natgillin/translations-raw huggingface dataset:
Svær hypertension (> 200 mmHg systolisk eller 110 mmHg diastolisk) forekommer hos 4, 7% af patienterne i denne patientpopulation.
Severe hypertension (> 200 mmHg systolic or 110 mmHg diastolic) occurred in 4.7% of this patient population.
24% af de behandlingsnaive mRCC- patienter, der får sunitinibmalat sammenlignet med 1% af patienterne, der får IFN- α.
Treatment-related hypertension was reported in approximately 24% of patients receiving sunitinib malate for treatment-naïve MRCC compared to 1% of patients receiving IFN-α.
Svær hypertension forekommer hos 5% af de behandlingsnaive patienter på sunitinibmalat og 1% af patienterne på IFN- α.
Severe hypertension occurred in 5% of treatment-naïve patients on sunitinib malate and 1% of patients on IFN-α.
Hæmatologisk Nedsat absolut neutrofiltal af sværhedsgrad 3 og 4 er rapporteret hos henholdsvis 10% og 1, 7% af patienterne i fase 3 GIST- studiet og hos henholdsvis 16% og 1, 6% af patienterne i fase 3 mRCC - studiet.
Haematological Decreased absolute neutrophil counts of grade 3 and 4 severity were reported in 10% and 1.7% of patients on the phase 3 GIST study, respectively, and in 16% and 1.6% of patients on the phase 3 MRCC study, respectively.
Nedsat trombocyttal af sværhedsgrad 3 og 4 er rappporteret hos henholdsvis 3, 7% og 0, 4% af patienterne i fase 3- GIST studiet og hos henholdsvis 8, 2% og 1, 1% af patienterne i fase 3 mRCC - studiet.
Decreased platelet counts of grade 3 and 4 severity were reported in 3.7% and 0.4% of patientson the phase 3 GIST study, respectively, and in 8.2% and 1.1% of patients on the phase 3 MRCC study, respectively.
Efter markedsføring er der rapporteret om sjældne fatale hæmatologiske tilfælde.
None of these events in the phase 3 studies were fatal, but rare fatal haematological events have been reported through post-marketing experience.
Fuldstændig blodtælling bør udføres i begyndelsen af hver behandlingscyklus hos patienter, der behandles med SUTENT.
Complete blood counts should be performed at the beginning of each treatment cycle for patients receiving treatment with SUTENT.
Disse hændelser omfatter fald i venstre ventrikels uddrivningsfraktion (LVEF) og hjertesvigt.
Cardiovascular Cardiovascular events, some of which were fatal, reported through post-marketing experience, have included left ventricular ejection fraction (LVEF) decrease and cardiac failure.
2% af SUTENT- behandlede GIST- patienter, hos 4% af cytokin- refraktære mRCC- patienter og hos 2% af placebobehandlede patienter.
In clinical trials, decreases in LVEF of ≥ 20% and below the lower limit of normal occurred in approximately 2% of SUTENT-treated GIST patients, 4% of cytokine-refractory MRCC patients, 2% of placebo-treated patients.
I den behandlingsnaive mRCC- undersøgelse har 21% af patienterne på SUTENT og 12% af patienterne på interferon- α (IFN - α) en LVEF- værdi, der er under den nedre referenceværdi.
In the treatment-naïve MRCC study, 21% patients on SUTENT and 12% of patients on interferon-α (IFN-α), had an LVEF value below the lower limit of normal.
1 patient (< 1%), som fik SUTENT, blev diagnosticeret med kronisk venstresidigt hjerteinsufficiens (CHF).
One (< 1%) patient who received SUTENT was diagnosed with congestive heart failure (CHF).
Behandlingsrelaterede bivirkninger som ” hjertesvigt ”, ” kronisk venstresidigt hjerteinsufficiens ” eller ” venstre ventrikelsvigt ” ses hos 0, 7% af patienterne med solide tumorer og hos 1% af patienterne, der
Treatment-related adverse events of ‘ cardiac failure’, ‘ cardiac failure congestive’ or ‘ left ventricular failure’ were reported in 0.7% of patients with solid tumours and 1% of patients treated with placebo.
Alle patienterne havde GIST.
All patients had GIST.
I fase 3 GIST- undersøgelsen (n=312) forekommer behandlingsrelaterede fatale hjertehændelser hos 1% af patienterne i den ene behandlingsgruppe i undersøgelsen (dvs.
In the phase 3 GIST study (n=312), treatment-related fatal cardiac events occurred in 1% of patients on each arm of the study (i. e.
SUTENT og placebogruppen).
SUTENT and placebo arms).
I en fase 2- undersøgelse hos cytokinfraktære mRCC- patienter oplevede 0, 9% af patienterne behandlingsrelateret fatal myokardieinfarkt.
In a phase 2 study in cytokine-refractory MRCC patients, 0.9% of patients experienced treatment-related fatal myocardial infarction and in the phase 3 study in treatment-naïve MRCC patients, 0.6% of patients on the IFN-α arm and 0 patients on the
I fase 3- undersøgelsen hos behandlingsnaive mRCC- patienter oplevede 0, 6% af patienterne i IFN- α- gruppen og 0% af patienterne SUTENT- gruppen fatale hjertehændelser.
4 SUTENT arm experienced fatal cardiac events.
Patienter, som havde haft hjertehændelser inden for 12 måneder før SUTENT- behandling, som f. eks. myokardieinfarkt (inklusive alvorlig/ ustabil angina), koronar/ perifer arterie bypass operation, symptomatisk kronisk venstresidigt hjerteinsufficiens (CHF), cerebrovaskulære hændelser eller transitorisk cerebral iskæmi eller lungeemboli blev ekskluderet fra de kliniske undersøgelser med SUTENT.
Patients who presented with cardiac events within 12 months prior to SUTENT administration, such as myocardial infarction (including severe/ unstable angina), coronary/ peripheral artery bypass graft, symptomatic congestive heart failure (CHF), cerebrovascular accident or transient ischemic attack, or pulmonary embolism were excluded from SUTENT clinical studies.
Disse patienter bør monitoreres omhyggeligt for kliniske tegn og symptomer på CHF, især hvis de har hjerte- risikofaktorer og/ eller arteriel sygdom i anamnesen.
Close monitoring for clinical signs and symptoms of CHF should be performed, especially in patients with cardiac risk factors and/ or history of coronary artery disease.
Lægen rådes til at opveje den kardiovaskulære bivirkningsrisiko mod den potentielle fordel ved lægemidlet.
Physicians are advised to weigh this risk against the potential benefits of the drug.
Disse patienter bør monitoreres omhyggeligt for kliniske tegn og symptomer på CHF, mens de får SUTENT.
These patients should be carefully monitored for clinical signs and symptoms of CHF while receiving SUTENT.
Baseline og regelmæssige vurderinger af LVEF bør overvejes, mens patienterne behandles med SUTENT.
Baseline and periodic evaluations of LVEF should also be considered while the patient is receiving SUTENT.
Ved tilstedeværelse af kliniske manifestationer på CHF anbefales seponering af SUTENT.
In the presence of clinical manifestations of CHF, discontinuation of SUTENT is recommended.
Dosis af SUTENT bør afbrydes og/ eller reduceres hos patienter unden kliniske tegn på CHF, men med en uddrivningsfraktion på < 50% - > 20% under baseline.
The dose of SUTENT should be interrupted and/ or reduced in patients without clinical evidence of CHF but with an ejection fraction< 50% and > 20% below baseline.
Forlængelse af QT- interval Data fra non- kliniske forsøg (in vivo og in vitro) med doser, der var højere end de anbefalede humane doser, tyder på, at sunitinib potentielt kan hæmme hjertets repolarisationsproces (f. eks forlængelse af QT- intervallet).
QT Interval prolongation Data from non-clinical (in vitro and in vivo) studies, at doses higher than the recommended human dose, indicate that sunitinib has the potential to inhibit the cardiac action potential repolarization process (e. g. prolongation of QT interval).
Disse ændringer er signifikante.
Increases in the QTc interval to over 500 msec occurred in 0.5% and changes from baseline in excess of 60 msec occurred in 1.1% of the 450 solid tumours patients; both these parameters are recognized as potentially significant changes.
SUTENT har vist forlængelse af QTcF- interval (Fredericas korrektion) ved ca. dobbelt terapeutisk koncentration.
At approximately twice therapeutic concentrations, SUTENT has been shown to prolong the QTcF Inteval (Frederica’ s Correction).
I en undersøgelse hos 24 patienter, i alderen 20- 87 år, med avanceret malign sygdom er forlængelse af QT- intervallet undersøgt.
QT interval prolongation was investigated in a trial in 24 patients, aged 20-87 years, with advanced malignancies.
Resultaterne af denne undersøgelse viste, at sunitinib havde en effekt på QTc (defineret som middel placebo- justeret ændring på > 10 msek med en 90% CI øvre grænse > 15 msek) ved terapeutisk koncentration (dag 3) ved brug af ” within- day ” baseline - korrektionsmetoden og ved højere end terapeutisk koncentration (dag 9) ved begge baseline - korrektionsmetoder.
The results of this study demonstrated that sunitinib had an effect on QTc (defined as a mean placebo-adjusted change of > 10 msec with a 90% CI upper limit > 15 msec) at therapeutic concentration (day 3) using the within-day baseline correction method, and at greater than therapeutic concentration (Day 9) using both baseline correction methods.
Ingen patienter havde en QTc- værdi > 500 msek.
No patients had a QTc value > 500 msec.
Den kliniske betydning af dette fund er imidlertid fortsat uklart.
Although an effect on QTcF was observed on Day 3 at 24 hours post-dose (i. e. at therapeutic plasma concentration expected after the recommended starting dose of 50 mg) with the within-day baseline correction method, the clinical significance of this finding is unclear.
Ved brug af gentagne EKG- målinger på tidspunkter svarende til enten terapeutisk eksponering eller højere end terapeutisk ekponering sås ikke udvikling af alvorlig QTc- forlængelse (dvs. lig med eller større end grad 3 ved CTCAE- version 3, 0) hos nogen af patienterne i den evaluerbare eller i ITT - populationen.
Using comprehensive serial ECG assessments at times corresponding to either therapeutic or greater than therapeutic exposures, none of the patients in the evaluable or ITT populations were observed to develop QTc prolongation considered as “ severe” (i. e. equal to or greater than Grade 3 by CTCAE version 3.0).
Ved terapeutisk plasmakoncentration var den maksimale middelændring af QTcF (Fredericas korrektion) fra baseline 9, 6 msek (90% CI 15, 1 msek).
At therapeutic plasma concentrations, the maximum QTcF (Frederica’ s correction) mean change from baseline was 9.6 msec (90% CI 15.1msec).
Ved ca. den dobbelte terapeutiske koncentration var den maksimale QTcF- ændring fra baseline 15, 4 msek (90% CI 22, 4 msek).
At approximately twice therapeutic concentrations, the maximum QTcF change from baseline was 15.4 msec (90% CI 22.4 msec).
Moxifloxacin (400 mg), der blev brugt som positiv kontrol, viste en maksimal middel QTcF- ændring på 5, 6 msek fra baseline.
Moxifloxacin (400 mg) used as a positive control showed a 5.6 msec maximum mean QTcF change from baseline.
Ingen patienter oplevede et QTc- interval større end Grad 2 (CTCAE- version 3, 0).
No subjects experienced an effect on the QTc inteval greater than Grade 2 (CTCAE version 3.0).
Ingen patienter fik hjertearytmi.
No patient presented with a cardiac arrhythmia.
Forlængelse af QT- intervallet kan føre til en øget risiko for ventrikulær arytmi herunder Torsade de pointes.
QT interval prolongation may lead to an increased risk of ventricular arrhythmias including Torsade de pointes.
Torsade de pointes er set hos < 0, 1% af patienterne, der har fået SUTENT.
Torsade de pointes has been observed in < 0.1% of SUTENT-exposed patients.
SUTENT bør anvendes med forsigtighed hos patienter med kendt forlængelse af QT- interval i anamnesen, patienter der tager antiarytmika, eller patienter med relevant præeksisterende hjertesygdom, bradykardi eller
SUTENT should be used with caution in patients with a known history of QT interval prolongation, patients who are taking antiarrhythmics, or patients with relevant pre-existing cardiac disease, bradycardia, or electrolyte disturbances.
4. 2 og 4. 5).
Concomitant treatment with potent CYP3A4 inhibitors, which may increase sunitinib plasma concentrations, should be used with caution and the dose of SUTENT reduced (see Section 4.2 and 4.5).
Venøse tromboemboliske hændelser Behandlingsrelaterede venøse tromboemboliske hændelser er rapporteret hos ca.
Venous Thromboembolic Events Treatment-related venous thromboembolic events were reported in approximately 1.0% of patients with solid tumours who received SUTENT on clinical trials, including GIST and MRCC.
5 ud af 7 var grad 3 dyb venetrombose (DVT), og 2 var grad 1 eller 2.
5 Seven patients (3%) on SUTENT and none on placebo in a phase 3 GIST study experienced venous thromboembolic events; five of the seven were Grade 3 deep venous thrombosis (DVT) and two were Grade 1 or 2.
Hos 4 ud af disse 7 GIST- patienter blev behandlingen seponeret efter første observation af DVT.
Four of these seven GIST patients discontinued treatment following first observation of DVT.
Behandlingsrelaterede venøse tromboemboliske hændelser er rapporteret hos 7 af patienterne (1, 9%), der fik SUTENT i fase 3 behandlingsnaiv mRCC- undersøgelse og hos 4 af patienterne (2%) i de 2 cytokin- refraktære mRCC- undersøgelser.
Seven patients (1.9%) receiving SUTENT in the phase 3 treatment-naïve MRCC study and four patients (2%) on the two cytokine-refractory MRCC studies had treatment-related venous thromboembolic events reported.
6 af disse patienter havde lungeemboli, 1 var grad 3 og 5 var grad 4, og 5 af disse patienter havde DVT, hver især med grad 1 og 2, og 3 med grad 3.
Six of these patients had pulmonary embolisms, one was Grade 3 and five were Grade 4, and five of these patients had DVT, one each with Grade 1 and 2, and three with Grade 3.
Hos de behandlingsnaive mRCC- patienter, der fik IFN- α, forekom 6 (2%) tromboemboliske hændelser; 1 patient (< 1%) oplevede en grad 3 DVT, og 5 patienter (1%) fik lungeemboli, 1 med grad 1 og 4 med grad 4.
In treatment-naïve MRCC patients receiving IFN-α, six (2%) venous thromboembolic events occurred; one patient (< 1%) experienced a Grade 3 DVT and five patients (1%) had pulmonary embolisms, one with Grade 1 and four with Grade 4.
Der er ikke rapporteret fatale tilfælde i GIST - og mRCC- registreringsstudier.
No cases with fatal outcome were reported in GIST and MRCC registrational studies.
4. 8).
Cases with fatal out- come had been observed in post-marketing setting (see respiratory events and section 4.8).
Respiratoriske hændelser Patienter, som havde haft lungeemboli indenfor de seneste 12 måneder, blev ekskluderet fra de kliniske undersøgelser med SUTENT.
Respiratory events Patients who presented with pulmonary embolism within the previous 12 months were excluded from SUTENT clinical studies.
Der er set behandlingsrelaterede lungehændelser (f. eks dyspnø, pleural effusion, lungeemboli eller lungeødem) hos 5% af patienterne med GIST og hos 14% af patienterne med mRCC, som blev behandlet med SUTENT i fase 3 registreringsstudier.
In patients who received SUTENT in Phase 3 registrational studies, treatment-related pulmonary events (i. e. dyspnoea, pleural effusion, pulmonary embolism or pulmonary oedema) were reported in approximately 5% of patients with GIST and in approximately 14% of patients with MRCC.
Sjældne fatale tilfælde blev rapporteret.
Rare cases with fatal outcome were reported.
8% af patienterne med solide tumorer, herunder GIST og mRCC, som blev behandlet med SUTENT i kliniske undersøgelser.
Approximately 8% of patients with solid tumours, including GIST and MRCC, who received SUTENT in clinical trials experienced treatment-related pulmonary events.
4. 4 - Venøse tromboemboliske hændelser).
Cases of Pulmonary embolism were observed in approximately 1.3% of patients with GIST and in approximately 0.8% of patients with MRCC, who received Sutent in Phase 3 studies (see section 4.4 - Venous Thromboembolic Events).
Skjoldbruskkirteldysfunktion Der anbefales laboratorieundersøgelse af skjoldbruskkirtelfunktionen ved baseline, og patienter med hypotyreose eller hypertyreose bør behandles efter gældende medicinsk praksis, før behandling med sunitinib initieres.
Thyroid Dysfunction Baseline laboratory measurement of thyroid function is recommended, and patients with hypothyroidism or hyperthyroidism should be treated as per standard medical practice prior to the start of sunitinib treatment.
Alle patienter, der er i sunitinibbehandling, bør observeres tæt for tegn og symptomer på skjoldbruskkirteldysfunktione.
All patients should be observed closely for signs and symptoms of thyroid dysfunction on sunitinib treatment.
Patienter med tegn og/ eller symptomer på skjoldbruskkirteldysfunktion bør have foretaget laboratorieundersøgelse af skjoldbruskkirtelfunktionen og behandles efter gældende medicinsk praksis.
Patients with signs and/ or symptoms suggestive of thyroid dysfunction should have laboratory monitoring of thyroid function performed and be treated as per standard medical practice.
Hypotyreose er indberettet som en bivirkning hos 7 patienter (4%) i de 2 cytokin- refraktære mRCC - undersøgelser; hos 9 patienter (2%) på SUTENT og hos 1 patient (< 1%) i IFN- α armen i den behandlingsnaive mRCC- undersøgelse.
Hypothyroidism was reported as an adverse event in 7 patients (4%) across the two cytokine-refractory MRCC studies; in nine patients (2%) on SUTENT and one patient (< 1%) in the IFN-α arm in the treatment- naïve MRCC study.
Derudover er der rapporteret TSH stigninger hos 4 cytokin - refraktære mRCC- patienter (2%).
Additionally, TSH elevations were reported in 4 cytokine-refractory MRCC patients (2%).
Samlet havde 7% af mRCC- populationen enten kliniske eller laboratoriemæssige tegn på behandlingsprovokeret hypotyreose.
Overall, 7% of the MRCC population had either clinical or laboratory evidence of treatment-emergent hypothyroidism.
Behandlingsprovokeret erhvervet hypotyreose er set hos 8 GIST- patienter (4%) på SUTENT versus 1 (1%) på placebo.
Treatment-emergent acquired hypothyroidism was noted in 8 GIST patients (4%) on SUTENT versus 1 (1%) on placebo.
Der er rapporteret om sjældne tilfælde af hypertyreose, hvoraf enkelte har været efterfulgt af hypotyreose i kliniske undersøgelser samt efter markedsføring af SUTENT.
Rare cases of hyperthyroidism, some followed by hypothyroidism, have been reported in clinical trials and through post-marketing experience.
Pankreatitis Der er set stigninger i serumlipase - og amylaseaktivitet hos patienter med forskellige solide tumorer i behandling med SUTENT.
Pancreatitis Increases in serum lipase and amylase activities were observed in patients with various solid tumours who received SUTENT.
Pankreatitis er set sjældent (< 1%) hos patienter, der får SUTENT for GIST eller mRCC.
Pancreatitis has been observed rarely (< 1%) in patients receiving SUTENT for GIST or MRCC.
Der er rapporteret om alvorlige tilfælde af pankreatitis, nogle fatale.
Cases of serious pancreatic events, some with fatal outcome, have been reported.
6 Ved symptomer på pankreatitis, bør behandling med SUTENT seponeres, og patienterne bør have relevant medicinsk behandling.
If symptoms of pancreatitis are present, patients should have SUTENT discontinued and be provided with appropriate supportive care.
Der er set leversvigt hos < 1% af disse patienter.
Hepatic Function Serious cases of SUTENT-related hepatobiliary events have been reported in patients with solid tumours; hepatic failure was observed in < 1% of these patients.
Der er rapporteret tilfælde af hepatobiliære hændelser, nogle fatale.
Cases of hepatobiliary events, some with fatal outcome, have been reported.
Behandling med SUTENT bør seponeres, og relevant medicinsk behandling initieres, hvis der er tegn eller symptomer på leversvigt.
If signs or symptoms of hepatic failure are present, SUTENT should be discontinued and appropriate supportive care should be provided.
Nyrefunktion Der er ikke foretaget sikkerhedsvurdering ved fortsat behandling med SUTENT hos patienter med moderat til alvorlig proteinuri.
6 Renal function The safety of continued SUTENT treatment in patients with moderate to severe proteinuria has not been systematically evaluated.
Der er rapporteret om tilfælde af proteinri og sjældne tilfælde af nefrotisk syndrome.
Cases of proteinuria and rare cases of nephrotic syndrome have been reported.
Behandling med SUTENT bør seponeres hos patienter med nefrotisk syndrom.
Discontinue SUTENT in patients with nephrotic syndrome.
Kramper I kliniske undersøgelser af SUTENT og fra erfaringer efter markedsføring er der set kramper hos forsøgspersoner med eller uden radiologisk evidens på metastaser i hjernen.
Seizures In clinical studies of SUTENT and from post-marketing experience, seizures have been observed in subjects with or without radiological evidence of brain metastases.
Derudover er der indberettet sjældne tilfælde (< 1%) af kramper og radiologisk evidens for reversibel posterior leukoencefalopati syndrom (RPLS).
In addition, there have been rare (< 1%) reports of subjects presenting with seizures and radiological evidence of reversible posterior leukoencephalopathy syndrome (RPLS).
Patienter med kramper og tegn/ symptomer i overensstemmelse med RPLS, som f. eks. hypertension, hovedpine, nedsat opmærksomhed, ændret psykisk funktion og synstab, herunder kortikalblindhed bør kontrolleres med medicinsk behandling herunder kontrol af hypertension.
Patients with seizures and signs/ symptoms consistent with RPLS, such as hypertension, headache, decreased alertness, altered mental functioning and visual loss, including cortical blindness should be controlled with medical management including control of hypertension.
Efter resolution kan behandlingen genoptages efter den behandlende læges skøn.
Temporary suspension of SUTENT is recommended; following resolution, treatment may be resumed at the discretion of the treating physician.
Lægemidler, som kan øge plasmakoncentrationen af sunitinib:
Drugs that may increase sunitinib plasma concentrations:
Samtidig anvendelse af sunitinibmalat og den potente CYP3A4- hæmmer, ketoconazol, gav efter en enkeltdosis sunitinibmalat hos raske forsøgspersoner en stigning på henholdsvis 49% og 51% i kompleksets [sunitinib + primær metabolit] Cmax og AUC0- ∞ værdi.
Concomitant administration of sunitinib malate with the potent CYP3A4 inhibitor, ketoconazole, resulted in a 49% and 51% increase of the complex [sunitinib + primary metabolite] Cmax and AUC0-∞ values, respectively, after a single dose of sunitinib malate in healthy volunteers.
Kombinationen med hæmmerne bør derfor undgås, eller det bør overvejes at vælge anden samtidig medicin med ingen eller minimal potentiale til at hæmme CYP3A4.
Administration of SUTENT with potent inhibitors of the CYP3A4 family (e. g. ritonavir, itraconazole, erythromycin, clarithromycin, grapefruit juice) may increase sunitinib concentrations Combination with inhibitors should therefore be avoided, or the selection of an alternate concomitant medication with no, or minimal potential to inhibit CYP3A4 should be considered.
4. 2).
If this is not possible, the dosage of SUTENT may need to be reduced to a minimum of 37.5 mg daily, based on careful monitoring of the tolerability (see section 4.2).
Lægemidler, som kan nedsætte plasmakoncentrationen af sunitinib:
Drugs that may decrease sunitinib plasma concentrations:
Samtidig anvendelse af SUTENT og CYP3A4- induktoren rifampin gav efter en enkeltdosis sunitinibmalat hos raske forsøgspersoner en reduktion på henholdsvis 23% og 46% i kompleksets [sunitinib + primær metabolit] Cmax og AUC0- ∞ værdi.
Concomitant use of SUTENT with the CYP3A4 inducer, rifampin, resulted in a 23% and 46% reduction of the complex [sunitinib + primary metabolite] Cmax and AUC0-∞ values, respectively, after a single dose of SUTENT in healthy volunteers.
Anvendelse af SUTENT sammen med potente induktorer af CYP3A4- familien (f. eks. dexamethason, phenytoin, carbamazepin, rifampin, phenobarbital eller Hypericum perforatum også kendt som prikbladet perikum) kan nedsætte sunitinibkoncentrationen.
John’ s Wort) may decrease sunitinib concentrations.
Kombinationen med induktorer bør derfor undgås, eller det bør overvejes at vælge anden samtidig medicin med ingen eller minimalt potentiale til at inducere CYP3A4.
Combination with inducers should therefore be avoided, or selection of an alternate concomitant medication with no, or minimal potential to induce CYP3A4 should be considered.