natgillin/translations-raw huggingface dataset:
Der blev set kardiovaskulær toksicitet (f.eks. forlængelse af PR- og QT-intervallet) hos cynomolgusaber efter intravenøs administration (100 mg/kg), men ikke efter gentagen oral dosering (1.379 mg/m²/dag).
Cardiovascular toxicity (e.g. PR- and QT-interval prolongation) was detectable in cynomolgus monkeys after intravenous administration (100 mg/kg) but not after repeated oral dosing (1,379 mg/m²/day).
5-fluorouracil 400 mg/m² intravenøs bolus, efterfulgt af
5-Fluorouracil 400 mg/m² intravenous bolus, followed by
• hvis du har et stærkt nedsat antal hvide blodceller eller blodplader (leucopeni, neutropeni eller trombocytopeni)
• if you have severely low levels of white cells or platelets in the blood (leukopenia, neutropenia or thrombocytopenia),
Se også afsnittet 'Tag ikke Capecitabine medac'.
See also section “Do not take Capecitabine medac”.
DPD-mangel
DPD deficiency
• til behandling af metastatisk kolorektalkræft (se pkt.
• for the treatment of metastatic colorectal cancer (see section 5.1).
ThyPaseaktiviteten var 4 gange større i primært kolorektalt tumorvæv end i det tilstødende normale væv.
ThyPase activity was measured and found to be 4 times greater in primary colorectal tumour than in adjacent normal tissue.
• Aktivt stof: capecitabin.
• The active substance is capecitabine.
Der er holdepunkter, for at metabolismen af 5-FU i den anabolske pathway blokerer metyleringen af desoxyuridylsyre til thymidylssyre og derved interfererer med desoxyribonukleinsyresyntesen (DNA).
There is evidence that the metabolism of 5-FU in the anabolic pathway blocks the methylation reaction of deoxyuridylic acid to thymidylic acid, thereby interfering with the synthesis of deoxyribonucleic acid (DNA).
filmovertrukne tabletter
Film-coated tablets
• hvis du har en alvorlig hudreaktion
• if you have a severe skin reaction.
Den mediane samlede overlevelse var 703 dage (95 % konfidensinterval: 671, 745) hos patienter, som blev behandlet med regimer, der indeholdt capecitabin, og 683 dage (95 % konfidensinterval: 646, 715) hos patienter, som blev behandlet med regimer, der indeholdt 5-FU.
Median overall survival time was 703 days (95 % CI: 671; 745) in patients treated with capecitabine-containing regimens and 683 days (95 % CI: 646; 715) in patients treated with 5-FU-containing regimens.
• svære hudreaktioner såsom hududslæt, sårdannelse og blæredannelse, som kan give sår i munden, næsen, kønsorganer, hænder, fødder og øjne (røde og opsvulmede øjne)
• severe skin reaction such as skin rash, ulceration and blistering which may involve ulcers of the mouth, nose, genitalia, hands, feet and eyes (red and swollen eyes)
Hvis du er gravid eller ammer, har mistanke om, at du er gravid, eller planlægger at blive gravid, skal du spørge din læge eller apoteketpersonalet til råds, før du tager dette lægemiddel.
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.You must not take Capecitabine medac if you are pregnant or think you might be.
Parametrene for capecitabin, 5'-DFCR og 5'-DFUR var ens på dag 1 og 14.
The parameters of capecitabine, 5'-DFCR and 5'-DFUR measured on days 1 and 14 were similar.
Hvis det ved starten af en behandlingsserie er indiceret at udsætte enten behandlingen med capecitabine eller det andet lægemiddel/de andre lægemidler, skal behandlingen med alle lægemidler udsættes, indtil betingelserne for genoptagelse af behandling med alle lægemidler er opfyldt.
At the beginning of a treatment cycle, if a treatment delay is indicated for either capecitabine or the other medicinal product(s), then administration of all therapy should be delayed until the requirements for restarting all medicinal products are met.
• fald i indholdet af natrium, magnesium eller kalcium i blodet, øget mængde blodsukker
• decrease in blood sodium, magnesium or calcium, increase in blood sugar
Hvis der optræder grad 2- eller 3 HFS, skal behandlingen med capecitabin afbrydes, indtil symptomerne forsvinder eller er aftaget i intensitet til grad 1.
If grade 2 or 3 HFS occurs, administration of capecitabine should be interrupted until the event resolves or decreases in intensity to grade 1.
Pakningsstørrelser: 28, 30, 56, 60, 84, 112 eller 120 filmovertrukne tabletter.
Pack sizes: 28, 30, 56, 60, 84, 112 or 120 film-coated tablets.
• hvis du er allergisk over for capecitabin eller et af de øvrige indholdsstoffer i Capecitabine medac (angivet i punkt 6).
• if you are allergic to capecitabine or any of the other ingredients of this medicine (listed in section 6).
• hvis du ved, at du ikke har nogen aktivitet af enzymet dihydropyrimidin dehydrogenase (DHP)
• if you know that you do not have any activity of the enzyme dihydropyrimidine dehydrogenase (DPD),
Dyb venethrombose, Hypertension, Petekkier,
Deep vein thrombosis, Hypertension, Petechiae,
I toksicitetsforsøg med gentagne doser førte daglig oral administration af capecitabin hos cynomolgusaber og mus til toksiske virkninger, typiske for fluorpyrimidiner, på det gastrointestinale, det lymfoide og det hæmatopoietiske system.
In repeat-dose toxicity studies, daily oral administration of capecitabine to cynomolgus monkeys and mice produced toxic effects on the gastrointestinal, lymphoid and haemopoietic systems, typical for fluoropyrimidines.
Det kan være, din læge vil have, at du for hver dosis skal tage en kombination af 150 mg-, 300 mg- og 500 mg-tabletter.
Your doctor may want you to take a combination of 150 mg, 300 mg and 500 mg tablets for each dose.
Fase I-studier, som evaluerede capecitabins effekt på enten docetaxels eller paclitaxels farmakokinetik og vice versa, viste ingen effekt af capecitabin på hverken docetaxels eller paclitaxels farmakokinetik (Cmax og AUC) og ingen effekt af docetaxel eller paclitaxel på 5'-DFUR's farmakokinetik.
Phase I studies evaluating the effect of capecitabine on the pharmacokinetics of either docetaxel or paclitaxel and vice versa showed no effect by capecitabine on the pharmacokinetics of docetaxel or paclitaxel (Cmax and AUC) and no effect by docetaxel or paclitaxel on the pharmacokinetics of 5'-DFUR.
Kontakt lægen eller apotekspersonalet, før du tager Capecitabine medac
Talk to your doctor or pharmacist before taking Capecitabine medac
Til patienter med let nyreinsufficiens (creatininclearance 51 - 80 ml/min ved baseline) er dosisjustering ikke nødvendig.
In patients with mild renal impairment (creatinine clearance 51 - 80 ml/min at baseline) no adjustment of the starting dose is recommended.
Det ses sjældent og er almindeligvis ikke forbundet med helbredsproblemer, med mindre man får bestemte lægemidler.
DPD deficiency is a rare condition present at birth that is not usually associated with health problems unless you receive certain medicines.
Pharmacare Premium Limited HHF 003, Hal Far Industrial Estate Birzebbugia BBG 3000, Malta
Pharmacare Premium Ltd HHF 003, Hal Far Industrial Estate Birzebbugia BBG 3000, Malta
Dosisjusteringer for særlige populationer
Posology adjustments for special populations
• smerter i led eller lemmer (ekstremiteter), bryst eller ryg
• pain in the joints or in the limbs (extremities), chest or back
I alle studierne kombineret var følgende kovarianter statistisk signifikant associeret med en øget risiko for udviklingen af HFS: stigende capecitabinstartdosis (gram), faldende kumulativ capecitabin-dosis (0,1 *kg), stigende relativ dosisintensitet i de første seks uger, længere behandlingsvarighed (uger), stigende alder (ved 10-års forøgelse), kvindeligt køn og med en god Eastern Cooperative Oncology Group (ECOG)-performancestatus ved baseline (0 versus ≥ 1).
In all studies combined, the following covariates were statistically significantly associated with an increased risk of developing HFS: increasing capecitabine starting dose (gram), decreasing cumulative capecitabine dose (0.1*kg), increasing relative dose intensity in the first six weeks, increasing duration of study treatment (weeks), increasing age (by 10 year increments), female gender, and good Eastern Cooperative Oncology Group (ECOG) performance status at baseline (0
besvimelse, nerveskader (neuropati) og problemer med følesansen
fainting, nerve damage (neuropathy) and problems with sensation
Patienter behandlet med XELIRI oplevede i langt højere grad gastrointestinal toksicitet sammenlignet med FOLFIRI (48 % og 14 % fik diarré ved henholdsvis XELIRI og FOLFIRI).
Patients treated with XELIRI experienced excessive gastrointestinal toxicity compared with FOLFIRI (diarrhoea 48 % and 14 % for XELIRI and FOLFIRI respectively).
Du kan få følgende bivirkninger, hvis du tager meget mere capecitabin, end du skal: utilpashed, diarré, betændelse eller sår i tarme eller munden, smerter eller blødning fra tarme eller mave, nedsat antal af visse blodceller (såkaldt knoglemarvsdepression).
You might get the following side effects if you take a lot more capecitabine than you should: feeling, or being sick, diarrhoea, inflammation or ulceration of the gut or mouth, pain or bleeding from the intestine or stomach, or bone marrow depression (reduction in certain kinds of blood cells).
Dihydropyrimidinase spalter pyrimidinringen til 5-fluoro-ureidopropionsyre (FUPA).
Dihydropyrimidinase cleaves the pyrimidine ring to yield 5-fluoro-ureidopropionic acid (FUPA).
• Patienter med kendt fuldstændig mangel på dihydropyrimidindehydrogenase (DPD)-aktivitet (se pkt.
• In patients with known complete absence of dihydropyrimidine dehydrogenase (DPD) activity
Patienter behandlet med XELIRI plus bevacizumab rapporterede signifikant højere incidenser af diarré, febril neutropeni og hånd- og fod hudreaktioner end patienter behandlet med FOLFIRI plus bevacizumab med signifikant højere frekevens af forsinkelse i behandling, dosisreduktioner og seponering af behandling.
Patients treated with XELIRI + bevacizumab reported a significantly higher incidence of diarrhoea, febrile neutropenia and hand-foot skin reactions than patients treated with FOLFIRI + bevacizumab with significantly increased treatment delays, dose reductions and treatment discontinuations.
Den normale dosis til voksne er 1.250 mg/m² legemsoverflade to gange dagligt (morgen og aften).
The usual dose for adults is 1,250 mg/m² of body surface area taken two times daily (morning and evening).
• interferon-alfa
• interferon alpha
Her følger to eksempler: En person, som vejer 64 kg, og som er 1,64 m høj, har et legemsoverfladeareal på 1,7 m² og skal tage 4 tabletter a 500 mg og 1 tablet a 150 mg to gange dagligt.
Two examples are provided here: A person whose body weight is 64 kg and height is 1.64 m has a body surface area of 1.7 m² and should take 4 tablets of 500 mg and 1 tablet of 150 mg two times daily.
Knoglemarvsdepression, +Febril neutropeni
Bone marrow depression, +Febrile neutropenia
I et klinisk farmakokinetisk interaktionsstudie øgede behandling med capecitabin, efter en enkelt dosis på 20 mg warfarin, S-warfarin-AUC med 57 %, og INR-værdien steg med 91 %.
In a clinical pharmacokinetic interaction study, after a single 20 mg dose of warfarin, capecitabine treatment increased the AUC of S-warfarin by 57 % with a 91 % increase in INR value.
De totale objektive responsrater i den totale randomiserede population var (investigators vurdering) 25,7 % (capecitabin) vs. 16,7 % (Mayo regime), p< 0,0002.
The overall objective response rates in the all-randomised population (investigator assessment) were 25.7 % (capecitabine) vs. 16.7 % (Mayo regimen); p < 0.0002.
Den overordnede sikkerhedsprofil for capecitabin er baseret på data fra flere end 3.000 patienter, der fik capecitabin-monoterapi eller capecitabin i kombination med forskellige kemoterapiregimer inden for flere indikationer.
The overall safety profile of capecitabine is based on data from over 3,000 patients treated with capecitabine as monotherapy or capecitabine in combination with different chemotherapy regimens in multiple indications.
• DPD-mangel: hvis du ved, at du har DPD-mangel, har du en øget risiko for akut tidlig indtræden af bivirkninger og svære, livstruende eller dødelige bivirkninger forårsaget af Capecitabine medac (f.eks. mundbetændelse, betændelseslignende reaktion (inflammation) i slimhinder, diarré, neutropeni og neurotoksicitet).
• DPD Deficiency: if you have a known DPD deficiency, you are at an increased risk of acute early-onset of toxicity and severe, life-threatening, or fatal adverse reactions caused by Capecitabine medac (e.g. stomatitis, mucosal inflammation, diarrhoea, neutropenia, and neurotoxicity).
Capecitabine medac indeholder capecitabin, som i sig selv ikke virker cytostatisk.
Capecitabine medac contains capecitabine, which itself is not a cytostatic medicine.
Capecitabin var dog ligesom andre nukleosidanaloger (dvs. 5-FU) klastogent på humane lymfocytter (in vitro), og der var en positiv trend i in vivo-mikronukleustesten på knoglemarv fra mus.
However, similar to other nucleoside analogues (i.e., 5-FU), capecitabine was clastogenic in human lymphocytes (in vitro) and a positive trend occurred in mouse bone marrow micronucleus tests (in vivo).
Hvis du har DPD-mangel uden at vide det og tager Capecitabine medac, har du en øget risiko for akut tidlig indtræden af bivirkningerne, anført i punkt 4 Bivirkninger, i svær form.
If you have an unrecognised DPD deficiency and take Capecitabine medac, you are at an increased risk of acute early-onset of severe forms of the side effects listed under section 4 Possible side effects.
Behandlingen med capecitabin-monoterapi kan genoptages, når bilirubin er faldet til ≤ 3,0 x UNL, eller levertransaminaserne er faldet til ≤ 2,5 x UNL.
Treatment with capecitabine monotherapy may be resumed when bilirubin decreases to ≤ 3.0 x ULN or hepatic aminotransferases decrease to ≤ 2.5 x ULN.
• medicin mod kramper eller rystelser (phenytoin)
• medicines for seizures or tremors (phenytoin)
Den mediane PFS var 5,6 måneder (capecitabin + cisplatin) versus 5,0 måneder (5-FU + cisplatin).
The median PFS was 5.6 months (capecitabine + cisplatin) versus 5.0 months (5-FU + cisplatin).
Dosisændring på grund af toksicitet, når capecitabin anvendes kontinuerligt i kombination med andre lægemidler
Dose modifications for toxicity when capecitabine is used continuously in combination with other medicinal products
Da der ikke findes sikkerheds- og effektdata hos patienter med leverinsufficiens, skal anvendelsen af capecitabin kontrolleres omhyggeligt hos patienter med let til moderat leverdysfunktion, uanset om der er levermetastaser eller ej.
In the absence of safety and efficacy data in patients with hepatic impairment, capecitabine use should be carefully monitored in patients with mild to moderate liver dysfunction, regardless of the presence or absence of liver metastasis.
Antal 150 mg tabletter, 300 mg tabletter og/eller 500 mg tabletter pr. dosering (hver dosering skal gives morgen og aften)
Number of 150 mg tablets, 300 mg tablets and/or 500 mg tablets per administration (each administration to be given morning and evening)
Patienter med moderat nyreinsufficiens fik hyppigere dosis reduceret (44 %) vs. 33 % og 32 % hos patienter med ingen eller let nyreinsufficiens og havde flere tidlige behandlingsophør (21 % behandlingsophør i de første to serier) vs. 5 % og 8 % hos patienter med ingen eller let nyreinsufficiens.
Patients with moderately impaired renal function show an increased rate of dose reduction (44 %) vs. 33 % and 32 % in patients with no or mild renal impairment and an increase in early withdrawals from treatment (21 % withdrawals during the first two cycles) vs. 5 % and 8 % in patients with no or mild renal impairment.
En analyse af sikkerhedsdata fra patienter ≥ 60 år, som behandledes med capecitabin-monoterapi, og en analyse af patienter, som behandledes med capecitabin plus docetaxel, viste en stigning i incidensen af behandlingsrelaterede bivirkninger af grad 3 og 4 og af behandlingsrelaterede alvorlige bivirkninger sammenlignet med patienter < 60 år.
An analysis of safety data in patients ≥ 60 years of age treated with capecitabine monotherapy and an analysis of patients treated with capecitabine plus docetaxel combination therapy showed an increase in the incidence of treatment-related grade 3 and 4 adverse reactions and treatment-related serious adverse reactions compared to patients < 60 years of age.
En metaanalyse af seks kliniske forsøg (studie SO14695, SO14796, M66001, NO16966, NO16967 og M17032) støtter, at capecitabin kan erstatte 5-FU i mono- og kombinationsbehandling af gastrointestinal kræft.
A meta-analysis of six clinical trials (studies SO14695, SO14796, M66001, NO16966, NO16967, M17032) supports capecitabine replacing 5-FU in mono- and combination treatment in gastrointestinal cancer.
Raten for 5 års samlet overlevelse var 78 % for XELOX versus 74 % for 5-FU/LV.
The 5 year OS rate was 78 % for XELOX versus 74 % for 5-FU/LV.
• uregelmæssig hjerterytme og hjertebanken (arytmier), brystsmerter og hjerteanfald (infarkt)
• irregular heartbeat and palpitations (arrhythmias), chest pain and heart attack (infarction)
En person, som vejer 80 kg, og som er 1,80 m høj, har et legemsoverfladeareal på 2,00 m² og skal tage 5 tabletter a 500 mg to gange dagligt.
A person whose body weight is 80 kg and height is 1.80 m has a body surface area of 2.00 m² and should take 5 tablets of 500 mg two times daily.
Tid indtil progressiv sygdom var længere i kombinationsarmen med capecitabin + docetaxel (p < 0,0001).
Time to progressive disease was superior in the capecitabine + docetaxel combination arm (p < 0.0001).
Hvis uplanlagte laboratorieresultater under en behandlingsserie viser, at neutrofiltallet falder til under 1,0 x 109/l, eller antallet af blodplader falder til under 75 x 109/l, bør behandling med capecitabin seponeres.
If unscheduled laboratory assessments during a treatment cycle show that the neutrophil count drops below 1.0 x 109/L or that the platelet count drops below 75 x 109/L treatment with capecitabine should be interrupted.
• I kombination med docetaxel: Der blev observeret en øget incidens af grad 3 eller 4 behandlingsrelaterede bivirkninger og behandlingsrelaterede alvorlige bivirkninger hos patienter på 60 år og derover (se pkt.
- In combination with docetaxel: an increased incidence of grade 3 or 4 treatment-related adverse reactions and treatment-related serious adverse reactions were observed in patients 60 years of age or more (see section 5.1).
De totale objektive responsrater i den totale randomiserede population (investigators vurdering) var 41,6 % (capecitabin + docetaxel) vs. 29,7 % (docetaxel alene); p = 0,0058.
The overall objective response rates in the all-randomised population (investigator assessment) were 41.6 % (capecitabine + docetaxel) vs. 29.7 % (docetaxel alone); p = 0.0058.
Vedrørende hånd- og fodsyndrom (HFS) og hyperbilirubinæmi se pkt.
For hand-foot syndrome (HFS) and hyperbilirubinaemia, see section 4.4.
Det blev vist, at XELOX var noninferior i forhold til FOLFOX-4 med hensyn til PFS i per-protokolpopulationen og intent-to-treatpopulationen (se tabel 9).
XELOX was demonstrated to be non-inferior to FOLFOX-4 in terms of PFS in the per-protocol population and intent-to-treat population (see table 9).
• som monoterapi til behandling af patienter med lokalt fremskreden eller metastatisk brystkræft efter svigt af taxaner og et kemoterapiregime indeholdende et antracyklin, eller hos hvem antracyklin-behandling ikke er indiceret.
• as monotherapy for the treatment of patients with locally advanced or metastatic breast cancer after failure of taxanes and an anthracycline containing chemotherapy regimen or for whom further anthracycline therapy is not indicated.
Et to-års carcinogenicitetsstudie på mus gav ikke holdepunkter, for at capecitabin var carcinogent.
A two-year mouse carcinogenicity study produced no evidence of carcinogenicity by capecitabine.
De bivirkninger, der af den behandlende investigator blev vurderet som muligvis, sandsynligvis eller tvivlsomt relateret til administrationen af capecitabin, er angivet i tabel 4 for capecitabin-monoterapi og i tabel 5 for capecitabin givet i kombination med forskellige kemoterapiregimer inden for flere indikationer.
ADRs considered by the investigator to be possibly, probably, or remotely related to the administration of capecitabine are listed in table 4 for capecitabine given as monotherapy and in table 5 for capecitabine given in combination with different chemotherapy regimens in multiple indications.
• blodprop i de dybe vener, højt eller lavt blodtryk, hedeture, kolde lemmer (ekstremiteter), lilla pletter på huden
• blood clots in the deep veins, high or low blood pressure, hot flushes, cold limbs (extremities),
øget indhold af kreatinin i blodet (tegn på nedsat nyrefunktion)
blood in the urine, increase in blood creatinine (sign of kidney dysfunction)
XELOX eller XELOX + Bevacizumab
XELOX or XELOX+ Bevacizumab
Ældre patienter (se pkt.
Elderly patients (see section 4.2)
Capecitabins farmakokinetik er undersøgt i dosisintervallet 502 - 3.514 mg/m²/dag.
The pharmacokinetics of capecitabine have been evaluated over a dose range of 5023,514 mg/m²/day.
De mest almindelige rapporterede og/eller klinisk relevante behandlingsrelaterede bivirkninger var gastrointestinale symptomer (specielt diarré, kvalme, opkastning, mavesmerter og stomatitis), HFS (palmo-plantar erytrodysæstesi), træthed, asteni, anoreksi, kardiotoksicitet, øget renal dysfunktion hos dem med præeksisterende kompromitteret nyrefunktion samt trombose/embolisme.
The most commonly reported and/or clinically relevant treatment-related ADRs were gastrointestinal disorders (especially diarrhoea, nausea, vomiting, abdominal pain, stomatitis), HFS (palmar-plantar erythrodysesthesia), fatigue, asthenia, anorexia, cardiotoxicity, increased renal dysfunction on those with pre-existing compromised renal function, and thrombosis/embolism.
• fedtknuder under huden (lipomer)
• lumps under the skin (lipoma)
Parameter: Samlet overlevelse PPP ITT
Parameter: Overall survival PPP
Selvom DPD-mangel ikke kan fastsættes præcist, er det kendt, at patienter med visse homozygote eller visse sammensatte heterozygote mutationer i DPYD-genlocuset (fx DPYD*2A, c.1679T>G, c.2846A>T og c.1236G>A/HapB3 varianter), som kan forårsage fuldstændigt eller næsten fuldstændigt fravær af DPD-enzymaktivitet (bestemt ved laboratorieprøver), har den højeste risiko for livstruende eller dødelig toksicitet, og disse patienter bør ikke behandles med capecitabin (se pkt.
Although DPD deficiency cannot be precisely defined, it is known that patients with certain homozygous or certain compound heterozygous mutations in the DPYD gene locus (e.g. DPYD*2A, c.1679T>G, c.2846A>T and c.1236G>A/HapB3 variants), which can cause complete or near complete absence of DPD enzymatic activity (as determined from laboratory assays), have the highest risk of life-threatening or fatal toxicity and should not be treated with capecitabine (see section 4.3).
Forholdet mellem koncentrationen af 5-FU i tumor og plasma var 21,4 (spændvidde: 3,9 - 59,9, n = 8), mens forholdet mellem normalt væv og plasma var 8,9 (spændvidde: 3,0 - 25,8, n = 8).
The ratio of 5-FU concentration in tumour to plasma was 21.4 (ranged from 3.9 to 59.9, n = 8) whereas the ratio in healthy tissues to plasma was 8.9 (ranged from 3.0 to 25.8, n = 8).
Folinsyre har imidlertid en effekt på capecitabins farmakodynamik, og dets toksicitet kan blive forstærket af folinsyre: Maksimum tolererbar dosis (MTD) af capecitabin efter behandling med capecitabin alene er ved intermitterende behandling 3.000 mg/m² pr. dag, hvorimod den kun er 2.000 mg/m² pr. dag, når capecitabin kombineres med folinsyre (30 mg oralt to gange dagligt).
However, folinic acid has an effect on the pharmacodynamics of capecitabine and its toxicity may be enhanced by folinic acid: the maximum tolerated dose (MTD) of capecitabine alone using the intermittent regimen is 3,000 mg/m² per day whereas it is only 2,000 mg/m² per day when capecitabine was combined with folinic acid (30 mg orally bid).