natgillin/translations-raw huggingface dataset:
Der er rapporteret tilfælde af alvorlig infektion (med eller uden neutropeni) herunder pneumoni.
Cases of serious infection (with or without neutropoenia), including pneumonia, have been reported.
Kun nogle få tilfælde var fatale.
Few cases had a fatal outcome.
Der er rapporteret sjældne tilfælde af myopati og/ eller rhabdomyolyse, nogle med akut nyresvigt.
Rare cases of myopathy and/ or rhabdomyolysis, some with acute renal failure, have been reported.
Blod - og lymfesystem:
13 Blood and lymphatic system disorders:
Der er i sjældne tilfælde rapporteret om mikroangiopati.
Rare cases of thrombotic microangiopathy have been reported.
Efter normalisering kan behandlingen genoptages efter lægens skøn.
Temporary suspension of SUTENT is recommended; following resolution, treatment may be resumed at the discretion of the treating physician.
Det endokrine system:
Endocrine Disorders:
4. 4).
Rare cases of hyperthyroidism, some followed by hypothyroidism, have been reported in clinical trials and through post-marketing experience (See also section 4.4).
Der er ikke foretaget sikkerhedsvurdering ved fortsat behandling med SUTENT hos patienter med moderat til alvorlig proteinuri.
The safety of continued SUTENT treatment in patients with moderate to severe proteinuria has not been systematically evaluated.
4. 4).
Discontinue SUTENT in patients with nephrotic syndrome (see also section 4.4).
14 4. 9 Overdosering
4.9 Overdose
Der er ikke rapporteret tilfælde af akut overdosering med SUTENT.
There is no experience of acute overdosage with SUTENT.
Der er ingen specifik antidot for overdosering med SUTENT, og behandling af overdosis er generelt understøttende.
There is no specific antidote for overdosage with SUTENT and treatment of overdose should consist of general supportive measures.
Hvis indiceret, kan elimination af ikke absorberet lægemiddel ske ved opkastning eller maveskylning.
If indicated, elimination of unabsorbed drug may be achieved by emesis or gastric lavage.
Antineoplastiske midler - Protein- tyrosinkinase- hæmmer, ATC- kode:
Antineoplastic agents - Protein-tyrosine kinase inhibitor, ATC Code:
L01XE04
LO1XE04
Sunitinibmalat hæmmer gentagne receptortyrosinkinaser (RTK), som indgår i tumorvækst, patologisk angiogenese og metastaserende progression af cancer.
Sunitinib malate inhibits multiple receptor tyrosine kinases (RTKs) that are implicated in tumour growth, pathologic angiogenesis, and metastatic progression of cancer.
Sunitinib er identificeret som en hæmmer af receptorerne for trombocytafledte vækstfaktorer (PDGFRα og PDGFβ), vaskulære endotel - vækstfaktorer (VEGFR1, VEGFR2 og VEGF3), stamcellefaktor (KIT), Fms- lignende tyrosinkinase- 3 (FLT3), kolonistimulerende faktor (CSF- 1R) og gliacelleafledt neurotrof faktor (RET).
Sunitinib was identified as inhibitor of platelet-derived growth factor receptors (PDGFRα and PDGFRβ), vascular endothelial growth factor receptors (VEGFR1, VEGFR2 and VEGFR3), stem cell factor receptor (KIT), Fms-like tyrosine kinase-3 (FLT3), colony stimulating factor receptor (CSF-1R), and the glial cell-line derived neurotrophic factor receptor (RET).
Effekten er baseret på tidspunktet for tumorprogression og stigning i overlevelse med GIST samt på henholdsvis progressions- fri overlevelse og objektiv responsrate for behandlingsnaiv og cytokin - refraktær mRCC.
CLINICAL STUDIES The clinical safety and efficacy of SUTENT has been studied in the treatment of patients with malignant gastrointestinal stromal tumour (GIST) who were resistant to imatinib (i. e. those who experienced disease progression during or following treatment with imatinib) or intolerant to imatinib (i. e. those who experienced significant toxicity during treatment with imatinib that precluded further treatment) and the treatment of patients with metastatic renal cell carcinoma (MRCC) Efficacy is based on time to tumour progression and an increase in survival in GIST and on progression free survival and objective response rates for treatment-naïve and cytokine-refractory MRCC respectively.
Gastrointestinale stromale tumorer Den første åbne, dosis- eskaleringsundersøgelse blev udført hos patienter med GIST efter behandlingssvigt med imatinib (median maksimal daglig dosis på 800 mg) på grund af resistens eller intolerans.
Gastrointestinal Stromal Tumours An initial open-label, dose-escalation study was conducted in patients with GIST after failure of imatinib (Median maximum daily dose 800 mg) due to resistance or intolerance.
55 patienter fik 50 mg og den anbefalede behandlingscyklus på 4 på hinanden følgende uger og 2 uger uden behandling (doseringsskema 4/ 2).
Ninety-seven patients were enrolled at various doses and schedules; 55 patients received 50 mg at the recommended treatment schedule 4 weeks on / 2 weeks off (“ schedule 4/ 2”).
I denne undersøgelse var mediantiden til progression (TTP) 34, 0 uger (95% CI = 22, 0 – 46, 0 uger).
In this study the median Time To Progression (TTP) was 34.0 weeks (95% CI = 22.0 – 46.0 weeks).
En fase 3, randomiseret, dobbelt- blind, placebokontrolleret undersøgelse med SUTENT blev udført hos patienter med GIST, som udviste intolerans over for, eller havde udviklet sygdomsprogression under eller efter behandling med imatinib (median maksimal daglig dosis på 800 mg).
A phase 3, randomized, double-blind, placebo-controlled study of SUTENT was conducted in patients with GIST who were intolerant to, or had experienced disease progression during or following treatment with, imatinib (Median maximum daily dose 800 mg).
I denne undersøgelse blev 312 patienter randomiseret (2: 1) til enten 50 mg SUTENT eller placebo, oralt 1 gang dagligt med doseringsskema 4/ 2 indtil sygdomsprogression, eller til de udgik af undersøgelsen af anden årsag (207 patienter fik SUTENT, og 105 patienter fik placebo).
In this study, 312 patients were randomized (2:1) to receive either 50 mg SUTENT or placebo, orally once daily on Schedule 4/ 2 until disease progression or withdrawal from the study for another reason (207 patients received SUTENT and 105 patients received placebo).
Undersøgelsens primære effektendepunkt var TTP, defineret som tiden fra randomisering til første dokumenterede objektive tumorprogression.
The primary efficacy endpoint of the study was TTP, defined as the time from randomization to first documentation of objective tumour progression.
Median TTP for SUTENT var 28, 9 uger (95% CI = 21, 3- 34, 1 uger) og var statistisk signifikant længere end TTP på 5, 1 uger (95% CI = 4, 4- 10, 1 uger) for placebo.
14 The median TTP on SUTENT was 28.9 weeks (95% CI = 21.3-34.1 weeks) and was statistically significantly longer than the TTP of 5.1 weeks (95% CI = 4.4-10.1 weeks) on placebo.
Forskellen i den samlede overlevelse var statistisk til fordel for SUTENT [hazard ratio:
The difference in overall survival was statistically in favour of SUTENT [hazard ratio:
0, 491 95% (CI 0, 290- 0, 831)].
0.491 (95%C. I.
Risiko for død var dobbelt så høj hos patienter i placebogruppen som i SUTENT- gruppen.
0.290- 0.831)]; the risk of death was 2 times higher in patients in the placebo arm compared to the SUTENT arm.
Fordelingen i procent på dødsfald var 14% for SUTENT versus 25% for placebo.
The percentages of deaths were 14% for SUTENT vs 25% for placebo.
Den samlede mediane overlevelse er ikke nået for nogen af behandlingsgrupperne ved tidspunktet for analysen.
Median overall survival had not yet been reached in either treatment arm at the time of analysis.
15 Behandlingsnaiv metastaserende renalcellecarcinom (mRCC) Der er udført en fase 3 randomiseret, multicenter, international undersøgelse, der evaluerer effekt og sikkerhed af sunitinib sammenlignet med IFN- α hos patienter med behandlingsnaiv metastaserende RCC.
Treatment-naïve Metastatic Renal cell Carcinoma (MRCC) A phase 3 randomized, multicenter, international, study evaluating the efficacy and safety of sunitinib compared with IFN-α in patients with treatment-naïve metastatic RCC was conducted.
De fik behandling med enten sunitinib i en gentagen cyklus på 6 uger, bestående af 4 uger på 50 mg daglig oral administration, efterfulgt af 2 ugers pause (doseringsskema 4/ 2) eller IFN- α, administreret som en subkutan injektion på 3 millioner enheder (MIE) den første uge, 6 MIE den anden uge og 9 MIE den tredje uge, og herefter 3 på hinanden følgende dage hver uge.
Seven hundred and fifty patients were randomized 1:1 to the treatment arms; they received treatment with either sunitinib in repeated 6-week cycles, consisting of 4 weeks of 50 mg daily oral administration followed by 2 weeks of rest (Schedule 4/ 2), or IFN-α, administered as a subcutaneous injection of 3 million units (MU) the first week, 6 MU the second week, and 9 MU the third week and thereafter on 3 non-consecutive days each week.
Det primære effektendepunkt var progressions- fri overlevelse (PFS).
The primary efficacy endpoint was progression free survival (PFS).
Risikoratioen var 0, 415 (95% CI:
In this study the median PFS for the sunitinib-treated group was 47.3 weeks compared with 22.0 weeks for the IFN-α -treated group; the hazard ratio was 0.415 (95% CI:
0, 320- 0, 539, p- værdien < 0, 001).
0.320-0.539, p-value < 0.001).
Cytokin- refraktær, metastaserende renalcellecarcinom En fase 2 undersøgelse af SUTENT blev udført hos patienter, som var refraktære før cytokinbehandling med interleukin- 2 eller interferon- alfa.
Cytokine-Refractory Metastatic Renal Cell Carcinoma A phase 2 study of SUTENT was conducted in patients who were refractory to prior cytokine therapy with interleukin-2 or interferon-α.
63 patienter fik en oral initialdosis på 50 mg SUTENT 1 gang dagligt i 4 på hinanden følgende uger efterfulgt af 2 ugers pause for at fuldføre en fuldstændig cyklus på 6 uger (doseringsskema 4/ 2).
Sixty-three patients received a starting dose of 50 mg of SUTENT orally, once daily for 4 consecutive weeks followed by a 2-week rest period, to comprise a complete cycle of 6 weeks (schedule 4/ 2).
Det primære effektendepunkt var den objektive responsrate (ORR) baseret på Response Evaluation Criteria in Solid Tumours (RECIST = respons evaluering af kriterier for solide tumorer).
The primary efficacy endpoint was objective response rate (ORR) based on Response Evaluation Criteria in Solid Tumours (RECIST).
I denne undersøgelse var den objektive responsrate 36, 5% (95% C. I.
In this study the objective response rate was 36.5% (95% C. I.
24, 7% - 49, 6%) og mediantiden til progression (TTP) var 37, 7 uger (95% C. I.
24.7% - 49.6%) and the median time to progression (TTP) was 37.7 weeks (95% C. I.
24, 0- 46, 4 uger).
24.0 - 46.4 weeks).
En bekræftende åben, enkelt- arm, mulitcenterundersøgelse, der evaluerede effekt og sikkerhed af SUTENT, blev udført hos patienter med mRCC, som var rekfraktære til tidligere cytokinbehandling.
A confirmatory, open-label, single-arm, multi-centre study evaluating the efficacy and safety of SUTENT was conducted in patients with MRCC who were refractory to prior cytokine therapy.
106 patienter fik mindst en 50 mg dosis af SUTENT efter doseringsskema 4/ 2.
One hundred and six patients received at least one 50 mg dose of SUTENT on schedule 4/ 2.
Det primære effektendepunkt i denne undersøgelse var objektiv responserate (ORR).
The primary efficacy endpoint of this study was Objective Response Rate (ORR).
Sekundære endepunkter omfattede TTP, varighed af respons (DR) og samlet overlevelse (OS).
Secondary endpoints included TTP, duration of response (DR) and overall survival (OS).
I denne undersøgelse var ORR 35, 8% (95% C. I.
In this study the ORR was 35,8% (95% C. I.
Median DR og OS er endnu ikke nået.
26.8% – 47.5%) The median DR and OS had not yet been reached.
Farmakokinetikken af sunitinib og sunitinibmalat er vurderet hos 135 raske forsøgspersoner og 266 patienter med solide tumorer.
The pharmacokinetics of sunitinib and sunitinib malate have been evaluated in 135 healthy volunteers and 266 patients with solid tumours.
Absorption Efter oral anvendelse af sunitinib ses den maksimale koncentration Cmax sædvanligvis 6- 12 timer (Tmax) efter indtagelse af dosis.
Absorption After oral administration of sunitinib, maximum concentrations (Cmax) are generally observed from 6 to 12 hours (Tmax) post-dose.
Fordeling Binding af sunitinib og dets aktive hovedmetabolit til human plasmaprotein er i in vitro undersøgelser henholdsvis 95% og 90%, og der er tilsyneladende ingen koncentrationsafhængighed.
Distribution Binding of sunitinib and its primary active metabolite to human plasma protein in in vitro assays was 95% and 90%, respectively, with no apparent concentration dependence.
Det tilsyneladende distributionsvolumen (V/ F) er stort for sunitinib – 2230 l – som tyder på distribution ind i vævene.
The apparent volume of distribution (V/ F) for sunitinib was large – 2230l -, indicating distribution into the tissues.
Metabolisme De kalkulerede in vitro Ki- værdier for alle undersøgte CYP- isoformer (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/ 5 og CYP4A9/ 11) tyder på, at sunitinib og dets aktive hovedmetabolit i enhver klinisk relevant grad hæmmer metaboliseringen af lægemidler, der metaboliseres af disse enzymer.
Metabolism The calculated in vitro Ki values for all CYP isoforms tested (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/ 5 AND CYP4A9/ 11) indicated that sunitinib and its
In vitro undersøgelser tyder på, at SUTENT hverken inducerer eller hæmmer vigtige CYP- enzymer, herunder CYP3A4.
In-vitro studies also indicate that SUTENT neither induces nor inhibits major CYP enzymes, including CYP3A4.
16 Biotransformation Sunitinib metaboliseres hovedsageligt af CYP3A4, det cytochrom P450- enzym som producerer dets aktive hovedmetabolit, og som derefter metaboliseres yderligere af CYP3A4.
Biotransformation Sunitinib is metabolized primarily by CYP3A4, the cytochrome P450 enzyme, which produces its primary active metabolite, which is then further metabolized by CYP3A4.
56% og 78%.
Concurrent administration of SUTENT with the potent CYP3A4 inducer, rifampin, resulted approximately in 56% and 78% reduction in sunitinib Cmax and AUC0-∞, values respectively, after a single dose of SUTENT in healthy volunteers.
Anvendelse af SUTENT sammen med andre induktorer af CYP3A4 - familien (f. eks. dexamethason, phenytoin, carbamazepin, rifampin, phenobarbital eller Hypericum perforatum også kendt som prikbladet perikum) kan nedsætte sunitinibkoncentrationen.
Administration of SUTENT with other inducers of the CYP3A4 family (e. g. dexamethasone, phenytoin, carbamazepine, phenobarbital or Hypericum perforatum, known also as St.
Elimination Udskillelse sker hovedsageligt via fæces (61%).
John’ s Wort) may decrease sunitinib concentrations.
Renal elimination af lægemiddel og metabolitter sker med 16% af den indgivne dosis.
Elimination Excretion is primarily via faeces (61%) with renal elimination of drug and metabolites accounting for 16% of the administered dose.
Sunitinib og dets hovedmetabolit er de vigtigste lægemiddelrelaterede forbindelser identificeret i plasma, urin og fæces med henholdsvis 91, 5%, 86, 4% og 73, 8% af radioaktivitet i poolede prøver.
Sunitinib and its primary active metabolite were the major drug-related compounds identified in plasma, urine and faeces, representing 91.5%, 86.4% and 73.8% of radioactivity in pooled samples, respectively.
Total oral clearance (CL/ F) er 34- 62 l/ time.
Total oral clearance (CL/ F) was 34-62 l/ hr.
Nedsatte organfunktioner Nedsat leverfunktion:
Organ Functions impairment Hepatic insufficiency:
Hos forsøgspersoner med mildt eller moderat nedsat leverfunktion (Child- Pugh klasse A og B) er systemisk eksponering efter en enkeltdosis SUTENT den samme som hos patienter med svært nedsat leverfunktion (Child- Pugh klasse A og B).
SUTENT was not studied in subjects with severe (Child-Pugh class C) hepatic impairment.
Undersøgelser af cancerpatienter ekskluderede patienter med ALAT eller ASAT > 2, 5 x den øvre referenceværdi, eller hvis levermetastaser var årsag til tallene > 5, 0 x den øvre referenceværdi.
Studies in cancer patients have excluded patients with ALT or AST > 2.5 x ULN (Upper Limit of Normal) or, if due to liver metastasis, > 5.0 x ULN.
Undersøgelser ekskluderede patienter med serumkreatinin > 2, 0 x den øvre referenceværdi.
No clinical studies have been performed in patients with impaired renal function Studies excluded patients with serum creatinine > 2.0 x ULN.
Analyser af populationsfarmakokinetik tyder på, at sunitinibs tilsyneladende clearance (CL/ F) ikke er påvirket af kreatininclearence inden for det vurderede område (42- 347 ml/ min).
Population pharmacokinetic analyses indicated that sunitinib apparent clearance (CL/ F) was not affected by creatinine clearance within the range evaluated (42-347 ml/ min).
40- 60 timer og 80- 110 timer efter oral indtagelse.
Plasma Pharmacokinetics Following oral administration in healthy volunteers, the elimination half-lives of sunitinib and its primary active desethyl metabolite are approximately 40 - 60 hours, and 80 - 110 hours, respectively.
Ved dosisintervallet 25- 100 mg er arealet under plasmakoncentrationstidskurven (AUC) og Cmax øget proportionalt med dosis.
In the dosing ranges of 25 to 100 mg, the area under the plasma concentration-time curve (AUC) and Cmax increase proportionally with dose.
Ved gentagen daglig dosis akkumuleres sunitinib 3- 4 gange og dets aktive hovedmetabolit akkumuleres 7- 10 gange.
With repeated daily administration, sunitinib accumulates 3- to 4-fold and its primary active metabolite accumulates 7- to 10-fold.
Steady state koncentrationen af sunitinib og dets aktive hovedmetabolit nås inden for 10- 14 dage.
Steady-state concentrations of sunitinib and its primary active metabolite are achieved within 10 to 14 days.
Dette er målkoncentrationen fra de prækliniske data for at kunne hæmme receptorfosforylering in vitro, hvilket resulterer i tumorstase/ vækstreduktion in vivo.
By day 14, combined plasma concentrations of sunitinib and is active metabolite are 62.9 - 101 ng/ ml which are target concentrations predicted from preclinical data to inhibit receptor phosphorylation in vitro and result in tumour stasis/ growth reduction in vivo.
Den aktive hovedmetabolit udgør 23- 37% af den totale eksponering.
The primary active metabolite comprises 23 to 37% of the total exposure.
Der er ikke set nogen signifikante ændringer i farmakokinetikken af sunitinib eller den aktive hovedmetabolit ved gentagen daglig dosis eller ved gentagen cyklus efter det undersøgte doseringsskema.
No significant changes in the pharmacokinetics of sunitinib or the primary, active metabolite are observed with repeated daily administration or with repeated cycles in the dosing regimens tested.
Farmakokinetikken var ens for alle undersøgte populationer, solide tumorer og hos raske forsøgspersoner.
The pharmacokinetics were similar in all solid tumour populations tested and in healthy volunteers.
Populationsfarmakokinetiske analyser af demografiske data tyder på, at dosisjustering ikke er nødvendig med hensyn til vægt eller ECOG score.
Population pharmacokinetic analyses of demographic data indicate that no dose adjustments are necessary for weight or ECOG score.
Tilgængelige data tyder på, at kvinder måske har 30% lavere tilsyneladende sunitinibclearance (CL/ F) end mænd; denne forskel kræver imidlertid ingen dosisjustering.
Available data indicate that females could have about 30% lower apparent clearance (CL/ F) of sunitinib than males: this difference however does not necessitate dose adjustments.
I gentagne dosistoksicitetsforsøg af op til 9 måneders varighed på rotter og aber var påvirkninger af det primære målorgan identificeret i den gastrointestinale kanal (emesis og diarré hos aber), binyre (kortikal kongestion og/ eller blødning hos rotter og aber og nekrose efterfulgt af fibrose hos rotter), blod- og lymfesystem (knoglemarvshypocellularitet og lymfoid udtømning i thymus, milt og lymfeknuder), eksokrin pancreas (acinar celledegranulering med enkeltcelle nekrose), spytkirtler
In rat and monkey repeated-dose toxicity studies up to 9-months duration, the primary target organ effects were identified in the gastrointestinal tract (emesis and diarrhoea in monkeys), adrenal gland (cortical congestion and/ or haemorrhage in rats and monkeys, with necrosis followed by fibrosis in rats),
17 (acinar hypertrofi), led (fortykkelse af vækstplade), uterus (atrofi) og ovarier (nedsat follikeludvikling).
16 haemolymphopoietic system (bone morrow hypocelularity, and lymphoid depletion of thymus, spleen, and lymph node), exocrine pancreas (acinar cell degranulation with single cell necrosis), salivary gland (acinar hypertrophy), bone joint (growth plate thickening), uterus (atrophy) and ovaries (decreased follicular development).
Alle fund opstod ved klinisk relevante sunitinib- plasmaeksponeringsniveauer.
All findings occurred at clinically relevant sunitinib plasma exposure levels.
Yderligere påvirkninger, som blev set i andre forsøg omfatter forlængelse af QTc- intervallet, LVEF - nedsættelse, hypofyseatrofi og testikel tubulær atrofi, øget mesangialceller i nyren, blødning i gastrointestinalkanalen og oral mukosa, og hypertrofi af hypofyseforlapceller.
Additional effects, observed in other studies included QTc interval prolongation, LVEF reduction, pituitary hypertrophy, and testicular tubular atrophy, increased mesangial cells in kidney, haemorrhage in GI tract and oral mucosa, and hypertrophy of anterior pituitary cells.
De fleste fund var reversible efter 2- 6 uger uden behandling.
Most of these findings were reversible after 2 to 6 weeks without treatment.
Genotoksicitet Sunitinibs genotoksiske potentiale er vurderet in vitro og in vivo.
Genotoxicity The genotoxic potential of sunitinib was assessed in vitro and in vivo.
Sunitib inducerer ikke strukturelle kromosomafvigelser i humane perifere blod- lymfocytter in vitro.
Sunitinib did not induce structural chromosome aberrations in human peripheral blood lymphocyte cells in vitro.
Polyploid (numeriske kromosomafvigelser) ses i humane perifere blod- lymfocytter in vitro, både ved tilstedeværelse og fravær af metabolisk aktivering.
Polyploidy (numerical chromosome aberrations) was observed in human peripheral blood lymphocytes in vitro, both in the presence and absence of metabolic activation.
Den genotoksiske virkning af den aktive hovedmetabolit er ikke vurderet.
The major active metabolite was not evaluated for genetic toxicity potential.
Karcinogenicitet Der er ikke udført karcinogenicitetsforsøg med sunitinibmalat.
Carcinogenicity Carcinogenicity studies with sunitinib malate have not been performed.
Reproduktionstoksicitet og udviklingstoksicitet Der ses ingen påvirkning af fertiliteten hos hanner eller hunner i reproduktionstoksicitetsforsøgene.
However, in repeated- dose toxicity studies performed in rats and monkeys, effects on female fertility were observed in the form of follicular atresia, degeneration of corpora lutea, endometrial changes in the uterus and decreased uterine and ovarian weights at clinically relevant systemic exposure levels.
Derimod er der i kroniske forsøg i rotter og aber forandringer i hunkønsorganerne i form af follikulær atresi, degeneration af corpora lutea, endometrielæsioner og nedsat vægt af uterus og ovarier, som viser sig ved klinisk relevant systemisk eksponering, og i hankønsorganerne hos rotter i form af tubulær testikelatrofi, nedsat forekomst af sædceller i bitestiklerne og nedsat forekomst af kolloid i prostata og sædblærer ved plasmakoncentrationer, der var 18 gange højere end i klinikken.
Effects on male fertility in rat were observed in the form of tubular atrophy in the testes, reduction of spermatozoa in epididimes and colloid depletion in prostate and seminal vesicles at plasma exposure levels 18-fold higher than is observed in clinic.