natgillin/translations-raw huggingface dataset:
Behandling med candesartancilexetil resulterede i en forbedret NYHA-funktionsklasse (p=0,008). 
Treatment with candesartan cilexetil resulted in improved NYHA functional class (p=0.008).
Hos patienter med let til moderat nedsat nyrefunktion steg Cmax og AUC for candesartan efter gentagne doseringer med henholdsvis ca. 50 % og 70 %, men t½ var uændret i sammenligning med patienter med normal nyrefunktion. 
In patients with mild to moderate renal impairment Cmax and AUC of candesartan increased during repeated dosing by approximately 50% and 70%, respectively, but t½ was not altered, compared to patients with normal renal function.
Evaluering af patienter med hjerteinsufficiens bør altid inkludere vurdering af nyrefunktionen, herunder monitorering af serum-kreatinin og serum-kalium. 
Evaluation of patients with heart failure should always comprise assessment of renal function including monitoring of serum creatinine and potassium.
En startdosis på 4 mg kan overvejes hos patienter med risiko for hypotension, som for eksempel patienter med muligt nedsat intravaskulært volumen (se pkt. 
An initial dose of 4 mg may be considered in patients at risk for hypotension, such as patients with possible volume depletion (see section 4.4).
Kan bevirke, at du føler dig utilpas eller svimmel. 
This may make you feel faint or dizzy.
Afsnit 4.6 Graviditet og amning 
Section 4.6 Pregnancy and Lactation
Doseringen for patienter med hjerteinsufficiens var den samme i alle medlemsstater. 
The posology for patients with heart failure was the same in all MSs.
Nogle personer kan føle træthed og svimmelhed, når de er i behandling med Atacand. 
Some people may feel tired or dizzy when taking Atacand.
Lægen kan øge dosis ved at fordoble den med intervaller på mindst 2 uger op til 32 mg én gang daglig. 
Your doctor may increase your dose by doubling the dose at intervals of at least 2 weeks up to 32 mg once a day.
Som en konsekvens heraf kan der være større behov for optitrering af Atacand og anden samtidig behandling for at opnå blodtrykskontrol hos sorte patienter end hos ikke-sorte patienter (se pkt. 
Consequently, uptitration of Atacand and concomitant therapy may be more frequently needed for blood pressure control in black patients than in non-black patients (see section 5.1).
KVALITATIV OG KVANTITATIV SAMMENSÆTNING [Udfyldes nationalt] 
QUALITATIVE AND QUANTITATIVE COMPOSITION
Virkninger på nyrerne (så som interstitiel nefritis, tubulær distension, basofile tubuli; øgede plasmakoncentrationer af urinstof og kreatinin) blev fremkaldt af candesartan og kunne være sekundære til den hypotensive effekt, der medfører ændring i den renale blodgennemstrømning. 
Effects on the kidneys (such as interstitial nephritis, tubular distension, basophilic tubules; increased plasma concentrations of urea and creatinine) were induced by candesartan which could be secondary to the hypotensive effect leading to alterations of renal perfusion.
Tilføjelse af hydrochlorthiazid til forskellige doser Atacand har vist en additiv antihypertensiv virkning. 
Addition of hydrochlorothiazide has been shown to have an additive antihypertensive effect with various doses of Atacand.
Ældre Det er ikke nødvendigt at justere startdosis hos ældre patienter. 
Elderly population No initial dose adjustment is necessary in elderly patients.
Lægemidler, der hæmmer renin-angiotensin-aldosteron-systemet, har en mindre udtalt antihypertensiv virkning hos sorte patienter (en typisk lav-renin population) end hos ikke-sorte patienter. 
Medicinal products that block the renin-angiotensin-aldosterone system have less pronounced antihypertensive effect in black patients (usually a low-renin population) than in non-black patients.
Indehaver af markedsføringstilladelsen og fremstiller [Se Bilag I - Udfyldes nationalt] {Fremstillers navn og adresse} <{tlf}> <{fax}> <{e-mail}> 
{Name and address of the manufacturer} <{tel}> <{fax}> <{e-mail}>
Hvis samtidig behandling er nødvendig, anbefales omhyggelig monitorering af serum-lithium-niveauer. 
If the combination proves necessary, careful monitoring of serum lithium levels is recommended.
• Heparin (blodfortyndende medicin). 
• Heparin (a medicine for thinning the blood).
Tal med lægen, hvis du oplever dette. 
If this happens contact your doctor.
Der er begrænset erfaring hos patienter med meget alvorlig eller slutstadium af nyreinsufficiens (Clkreatinin < 15 ml/minut). 
There is limited experience in patients with very severe or end-stage renal impairment (Clcreatinine < 15 ml/min).
Behandling med candesartancilexetil reducerer mortalitet, reducerer indlæggelser pga. hjerteinsufficiens og forbedrer symptomerne hos patienter med nedsat systolisk funktion af venstre ventrikel som vist i CHARM-programmet (Candesartan in Heart failure - Assessment of Reduction in Mortality and morbidity). 
Treatment with candesartan cilexetil reduces mortality, reduces hospitalisation due to heart failure, and improves symptoms in patients with left ventricular systolic dysfunction as shown in the Candesartan in Heart failure - Assessment of Reduction in Mortality and morbidity (CHARM) programme.
Candesartan var ligeledes effektivt hos patienter, der tog både betablokkere og ACEhæmmere samtidig, og fordelen var til stede, uanset om patienterne fik de målsatte doser ACEhæmmere, som anbefales i behandlingsguidelines eller ej. 
Candesartan was effective also in patients taking both beta-blockers and ACE inhibitors at the same time, and the benefit was obtained whether or not patients were taking ACE inhibitors at the target dose recommended by treatment guidelines.
I særdeleshed blev opdateringer overvejet om en mulig dosisøgning op til 32 mg, øget antihypertensiv effekt, når candesartan gives i kombination med andre lægemidler, inklusive hydrochlorothiazid og calciumblokkere som amlodipin eller felodipin. 
In particular, updates on the potential dose increase up to 32 mg, increased antihypertensive effect when candesartan is combined with other medicinal products, including hydrochlorothiazide and CCB such as amlodipine or felodipine were considered.
Ifølge denne definition var de hyppigst rapporterede bivirkninger svimmelhed, hovedpine og luftvejsinfektion. 
By this definition, the most commonly reported adverse reactions were dizziness/vertigo, headache and respiratory infection.
• hvis du har en alvorlig leversygdom eller galdevejstillukning (problemer med at udskille galde fra galdeblæren). 
• if you have severe liver disease or biliary obstruction (a problem with the drainage of the bile from the gall bladder).
CHMP/PhVWP's rapport om brug af ACE-hæmmere og angiotensin II-receptorantagonister (AIIRA'er) i graviditetens første trimester (EMEA/CHMP/PhVWP/474692/2007) tyder imidlertid på, at en kontraindikation i graviditetens første trimester ikke er retfærdiggjort. 
However, the CHMP/PhVWP report on the use of ACE inhibitors and Angiotensin II Receptor Antagonists (ARBs) during the 1st trimester of pregnancy (EMEA/CHMP/PhVWP/474692/2007)
Indikationen hjerteinsufficiens var godkendt i alle medlemsstater. 
The heart failure indication was approved in all MSs.
På baggrund af ovenstående anser CHMP benefit/risk-forholdet for Atacand for positivt og de harmoniserede produktinformationsdokumenter som egnede til godkendelse. 
Based on the above the CHMP considers the benefit/risk ratio of Atacand to be favourable and the harmonised PI to be approvable.
Det er nødvendigt at behandle 14 patienter i hele studiets varighed for at forhindre én patient i at dø af en kardiovaskulær hændelse eller i at blive indlagt for behandling af hjerteinsufficiens. 
Fourteen patients needed to be treated for the duration of the study to prevent one patient from dying of a cardiovascular event or being hospitalised for treatment of heart failure.
Du bemærker eventuelt træthed, at din hud eller det hvide i dine øjne får en gullig farve eller influenzalignende symptomer. 
You may notice tiredness, yellowing of your skin and the whites of your eyes and flu like symptoms.
Det bør dog tages i betragtning, at der kan optræde svimmelhed og træthed under behandlingen. 
However, it should be taken into account that occasionally dizziness or weariness may occur during treatment with Atacand.
Candesartan hæmmer ikke ACE, som omdanner angiotensin I til angiotensin II og nedbryder bradykinin. 
Candesartan does not inhibit ACE, which converts angiotensin I to angiotensin II and degrades bradykinin.
Resultater fra to kliniske undersøgelser, som undersøgte den farmakokinetiske profil af candesartan hos patienter med leverinsufficiens, og publikationen af Hoogkamer et al 1998, hvor en startdosis på 12 mg blev anvendt, tyder på, at let til moderat leverinsufficiens ikke har nogen relevant effekt på farmakokinetikken for candesartan. 
Results from two clinical studies investigating the pharmacokinetic (PK) profile of candesartan in patients with impaired hepatic function and the publication by Hoogkamer et al 1998, where a starting dose of 12 mg was used, indicate that mild to moderate hepatic impairment has no relevant effect on candesartan PK, and thus no dose adjustment is required.
Patienter med nedsat intravaskulært volumen 
Patients with intravascular volume depletion
Ligeledes kan der opstå hypotension hos hypertensive patienter med nedsat intravaskulært volumen, såsom patienter der behandles med høje doser diuretika. 
It may also occur in hypertensive patients with intravascular volume depletion such as those receiving high dose diuretics.
CHMP var også enige i inklusionen af en kontraindikation hos patienter med overfølsomhed over for candesartan eller over for et eller flere af hjælpestofferne og hos patienter med svært nedsat leverfunktion og/eller cholestase. 
The CHMP also agreed with the inclusion of a contraindication in patients with hypersensitivity to candersartan or to any of its excipients and in patients with severe hepatic impairment and/or cholestasis.
Effekten af candesartancilexetil 8-16 mg (gennemsnitsdosis 12 mg) én gang daglig på kardiovaskulær morbiditet og mortalitet blev undersøgt i et randomiseret klinisk forsøg med 4.937 ældre patienter (alder 70-89 år; 21 % 80 år eller derover) med let til moderat hypertension, fulgt i gennemsnitligt 3,7 år (SCOPE: Study on Cognition and Prognosis in the Elderly). 
The effects of candesartan cilexetil 8-16 mg (mean dose 12 mg), once daily, on cardiovascular morbidity and mortality were evaluated in a randomised clinical trial with 4,937 elderly patients (aged 70-89 years; 21% aged 80 or above) with mild to moderate hypertension followed for a mean of 3.7 years (Study on COgnition and Prognosis in the Elderly).
[Se Bilag I - Udfyldes nationalt] 
[See Annex I - to be completed nationally]
CHARM var et placebo-kontrolleret, dobbeltblindet studieprogram hos patienter med kronisk hjerteinsufficiens (CHF), NYHA-funktionsklasse II til IV, og bestod af tre separate studier: CHARMAlternative (n=2.028) med patienter med LVEF ≤ 40 %, som pga. intolerans (hovedsageligt på grund af hoste, 72 %) ikke var i ACE-hæmmer behandling, CHARM-Added (n=2.548) med patienter med LVEF ≤ 40 % og behandlet med en ACE-hæmmer samt CHARM-Preserved (n=3.023) med patienter med LVEF > 40 %. 
This placebo controlled, double-blind study programme in chronic heart failure (CHF) patients with NYHA functional class II to IV consisted of three separate studies: CHARM-Alternative (n=2,028) in patients with LVEF  40% not treated with an ACE inhibitor because of intolerance (mainly due to cough, 72%), CHARM-Added (n=2,548) in patients with LVEF  40% and treated with an ACE inhibitor, and CHARM-Preserved (n=3,023) in patients with LVEF > 40%.
• hævelse af ansigt, læber, tunge og/eller hals, hvilket kan give synkebesvær 
• swelling of the face, lips, tongue and/or throat, which may cause difficulties in swallowing
Det er nødvendigt at behandle 23 patienter i hele studiets varighed for at forhindre én patient i at dø af en kardiovaskulær hændelse eller i at blive indlagt for behandling af hjerteinsufficiens. 
Twenty-three patients needed to be treated for the duration of the study to prevent one patient from dying of a cardiovascular event or being hospitalised for treatment of heart failure.
Generelt havde Atacand ingen indflydelse af klinisk betydning på laboratorieværdier målt rutinemæssigt. 
In general, there were no clinically important influences of Atacand on routine laboratory variables.
En øget antihypertensiv virkning kan også ses, når candesartancilexetil gives samtidig med amlodipin eller felodipin. 
An increased antihypertensive effect is also seen when candesartan cilexetil is combined with amlodipine or felodipine.
I en 3-måneders klinisk undersøgelse af hypertensive patienter med type 2-diabetes og mikroalbuminuri nedsatte den antihypertensive behandling med candesartancilexetil udskillelsen af albumin i urinen (albumin/kreatinin-ratio, middelværdi: 30 % med 95 % konfidensinterval: 15-42 %). 
In a 3-month clinical study in hypertensive patients with type 2 diabetes mellitus and microalbuminuria, antihypertensive treatment with candesartan cilexetil reduced urinary albumin excretion (albumin/creatinine ratio, mean 30%, 95%CI 15-42%).
Det aktive stof er candesartancilexetil. 
The active ingredient is candesartan cilexetil.
De hyppigst rapporterede bivirkninger var hyperkaliæmi, hypotension og nedsat nyrefunktion. 
The most commonly reported adverse reactions were hyperkalaemia, hypotension and renal impairment.
Trough blodtryksreduktionen (systolisk/diastolisk) var 13,1/10,5 mmHg ved 32 mg candesartancilexetil én gang daglig og 10,0/8,7 mmHg ved 100 mg losartankalium én gang daglig (forskellen i blodtryksreduktion var 3,1/1,8 mmHg, p<0,0001/p<0,0001). 
The trough blood pressure reduction (systolic/diastolic) was 13.1/10.5 mmHg with candesartan cilexetil 32 mg once daily and 10.0/8.7 mmHg with losartan potassium 100 mg once daily (difference in blood pressure reduction 3.1/1.8 mmHg, p<0.0001/p<0.0001).
I prækliniske sikkerhedsundersøgelser med høje doser påvirkede candesartan nyrerne og de røde blodlegemer hos mus, rotter, hunde og aber. 
In preclinical safety studies candesartan had effects on the kidneys and on red cell parameters at high doses in mice, rats, dogs and monkeys.
• Påvirkning af nyrefunktionen, især hvis du allerede har nyreproblemer eller hjertesvigt. 
• Effects on how your kidneys work, especially if you already have kidney problems or heart failure.
Som for ACE hæmmere kan samtidig anvendelse af AIIRA'er og NSAID'er medføre øget risiko for forværring af nyrefunktionen, inklusive mulig akut nyresvigt og en stigning i serum-kalium, især hos patienter med allerede nedsat nyrefunktion. 
As with ACE inhibitors, concomitant use of AIIRAs and NSAIDs may lead to an increased risk of worsening of renal function, including possible acute renal failure, and an increase in serum potassium, especially in patients with poor pre-existing renal function.
Det er ikke nødvendigt at justere startdosis til ældre patienter eller til patienter med nedsat intravaskulært volumen, nyreinsufficiens eller let til moderat leverinsufficiens. 
No initial dose adjustment is necessary for elderly patients or in patients with intravascular volume depletion or renal impairment or mild to moderate hepatic impairment.
Den totale plasma-clearance af candesartan er ca. 0,37 ml/min/kg med en renal clearance på ca. 
Total plasma clearance of candesartan is about 0.37 ml/min/kg, with a renal clearance of about 0.19 ml/min/kg.
I det kliniske studieprogram CHARM, hvor Atacand i doser op til 32 mg (n=3.803) blev sammenlignet med placebo (n=3.796), seponerede 21,0 % i candesartancilexetil-gruppen og 16,1 % i placebo-gruppen behandlingen på grund af bivirkninger. 
In the CHARM clinical programme, comparing Atacand in doses up to 32 mg (n=3,803) to placebo (n=3,796), 21.0% of the candesartan cilexetil group and 16.1% of the placebo group discontinued treatment because of adverse events.
Behandling med candesartancilexetil resulterede i en forbedret NYHA funktionsklasse (p=0,020). 
Treatment with candesartan cilexetil resulted in improved NYHA functional class (p=0.020).
Almindelig Hypotension 
Common Hypotension
Grækenland AstraZeneca SA Theotokopoulou 4 & Astronafton 151 25 Maroussi Greece 
AstraZeneca SA Theotokopoulou 4 & Astrnafton 151 25 Maroussi Greece
Særlige patientgrupper 
Special patient populations
Behandling af hypertension 
Treatment of Hypertension
• Hævelse i ansigt, læber, tunge og/eller hals. 
• Swelling of the face, lips, tongue and/or throat.
Stenose i aorta- og mitralklapper (obstruktiv hypertrofisk kardiomyopati) Som for andre vasodilatatorer er særlig forsigtighed indiceret hos patienter, der lider af hæmodynamisk relevant stenose i aorta- eller mitralklapper eller obstruktiv hypertrofisk kardiomyopati. 
Aortic and mitral valve stenosis (obstructive hypertrophic cardiomyopathy) As with other vasodilators, special caution is indicated in patients suffering from haemodynamically relevant aortic or mitral valve stenosis, or obstructive hypertrophic cardiomyopathy.
Afsnit 4.1 Terapeutiske indikationer 
Section 4.1 Therapeutic indications
• Vanddrivende medicin (diuretika). 
• Water tablets (diuretics).
Behandling af hjerteinsufficiens 
Treatment of Heart Failure
Anæstesi og kirurgi 
Anaesthesia and surgery
CHMP vedtog således, baseret på bedømmelsen af forslag og svar fra indehaveren af markedsføringstilladelsen og efter drøftelser i udvalget, at harmonisere sæt af produktinformationsdokumenter for Atacand og tilknyttede navne. 
In conclusion, based on the assessment of the MAH proposal and responses, and following the discussions of the committee, the CHMP adopted harmonised sets of PI documents for Atacand and associated names.
Atacand kan anvendes sammen med anden behandling mod hjerteinsufficiens, inkluderende ACEhæmmere, betablokkere, diuretika og digitalis eller en kombination af disse præparater. 
Atacand can be administered with other heart failure treatment, including ACE inhibitors, beta-blockers, diuretics and digitalis or a combination of these medicinal products.
Advarsler vedrørende nyreinsufficiens, samtidig behandling med en ACE-hæmmer ved hjerteinsufficiens, hæmodialyse, nyrearteriestenose, nyretransplantation, hypotension, anæstesi og operation, aorta- og mitralklapstenose, primær hyperaldosteronisme og hyperkaliæmi blev harmoniseret. 
Warnings regarding renal impairment, concomitant therapy with an ACE inhibitor in heart failure, haemodialysis, renal artery stenosis, kidney transplantation, hypotension, anaesthesia and surgery, aortic and mitral valve stenosis, primary hyperaldosteronism and hyperkalaemia were harmonised.
Startdosis er 4 mg til patienter med nedsat nyrefunktion, inklusive patienter i hæmodialyse. 
The starting dose is 4 mg in patients with renal impairment, including patients on haemodialysis.
Som for andre lægemidler, der hæmmer renin-angiotensin-aldosteronsystemet, kan der forventes ændring i nyrefunktionen hos disponerede patienter, der behandles med Atacand. 
As with other agents inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible patients treated with Atacand.
Som for andre hæmmere af renin-angiotensin-aldosteron-systemet er der set mindre fald i hæmoglobin. 
As for other inhibitors of the renin-angiotensin-aldosterone system, small decreases in haemoglobin have been seen.
Hyperkaliæmi og nedsat nyrefunktion er almindelig hos patienter, der behandles med Atacand på indikationen hjerteinsufficiens. 
Hyperkalaemia and renal impairment are common in patients treated with Atacand for the indication of heart failure.
Der r ingen erfaringer hos patienter med stærkt nedsat leverfunktion. 
There is no experience in patients with severe hepatic impairment.
I en samlet analyse af resultaterne fra kliniske forsøg med hypertensive patienter blev bivirkninger ved candesartancilexetil defineret på basis af en hyppighed, der var mindst 1 % højere for candesartancilexetil end for placebo. 
In a pooled analysis of clinical trial data of hypertensive patients, adverse reactions with candesartan cilexetil were defined based on an incidence of adverse events with candesartan cilexetil at least 1% higher than the incidence seen with placebo.
Der var 26,7 hændelser pr. 1.000 patientår i candesartan-gruppen versus 30,0 hændelser pr. 1.000 patientår i kontrolgruppen (relativ risiko: 0,89; 95 % konfidensinterval: 0,75-1,06; p=0,19). 
There were 26.7 events per 1000 patient-years in the candesartan group versus 30.0 events per 1000 patient-years in the control group (relative risk 0.89, 95%CI 0.75 to 1.06, p=0.19).
BILAG I FORTEGNELSE OVER LÆGEMIDLERNES NAVNE, LÆGEMIDDELFORM(ER), STYRKE(R), INDGIVELSESVEJ(E), ANSØGER(E), INDEHAVER(E) AF MARKEDSFØRINGSTILLADELSE(R) I MEDLEMSSTATERNE 
LIST OF THE NAMES, PHARMACEUTICAL FORM, STRENGTH OF THE MEDICINAL PRODUCT, ROUTES OF ADMINISTRATION, MARKETING AUTHORISATION HOLDERS IN THE MEMBER STATES
Luxembourg NV AstraZeneca SA Egide Van Ophemstraat 110 B-1180 Bruxelles 
Luxembourg NV AstraZeneca SA Egide Van Ophemstraat 110 B-1180 Brussels
Stærkt nedsat leverfunktion og/eller kolestase. 
Severe hepatic impairment and/or cholestasis.
Derfor anbefales periodisk monitorering af serumkalium, og kombinationen af en ACE-hæmmer, et kaliumsparende diuretikum og candesartan kan ikke anbefales og bør kun overvejes efter nøje evaluering af de potentielle fordele og risici. 
Therefore, periodic monitoring of serum potassium is recommended and the combination of an ACE inhibitor, a potassium-sparing diuretic and candesartan is not recommended and should be considered only after careful evaluation of the potential benefits and risks.
Det er kendt, at AIIRA-behandling i andet og tredje trimester forårsager human føtotoksicitet (nedsat nyrefunktion, oligohydramnios, forsinket ossifikation af kraniet) og neonatal toksicitet (nyresvigt, hypotension, hyperkaliæmi) (se pkt. 
Exposure to AIIRA therapy during the second and third trimesters is known to induce human fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia) (see section 5.3).
AUC for candesartan hos patienter i hæmodialyse var i samme størrelsesorden som den, der ses hos patienter med stærkt nedsat yrefunktion. 
The AUC of candesartan in patients undergoing haemodialysis was similar to that in patients with severe renal impairment.
Dog blev mortaliteten af alle årsager også opgjort i poolede data, CHARMAlternative og CHARM-Added, HR 0,88 (95 % konfidensinterval: 0,79-0,98; p=0,018) og alle tre studier, HR 0,91 (95 % konfidensinterval: 0,83-1,00; p=0,055). 
However, all-cause mortality was also assessed in pooled populations, CHARMAlternative and CHARM-Added, HR 0.88 (95%CI: 0.79 to 0.98, p=0.018) and all three studies, HR 0.91 (95%CI: 0.83 to 1.00, p=0.055).
Vær ekstra forsigtig med at tage Atacand 
Take special care with Atacand
Brug af AIIRA'er anbefales ikke i første trimester (se pkt. 
The use of AIIRAs is not recommended during the first trimester of pregnancy (see section 4.4).
Imidlertid viste en analyse af det primære sammensatte endpoint, kardiovaskulære dødsfald eller hospitalsindlæggelse på grund af hjerteinsufficiens hos NYHA-klassificerede undergrupper i undersøgelser med lav EF (CHARMAlternative og CHARM-Added pooled, en del af CHARM programmet) risikorater under 1,0 til fordel for candesartan sammenlignet med placebo i hver af NYHA-undergrupperne. 
It is acknowledged that there is limited data in this population, however, analysis of the primary composite endpoint, cardiovascular death or hospitalisation due to heart failure by NYHA class subgroups in the low EF trials (CHARMAlternative and CHARM-Added pooled, part of the CHARM programme), revealed Hazard Ratios (HR) below 1.0 in favour of candesartan compared to placebo in each of the NYHA subgroups.
Indikationen hypertension 
Hypertension indication
Optitrering til måldosen på 32 mg én gang dagligt (maksimumdosis) eller den højeste tolererede dosis sker ved at fordoble dosis i intervaller på mindst 2 uger. 
Up-titration to the target dose of 32 mg once daily (maximum dose) or the highest tolerated dose is done by doubling the dose at intervals of at least 2 weeks.