazide, administered concomitantly, at the same dose as the combination.

04.2 Posology and method of administration

Dosage

The recommended dose of Rasilez HCT is one tablet once a day.

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

Posology in patients inadequately controlled on aliskiren or hydrochlorothiazide alone

It is recommended to identify the effective dose of each of the two components before switching to the fixed combination. When clinically appropriate, a direct switch from monotherapy to fixed combination can be considered.

Rasilez HCT 150 mg / 12.5 mg may be administered to patients in whom adequate blood pressure control is not achieved with aliskiren 150 mg or hydrochlorothiazide 12.5 mg alone.

If blood pressure control is not achieved after 2-4 weeks of therapy, the dose can be increased to a maximum of Rasilez HCT 300 mg / 25 mg per day. Dosage should be individualized and adjusted according to the patient's clinical response.

Posology as replacement therapy

For convenience, patients treated with aliskiren and hydrochlorothiazide as separate tablets can be switched to a Rasilez HCT fixed combination tablet containing the same dose of the active substances.

Special populations

Renal impairment

Due to the hydrochlorothiazide component, the use of Rasilez HCT is contraindicated in patients with anuria and in patients with severe renal impairment (glomerular filtration rate (GFR) 2). No adjustment of the starting dose is required in patients with renal impairment due to mild to moderate (see sections 4.4 and 5.2).

Hepatic impairment

Rasilez HCT is contraindicated in patients with severe hepatic impairment and should be used with caution in patients with mild to moderate hepatic impairment or in patients with progressive liver disease. No starting dose adjustment is required in patients with mild to moderate hepatic impairment (see sections 4.3, 4.4 and 5.2).

Elderly (over 65 years old)

In elderly patients, the recommended starting dose of aliskiren is 150 mg. In the majority of elderly patients no further clinically significant reduction in blood pressure was observed with dose escalation to 300 mg.

Pediatric population

The safety and efficacy of Rasilez HCT in children aged below 18 years have not yet been established. There are no data available.

Method of administration

Oral use. The tablets should be swallowed whole with some water. Rasilez HCT should be taken with a light meal once a day, preferably at the same time each day. Co-administration with fruit juice and / or drinks containing plant extracts (including herbal infusions) (see section 4.5).

04.3 Contraindications

• Hypersensitivity to the active substances or to any of the excipients listed in section 6.1, or to other derivatives of sulfonamide.

• History of angioedema with aliskiren.

• Hereditary or idiopathic angioedema.

• Second and third trimester of pregnancy (see section 4.6).

• Anuria.

• Severe renal impairment (GFR 2).

• Hyponatremia, hypercalcemia, symptomatic hyperuricaemia and refractory hypokalaemia.

• Severe hepatic impairment.

• The concomitant use of aliskiren with cyclosporine and itraconazole, two potent inhibitors of P-glycoprotein (P-gp), and with other potent P-gp inhibitors (eg quinidine) is contraindicated (see section 4.5).

• The concomitant use of Rasilez HCT with an ACEI or an ARB is contraindicated in patients with diabetes mellitus or renal impairment (GFR 2) (see sections 4.5 and 5.1).

04.4 Special warnings and appropriate precautions for use

General informations

In the event of severe and persistent diarrhea, Rasilez HCT therapy should be discontinued (see section 4.8).

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

Hypotension, syncope, stroke, hyperkalaemia and decreased renal function (including acute renal failure) have been reported in sensitive individuals, especially in the case of combination of medicinal products affecting this system (see section 5.1). Dual blockade of the RAAS by administering aliskiren with an ACEI or ARB is therefore not recommended. If dual block therapy is considered absolutely necessary, this should only be done under the supervision of a specialist and with close and frequent monitoring of kidney function, electrolytes and blood pressure.

Heart failure

Aliskiren should be used with caution in patients with severe congestive heart failure (New York Heart Association (NYHA) functional class III-IV) (see section 5.1). Rasilez HCT should be used with caution in patients with heart failure due to limited data on safety and efficacy.

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

Risk of symptomatic hypotension

Symptomatic hypotension may occur after initiation of treatment with Rasilez HCT in the following cases:

• Patients with severe water or sodium depletion (eg those on high dose diuretic therapy) or

• Combined use of aliskiren with other medicines that affect the RAAS.

Volume or sodium depletion should be corrected before starting Rasilez HCT administration or treatment initiated under close medical supervision.

Electrolyte imbalance

Treatment with Rasilez HCT should only be initiated after correcting the hypokalaemia and any concomitant hypomagnesaemia. Thiazide diuretics may precipitate new onset "hypokalaemia or exacerbate pre-existing hypokalaemia. Thiazide diuretics should be administered with caution in patients with conditions that lead to increased potassium loss, such as salt-wasting nephropathy and prerenal (cardiogenic) impairment." ) of renal function. If hypokalaemia develops during treatment with hydrochlorothiazide, treatment with Rasilez HCT should be stopped until stable correction of the potassium balance. Although hypokalaemia may develop with the use of thiazide diuretics, concomitant therapy with aliskiren may reduce diuretic-induced hypokalaemia. The risk of hypokalaemia is greater in patients with liver cirrhosis, in patients with profuse diuresis, in patients with inadequate oral electrolyte intake and in patients on concomitant treatment with corticosteroids or hormones adrenocorticotropic ( ACTH) (see sections 4.5 and 4.8).

Conversely, increases in serum potassium have been observed with aliskiren in post-marketing experience which may be exacerbated by use in combination with other substances acting on the RAAS or with non-steroidal anti-inflammatory drugs (NSAIDs). Consistent with standard medical practice, if co-administration is deemed necessary, periodic evaluation of renal function including that of serum electrolytes is recommended (see sections 4.5 and 4.8).

Thiazide diuretics can precipitate "new onset hyponatremia and" hypochloraemic alkalosis or exacerbate pre-existing hyponatraemia. Hyponatremia accompanied by neurological symptoms (nausea, progressive disorientation, apathy) has been observed. Treatment with hydrochlorothiazide should only be initiated after correction of pre-existing hyponatraemia. In case of severe or rapid onset hyponatraemia during Rasilez HCT therapy, treatment should be suspended until natremia is normalized.

There is no evidence that Rasilez HCT reduces or prevents diuretic-induced hyponatraemia. Chloride deficiency is usually mild and usually does not require treatment.

All patients being treated with thiazide diuretics should be monitored periodically for electrolyte imbalances, particularly potassium, sodium and magnesium.

Thiazides reduce urinary excretion of calcium and, in the absence of known disturbances of calcium metabolism, can cause an intermittent and mild increase in serum calcium. Rasilez HCT is contraindicated in patients with hypercalcaemia and should only be used after correcting a pre -existing hypercalcaemia. Rasilez HCT should be discontinued if hypercalcaemia develops during treatment. Serum calcium levels should be monitored periodically during treatment with thiazides. Marked hypercalcaemia may be indicative of latent hyperparathyroidism. Administration of thiazides should be discontinued first. to perform parathyroid function tests.

Renal impairment and kidney transplant

Thiazide diuretics may precipitate azotaemia in patients with chronic kidney disease. When Rasilez HCT is used in patients with impaired renal function, periodic monitoring of serum electrolytes, including potassium, creatinine and serum uric acid levels is recommended. Rasilez HCT is contraindicated in patients with severe renal impairment, 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 with the administration of Rasilez HCT in patients who have recently undergone kidney transplantation.

As with other medicinal products acting on the RAAS, caution should be exercised when aliskiren is administered in the presence of conditions predisposing to renal dysfunction such as hypovolaemia (e.g. caused by haemorrhage, severe or prolonged diarrhea, prolonged vomiting, etc.), heart disease , liver disease, diabetes mellitus or kidney disease. Acute renal failure, reversible upon discontinuation of treatment, has been reported in at-risk patients treated with aliskiren in post-marketing experience. In the event of any signs of renal insufficiency occurring, treatment with aliskiren should be promptly discontinued.

Hepatic impairment

No data are available with Rasilez HCT in patients with hepatic impairment. Rasilez HCT is contraindicated in patients with severe hepatic impairment and should be used with caution in patients with mild to moderate hepatic impairment or progressive liver disease. No initial dosage adjustment is required in patients with mild to moderate hepatic impairment (see sections 4.2, 4.3 and 5.2).

Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy

As with other vasodilators, particular caution is advised in patients with aortic and mitral stenosis or obstructive hypertrophic cardiomyopathy.

Renal artery stenosis and renovascular hypertension

There are no data from controlled clinical trials on the use of Rasilez HCT in patients with unilateral or bilateral renal artery stenosis or single kidney stenosis. However, as with other medicinal products acting on the RAAS, there is an increased risk of renal failure, including acute renal failure, when patients with renal artery stenosis are treated with aliskiren. Therefore, caution should be exercised in these patients. onset of renal failure, treatment should be stopped.

Anaphylactic reactions and angioedema

In post-marketing experience anaphylactic reactions have been observed during treatment with aliskiren (see section 4.8). As with other medicinal products that affect the RAAS, angioedema or symptoms suggestive of angioedema (swelling of the face) have been reported in patients treated with aliskiren. , lips, throat and / or tongue).

A percentage of these patients had a history of angioedema or symptoms suggestive of angioedema which in some cases accompanied the use of other medicinal products potentially causing angioedema, including RAAS blockers (angiotensin converting enzyme inhibitors or blockers angiotensin receptor) (see section 4.8).

Angioedema and angioedema-like reactions have been reported in post-marketing experience following administration of aliskiren in combination with ACEI and / or ARB (see section 4.8).

Particular caution is required in patients with a predisposition to hypersensitivity.

Patients with a history of angioedema may have an increased risk of developing angioedema during treatment with aliskiren (see sections 4.3 and 4.8). Therefore, caution should 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), particularly at the initiation of treatment.

In the event of anaphylactic reactions or angioedema occurring, Rasilez HCT should be promptly discontinued and appropriate therapy instituted as well as monitoring until complete and permanent resolution of the onset signs and symptoms. Patients should be advised to report to their physician any signs suggestive of allergic reactions, particularly difficulty in breathing or swallowing, swelling of the face, extremities, eyes, lips or tongue. If there is involvement of the tongue, glottis or larynx, adrenaline should be administered. In addition, the necessary measures must be taken to maintain a clear airway.

Systemic lupus erythematosus

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

Effects on metabolism and on the endocrine system

Thiazide diuretics, including hydrochlorothiazide, may impair glucose tolerance and raise serum cholesterol and triglyceride and uric acid levels. In diabetic patients, dose adjustments of insulin or oral hypoglycemic agents may be required.

Due to the hydrochlorothiazide component, Rasilez HCT is contraindicated in symptomatic hyperuricaemia (see section 4.3). Hydrochlorothiazide may raise serum uric acid levels due to decreased uric acid clearance and may cause or exacerbate hyperuricaemia as well as precipitate the gout in predisposed patients.

Thiazides reduce urinary excretion of calcium and, in the absence of known disturbances of calcium metabolism, may cause a mild and intermittent increase in serum calcium. Rasilez HCT is contraindicated in patients with hypercalcaemia and should only be used after correcting a pre -existing hypercalcaemia. Rasilez HCT should be discontinued if hypercalcaemia develops during treatment. Serum calcium levels should be monitored periodically during treatment with thiazides. Marked hypercalcaemia may be evidence of latent hyperparathyroidism. Administration of thiazides should be discontinued first. to perform parathyroid function tests.

Photosensitivity

Cases of photosensitivity reactions have been reported during treatment with thiazide diuretics (see section 4.8). If photosensitivity reactions occur during treatment with Rasilez HCT, it is recommended that treatment be discontinued. If it is considered necessary to resume administration of the diuretic, it is recommended to protect the parts exposed to the sun or artificial UVA rays.

Acute angle-closure glaucoma

Hydrochlorothiazide, a sulphonamide, has been associated with an idiosyncratic reaction resulting in transient acute myopia and acute narrow-angle glaucoma. Symptoms include acute onset decreased visual acuity or eye pain and typically occur within hours to weeks of Treatment initiation. Untreated acute angle-closure glaucoma can lead to permanent vision loss. Primary treatment is the fastest possible discontinuation of hydrochlorothiazide. Prompt medical or surgical treatment may need to be considered in case of blood pressure. intraocular is not controlled Risk factors for the development of acute angle glaucoma may include a history of allergy to sulfonamides or penicillin.

General

In the event of severe and persistent diarrhea, Rasilez HCT therapy should be discontinued.

As with any antihypertensive agent, excessive reduction in blood pressure in patients with ischemic heart disease or ischemic cardiovascular disease could cause myocardial infarction or stroke.

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

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 medicine.

Rasilez HCT contains wheat starch. This medicine can be given to people with celiac disease. People with wheat allergy (other than celiac disease) should not take this medicine.

04.5 Interactions with other medicinal products and other forms of interaction

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. other kaliuretic diuretics, corticosteroids, laxatives, adrenocorticotropic hormone (ACTH), amphotericin, carbenoxolone, penicillin G, salicylic acid derivatives). Conversely, concomitant use of other agents acting on the RAAS, NSAIDs or agents that increase serum potassium levels (eg. Potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes, heparin) may lead to to increases in serum potassium. Caution is advised if concomitant use with an agent that alters serum potassium levels is necessary (see sections 4.4 and 5.1).

Medicinal products affected by changes in serum potassium: Periodic monitoring of serum potassium is recommended when Rasilez HCT is administered with medicinal products affected by serum potassium alterations (e.g. digitalis glucosides, antiarrhythmics).

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

In some patients with impaired renal function (dehydrated patients or elderly patients) the concomitant administration of aliskiren and hydrochlorothiazide together with NSAIDs may lead to further deterioration of renal function, including possible acute renal failure, which is usually reversible. Therefore, the combination of Rasilez HCT with an NSAID requires caution, particularly in elderly patients.

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

Additional information on aliskiren interactions

Contraindicated (see section 4.3)

Potent P-glycoprotein (P-gp) inhibitors

A single dose interaction study conducted in healthy volunteers demonstrated that cyclosporine (200 and 600 mg) increases the Cmax of aliskiren 75 mg by approximately 2.5-fold and the "AUC by approximately 5-fold. The" increase may be greater than higher doses of aliskiren. In healthy volunteers, itraconazole (100 mg) increases the AUC and Cmax of aliskiren (150 mg) by 6.5 and 5.8-fold, respectively. Therefore, concomitant use of aliskiren and potent P-gp inhibitors is contraindicated (see section 4.3).

Not recommended (see section 4.2)

Fruit juice and drinks containing plant extracts

Administration of fruit juice and aliskiren resulted in a decrease in the AUC and Cmax of aliskiren. Concomitant administration of grapefruit juice with aliskiren 150 mg resulted in a 61% decrease in the AUC of aliskiren and concomitant administration with aliskiren 300 mg produced a 38% reduction in the AUC of aliskiren. Co-administration of orange or apple juice with aliskiren 150 mg produced a 62% reduction in the AUC of aliskiren or a 63% reduction in the "AUC of aliskiren, respectively. It is possible that this reduction is due to an inhibition of the uptake of aliskiren mediated by organic anion transporting polypeptides caused by fruit juice components in the gastrointestinal tract." Therefore fruit juice should not be taken together with Rasilez HCT due to the risk of therapeutic failure. The effect of herbal extracts drinks (including herbal infusions) on the absorption of aliskiren has not been investigated. However, compounds potentially inhibiting the absorption of aliskiren mediated by organic anion-carrying polypeptides are widely present in fruit, vegetables and many other plant products. Therefore, beverages containing plant extracts, including herbal infusions, should not be consumed. together with Rasilez HCT.

Dual blockade of the RAAS with aliskiren, ARB or ACEI

Clinical trial data have shown that dual blockade of the RAAS through the combined use of ACEI, ARB or aliskiren is associated with a higher frequency of adverse events such as hypotension, stroke, hyperkalaemia and decreased renal function (including renal insufficiency). renal acute) compared to the use of a single agent active on the RAAS system (see sections 4.3, 4.4 and 5.1).

Concomitant use requires caution

Interactions with the P-gp

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

Moderate inhibitors of P-gp

Co-administration of ketoconazole (200 mg) or verapamil (240 mg) and 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 to be expected in the range that would be reached if the dose of aliskiren were doubled; doses of aliskiren up to 600 mg, which is twice the maximum recommended therapeutic dose, were well tolerated in controlled clinical trials. Preclinical studies indicate that co-administration of aliskiren and ketoconazole increases the gastrointestinal absorption of aliskiren and decreases its biliary excretion. Therefore, caution should be exercised when aliskiren is administered with ketoconazole, verapamil or other moderate P-gp inhibitors (clarithromycin, telithromycin, erythromycin, amiodarone).

Medicines that alter serum potassium levels

The concomitant use of other agents acting on the RAAS, NSAIDs or agents that increase serum potassium levels (eg. Potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes, heparin) may lead to increases in serum potassium. Serum Potassium Caution is advised if concomitant use with an agent that alters serum potassium levels is necessary.

Non-steroidal anti-inflammatory drugs (NSAIDs)

As with other substances acting on the RAAS, NSAIDs may reduce the antihypertensive effect of aliskiren. In some patients with impaired renal function (dehydrated patients or elderly patients) concomitant administration of aliskiren and NSAIDs may lead to further deterioration of renal function , including possible acute renal failure, which is usually reversible Therefore, the combination of aliskiren with an NSAID requires caution, particularly in elderly patients.

Furosemide and torasemide

Oral co-administration of aliskiren and furosemide did not alter the pharmacokinetics of aliskiren but reduced furosemide exposure by 20-30% (the effect of aliskiren on intramuscular or intravenous furosemide has not been investigated). After multiple doses of furosemide (60 mg / day) administered concomitantly with aliskiren (300 mg / day) to patients with heart failure, urinary sodium excretion and urine volume were reduced during the first 4 hours by 31%. and 24%, respectively, compared to furosemide alone. The mean weight of patients treated concurrently with furosemide and aliskiren 300 mg (84.6 kg) was greater than the weight of patients treated with furosemide alone (83.4 kg). aliskiren 150 mg / day small changes in the pharmacokinetics and efficacy of furosemide were observed.

Available clinical data did not indicate the use of higher doses of torasemide following co-administration with aliskiren. Renal excretion of torasemide is known to be mediated by organic anion transporters (OAT). Aliskiren is minimally excreted by the kidney, and only 0.6% of the dose is recovered in the urine after oral administration (see section 5.2). However, since aliskiren has been shown to be a substrate for the organic anion transport polypeptide 1A2 (OATP1A2) (see interaction with organic anion transport polypeptide (OATP) inhibitors), aliskiren may reduce plasma exposure. to torasemide through an "interference with the absorption process.

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

Warfarin

The effect of aliskiren on warfarin pharmacokinetics has not been evaluated.

Interactions with food

Meals (low or high fat) have been shown to substantially reduce the absorption of aliskiren (see section 4.2). Available clinical data do not suggest an additive effect of the different types of foods and / or beverages, however the bioavailability reduction potential of aliskiren due to this additive effect has not been studied and therefore cannot be excluded. Concomitant administration of aliskiren with fruit juice or drinks containing plant extracts, including herbal infusions, should be avoided.

No interaction

• Substances investigated in clinical pharmacokinetic studies include acenocoumarol, atenolol, celecoxib, pioglitazone, allopurinol, isosorbide-5-mononitrate and hydrochlorothiazide. No interactions were found.

• Co-administration of aliskiren and metformin (? 28%), amlodipine (↑ 29%) or cimetidine (↑ 19%) produced a change in the Cmax or AUC of aliskiren of between 20% and 30%. of administration with atorvastatin, the steady-state AUC and Cmax of aliskiren increased by 50%. Co-administration of aliskiren does not significantly affect the pharmacokinetics of atorvastatin, metformin or amlodipine. Therefore, no dose adjustment of aliskiren or these concomitantly administered medicinal products is necessary.

• The bioavailability of digoxin and verapamil may be slightly decreased by aliskiren.

• Interactions with cytochrome P450 (CYP450)

Aliskiren does not inhibit CYP450 isozymes (CYP1A2, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A). Aliskiren does not induce CYP3A4. Therefore, influences of aliskiren on the systemic exposure of substances that inhibit, induce or are metabolised by these enzymes are not to be expected. Aliskiren is minimally metabolised by CYP450 enzymes. Therefore, interactions due to inhibition or induction of the isoenzymes are not to be expected. CYP450. However, CYP3A4 inhibitors also frequently affect P-gp. Consequently, an increase in aliskiren exposure can be expected when co-administered with CYP3A4 inhibitors that also inhibit P-gp (see interactions with the P-gp in paragraph 4.5).

• P-gp substrates or weak inhibitors

No relevant interactions were observed with atenolol, digoxin, amlodipine or cimetidine. When co-administered with atorvastatin (80 mg), steady state AUC and Cmax of aliskiren (300 mg) increased by 50%. In experimental animal models, P-gp was shown to play a major role in bioavailability of aliskiren Inducers of P-gp (St. John's wort, rifampicin) may therefore reduce the bioavailability of aliskiren.

• Inhibitors of organic anion transport polypeptides (OATPs)

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

Additional information on hydrochlorothiazide interactions

When administered concomitantly, 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 by hydrochlorothiazide.Co-administration of lithium and hydrochlorothiazide is not recommended. If such a combination proves necessary, careful monitoring of serum lithium levels is recommended during concomitant use of the two medicinal products.

Medicines that can induce Torsades de Pointes: Due to the risk of hypokalaemia, hydrochlorothiazide should be administered with caution when combined with medicinal products that can induce torsade de pointes, in particular Class Ia and Class III antiarrhythmics and some antipsychotics.

Medicinal products affecting serum sodium levels: The hyponatremic effect of diuretics may be intensified by the concomitant administration of medicinal products such as antidepressants, antipsychotics, antiepileptics, etc. Caution is indicated in the long-term administration of these medicinal products.

Pressor amines (e.g. norepinephrine, adrenaline): Hydrochlorothiazide may reduce the response to pressor amines such as noradrenaline. The clinical significance of this effect is uncertain and insufficient to rule out their use.

Digoxin or other digitalis glycosides: Thiazide-induced hypokalaemia or hypomagnesaemia may occur as side effects, favoring the onset of digitalis-induced cardiac arrhythmias.

Vitamin D and calcium salts: Administration of thiazide diuretics, including hydrochlorothiazide, and vitamin D or calcium salts may potentiate the increase in serum calcium. Concomitant use of thiazide-type diuretics may lead to hypercalcaemia in patients predisposed to hypercalcaemia (eg with hyperparathyroidism, neoplasms or vitamin D mediated conditions) by increasing tubular calcium reabsorption.

Antidiabetic agents (e.g. insulin and oral antidiabetic agents): Thiazides can impair glucose tolerance. Dose adjustment of the antidiabetic medicinal product may be required (see section 4.4). Metformin should be used with caution due to the risk of lactic acidosis induced by possible functional renal failure associated with hydrochlorothiazide.

Beta blockers and diazoxide: The concomitant use of thiazide diuretics, including hydrochlorothiazide, and beta-blockers may increase the risk of hyperglycaemia. Thiazide diuretics, including hydrochlorothiazide, may enhance the hyperglycemic effect of diazoxide.

Medicines used in the treatment of gout: The dosage of uricosuric medicinal products may need to be adjusted as hydrochlorothiazide may increase serum uric acid levels. The dosage of probenecid or sulfinpyrazone may need to be increased. Co-administration of thiazide diuretics, including hydrochlorothiazide, may increase the dose. incidence of hypersensitivity reactions to allopurinol.

Anticholinergics and other medicinal products affecting gastric motility: The bioavailability of thiazide-type diuretics may be increased by anticholinergic drugs (e.g. atropine, biperiden), apparently due to a decrease in gastrointestinal motility and stomach emptying rate. Conversely, prokinetic substances such as cisapride are expected to decrease the bioavailability of thiazide-type diuretics.

Amantadina: 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 lead to a sub-therapeutic effect of thiazide diuretics. However, staggering the dose of hydrochlorothiazide and resin to administer hydrochlorothiazide at least 4 hours before or 4-6 hours after resin administration could minimize interactions.

Cytotoxic agents: Thiazides, including hydrochlorothiazide, can reduce the renal excretion of cytotoxic drugs (eg, cyclophosphamide, methotrexate) and enhance their myelosuppressive effects.

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

Alcohol, barbiturates or narcotics: Concomitant administration of thiazide diuretics with substances that also have a blood pressure lowering effect (eg by reducing sympathetic nervous system activity or through direct vasodilation) may potentiate orthostatic hypotension.

Methyldopa: There have been isolated reports of haemolytic anemia occurring with the concomitant use of hydrochlorothiazide and methyldopa.

Iodized contrast agents: In case of diuretic-induced dehydration, the risk of acute renal failure increases, especially with high doses of iodized products. Patients must be rehydrated prior to administration.

04.6 Pregnancy and breastfeeding

Pregnancy

There are no data regarding the use of aliskiren in pregnant women. Aliskiren was not teratogenic in rats or rabbits (see section 5.3). Other substances that directly affect the RAAS have been associated with severe fetal malformations and neonatal death when used. during the second and third trimester of pregnancy. Experience with the use of hydrochlorothiazide during pregnancy, especially during the first trimester, is limited. Animal studies are insufficient.

Hydrochlorothiazide crosses the placenta. According to the pharmacological mechanism of action of hydrochlorothiazide, its use during the second and third trimester of pregnancy can compromise fetal-placental perfusion and cause fetal and neonatal effects such as jaundice, balance disturbance. electrolyte and thrombocytopenia.

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

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

No specific clinical studies have been conducted 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 trimester of pregnancy (see section 4.3). Switching to an appropriate alternative treatment should be made prior to a planned pregnancy. If pregnancy is detected during therapy, Rasilez HCT use should be discontinued as soon as possible.

Feeding time

It is unknown whether aliskiren is excreted in human milk. In rats, aliskiren was observed to be excreted in milk.

Hydrochlorothiazide is excreted in human milk in small quantities. Thiazides in high doses cause intense diuresis which can inhibit milk production.

The use of Rasilez HCT while breastfeeding is not recommended. If Rasilez HCT is used during breastfeeding, the dosage should be kept as low as possible.

Fertility

There are no clinical data on fertility.

04.7 Effects on ability to drive and use machines

When driving vehicles or operating machines it must be taken into account that dizziness or somnolence may occasionally occur with Rasilez HCT.

04.8 Undesirable effects

Summary of the safety profile

The safety of Rasilez HCT has been evaluated in 9 clinical studies with more than 3,900 patients, including over 700 patients treated for over 6 months and 190 patients treated for over 1 year. The incidence of adverse reactions was not associated with gender, age, body mass index, race or ethnicity. Treatment with Rasilez HCT resulted in an "overall incidence of adverse reactions similar to placebo at doses up to 300 mg / 25 mg. Adverse reactions were generally mild and transient in nature and required discontinuation of therapy only infrequently. The most common adverse reaction observed with Rasilez HCT is diarrhea. Adverse reactions previously reported for one of the individual components of Rasilez HCT (aliskiren and hydrochlorothiazide) and included in the tabulated list of adverse reactions may occur with Rasilez HCT.

Tabulated list of adverse reactions

The frequency of adverse reactions listed below is defined using the following convention: very common (≥ 1/10); common (≥ 1/100,

Disorders of the blood and lymphatic system Rare Thrombocytopenia, sometimes with purpurah Very rare Agranulocytosish, bone marrow depressionh, haemolytic anemiah, leukopeniah Not known Aplastic anemiah Disorders of the immune system Rare Anaphylactic reactions, hypersensitivity reactionsa, h Metabolism and nutrition disorders Very common Hypokalemiah common Hyperuricemiah, hypomagnesiemiah, hyponatremiah Rare Hypercalcemiah, hyperglycemiah, worsening of diabetic metabolic statush Very rare Hypochloremic alkalosis Psychiatric disorders Rare Depressionh, sleep disturbancesh Nervous system disorders Rare Cefaleah, paraesthesiah Eye disorders Rare Visual impairment h Not known Acute angle-closure glaucomah Ear and labyrinth disorders Not known Vertiginea Cardiac pathologies common Dizziness, h Uncommon Palpitationa, peripheral edemaa Rare Cardiac arrhythmiash Vascular pathologies common Orthostatic hypotensionh Uncommon Hypotension c, a Respiratory, thoracic and mediastinal disorders Uncommon Cough Very rare Respiratory distress (including pneumonia and pulmonary edema) h Gastrointestinal disorders common Diarrheac, a, h, decreased appetiteh, nausea and vomitinga, h Rare Abdominal discomforth, constipationh Very rare Pancreatiteh Hepatobiliary disorders Rare Intrahepatic cholestasish, jaundice, h Not known Hepatic disorders, *, hepatitis, hepatic failure, ** Skin and subcutaneous tissue disorders common Urticaria and other forms of rash a, h Uncommon Severe cutaneous adverse reactions (SCARs) including Stevens Johnsona syndrome, toxic epidermal necrolysis (TEN) a, oral mucosal reactionsa, pruritus Rare Angioedemaa, erythemaa, photosensitivity reactionsh Very rare Reactions similar to cutaneous lupus erythematosush, reactivation of cutaneous lupus erythematosush, necrotizing vasculitis and toxic epidermal necrolysish Not known Erythema multiformeh Musculoskeletal and connective tissue disorders common Arthralgia Not known Muscle spasmh Renal and urinary disorders Uncommon Acute renal failurea, h, impaired renal functiona Not known Renal dysfunctionh Diseases of the reproductive system and breast common Impotenceh General disorders and administration site conditions Not known Astheniah, piressiah Diagnostic tests Very common Increase in cholesterol and triglycerides common Hyperkalemiaa Uncommon Increased liver enzymes Rare Decrease in hemoglobina, decrease in hematocrita, increase in plasma creatrinina, glycosuriah

c Adverse reactions observed with Rasilez HCT

a Adverse reactions observed alone with aliskiren

h Adverse reactions observed alone with hydrochlorothiazide

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

** Including one case of "fulminant hepatic failure" observed in post-marketing experience, for which a correlation with aliskiren cannot be excluded.

Diarrhea: For aliskiren, diarrhea is a dose-dependent adverse reaction. In controlled clinical trials, the incidence of diarrhea was 1.3% in patients treated with Rasilez HCT compared with 1.4% in patients treated with aliskiren or 1.9% in patients treated with hydrochlorothiazide.

Serum potassiumIn 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 nearly balanced each other in many patients. In other patients, one or the other effect may predominate. Periodic serum potassium measurements should be performed at appropriate intervals to detect possible electrolyte imbalance in patients at risk (see sections 4.4 and 4.5).

Additional information on the individual components

Previously reported adverse reactions with any of the individual components may occur with Rasilez HCT even if not observed in clinical studies.

Aliskiren

Description of some adverse reactions:

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

In controlled clinical trials, angioedema and hypersensitivity reactions occurred rarely during treatment with aliskiren, with an incidence comparable to treatment with placebo or comparator drugs.

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

Angioedema and angioedema-like reactions have been reported in post-marketing experience following administration of aliskiren in combination with ACEI and / or ARB.

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

In the event of any manifestation that may suggest a hypersensitivity / angioedema reaction (particularly difficulty in breathing or swallowing, rash, itching, hives or swelling of the face, extremities, eyes, lips and / or tongue, dizziness) i patients should stop treatment and contact their physician (see section 4.4).

Arthralgia has been reported in post-marketing experience. In some cases it has occurred as part of a hypersensitivity reaction.

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

Hemoglobin and hematocrit: Slight decreases in hemoglobin and hematocrit were observed (mean decreases of approximately 0.05 mmol / l and 0.16 percent volume, respectively). No patient discontinued therapy due to the onset of anemia. This effect has also been observed with other substances acting on the RAAS, such as ACEI and ARB.

Serum potassium: Elevations in serum potassium have been observed with aliskiren and these may be exacerbated by concomitant use of other agents acting on the RAAS or NSAIDs. Consistent with standard medical practice, if co-administration is deemed necessary, evaluation is recommended. periodic of renal function including that of serum electrolytes.

Pediatric population: Based on the limited amount of safety data available from an aliskiren treatment pharmacokinetic study in 39 hypertensive children aged 6-17 years of age, the frequency, type and severity of adverse reactions in children are expected to be similar to those observed. in hypertensive adults. Like other RAAS blockers, headache is a common adverse event in children treated with aliskiren.

Hydrochlorothiazide

Hydrochlorothiazide has been prescribed extensively for many years, frequently at doses higher than those contained in Rasilez HCT. The adverse reactions listed in the table above, which are marked with the reference "h", have been reported in patients treated with diuretics alone. thiazides, including hydrochlorothiazide.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system.

04.9 Overdose

Symptoms

The most likely manifestation of an overdose would be hypotension, which is related to the antihypertensive effect of aliskiren.

Overdose with hydrochlorothiazide is associated with electrolyte depletion (hypokalaemia, hypochloraemia, hyponatremia) and dehydration caused by excessive diuresis. The most common signs and symptoms of overdose are nausea and sleepiness. Hypokalaemia may induce muscle spasms and / or accentuate cardiac arrhythmias associated with the concomitant use of digitalis glycosides or certain antiarrhythmic drugs.

Treatment

If symptomatic hypotension occurs, supportive treatment should be initiated.

In a study conducted in patients with end-stage renal disease (End Stage Renal Disease, ESRD) undergoing hemodialysis, the dialysis clearance of aliskiren was shown to be low (

05.0 PHARMACOLOGICAL PROPERTIES

05.1 Pharmacodynamic properties

Pharmacotherapeutic group: Substances acting on the renin-angiotensin system; renin inhibitors (aliskiren) in combination with diuretics (hydrochlorothiazide), ATC code: C09XA52

Rasilez HCT is the combination of two antihypertensive compounds to control blood pressure in patients with essential hypertension: Aliskiren belongs to the class of direct renin and hydrochlorothiazide inhibitors to that of thiazide diuretics. The combination of these active ingredients with mechanisms of action. complementary products exerts an additive antihypertensive effect, reducing blood pressure to a greater extent than any single active ingredient used alone.

Aliskiren

Aliskiren is a potent and selective orally active non-peptide direct human renin inhibitor.

By inhibiting the enzyme renin, aliskiren inhibits the RAAS at the point of activation, blocking the conversion of angiotensinogen to angiotensin I and reducing the levels of angiotensin I and angiotensin II. While other agents that inhibit the RAAS (enzyme inhibitors conversion of angiotensin (ACEI) and angiotensin II receptor antagonists (ARB)) cause a compensatory increase in plasma renin activity (PRA), in hypertensive patients treatment with aliskiren reduces PRA by approximately 50-80% Similar reductions were seen when aliskiren was combined with other antihypertensive agents The clinical implications of the effects on PRA are currently unknown.

In hypertensive patients, administration of aliskiren at doses of 150 mg and 300 mg once daily induces dose-dependent reductions in both systolic and diastolic blood pressure, which are maintained over the entire 24 hour interval between doses (maintaining the benefit early in the morning), with a mean peak-trough ratio for diastolic response that for the 300 mg dose reaches up to 98%. "85-90% of the maximum antihypertensive effect was observed after 2 weeks. L" antihypertensive effect was maintained in long-term treatment (12 months), and was independent of age, sex, body mass index and ethnicity.

Studies on the combination therapy of aliskiren with the diuretic hydrochlorothiazide, the calcium channel blocker amlodipine and the beta blocker atenolol are available. These associations were effective and well tolerated.

The efficacy and safety of aliskiren-based therapy were compared with ramipril-based therapy in a 9-month non-inferiority study in 901 elderly patients (≥ 65 years) with essential systolic hypertension. They were administered. 150 mg or 300 mg per day of aliskiren or 5 mg or 10 mg per day of ramipril 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. After a 12-week period, aliskiren alone produced a reduction in systolic / diastolic blood pressure of 14.0 / 5.1 mmHg, compared to 11.6 / 3.6 mmHg with ramipril, consistent with the fact that aliskiren is not inferior to ramipril at selected dosages and the differences in systolic and diastolic pressure were statistically significant. Tolerability was comparable in both treatment arms, however cough was reported more often for ramipril treatment versus aliskiren treatment (14.2% vs. 4.4%), while diarrhea was more common with aliskiren treatment than with ramipril (6.6% vs. 5.0%).

In an 8-week study in 754 elderly (≥ 65 years) and very elderly (30% ≥ 75 years) hypertensive patients aliskiren at doses of 75 mg, 150 mg and 300 mg produced a statistically significantly greater reduction than placebo. blood pressure (systolic and diastolic). No additional blood pressure lowering effects were observed with aliskiren 300 mg compared with aliskiren 150 mg. All three dosages were well tolerated in elderly and very elderly patients.

There was no evidence of first dose hypotension or any effect on heart rate in patients treated in controlled clinical trials. With discontinuation of treatment, blood pressure gradually returned to baseline levels over several weeks, with no evidence of effects. rebound for blood pressure or PRA.

In a 36-week study involving 820 patients with ischemic left ventricular dysfunction, no changes in ventricular remodeling, as assessed as left ventricular end-systolic volume, were seen with aliskiren versus placebo given on top of background therapy.

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

The cardiovascular and / or renal benefits of aliskiren were evaluated in a double-blind, randomized, placebo-controlled study in 8,606 patients with type 2 diabetes and chronic kidney disease (as evidenced by proteinuria and / or GFR 2) with or without cardiovascular disease. Blood pressure was well controlled at baseline in most patients. The primary end point was a composite of cardiovascular and renal complications.

In this study, aliskiren 300 mg was compared to placebo in addition to standard therapy which included an angiotensin converting enzyme inhibitor or angiotensin receptor blocker. The study was terminated prematurely as it was unlikely that participants benefited from the use of aliskiren. The final results of the study indicated a hazard ratio for the primary endpoint of 1.097 in favor of placebo (95.4% confidence interval: 0.987, 1.218, two-sided test p = 0.0787). addition, an increased incidence of adverse events was observed with aliskiren compared to placebo (38.2% versus 30.3%). In particular, an increase in the incidence of renal dysfunction (14.5% versus 12.4%), hyperkalaemia (39.1% versus 29.0%), hypotension related events (19.9% versus 16, 3%) and stroke, an event predicted in the endpoint (3.4% versus 2.7%). The increase in the incidence of stroke was greater in patients with renal insufficiency.

Aliskiren 150 mg (increased to 300 mg if tolerated) as an adjunct to conventional therapy was evaluated in a randomized, double-blind, placebo-controlled study of 1,639 patients with reduced ejection fraction hospitalized for an episode of acute heart failure (NYHA class III- IV) hemodynamically stable at baseline. The primary endpoint was cardiovascular death or re-hospitalization for heart failure within 6 months; secondary endpoints were assessed within 12 months.

The study did not demonstrate a benefit of aliskiren when given as an adjunct to standard therapy for acute heart failure and demonstrated an increased risk of cardiovascular events in patients with diabetes mellitus. The study results indicate a non-significant effect of aliskiren with a hazard ratio of 0.92 (95% confidence interval: 0.76-1.12; p = 0.41, aliskiren vs placebo). Different effects of aliskiren treatment on overall mortality within 12 months have been reported depending on the degree of diabetes mellitus. In the subgroup of patients with diabetes mellitus the hazard ratio was 1.64 in favor of placebo (95% confidence interval: 1.15-2.23), while the hazard ratio in the subgroup of patients without diabetes was 0.69 in favor of aliskiren (95% confidence interval: 0.50-0.94); p-value for interaction was = 0.0003. An increased incidence of hyperkalaemia (20.9% vs 17.5%), renal impairment / renal failure (16.6%) was observed in the aliskiren group. vs 12.1%) and hypotension (17.1% vs 12.6%) compared to placebo and this increase was greater in patients with diabetes.

Hydrochlorothiazide

The site of action of thiazide diuretics is predominantly in the distal convoluted renal tubule. The presence of a high-affinity receptor in the renal cortex was observed which was the primary binding site for the action of thiazide diuretics and the inhibition of NaCl transport in the distal convoluted tubule. The mechanism of action of thiazides is implemented through the inhibition of the transport of Na + Cl-, by competition with the Cl- site, thus altering the mechanism of electrolyte reabsorption: directly increasing the excretion of sodium and chlorine in quantity equivalents and indirectly reducing the plasma volume through this diuretic action, with a consequent increase in the activity of plasma renin, the secretion of aldosterone and the loss of urinary potassium and a decrease in serum potassium.

Aliskiren / hydrochlorothiazide

In clinical studies, more than 3,900 hypertensive patients were treated with Rasilez HCT once daily.

In hypertensive patients, once daily administration of Rasilez HCT resulted in dose-dependent reductions in both systolic and diastolic blood pressure, which were maintained over the entire 24 hour interval between doses. The antihypertensive effect is largely manifested within 1. week and maximum effect is usually seen within 4 weeks. The antihypertensive effect was maintained during long-term treatment and was independent of age, sex, body mass index and ethnicity. The antihypertensive effect after a single dose of the combination persists for 24 hours. After stopping treatment with aliskiren (aliskiren alone or with hydrochlorothiazide), blood pressure gradually returns to pre-treatment values (3-4 weeks) with no evidence of a rebound effect.

Rasilez HCT was studied in a placebo-controlled clinical trial which included 2,762 hypertensive patients with diastolic blood pressure ≥ 95 mmHg and

When administered to hypertensive patients with markedly elevated blood pressure (systolic blood pressure ≥ 160 mmHg and / or diastolic blood pressure ≥ 100 mmHg), Rasilez HCT in doses ranging from 150 mg / 12.5 mg to 300 mg / 25 mg administered without gradual increase from monotherapy has been shown to control systolic / diastolic blood pressure values (cardiovascular risks. With combination therapy, hypotension and related adverse events were uncommon without an increased incidence in elderly patients.

In a study of 880 randomized patients who did not respond adequately to treatment with aliskiren 300 mg, the combination of aliskiren / hydrochlorothiazide 300 mg / 25 mg produced reductions in systolic / diastolic blood pressure of 15.8 / 11.0 mmHg, values that were significantly higher than those obtained with aliskiren 300 mg monotherapy. In a study of 722 randomized patients who did not respond adequately to treatment with hydrochlorothiazide 25 mg, the combination of aliskiren / hydrochlorothiazide 300 mg / 25 mg produced reductions systolic / diastolic blood pressure of 16.78 / 10.7 mmHg, values which were significantly higher than those obtained with hydrochlorothiazide 25 mg alone.

In another clinical study, the efficacy and safety of Rasilez HCT were also evaluated in 489 obese hypertensive patients who had not responded adequately to treatment with hydrochlorothiazide 25 mg (baseline systolic / diastolic blood pressure 149.4 / 96.8 mmHg) In this difficult-to-treat population, Rasilez HCT produced a reduction in blood pressure (systolic / diastolic) of 15.8 / 11.9 mmHg compared with a reduction of 15.4 / 11.3 mmHg achieved with irbesartan / hydrochlorothiazide, of 13.6 / 10.3 mmHg obtained with amlodipine / hydrochlorothiazide and 8.6 / 7.9 mmHg obtained with hydrochlorothiazide alone, with a safety profile comparable to that of hydrochlorothiazide alone.

In a study of 183 randomized patients with severe hypertension (mean diastolic blood pressure measured in a sitting position ≥ 105 and

Pediatric population

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

05.2 Pharmacokinetic properties

Aliskiren

Absorption

Following oral absorption, the peak plasma concentration of aliskiren is reached after 1-3 hours. The absolute bioavailability of aliskiren is approximately 2-3%. Meals with high fat content reduce Cmax by 85% and "AUC by 70%. At steady state, low-fat meals reduce Cmax by 76% and AUC0-tau by 67% in hypertensive patients." Following once daily dosing, steady-state plasma concentrations are reached within 5-7 days and steady-state levels are approximately 2-fold higher than the starting dose.

Distribution

Following intravenous administration, the mean steady-state volume of distribution is approximately 135 liters, suggesting that aliskiren distributes extensively into the extravascular space. Plasma protein binding of Aliskiren is moderate (47-51%) and independent of concentration.

Biotransformation and elimination

The mean half-life is approximately 40 hours (range 34-41 hours). Aliskiren is eliminated primarily as unchanged compound in the faeces (recovery of the radioactive oral dose = 91%). Approximately 1.4% of the total oral dose is metabolised. . The enzyme responsible for metabolism is CYP3A4. Following oral administration, approximately 0.6% of the dose is recovered in the urine. After intravenous administration, the mean plasma clearance is approximately 9 l / h.

Linearity

Exposure to aliskiren increases little more than in proportion to the increase in dose. After single dose administration in the dosage range of 75 to 600 mg, doubling the dose results in a ~ 2.3-fold increase in AUC and 2.6-fold increase in Cmax. The mechanisms responsible for the deviation from dose proportionality have not been identified. One possible mechanism is transporter saturation at the absorption site or hepatobiliary clearance.

Pediatric population

In a treatment pharmacokinetic study with aliskiren in 39 hypertensive pediatric patients (6-17 years of age) treated with daily doses of 2 mg / kg or 6 mg / kg of aliskiren administered in granule form (3.125 mg / tablet) , the pharmacokinetic parameters were similar to those in adults. Available data did not suggest a significant effect of age, body weight or gender on systemic exposure to aliskiren (see section 4.2).

Hydrochlorothiazide

Absorption

After oral administration, hydrochlorothiazide is rapidly absorbed (tmax approximately 2 hours) In the therapeutic range, the increase in mean AUC is linear and dose proportional.

The effects of food on the absorption of hydrochlorothiazide, if any, are of limited clinical importance. After oral administration, the absolute bioavailability of hydrochlorothiazide is 70%.

Distribution

The apparent volume of distribution is 4-8 L / kg. Circulating hydrochlorothiazide is bound to serum proteins (40-70%), predominantly to serum albumin. Hydrochlorothiazide also accumulates in erythrocytes in amounts approximately 3 times higher than plasma levels.

Biotransformation and elimination

Hydrochlorothiazide is eliminated primarily as unchanged compound. Hydrochlorothiazide is eliminated from plasma with a mean half-life of between 6 and 15 hours in the terminal elimination phase. accumulation is minimal when the drug is administered once daily. More than 95% of the absorbed dose is excreted as unchanged compound in the urine. Renal clearance is due to passive filtration and active secretion into the renal tubule.

Aliskiren / hydrochlorothiazide

After oral administration of Rasilez HCT tablets, peak plasma concentrations are reached on average 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 given as single monotherapy. Comparable food effects were observed for Rasilez HCT and for the individual monotherapies.

Characteristics of patients

Rasilez HCT, given once daily, is an effective antihypertensive treatment in adult patients, regardless of gender, age, body mass index and ethnicity.

The pharmacokinetics of aliskiren were not significantly changed in patients with mild to moderate hepatic impairment. 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 with Rasilez HCT. Rasilez HCT is contraindicated in patients with severe hepatic impairment (see section 4.3).

No starting dose adjustment is required in patients with mild to moderate renal impairment (see sections 4.2 and 4.4). In the presence of renal impairment, mean peak plasma levels and AUC values of hydrochlorothiazide are increased and the rate of urinary excretion is reduced. In patients with mild to moderate renal impairment, a 3-fold increase was observed. AUC of hydrochlorothiazide. In patients with severe renal impairment, an 8-fold increase in AUC was observed.

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

No initial dose adjustment of Rasilez HCT is required in elderly patients. Limited data suggest that the systemic clearance of hydrochlorothiazide is reduced in both healthy and hypertensive elderly compared to healthy young volunteers.

No pharmacokinetic data on Rasilez HCT are available in the pediatric population.

05.3 Preclinical safety data

Studies of Safety Pharmacology with aliskiren did not reveal any adverse effects on central nervous, respiratory or cardiovascular functions. The results of repeated dose toxicity studies in animals are consistent with the known local irritation potential or expected pharmacological effect of aliskiren. No carcinogenic potential was found for aliskiren in a 2 year rat study and a 6 year study. months in transgenic mice One colon adenoma and one cecum adenocarcinoma found in rats at the dose of 1,500 mg / kg / day were not statistically significant.

Aliskiren was shown to be free of any mutagenic potential, embryo-fetal toxicity or teratogenicity. Fertility, pre-natal and post-natal development were not affected in the rat.

Preclinical evaluations to support human administration of hydrochlorothiazide include genotoxicity assays in vitro and reproductive toxicity and carcinogenicity studies in rodents. For hydrochlorothiazide, detailed clinical data are available which are reported in the relevant sections.

The findings observed in the 2- and 13-week toxicity studies were consistent with that observed previously for aliskiren or hydrochlorothiazide alone. No unexpected new evidence relevant for use in humans was observed. In the 13-week toxicity study in ratosis, an increase in cell vacuolation of the glomerular zone in the adrenal gland is observed. The evidence was observed in animals treated with hydrochlorothiazide but not in animals treated with aliskiren alone or the vehicle. There is no evidence of an enhancement of this evidence with the fixed combination of aliskiren / hydrochlorothiazide as it appears only with a minimum degree of severity in all animals.