natgillin/translations-raw huggingface dataset:
I samtlige af behandlingsgrupperne fik patienterne typisk mellem 2 og 4 antihypertensive stoffer (fx diuretikum, betablokker, alfablokker), for at opnå en foruddefineret blodtryksværdi på ≤ 135/ 85 mmHg eller en 10 mmHg reduktion i systolisk tryk, hvis baseline var > 160 mmHg.
Patients in all treatment groups typically received between 2 and 4 antihypertensive agents (e. g., diuretics, beta blockers, alpha blockers) to reach a predefined blood pressure goal of ≤ 135/ 85 mmHg or a 10 mmHg reduction in systolic pressure if baseline was > 160 mmHg.
Tres procent (60%) af patienterne i placebogruppen nåede denne blodtryksværdi, mens tallet var henholdsvis 76% og 78% for irbesartan og amlodipin.
Sixty per cent (60%) of patients in the placebo group reached this target blood pressure whereas this figure was 76% and 78% in the irbesartan and amlodipine groups respectively.
Irbesartan reducerede signifikant den relative risiko i det kombinerede primære endepunkt med fordobling af serum- kreatinin, slutstadium af nyresygdom (ESRD) eller totalmortalitet.
Irbesartan significantly reduced the relative risk in the primary combined endpoint of doubling serum creatinine, end-stage renal disease (ESRD) or all-cause mortality.
33% af patienterne i irbesartangruppen nåede det primære kombinerede nyreendepunkt sammenlignet med henholdsvis 39% og 41% i placebo - og amlodipin- gruppen (20% relativ risikoreduktion versus placebo (p = 0, 024) og 23% relativ risiko
When the individual components of the primary endpoint were
Da de individuelle komponenter af det primære endepunkt blev analyseret, blev der ikke observeret nogeneffekt på totalmortalitet, mens der sås en positiv tendens i reduktionen i ESRD og en signifikant reduktion i fordoblingen af serum- kreatinin.
8 analysed, no effect in all cause mortality was observed, while a positive trend in the reduction in ESRD and a significant reduction in doubling of serum creatinine were observed.
Subgrupper opdelt efter køn, race, alder, varighed af diabetes, baseline- blodtryk, serum- kreatinin og udskillelsesrate af albumin er undersøgt for behandlingseffekt.
Subgroups consisting of gender, race, age, duration of diabetes, baseline blood pressure, serum creatinine, and albumin excretion rate were assessed for treatment effect.
Alligevel var der ingen forskel blandt de tre grupper hvad angår det sekundære endepunkt af fatal og ikke- fatal kardiovaskulær hændelse.
As for the secondary endpoint of fatal and non-fatal cardiovascular events, there was no difference among the three groups in the overall population, although an increased incidence of non-fatal MI was seen for women and a decreased incidence of non-fatal MI was seen in males in the irbesartan group versus the placebo- based regimen.
Der sås øget hyppighed af ikke- fatalt MI og slagtilfælde hos kvinder i det irbesartan- baserede regime versus det amlodipin - baserede regime, mens frekvensen af hospitalindlæggelse på grund af hjertefejl blev reduceret i den samlede population.
An increased incidence of non-fatal MI and stroke was seen in females in the irbesartan-based regimen versus the amlodipine-based regimen, while hospitalization due to heart failure was reduced in the overall population.
IRMA 2- studiet (Effects of Irbesartan on Microalbuminuria in Hypertensive Patients with type 2 Diabetes Mellitus) viste, at irbesartan 300 mg forsinker progression til klinisk proteinuri hos patienter med mikroalbuminuri.
The study of the “ Effects of Irbesartan on Microalbuminuria in Hypertensive Patients with type 2 Diabetes Mellitus (IRMA 2 )” shows that irbesartan 300 mg delays progression to overt proteinuria in patients with microalbuminuria.
IRMA 2 var et placebo- kontrolleret dobbeltblindt morbiditetsstudie med 590 patienter med type 2- diabetes, mikroalbuminuri (30- 300 mg/ dag) og normal nyrefunktion (serum - kreatinin ≤ 1, 5 mg/ dl hos mænd og < 1, 1 mg/ dl hos kvinder).
IRMA 2 was a placebo-controlled double blind morbidity study in 590 patients with type 2 diabetes, microalbuminuria (30-300 mg/ day) and normal renal function (serum creatinine ≤ 1.5 mg/ dl in males and < 1.1 mg/ dl in females).
Studiet undersøgte langtidsvirkningerne (2 år) af Irbesartan BMS med henblik på progression til klinisk proteinuri (urinalbumin udskillelsesrate (UAER) > 300 mg/ dag og en stigning i UAER på mindst 30% i forhold til baseline).
The study examined the long-term effects (2 years) of Irbesartan BMS on the progression to clinical (overt) proteinuria (urinary albumin excretion rate (UAER) > 300 mg/ day, and an increase in UAER of at least 30% from baseline).
Yderligere antihypertensive præparater (eksklusiv ACE- hæmmere, angiotensin II- receptorantagonister og dihydropyridin- calciumblokkere) blev tilføjet efter behov for at nå blodtryksmålet.
Additional antihypertensive agents (excluding ACE inhibitors, angiotensin II receptor antagonists and dihydropyridine calcium blockers) were added as needed to help achieve the blood pressure goal.
Der var dog færre patienter i irbesartan- gruppen der fik 300 mg (5, 2%) som nåede endepunktet, klinisk proteinuri, sammenlignet med placebogruppen (14, 9%) ogi irbesartan - gruppen der fik 150 mg (9, 7%), hvilket viste en relativ risikoreduktion på 70% versus placebo (p = 0, 0004) ved den højere dosis.
While similar blood pressure was achieved in all treatment groups, fewer subjects in the irbesartan 300 mg group (5.2%) than in the placebo (14.9%) or in the irbesartan 150 mg group (9.7%) reached the endpoint of overt proteinuria, demonstrating a 70% relative risk reduction versus placebo (p = 0.0004) for the higher dose.
Der sås ikke efterfølgende forbedringer i den glomerulære filtrationshastighed (GFR) under behandlingen i de første 3 måneder.
An accompanying improvement in the glomerular filtration rate (GFR) was not observed during the first three months of treatment.
Forhaling af progression til klinisk proteinuri var tydelig allerede efter 3 måneder, og den varede ved gennem hele 2- års perioden.
The slowing in the progression to clinical proteinuria was evident as early as three months and continued over the 2 year period.
Regression til normo albuminuri (< 30 mg/ dag) forekom hyppigere i gruppen der fik Irbesartan BMS 300 mg (34%) end i placebogruppen (21%).
Regression to normoalbuminuria (< 30 mg/ day) was more frequent in the Irbesartan BMS 300 mg group (34%) than in the placebo group (21%).
Fordelingsvolumen er 53- 93 liter.
The volume of distribution is 53-93 litres.
Irbesartan udviser lineær og dosisproportional farmakokinetik i et dosisinterval på 10- 600 mg.
Irbesartan exhibits linear and dose proportional pharmacokinetics over the dose range of 10 to 600 mg.
Spidskoncentration i plasma opnås 1, 5- 2 timer efter peroral administration.
Peak plasma concentrations are attained at 1.5-2 hours after oral administration.
Total body - og nyreclearance er henholdsvis 157- 176 og 3- 3, 5 ml/ min.
The total body and renal clearance are 157-176 and 3-3.5 ml/ min, respectively.
Irbesartan AUC - og Cmax - værdier var også noget større hos ældre patienter (≥ 65 år) end hos yngre patienter (18- 40 år). Den terminale halveringstid ændredes dog ikke signifikant.
Irbesartan AUC and Cmax values were also somewhat greater in elderly subjects (≥ 65 years) than those of young subjects (18-40 years).
Efter enten peroral eller intravenøs administration af 14C irbesartan, genfindes ca.
Irbesartan and its metabolites are eliminated by both biliary and renal pathways.
Farmakokinetik af irbesartan evalueredes hos 23 hypertensive børn efter administration af enkeltdosis irbesartan og gentagne doser irbesartan (2 mg/ kg) i doser på op til maksimalt 150 mg dagligt i 4 uger.
The pharmacokinetics of irbesartan were evaluated in 23 hypertensive children after the administration of single and multiple daily doses of irbesartan (2 mg/ kg) up to a maximum daily dose of 150 mg for four weeks.
Resultaterne viste at Cmax, AUC og clearance var sammenlignelig med det hos voksne, der er blevet behandlet med 150 mg irbesartan dagligt.
Results showed that Cmax, AUC and clearance rates were comparable to those observed in adult patients receiving 150 mg irbesartan daily.
I ikke- kliniske sikkerhedsstudier forårsagede høje doser irbesartan (≥ 250 mg/ kg/ dag hos rotter og ≥ 100 mg/ kg/ dag hos marekatte) en reduktion af røde blodlegeme- parametre (erytrocytter, hæmoglobin, hæmatokrit).
In non-clinical safety studies, high doses of irbesartan (≥ 250 mg/ kg/ day in rats and ≥ 100 mg/ kg/ day in macaques) caused a reduction of red blood cell parameters (erythrocytes, haemoglobin, haematocrit).
Dette anses for at være en sekundær effekt af stoffets hypotensive virkning, som medfører nedsat nyreperfusion.
At very high doses (≥ 500 mg/ kg/ day) degenerative changes in the kidney (such as interstitial nephritis, tubular distension, basophilic tubules, increased plasma concentrations of urea and creatinine) were induced by irbesartan in the rat and the macaque and are considered secondary to the hypotensive effects of the medicinal product which led to decreased renal perfusion.
Herudover inducerede irbesartan hyperplasi/ hypertrofi af de juxtaglomerulære celler (hos rotter ved ≥ 90 mg/ kg/ dag, hos marekatte ved ≥ 10 mg/ kg/ dag).
Furthermore, irbesartan induced hyperplasia/ hypertrophy of the juxtaglomerular cells (in rats at ≥ 90 mg/ kg/ day, in macaques at ≥ 10 mg/ kg/ day).
Alle disse forandringer anses at være forårsaget af irbesartans farmakologiske virkning.
All of these changes were considered to be caused by the pharmacological action of irbesartan.
10 6. 3 Opbevaringstid
6.3 Shelf life
14 tabletter 28 tabletter 56 tabletter 98 tabletter PVC/ PVDC/ aluminiumblistere
14 tablets 28 tablets 56 tablets 98 tablets PVC/ PVDC/ Aluminium blisters
56 x 1 tabletter PVC/ PVDC/ perforerede aluminiumblistere med enkeltdosis
56 x 1 tablets PVC/ PVDC/ Aluminium perforated unit dose blisters
BRISTOL- MYERS SQUIBB PHARMA EEIG Uxbridge Business Park Sanderson Road Uxbridge UB8 1DH - Storbritannien
BRISTOL-MYERS SQUIBB PHARMA EEIG Uxbridge Business Park Sanderson Road Uxbridge UB8 1DH - United Kingdom
DATO FOR FØRSTE MARKEDFØRINGSTILLADELSE/ FORNYELSE AF TILLADELSEN
DATE OF FIRST AUTHORISATION / RENEWAL OF THE AUTHORISATION
19. januar 2007 Dato for seneste genregistrering:
19 January 2007 Date of last renewal:
Hver tablet indeholder 150 mg irbesartan.
Each tablet contains 150 mg irbesartan.
Hvide til mathvide, bikonvekse og ovale med et hjerte indgraveret på den ene side, og nummeret 2772 indgraveret på den anden side.
White to off-white, biconvex, and oval-shaped with a heart debossed on one side and the number 2772 engraved on the other side.
Selvom initialdosis på 75 mg bør overvejes til patienter > 75 år, er det sædvanligvis ikke nødvendigt at dosisjustere ældre patienter.
12 Elderly patients: although consideration should be given to initiating therapy with 75 mg in patients over 75 years of age, dosage adjustment is not usually necessary for the elderly.
5. 1).
13 As observed for angiotensin converting enzyme inhibitors, irbesartan and the other angiotensin antagonists are apparently less effective in lowering blood pressure in black people than in non-blacks, possibly because of higher prevalence of low-renin states in the black hypertensive population (see section 5.1).
15 Sygdomme i åndedrætsorganer, brysthule og mediastinum:
15 Respiratory, thoracic and mediastinal disorders:
16 Sygdomme i nervesystemet:
16 Nervous system disorders:
17 Klinisk effekt:
17 Clinical efficacy:
Da de individuelle komponenter af det primære endepunkt blev analyseret, blev der ikke observeret nogeneffekt på totalmortalitet, mens der sås en positiv tendens i reduktionen i ESRD og en signifikant reduktion i fordoblingen af serum- kreatinin.
18 analysed, no effect in all cause mortality was observed, while a positive trend in the reduction in ESRD and a significant reduction in doubling of serum creatinine were observed.
19 Irbesartan og dets metabolitter udskilles gennem både galde og nyrer.
19 However the terminal half-life was not significantly altered.
Efter enten peroral eller intravenøs administration af 14C irbesartan, genfindes ca.
No dosage adjustment is necessary in elderly patients.
20 6. 3 Opbevaringstid
20 6.2 Incompatibilities
Hver tablet indeholder 300 mg irbesartan.
Each tablet contains 300 mg irbesartan.
Hvide til mathvide, bikonvekse og ovale med et hjerte indgraveret på den ene side, og nummeret 2773 indgraveret på den anden side.
White to off-white, biconvex, and oval-shaped with a heart debossed on one side and the number 2773 engraved on the other side.
Selvom initialdosis på 75 mg bør overvejes til patienter > 75 år, er det sædvanligvis ikke nødvendigt at dosisjustere ældre patienter.
22 Elderly patients: although consideration should be given to initiating therapy with 75 mg in patients over 75 years of age, dosage adjustment is not usually necessary for the elderly.
5. 1).
23 As observed for angiotensin converting enzyme inhibitors, irbesartan and the other angiotensin antagonists are apparently less effective in lowering blood pressure in black people than in non-blacks, possibly because of higher prevalence of low-renin states in the black hypertensive population (see section 5.1).
24 4. 6 Graviditet og amning
24 4.6 Pregnancy and lactation
25 Sygdomme i åndedrætsorganer, brysthule og mediastinum:
25 Respiratory, thoracic and mediastinal disorders:
26 Sygdomme i nervesystemet:
26 Nervous system disorders:
27 Klinisk effekt:
27 Clinical efficacy:
Da de individuelle komponenter af det primære endepunkt blev analyseret, blev der ikke observeret nogeneffekt på totalmortalitet, mens der sås en positiv tendens i reduktionen i ESRD og en signifikant reduktion i fordoblingen af serum- kreatinin.
28 analysed, no effect in all cause mortality was observed, while a positive trend in the reduction in ESRD and a significant reduction in doubling of serum creatinine were observed.
29 Irbesartan og dets metabolitter udskilles gennem både galde og nyrer.
29 However the terminal half-life was not significantly altered.
30 6. 3 Opbevaringstid
30 6.2 Incompatibilities
Hver filmovertrukken tablet indeholder 75 mg irbesartan.
Each film-coated tablet contains 75 mg irbesartan.
25, 50 mg lactosemonohydrat per filmovertrukken tablet.
25.50 mg of lactose monohydrate per film-coated tablet.
Ved en dosis på 150 mg, 1 gang dagligt, giver Irbesartan BMS generelt en bedre 24 - timers blodtrykskontrol end 75 mg.
Irbesartan BMS at a dose of 150 mg once daily generally provides a better 24 hour blood pressure control than 75 mg.
Hos patienter som ikke er tilstrækkeligt kontrolleret på 150 mg, 1 gang dagligt, kan dosis af Irbesartan BMS øges til 300 mg, eller andre antihypertensiva kan tilføjes.
In patients insufficiently controlled with 150 mg once daily, the dose of Irbesartan BMS can be increased to 300 mg, or other anti-hypertensive agents can be added.
Dosis bør efterfølgende titreres op til 300 mg, 1 gang dagligt, som den foretrukne vedligeholdelsesdosering til behandling af nyresygdom.
In hypertensive type 2 diabetic patients, therapy should be initiated at 150 mg irbesartan once daily and titrated up to 300 mg once daily as the preferred maintenance dose for treatment of renal disease.
Det er ikke nødvendigt, at dosisjustere patienter med nedsat nyrefunktion.
Renal impairment: no dosage adjustment is necessary in patients with impaired renal function.
Selvom initialdosis på 75 mg bør overvejes til patienter > 75 år, er det sædvanligvis ikke nødvendigt at dosisjustere sædvanligvis ældre patienter.
32 Elderly patients: although consideration should be given to initiating therapy with 75 mg in patients over 75 years of age, dosage adjustment is not usually necessary for the elderly.
Der er øget risiko for alvorlig hypotension og nyreinsufficiens, hvis patienter med bilateral nyrearteriestenose, eller stenose af arterien til deres eneste fungerende nyre, behandles med lægemidler der påvirker renin- angiotensin- aldosteronsystemet.
Renovascular hypertension: there is an increased risk of severe hypotension and renal insufficiency when patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney are treated with medicinal products that affect the renin-angiotensin-aldosterone system.
Der anbefales periodisk kontrol af serum- kalium og serum- kreatinin hvis Irbesartan BMS anvendes til patienter med nedsat nyrefunktion.
Renal impairment and kidney transplantation: when Irbesartan BMS is used in patients with impaired renal function, a periodic monitoring of potassium and creatinine serum levels is recommended.
Som med andre stoffer, der påvirker renin- angiotensin- aldosteronsystemet, kan der opstå hyperkaliæmi under behandling med Irbesartan BMS, specielt i tilfælde af nyrefunktions - nedsættelse, klinisk proteinuri på grund af diabetisk nyresygdom og/ eller hjertefejl.
Hyperkalaemia: as with other medicinal products that affect the renin-angiotensin-aldosterone system, hyperkalaemia may occur during the treatment with Irbesartan BMS, especially in the presence of renal impairment, overt proteinuria due to diabetic renal disease, and/ or heart failure.
5. 1).
33 As observed for angiotensin converting enzyme inhibitors, irbesartan and the other angiotensin antagonists are apparently less effective in lowering blood pressure in black people than in non-blacks, possibly because of higher prevalence of low-renin states in the black hypertensive population (see section 5.1).
Når angiotensin II antagonister administreres samtidig med nonsteroide antiinflammatoriske lægemidler (fx selektive COX- 2- hæmmere, acetylsalicylsyre (> 3 g/ dag) og non- selektive NSAID) kan den antihypertensive virkning svækkes.
Non-steroidal anti-inflammatory drugs: when angiotensin II antagonists are administered simultaneously with non-steroidal anti- inflammatory drugs (i. e. selective COX-2 inhibitors, acetylsalicylic acid (> 3 g/ day) and non-selective NSAIDs), attenuation of the antihypertensive effect may occur.
34 4. 6 Graviditet og amning
34 4.6 Pregnancy and lactation
Der er kendt at behandling med AIIRAer under anden og tredje trimester kan inducere human føtotoksicitet (nedsat nyrefunktion, oligohydramnios, hæmning af kraniets knogledannelse) og neonatal toksicitet (nyresvigt, hypotension, hyperkalæmi) (se pkt.
AIIRAs therapy exposure 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).
Der er i placebokontrollerede undersøgelser med hypertensive patienter ikke set forskel i den samlede bivirkningshyppighed mellem irbesartan- grupperne (56, 2%) og placebogrupperne (56, 5%).
Hypertension: in placebo-controlled trials in patients with hypertension, the overall incidence of adverse events did not differ between the irbesartan (56.2%) and the placebo groups (56.5%).
35 Sygdomme i åndedrætsorganer, brysthule og mediastinum:
35 Respiratory, thoracic and mediastinal disorders:
Der blev almindeligvis observeret signifikant stigning i plasma- kreatinkinase (1, 7%) hos irbesartan- behandlede patienter.
significant increases in plasma creatine kinase were commonly observed (1.7%) in irbesartan treated subjects.
Som med andre angiotensinII- receptorantagonister er der rapporteret sjældne tilfælde af overfølsomhedsreaktioner, fx udslæt, urticaria, angioødem
As with other angiotensin-II receptor antagonists, rare cases of hypersensitivity reactions such as rash, urticaria, angioedema have been reported
36 Sygdomme i nervesystemet:
36 Nervous system disorders:
4. 4).
Impaired renal function including cases of renal failure in patients at risk (see section 4.4)
Farmakoterapeutisk klassifikation: angiotensin II- antagonister, almindelige.
Pharmacotherapeutic group: angiotensin-II antagonists, plain.
Stoffet antages at blokere alle virkninger af angiotensin II som bliver medieret af AT1- receptoren, uafhængigt af angiotensin- II- syntesens kilde eller rute.
Mechanism of action: it is expected to block all actions of angiotensin-II mediated by the AT1 receptor, regardless of the source or route of synthesis of angiotensin-II.
37 Klinisk effekt:
37 Clinical efficacy:
Ligesom for andre lægemidler, der påvirker renin- angiotensinsystemet, gælder det at sorte hypertensionspatienter responderer betydeligt dårligere på irbesartanmonoterapi.
As is the case with other medicinal products that affect the renin-angiotensin system, black hypertensive patients have notably less response to irbesartan monotherapy.
IDNT er et kontrolleret dobbeltblindt morbiditets - og mortalitetsstudie som sammenlignede Irbesartan BMS, amlodipin og placebo.
IDNT was a double blind, controlled, morbidity and mortality trial comparing Irbesartan BMS, amlodipine and placebo.
I samtlige af behandlingsgrupperne fik patienterne typisk mellem 2 og 4 antihypertensive stoffer (fx diuretikum, betablokker, alfablokker) for at opnå en foruddefineret blodtryksværdi på ≤ 135/ 85 mmHg eller en 10 mmHg reduktion i systolisk tryk, hvis baseline var > 160 mmHg.
Patients in all treatment groups typically received between 2 and 4 antihypertensive agents (e. g., diuretics, beta blockers, alpha blockers) to reach a predefined blood pressure goal of ≤ 135/ 85 mmHg or a 10 mmHg reduction in systolic pressure if baseline was > 160 mmHg.
Da de individuelle komponenter af det primære endepunkt blev analyseret, blev der ikke observeret nogen effekt på totalmortalitet, mens der sås en positiv tendens i reduktionen i ESRD og en signifikant reduktion i fordoblingen af serum- kreatinin.
38 analysed, no effect in all cause mortality was observed, while a positive trend in the reduction in ESRD and a significant reduction in doubling of serum creatinine were observed.
Alligevel var der ingen forskel blandt de tre grupper i den overordnede population, hvad angår det sekundære endepunkt af fatal og ikke- fatal kardiovaskulær hændelse.
As for the secondary endpoint of fatal and non-fatal cardiovascular events, there was no difference among the three groups in the overall population, although an increased incidence of non-fatal MI was seen for women and a decreased incidence of non-fatal MI was seen in males in the irbesartan group versus the placebo- based regimen.
Der sås øget hyppighed af ikke- fatalt MI og slagtilfælde hos kvinder i det irbesartan - baserede regime versus det amlodipin- baserede regime, mens frekvensen af hospitalsindlæggelse på grund af hjertefejl blev reduceret i den samlede population.
An increased incidence of non-fatal MI and stroke was seen in females in the irbesartan-based regimen versus the amlodipine-based regimen, while hospitalization due to heart failure was reduced in the overall population.
Der er dog ikke identificeret nogen entydig forklaring for disse fund hos kvinder..
However, no proper explanation for these findings in women has been identified.
Regression til normo albuminuri (< 30 mg/ dag) forekom hyppigere i gruppen, der fik Irbesartan BMS 300 mg (34%) end i placebogruppen (21%).
Regression to normoalbuminuria (< 30 mg/ day) was more frequent in the Irbesartan BMS 300 mg group (34%) than in the placebo group (21%).
Fordelingsvolumen er 53- 93 liter.
The volume of distribution is 53 - 93 litres.
Spidskoncentration i plasma opnås 1, 5- 2 timer efter peroral administration.
Peak plasma concentrations are attained at 1.5 - 2 hours after oral administration.
Total body - og nyreclearance er henholdsvis 157- 176 og 3- 3, 5 ml/ min.
The total body and renal clearance are 157 - 176 and 3 - 3.5 ml/ min, respectively.
Den terminal halveringstid for irbesartan er 11- 15 timer.
The terminal elimination half-life of irbesartan is 11 - 15 hours.
Irbesartan AUC - og Cmax - værdier var også
Irbesartan AUC and Cmax values were also somewhat greater in elderly subjects (≥ 65 years) than those of young subjects
39 noget større hos ældre patienter (≥ 65 år) end hos yngre patienter (18- 40 år). Den terminale halveringstid ændredes dog ikke signifikant.
However the terminal half-life was not significantly altered.