natgillin/translations-raw huggingface dataset:
Det anbefales ikke at anvende lægemidlet under de første tre måneder af graviditeten.
Its use during the first three months of pregnancy is not recommended.
Udvalget for Humanmedicinske Lægemidler (CHMP) konkluderede, at fordelene ved Rasilez HCT er større end risiciene til behandling af essentiel hypertension hos voksne, hvis blodtryk ikke er tilstrækkeligt behandlet med aliskiren eller hydrochlorthiazid anvendt alene, eller hvis blodtryk er tilstrækkeligt behandlet med aliskiren og hydrochlorthiazid, givet samtidigt, på samme dosisniveau som i kombinationen.
The Committee for Medicinal Products for Human Use (CHMP) decided that Rasilez HCT’ s benefits are greater than its risks for the treatment of essential hypertension in adults whose blood pressure is not adequately controlled on aliskiren or hydrochlorothiazide used alone, or adequately controlled with aliskiren and hydrochlorothiazide, given concurrently, at the same dose level as in the combination.
Udvalget anbefalede udstedelse af markedsføringstilladelse for Rasilez HCT.
The Committee recommended that Rasilez HCT be given marketing authorisation.
Andre oplysninger om Rasilez HCT:
Other information about Rasilez HCT:
Europa- Kommissionen udstedte en markedsføringstilladelse med gyldighed i hele Den Europæiske Union for Rasilez HCT til Novartis Europharm Limited den 16. januar 2009.
The European Commission granted a marketing authorisation valid throughout the EU for Rasilez HCT to Novartis Europharm Limited on 16 January 2009.
Den fuldstændige EPAR for Rasilez HCT findes her.
The full EPAR for Rasilez HCT can be found here.
2/ 3 Dette sammendrag blev sidst ajourført i 12- 2008.
2/ 3 This summary was last updated in 12-2008.
Rasilez HCT 150 mg/ 12, 5 mg filmovertrukne tabletter
Rasilez HCT 150 mg/ 12.5 mg film-coated tablets
Hver filmovertrukken tablet indeholder 150 mg aliskiren (som hemifumarat) og 12, 5 mg hydrochlorthiazid.
Each film-coated tablet contains 150 mg aliskiren (as hemifumarate) and 12.5 mg hydrochlorothiazide.
Hver tablet indeholder 25 mg laktosemonohydrat og 24, 5 mg hvedestivelse.
Each tablet contains 25 mg lactose monohydrate and 24.5 mg wheat starch.
Hvid, udadbuet, oval, filmovertrukken tablet, præget med ” LCI ” på den ene side og ” NVR ” på den anden.
White, biconvex, ovaloid film-coated tablet imprinted with “ LCI” on one side and “ NVR” on the other.
Rasilez HCT bør tages sammen med et let måltid mad én gang dagligt, fortrinsvis på samme tidspunkt hver dag.
Rasilez HCT should be taken with a light meal once a day, preferably at the same time each day.
Grapefrugtjuice må ikke tages sammen med Rasilez HCT.
Grapefruit juice should not be taken together with Rasilez HCT.
Rasilez HCT 150 mg/ 12, 5 mg kan gives til patienter, hvis blodtryk ikke er tilstrækkeligt behandlet med aliskiren 150 mg eller hydrochlorthiazid 12, 5 mg anvendt alene.
Rasilez HCT 150 mg / 12.5 mg may be administered in patients whose blood pressure is not adequately controlled with aliskiren 150 mg or hydrochlorothiazide 12.5 mg alone.
Hvis blodtrykket ikke er under kontrol efter 2- 4 ugers behandling kan dosis titreres op til en maksimal daglig dosis på 300 mg/ 25 mg Rasilez HCT.
If blood pressure remains uncontrolled after 2-4 weeks of therapy, the dose may be titrated up to a maximum of Rasilez HCT 300 mg/ 25 mg daily.
Dosis børe være individuel og tilpasses patientens kliniske respons.
Dosing should be individualised and adjusted according to the patient’ s clinical response.
2 Dosering ved erstatningsterapi Patienter, som får aliskiren og hydrochlorthiazid fra hver sin tablet, kan for nemhedens skyld skifte til Rasilez HCT med den samme dosis af hver komponent.
2 Posology as substitution therapy For convenience, patients receiving aliskiren and hydrochlorothiazide from separate tablets may be switched to a fixed combination tablet of Rasilez HCT containing the same component doses.
4. 4 og 5. 2).
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).
4. 3 og 5. 2).
Due to the hydrochlorothiazide component, Rasilez HCT is contraindicated for use in patients with severe renal impairment (glomerular filtration rate (GFR) < 30 ml/ min/ 1.73 m2) (see sections 4.3 and 5.2).
Nedsat leverfunktion Thiazider bør anvendes med forsigtighed til patienter med nedsat leverfunktion.
Hepatic impairment Thiazides should be used with caution in patients with impaired hepatic function.
Der kræves ingen justering af initialdosis for patienter med mildt til moderat nedsat leverfunktion (se pkt.
No adjustment of the initial dose is required for patients with mild to moderate hepatic impairment (see section 5.2).
4. 3 og 4. 4).
Due to the hydrochlorothiazide component, Rasilez HCT is contraindicated in patients with severe hepatic impairment (see sections 4.3 and 4.4).
Ældre patienter (over 65 år) Der kræves ingen justering af initialdosis for ældre patienter.
Elderly patients (over 65 years) No adjustment of the initial dose is required in elderly patients.
5. 2).
Paediatric patients Rasilez HCT is not recommended for use in children and adolescents below age 18 due to a lack of data on safety and efficacy (see section 5.2).
4. 5).
− 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. − Second and third trimesters of pregnancy, lactation (see section 4.6). − Severe renal impairment (GFR < 30 ml/ min/ 1.73 m2). − Refractory hypokalaemia, hypercalcaemia. − Severe hepatic impairment. − The concomitant use of aliskiren with ciclosporin, a highly potent P-glycoprotein (P-gp) inhibitor, and other potent P-gp inhibitors (quinidine, verapamil), is contraindicated (see section 4.5).
Hjertesvigt Aliskiren bør anvendes med forsigtighed til patienter med svær hjertesvigt (New York Heart Association (NYHA) klasse III- IV).
Heart failure Aliskiren should be used with caution in patients with serious congestive heart failure (New York Heart Association (NYHA) functional class III-IV).
Rasilez HCT skal anvendes med forsigtighed til patienter med hjertesvigt pga. begrænsede kliniske effekt - og sikkerhedsdata.
Rasilez HCT should be used with caution in patients with heart failure due to limited clinical efficacy and safety data.
Angioødem Som ved andre stoffer, der virker på renin- angiotensin- systemet er angioødem blevet rapporteret hos patienter, som behandles med aliskiren.
Angioedema As with other agents acting on the renin -angiotensin system, angioedema has been reported in patients treated with aliskiren.
Hvis angioødem opstår, skal Rasilez HCT seponeres med det samme, og der skal gives relevant behandling og monitorering indtil komplet og vedvarende resolution af tegn og symptomer indtræffer.
If angioedema occurs, Rasilez HCT should be promptly discontinued and appropriate therapy and monitoring provided until complete and sustained resolution of signs and symptoms has occurred.
Intravaskulær væskemangel Symptomatisk hypotension kan forekomme hos patienter med væske - og/ eller saltmangel som et resultat af kraftig diuretikabehandling, diæt med begrænset saltindtag, diarré eller opkastning.
Intravascular volume depletion Symptomatic hypotension may occur in patients who are volume and/ or sodium depleted as a result of vigorous diuretic therapy, dietary salt restriction, diarrhoea or vomiting.
Sådanne tilstande skal korrigeres før administration af Rasilez HCT.
Such conditions should be corrected before the administration of Rasilez HCT.
3 Elektrolytubalance Som for enhver patient, der modtager diuretikabehandling, skal der foretages en regelmæssig bestemmelse af serumelektrolytter med passende intervaller.
3 Electrolyte imbalance As for any patient receiving diuretic therapy, periodic determination of serum electrolytes should be performed at appropriate intervals.
Thiazider, herunder hydrochlorthiazid, kan resultere i elektrolytubalance (herunder hypokaliæmi, hyponatriæmi og hypokloræmisk alkalose).
Thiazides, including hydrochlorothiazide, can cause fluid or electrolyte imbalance (including hypokalaemia, hyponatraemia and hypochloraemic alkalosis).
4. 8).
Warning signs of fluid or electrolyte imbalance are dry mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pain or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea or vomiting (see section 4.8).
4. 5 og 4. 8).
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).
Omvendt kan hyperkaliæmi forekomme pga. aliskirenkomponenten i Rasilez HCT.
Conversely, due to the aliskiren component of Rasilez HCT, hyperkalaemia might occur.
Selvom klinisk signifikant hyperkaliæmi ikke er blevet dokumenteret med Rasilez HCT, omfatter risikofaktorer for udvikling af hyperkaliæmi nedsat nyrefunktion og/ eller hjertesvigt og diabetes mellitus.
Although clinically significant hyperkalaemia has not been documented with Rasilez HCT, risk factors for the development of hyperkalaemia include renal insufficiency and/ or heart failure, and diabetes mellitus.
Der anbefales tilstrækkelig overvågning af serumkalium hos patienter med risikofaktorer.
Adequate monitoring of serum potassium in patients at risk is recommended.
4. 5 og 4. 8).
Caution is required when co-administering potassium-sparing diuretics, potassium supplements or potassium-containing salts substitutes with Rasilez HCT (see sections 4.5 and 4.8).
Thiazider kan nedsætte calciumudskillelse i urin og forårsage en tilbagevendende og let stigning i serumcalcium ved fraværet af kendte calciummetabolismesygdomme.
Thiazides may reduce urinary calcium excretion and cause an intermittent and slight elevation of serum calcium in the absence of known disorders of calcium metabolism.
Markant hypercalcæmi kan være tegn på skjult hyperparatyroidisme.
Marked hypercalcaemia may be evidence of hidden hyperparathyroidism.
Thiazider bør seponeres før udførelse af test for parathyroidea- funktion.
Thiazides should be discontinued before carrying out tests for parathyroid function.
4. 5).
Thiazides have been shown to increase the urinary excretion of magnesium, which may result in hypomagnesaemia (see also section 4.5).
Nedsat nyrefunktion og nyretransplantation Der anbefales regelmæssig overvågning af kalium -, kreatinin - og urinsyreserumniveauer, når Rasilez HCT gives til patienter med nedsat nyrefunktion.
Renal impairment and kidney transplantation When Rasilez HCT is used in patients with impaired renal function, periodic monitoring of potassium, creatinine and uric acid serum levels is recommended.
Der er ingen erfaring vedrørende brugen af Rasilez HCT til patienter, der for nylig har fået foretaget en nyretransplantation.
There is no experience regarding the administration of Rasilez HCT in patients who have recently undergone kidney transplantation.
Dosisjustering er ikke nødvendig hos patienter med nedsat nyrefunktion, hvis GFR er ≥ 30 ml/ min/ 1, 73 m2.
No dosage adjustment is necessary in patients with renal impairment whose GFR is ≥ 30 ml/ min/ 1.73 m2.
Hos patienter med mildt til moderat nedsat nyrefunktion (GFR ≥ 30 ml/ min/ 1, 73 m2, men < 60 ml/ min/ 1, 73 m2), skal Rasilez HCT imidlertid gives med forsigtighed.
However, in patients with mild to moderate renal impairment (GFR ≥ 30 ml/ min/ 1.73 m2 but < 60 ml/ min/ 1.73 m2), Rasilez HCT should be administered with caution.
Som for andre stoffer, der virker på renin- angiotensin- systemet skal der udvises forsigtighed, når aliskiren gives til patienter, der er prædisponerede for renal dysfunktion, som hypovolæmi (f. eks. pga. blodtab, alvorlig og vedvarende diarré, vedvarende opkastning), hjertelidelse, leverlidelse eller nyrelidelse.
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 or kidney disease.
Nedsat leverfunktion Thiazider skal anvendes med forsigtighed til patienter med nedsat leverfunktion eller progressiv leversygdom, eftersom små ændringer i væske - og elektrolytbalancen kan fremkalde hepatisk coma.
Hepatic impairment Thiazides should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma.
Der er ingen klinisk erfaring med Rasilez HCT til patienter med nedsat leverfunktion.
There is no clinical experience with Rasilez HCT in patients with hepatic impairment.
4 Moderate P- gp- hæmmere Samtidig administration af 300 mg aliskiren og 200 mg ketoconazol resulterede i en 76% stigning i aliskirens AUC, men P- gp- hæmmere som ketoconazol kan forventes at øge vævskoncentrationerne mere end plasmakoncentrationerne.
Moderate P-gp inhibitors Co-administration of aliskiren 300 mg with ketoconazole 200 mg resulted in a 76% increase in aliskiren AUC but P-gp inhibitors such as ketoconazole are expected to increase tissue concentrations
Aorta - og mitralklapstenose, obstruktiv hypertrofisk kardiomyopati Som ved andre vasodilatorer skal der udvises særlig forsigtighed over for patienter, der lider af aorta - eller mitralklapstenose eller hypertrofisk obstruktiv kardiomyopati.
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.
Nyrearteriestenose og renovaskulær hypertension Der er ingen tilgængelige kontrollerede kliniske data om brug af Rasilez HCT til patienter med unilateral eller bilateral nyrearteriestenose eller brug af Rasilez HCT hos patienter med en nyre.
Renal artery stenosis and renovascular hypertension No controlled clinical data are available on the use of Rasilez HCT in patients with unilateral or bilateral renal artery stenosis, or stenosis to a solitary kidney.
Der er dog, ligesom for andre stoffer, der virker på renin- angiotensin- systemet, en øget risiko for nyreinsufficiens, inklusive nyresvigt, når patienter med nyrearteriestenose behandles med aliskiren.
However, as with other agents acting on the renin-angiotensin system, there is an increased risk of renal insufficiency, including renal failure, when patients with renal artery stenosis are treated with aliskiren.
Metaboliske og endokrine virkninger Behandling med thiazid kan nedsætte glukosetolerancen.
Metabolic and endocrine effects Thiazide therapy may impair glucose tolerance.
Til diabetiske patienter kan det kræve dosisjusteringer af insulin eller orale hypoglykæmiske stoffer.
In diabetic patients dosage adjustments of insulin or oral hypoglycaemic agents may be required.
Latent diabetes mellitus kan forekomme under thaizidbehandling.
Latent diabetes mellitus may occur during thiazide therapy.
Der er på nuværende tidspunkt ingen tilgængelige data fra kliniske studier, som specifikt var designet til at evaluere sikkerheden af Rasilez HCT hos diabetiske patienter.
To date, no data are available from clinical studies that were specifically-designed to evaluate the safety of Rasilez HCT in diabetic patients.
Stigninger i kolesterol - og triglyceridniveauer har været forbundet med thiaziddiuretisk behandling.
Increases in cholesterol and triglyceride levels have been associated with thiazide diuretic therapy.
Hyperurikæmi kan forekomme eller umaskeret urinsyregigt kan fremkaldes hos visse patienter, der får thiazidbehandling.
Hyperuricaemia may occur or frank gout may be precipitated in certain patients receiving thiazide therapy.
Generelt I tilfælde af alvorlig og vedvarende diarré bør behandling med Rasilez HCT stoppes.
General In the event of severe and persistent diarrhoea, Rasilez HCT therapy should be stopped.
Overfølsomhedsreaktioner over for hydrochlorthiazid kan forekomme hos patienter med eller uden allergi eller bronkial astma i anamnesen, men er mere sandsynlige hos patienter med en sådan anamnese.
Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of allergy or bronchial asthma, but are more likely in patients with such a history.
Der har været rapporteret forværring eller aktivering af systemisk lupus erythematosus ved brugen af thiaziddiuretika.
Exacerbation or activation of systemic lupus erythematosus has been reported with the use of thiazide diuretics.
Hjælpestoffer Rasilez HCT indeholder laktose.
Excipients Rasilez HCT contains lactose.
Hydrochlorthiazids kaliumudtømmende virkning dæmpes ved aliskirens kaliumbesparende virkning.
The potassium-depleting effect of hydrochlorothiazide is attenuated by the potassium-sparing effect of aliskiren.
Denne virkning af hydrochlorthiazid på serumkalium ville imidlertid forventes at blive gjort mere virkningsfuld af andre lægemidler forbundet med kaliumtab og hypokaliæmi (f. eks. andre kaliuretiske diuretika, afføringsmidler, amphotericin, carbenoxolon, natriumpenicillin G, kortikosterioider, ACTH, salicylsyrederivater).
However, this effect of hydrochlorothiazide on serum potassium would be expected to be potentiated by other medicinal products associated with potassium loss and hypokalaemia (e. g. other kaliuretic diuretics, laxatives, amphotericin, carbenoxolone, penicillin G sodium, corticosteroids, ACTH, salicylic acid derivatives).
Omvendt, baseret på erfaringerne med anvendelsen af andre lægemidler, som påvirker renin- angiotensin- systemet (RAS), kan samtidig brug af kaliumbesparende diuretika, kaliumtilskud, kaliumholdige salterstatninger eller andre lægemidler, som øger koncentrationen af kalium i serum (f. eks. heparin), føre til stigninger 5 serumkalium.
Conversely, based on experience with the use of other medicinal products that blunt the renin-angiotensin system (RAS), concomitant use of potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium or other medicinal products that may increase serum potassium levels (e. g. heparin sodium) may lead to increases in serum potassium.
4. 4 og 4. 8).
Adequate monitoring of serum potassium in patients at risk is recommended (see sections 4.4 and 4.8).
Lægemidler, der påvirkes af serumkaliumforstyrrelser:
Medicinal products affected by serum potassium disturbances:
Regelmæssig overvågning af serumkalium anbefales, når Rasilez HCT administreres sammen med lægemidler, der påvirkes af serumkaliumforstyrrelser (f. eks. digitalis glykosider, antiarytmika).
Periodic monitoring of serum potassium is recommended when Rasilez HCT is administered with medicinal products affected by serum potassium disturbances (e. g. digitalis glycosides, antiarrhythmics).
Andre antihypertensiva:
5 Other antihypertensive agents:
Rasilez HCT' s antihypertensive virkning kan øges ved samtidig brug af andre antihypertensiva.
The antihypertensive effect of Rasilez HCT may be increased with the concomitant use of other antihypertensive agents.
Yderligere information om interaktioner med aliskiren Aliskiren har ingen kendte, klinisk relevante interaktioner med lægemidler, som typisk bruges til behandling af hypertension eller diabetes.
Additional information on aliskiren interactions Aliskiren has no known clinically relevant interactions with medicinal products commonly used to treat hypertension or diabetes.
Stoffer, som er undersøgt i kliniske, farmakokinetiske studier af aliskiren, inkluderer acenocoumarol, atenolol, celecoxib, fenofibrat, pioglitazon, allopurinol, isosorbid- 5- mononitrat, irbesartan, digoxin, ramipril, valsartan, metformin, amlodipin, atorvastatin, cimetidin og hydrochlorthiazid.
Compounds that have been investigated in aliskiren clinical pharmacokinetic studies include acenocoumarol, atenolol, celecoxib, fenofibrate, pioglitazone, allopurinol, isosorbide-5-mononitrate, irbesartan, digoxin, ramipril, valsartan, metformin, amlodipine, atorvastatin, cimetidine and hydrochlorothiazide.
Dosisjustering for aliskiren eller disse samtidigt administrerede lægemidler er derfor ikke nødvendig.
As a result no dose adjustment for aliskiren or these co-administered medicinal products is necessary.
Interaktioner med P- glycoprotein:
P-glycoprotein interactions:
I prækliniske forsøg er det vist, at MDR1/ Mdr1a/ 1b (P- gp) er det vigtigste efflukssystem involveret i aliskirens intestinale absorption og galdeudskillelse.
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.
Induktorer af P- gp (perikum, rifampicin) kan muligvis derfor nedsætte aliskirens biotilgængelighed.
John’ s wort, rifampicin) might therefore decrease the bioavailability of aliskiren.
Derfor kan P - gp- induktorer øge vævskoncentrationen mere end plasmakoncentrationen.
Therefore, P-gp inhibitors may increase tissue levels more than plasma levels.
Potente P- gp- hæmmere:
P-gp potent inhibitors:
Et interaktionsforsøg med raske frivillige personer, hvor dosis blev administreret en gang, har vist, at ciclosporin (200 og 600 mg) øger Cmax af 75 mg aliskiren cirka 2, 5 gange og AUC cirka 5 gange.
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.
Moderate P- gp- hæmmere:
Moderate P-gp inhibitors:
Administration af ketoconazol (200 mg) sammen med aliskiren (300 mg) resulterede i en 80% stigning i plasmaniveauerne for aliskiren (AUC og Cmax).
Co-administration of ketoconazole (200 mg) with aliskiren (300 mg) resulted in an 80% increase in plasma levels of aliskiren (AUC and Cmax).
Aliskirendoser på op til 600 mg eller det dobbelte af den højeste, anbefalede terapeutiske dosis er fundet at være veltolererede i kontrollerede kliniske forsøg.
The change in plasma levels of aliskiren in the presence of ketoconazole 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.
Der skal derfor udvises forsigtighed, hvis aliskiren gives sammen med ketoconazol eller andre moderate P - gp- hæmmere (itraconazol, clarithromycin, telithromycin, erythromycin, amiodaron).
Therefore, caution should be exercised when aliskiren is administered with ketoconazole or other moderate P-gp inhibitors (itraconazol, clarithromycin, telithromycin, erythromycin, amiodarone).
P- gp- substrater eller svage hæmmere:
P-gp substrates or weak inhibitors:
Grapefrugtjuice:
Grapefruit juice:
På grund af manglende data om mulig interaktion mellem grapefrugtjuice og aliskiren kan denne interaktion ikke udelukkes.
Due to the lack of data a potential interaction between grapefruit juice and aliskiren cannot be excluded.
Grapefrugt juice må ikke tages sammen med Rasilez HCT.
Grapefruit juice should not be taken together with Rasilez HCT.
6 Furosemid:
Furosemide:
Når aliskiren blev administreret sammen med furosemid, faldt AUC og Cmax for furosemid med henholdsvis 28% og 49%.
When aliskiren was co-administered with furosemide, the AUC and Cmax of furosemide were reduced by 28% and 49%, respectively.
Det anbefales derfor at monitorere virkningen ved initiering og justering af furosemidbehandling for at undgå potentiel underudnyttelse i kliniske situationer med volumen- overload.
It is therefore recommended to monitor the effects when initiating and adjusting furosemide therapy to avoid possible underutilisation in clinical situations of volume overload.
Non- steroide anti- inflammatoriske lægemidler (NSAID):
Non-steroidal anti-inflammatory drugs (NSAIDs):
Som for andre stoffer, der virker på renin - angiotensin- systemet, kan NSAID reducere aliskirens antihypertensive effekt.
As with other agents acting on the renin-angiotensin system, NSAIDs may reduce the anti-hypertensive effect of aliskiren.