natgillin/translations-raw huggingface dataset:
Dexamethason blev administreret i kombination med bortezomib til 83 patienter i cyklus 1, mens yderligere 11 patienter fik dexamethason i løbet af efterfølgende bortezomib-behandlingscyklusser.
Dexamethasone was administered in combination with bortezomib to 83 patients in Cycle 1 with an additional 11 patients receiving dexamethasone during the course of bortezomib retreatment cycles.
Ud over perifer neuropati kan der forekomme autonom neuropati ved nogle bivirkninger, f.eks. postural hypotension og svær forstoppelse med ileus.
In addition to peripheral neuropathy, there may be a contribution of autonomic neuropathy to some adverse reactions such as postural hypotension and severe constipation with ileus.
Hæmatologisk toksicitet i løbet af en cyklus: - Hvis der observeres langvarig grad 4neutropeni eller trombocytopeni, eller trombocytopeni med blødning i den foregående cyklus
Haematological toxicity during a cycle - If prolonged Grade 4 neutropenia or thrombocytopenia, or thrombocytopenia with bleeding is observed in the previous cycle
Bortezomib er meget selektivt for proteasom.
Bortezomib is highly selective for the proteasome.
Resultater fra in vitro-, ex vivo- og dyremodelforsøg med bortezomib tyder på, at bortezomib øger osteoblastdifferentieringen og -aktiviteten samt hæmmer osteoklastfunktionen.
Data from in vitro, ex-vivo, and animal models with bortezomib suggest that it increases osteoblast differentiation and activity and inhibits osteoclast function.
Der er gennemført et åbent, randomiseret, fase III-non-inferiority-studie til sammenligning af effekt og sikkerhed af subkutan administration af bortezomib versus intravenøs administration.
An open label, randomised, Phase III non-inferiority study compared the efficacy and safety of the subcutaneous administration of bortezomib versus the intravenous administration.
I bortezomibs koncentrationsinterval på 0,01-1,0 µg/ml var in vitro-proteinbindingen gennemsnitligt 82,9 % i humant plasma.
Over a bortezomib concentration range of 0.01 to 1.0 μg/ml, the in vitro protein binding averaged 82.9% in human plasma.
Reducer Bortezomib SUN til 0,7 mg/m2 i første behandlingscyklus.
Reduce Bortezomib SUN to 0.7 mg/m2 in the first treatment cycle.
Geometrisk middel (%CV) for clearance var 7,79 (25 %) l/t/m2, fordelingsvolumen ved steady state var 834 (39 %) l/m2 og eliminationshalveringstiden var 100 (44 %) timer.
Geometric mean (%CV) clearance was 7.79 (25%) l/hr/m2, volume of distribution at steady-state was 834 (39%) l/m2, and the elimination half-life was 100 (44%) hours.
Død som følge af “progredierende sygdom” forekom hos 18 % i den subkutane gruppe og hos 9 % i den intravenøse gruppe.
Incidence of death from “Progressive disease” was 18% in the subcutaneous group and 9% in the intravenous group.
Den geometriske gennemsnitsratio AUClast var 0,99, og 90-%-konfidensintervaller var 80,18 %
The AUClast geometric mean ratio was 0.99 and 90% confidence intervals were 80.18%-122.80%.
Størstedelen af patienterne i begge grupper fuldførte behandlingen, 80 % i BzmbR-CAP-gruppen og 82 % i R-CHOP-gruppen.
The majority of the patients in both groups completed treatment, 80% in the BzmbR-CAP group and 82% in the R-CHOP group.
Gastrointestinal toksicitet, inklusive kvalme, diarré, opkastning og forstoppelse, er meget almindelig ved behandling med bortezomib.
Gastrointestinal toxicity, including nausea, diarrhoea, vomiting and constipation are very common with bortezomib treatment.
- Ikke-hæmatologisk toksicitet skal være bedret til grad 1 eller baseline-niveau.
- Non-haematological toxicities should have resolved to Grade 1 or baseline.
Hvis du har mantle-celle-lymfom og får lægemidlet rituximab sammen med Bortezomib SUN, skal du fortælle det til din læge: - hvis du tror, du har en hepatitisinfektion nu, eller hvis du har haft det engang.
If you have mantle cell lymphoma and are given the medicine rituximab with Bortezomib SUN you should tell your doctor: - if you think you have hepatitis infection now or have had it in the past.
Andre rapporter om leverreaktioner omfatter øget leverenzymtal, hyperbilirubinæmi og hepatitis.
Other reported hepatic reactions include increases in liver enzymes, hyperbilirubinaemia, and hepatitis.
Den inkluderer desuden bivirkninger, som blev identificeret i BzmbR-CAP-armen, og som af investigatorerne blev anset for at have mindst en mulig eller sandsynlig årsagssammenhæng med bortezomib, baseret på historiske data i myelomatosestudierne.
Also included are adverse drug reactions identified in the BzmbR-CAP arm that were considered by investigators to have at least a possible or probable causal relationship to bortezomib based on historical data in the multiple myeloma studies.
Den gennemsnitlige eliminationshalveringstid (t1/2) for bortezomib efter gentagne doser var mellem 40 og 193 timer.
The mean elimination half-life (t1/2) of bortezomib upon multiple dosing ranged from 40-193 hours.
Patienternes gennemsnitsalder i studiet var 57 år, 55 % var mænd, og 48 % af patienterne blev cytogenetisk klassificeret som højrisiko.
Median age of the patients in the study was 57 years, 55% were male and 48% of patients had high-risk cytogenetics.
"Matchet par"-analysen er en statistisk metode, hvor patienter i behandlingsgruppen (f.eks. bortezomib i kombination med dexamethason) og patienter i sammenligningsgruppen (f.eks. bortezomib) gøres sammenlignelige med hensyn til confounding-faktorer, idet forsøgspersonerne sammensættes individuelt i par.
The matched-pair analysis is a statistical method in which patients in the treatment group (e.g. bortezomib in combination with dexamethasone) and patients in the comparison group (e.g. bortezomib) are made comparable with respect to confounding factors by individually pairing study subjects.
Den samlede bedste responsrate (CR+PR) ved genbehandling af 130 patienter var 38,5 % (95 % CI: 30,1-47,4).
The overall best response rate (CR + PR), to retreatment in 130 patients was 38.5% (95% CI: 30.1, 47.4).
Tel. +49 (0) 214 403 99 192
Deutschland tel. +49 (0) 214 403 99 192
Klinisk virkning ved subkutan administration af bortezomib hos patienter med recidiverende/refraktær myelomatose
Clinical efficacy with subcutaneous administration of bortezomib in patients with relapsed/refractory multiple myeloma
Hepatitis B-virus (HBV)-reaktivering og -infektion Når rituximab anvendes i kombination med bortezomib, skal patienter, som har risiko for infektion med HBV, altid screenes for HBV, inden behandlingen startes.
Hepatitis B Virus (HBV) reactivation and infection When rituximab is used in combination with bortezomib, HBV screening must always be performed in patients at risk of infection with HBV before initiation of treatment.
Skulle overdosering mod al forventning ske, vil din læge overvåge dig for tegn på bivirkninger.
In the unlikely event of an overdose, your doctor will monitor you for side effects.
Der er rapporteret sjældne tilfælde af leversvigt hos patienter, der får bortezomib og andre lægemidler samtidig og med alvorlige tilgrundliggende helbredsproblemer.
Rare cases of hepatic failure have been reported in patients receiving bortezomib and concomitant medicinal products and with serious underlying medical conditions.
Den færdige koncentration i opløsningen vil være 1 mg/ml.
The concentration of the resulting solution will be 1 mg/ml.
Det anbefales, at patienter monitoreres omhyggeligt for symptomer på neuropati, f.eks. brændende fornemmelse, hyperæstesi, hypæstesi, paræstesi, ubehag, neuropatiske smerter eller svækkelse.
It is recommended that patients be carefully monitored for symptoms of neuropathy such as a burning sensation, hyperesthesia, hypoesthesia, paraesthesia, discomfort, neuropathic pain or weakness.
Tabel 1: Anbefalede* dosisændringer ved bortezomib-relateret neuropati Sværhedsgrad af neuropati
Table 1: Recommended* posology modifications for bortezomib-related neuropathy Severity of neuropathy
Graden bestemt i henhold til det amerikanske National Cancer Institute's Common Toxicity Criteria (CTCAE) version 4.0.
Grading based on NCI Common Toxicity Criteria CTCAE v 4.0.
• rådgivning om intravenøs og subkutan administration, herunder at der bør skiftes mellem injektionssteder ved s.c. anvendelse
• advice on method of administration for both IV and SC use, including the need to rotate injection sites for SC use
Ortostatisk/postural hypotension var ikke akut relateret til bolusinjektion af bortezomib.
Orthostatic/postural hypotension was not acutely related to bolus infusion of bortezomib.
Bortezomib var positivt for klastogen aktivitet (strukturelle kromosomafvigelser) i in vitro-analysen af kromosomafvigelser ved hjælp af ovarieceller fra kinesiske hamstre (CHO) i koncentrationer så lave som 3,125 µg/ml, som var den laveste vurderede koncentration.
Bortezomib was positive for clastogenic activity (structural chromosomal aberrations) in the in vitro chromosomal aberration assay using Chinese hamster ovary (CHO) cells at concentrations as low as 3.125 μg/ml, which was the lowest concentration evaluated.
Progressionsfri overlevelse (IRC)a Hændelser n (%)
Progression free survival (IRC)a Events n (%)
- Øvrige indholdsstoffer: Mannitol (E421).
- The other ingredient is mannitol (E421).
Normal leverfunktion skal bekræftes, og der skal udvises forsigtighed ved patienter, der behandles med orale hypoglæmika (se pkt.
Normal liver function should be confirmed and caution should be exercised in patients receiving oral hypoglycemics (see section 4.5).
I fase II-studiet kunne de patienter, som ikke havde et optimalt respons på behandlingen med bortezomib alene, få højdosis-dexamethason sammen med bortezomib.
In the Phase II study, patients who did not obtain an optimal response to therapy with bortezomib alone were able to receive high-dose dexamethasone in conjunction with bortezomib.
Hvis du får thalidomid, skal du være særlig opmærksom på kravene til graviditetsprøver og prævention (se under "Graviditet og amning" i dette punkt).
When thalidomide is used, particular attention to pregnancy testing and prevention requirements is needed (see Pregnancy and breast-feeding in this section).
Responsrate populatione n = 668
Response rate populatione n=668
Efter en intravenøs bolus- eller subkutan injektion af en dosis på 1,3 mg/m2 hos patienter med myelomatose (n=14 i den intravenøse gruppe, n=17 i den subkutane gruppe) sås samme totale systemiske eksponering efter gentagne doser (AUClast) for subkutan og intravenøs administration.
Following an intravenous bolus or subcutaneous injection of a 1.3 mg/m2 dose to patients with multiple myeloma (n=14 in the intravenous group, n=17 in the subcutaneous group), the total systemic exposure after repeat dose administration (AUClast) was equivalent for subcutaneous and intravenous administrations.
Forekomsten af alle grader af perifer neuropati efter intravenøs administration af bortezomib var lavere i de ældre studier med bortezomib administreret intravenøst end i studie MMY-3021.
The incidence of all grade peripheral neuropathy with bortezomib administered intravenously was lower in the historical studies with bortezomib administered intravenously than in study MMY-3021.
Kontroller, at den korrekte dosis anvendes til subkutan administration (2,5 mg/ml).
Be sure that the correct dose is being given for the subcutaneous route of administration (2.5 mg/ml).
Dosisjusteringer under behandlingen af patienter med tidligere ubehandlet mantle-celle-lymfom Før påbegyndelse af en ny behandlingscyklus:
Dose adjustments during treatment for patients with previously untreated mantle cell lymphoma Prior to initiating a new cycle of therapy:
OR; 95 % CI; p-værdia
OR; 95% CI; P valuea
I fase III-studiet førte behandlingen med bortezomib til signifikant længere tid indtil progression, en signifikant længere overlevelse og en signifikant højere responsrate sammenlignet med behandling med dexamethason (se tabel 14) hos alle patienter samt hos patienter, som tidligere havde fået én behandling.
In the Phase III study, treatment with bortezomib led to a significantly longer time to progression, a significantly prolonged survival and a significantly higher response rate, compared to treatment with dexamethasone (see Table 14), in all patients as well as in patients who have received 1 prior line of therapy.
Nadir for det gennemsnitlige trombocyttal var ca. 40 % af værdien ved baseline i myelomatose-studier med monoterapi og 50 % i MCL-studiet.
The mean platelet count nadir measured was approximately 40% of baseline in the single-agent multiple myeloma studies and 50% in the MCL study.
Følgende bivirkninger (grad ≥ 3) blev observeret med en hyppigere forekomst i behandlingsregimet med bortezomib sammenlignet med et historisk kontrolstudie, i hvilket baggrundsregimet blev givet alene: I blok 1 perifer sensorisk neuropati (3 % kontra 0 %), ileus (2,1 % kontra 0 %), hypoksi (8 % kontra 2 %).
The following adverse reactions (Grade ≥ 3) were observed at a higher incidence in the bortezomib containing treatment regimen as compared with a historical control study in which the backbone regimen was given alone: in Block 1 peripheral sensory neuropathy (3% versus 0%); ileus (2.1% versus 0%); hypoxia (8% versus 2%).
Der skal gå mindst 72 timer mellem 2 doser Bortezomib SUN.
At least 72 hours should elapse between consecutive doses of Bortezomib SUN.
Der er rapporteret akut udvikling eller forværring af kongestiv hjerteinsufficiens og/eller ny forekomst af nedsat ejektionsfraktion fra venstre ventrikel ved behandling med bortezomib.
Acute development or exacerbation of congestive heart failure, and/or new onset of decreased left ventricular ejection fraction has been reported during bortezomib treatment.
Tabel 8: Bivirkninger hos patienter med mantle-celle-lymfom, som blev behandlet med BzmbR-CAP i et klinisk studie
Table 8: Adverse reactions in patients with Mantle Cell Lymphoma treated with BzmbR-CAP in a clinical trial
Patienter, der ikke opnåede et optimalt respons (mindre end et komplet respons [CR]) på behandlingen med bortezomib alene efter 4 cyklusser, fik desuden dexamethason 20 mg dagligt samme dag som og dagen efter administration af bortezomib.
Patients who did not obtain an optimal response (less than Complete Response [CR]) to therapy with bortezomib alone after 4 cycles were allowed to receive dexamethasone 20 mg daily on the day of and after bortezomib administration.
Thoraxrøntgen anbefales før behandling for at tjene som udgangspunkt for potentielle lungeforandringer efter behandling.
A pre-treatment chest radiograph is recommended to serve as a baseline for potential post-treatment pulmonary changes.
I BzmbR-CAP-gruppen fik 22,5 % af patienterne trombocyttransfusioner sammenlignet med 2,9 % af patienterne i R-CHOP-gruppen.
In the BzmbR-CAP group, 22.5% of patients received platelet transfusions compared to 2.9% of patients in the R-CHOP group.
Samlet blev bortezomib givet til 3.974 patienter til behandling af myelomatose.
Overall, bortezomib was administered for the treatment of multiple myeloma in 3,974 patients.
Patienter, der udviklede ortostatisk hypotension ved bortezomib (som intravenøs injektion), viste ikke tegn på ortostatisk hypotension før behandlingen med bortezomib.
Patients who developed orthostatic hypotension on bortezomib (injected intravenously) did not have evidence of orthostatic hypotension prior to treatment with bortezomib.
Tabel 13: Effektresultater fra studiet MMY-3010 Endepunkter
Table 13: Efficacy results from study MMY-3010 Endpoints
Dag 1, 2, 3, 4 Dag 8, 9, 10, 11
Day 1, 2, 3, 4 Day 8, 9, 10, 11
Forekomsten af død efter behandlingen var 5 % i den subkutane gruppe og 7 % i den intravenøse gruppe.
The incidence of death on treatment was 5% in the subcutaneous treatment group and 7% in the intravenous treatment group.
Bortezomib påvirker i moderat grad evnen til at føre motorkøretøj og betjene maskiner.
Bortezomib may have a moderate influence on the ability to drive and use machines.
Der skal udvises forsigtighed, når bortezomib kombineres med CYP3A4- eller CYP2C19substrater (se pkt.
Caution should be exercised when bortezomib is combined with CYP3A4 or CYP2C19 substrates (see section 4.5).
Der blev observeret en statistisk signifikant fordel (p < 0,001) for BzmbR-CAP-gruppen i forhold til R-CHOP-gruppen for TTP (median 30,5 kontra 16,1 måneder), TNT (median 44,5 kontra 24,8 måneder) og TFI (median 40,6 kontra 20,5 måneder).
A statistically significant benefit (p < 0.001) in favour of the BzmbR-CAP treatment group over the R-CHOP group was observed for TTP (median 30.5 versus 16.1 months), TNT (median 44.5 versus 24.8 months) and TFI (median 40.6 versus 20.5 months).
Dosisændringer
Posology modification
Grad 2 med smerter eller grad 3 (svære symptomer, der begrænser personlig pleje (personlig ADL***)
Grade 2 with pain or Grade 3 (severe symptoms; limiting self care ADL***)
Tabel 2: Anbefalet dosering for Bortezomib SUN i kombination med melphalan og prednison Bortezomib SUN to gange om ugen (cyklus 1-4)
Table 2: Recommended posology for Bortezomib SUN in combination with melphalan and prednisone Twice weekly Bortezomib SUN (cycles 1-4)
Hæmning af proteasom resulterer i cellecyklusstop og apoptose.
Inhibition of the proteasome results in cell cycle arrest and apoptosis.
Begrundelser for ændring af betingelserne for markedsføringstilladelsen/-tilladelserne På baggrund af de videnskabelige konklusioner for bortezomib er CHMP af den opfattelse, at benefit/risk-forholdet for det lægemiddel/de lægemidler, der indeholder bortezomib, forbliver uændret under forudsætning af, at de foreslåede ændringer indføres i produktinformationen.
Grounds for the variation to the terms of the marketing authorisation(s) On the basis of the scientific conclusions for bortezomib the CHMP is of the opinion that the benefitrisk balance of the medicinal product(s) containing bortezomib is unchanged subject to the proposed changes to the product information.
Da bortezomib er et cytotoksisk stof, som hurtigt kan dræbe maligne plasmaceller og MCL-celler, kan der opstå komplikationer i form af tumorlysesyndrom.
Because bortezomib is a cytotoxic agent and can rapidly kill malignant plasma cells and MCL cells, the complications of tumour lysis syndrome may occur.
Forholdet mellem fordele og risici skal overvejes, før behandlingen med bortezomib fortsætter.
The benefit/risk ratio should be considered prior to continuing bortezomib therapy.
1.3 Det rekonstituerede produkt er uden konserveringsmidler og skal anvendes umiddelbart efter præparation.
1.3 The reconstituted product is preservative free and should be used immediately after preparation.
g p-værdi fra Cochran-Mantel-Haenszel chi-square-test med IPI og sygdomsstadie som stratifikationsfaktorer.
g P-value from the Cochran Mantel-Haenszel chi-square test, with IPI and stage of disease as stratification factors.
• Brochure om rekonstitution, dosering og administration
• Reconstitution, dosing and administration booklet
EVENTUELLE SÆRLIGE FORHOLDSREGLER VED BORTSKAFFELSE AF IKKEANVENDT LÆGEMIDDEL SAMT AFFALD HERAF
SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE
Profylaktisk brug af granulocyt-kolonistimulerende faktorer skal overvejes i tilfælde af gentagne udsættelser af cyklusadministration.
Prophylactic use of granulocyte colony stimulating factors should be considered in case of repeated delays in cycle administration.
Komplet blodtælling (CBC) med differentialtælling og inklusive trombocyttal skal gennemføres hyppigt under behandlingen med bortezomib.
Complete blood counts (CBC) with differential and including platelet counts should be frequently monitored throughout treatment with bortezomib.
- Sprøjt opløsningen som en 35 sek. intravenøs bolusinjektion gennem et perifert eller centralt intravenøst kateter ind i en vene.
- Inject the solution as a 3-5 second bolus intravenous injection through a peripheral or central intravenous catheter into a vein.
d Log-rank-test justeret for stratifikationsfaktorer: ISS-score og antal tidligere linjer.
d Log rank test adjusted for stratification factors: ISS staging and number of prior lines.
I de enkelte medlemslande skal indehaveren af markedsføringstilladelsen blive enig med den relevante nationale myndighed om format og indhold af uddannelsespakken.
• Additional risk minimisation measures In each Member State, the Marketing Authorisation Holder (MAH) shall agree the content and format of the educational material with the national competent authority.
Analysen påviste forbedret ORR (CR+PR) (oddsratio 3,769; 95 % CI 2,045-6,947; p < 0,001), PFS (hazard-ratio 0,511; 95 % CI 0,309-0,845; p = 0,008), TTP (hazard-ratio 0,385; 95 % CI 0,212-0,698; p = 0,001) for bortezomib sammen med dexamethason over bortezomib som monoterapi.
The analysis demonstrated improved ORR (CR+PR) (odds ratio 3.769; 95% CI 2.045-6.947; p < 0.001), PFS (hazard ratio 0.511; 95% CI 0.309-0.845; p=0.008), TTP (hazard ratio 0.385; 95% CI 0.212-0.698; p=0.001) for bortezomib in combination with dexamethasone over bortezomib monotherapy.
Opløsningen skal indgives subkutant i en vinkel på 45-90°.
The solution should be injected subcutaneously, at a 45-90° angle.
Antiviral profylakse anbefales hos patienter, der bliver behandlet med bortezomib.
Antiviral prophylaxis is recommended in patients being treated with bortezomib.
Tabel 15: Oversigt over effektanalyser til sammenligning af subkutan og intravenøs administration af bortezomib
Table 15: Summary of efficacy analyses comparing subcutaneous and intravenous administrations of bortezomib
Se tabel 5 nedenfor vedrørende dosisjusteringer.
For dose adjustments, see Table 5 below.
Yderligere bivirkninger, som blev identificeret i forbindelse med brug af kombinationsbehandling (BzmbR-CAP), var hepatitis Binfektion (< 1 %) og myokardieiskæmi (1,3 %).
Additional adverse drug reactions identified associated with the use of the combination therapy (BzmbR-CAP) were hepatitis B infection (< 1%) and myocardial ischaemia (1.3%).
De to behandlingsgrupper var sammenlignelige, hvad angår den samlede forekomst af alle grader af blødningshændelser (6,3 % i BzmbR-CAP-gruppen og 5,0 % i R-CHOP-gruppen) såvel som blødningshændelser af grad 3 og højere (BzmbR-CAP: 4 patienter [1,7 %]; R-CHOP: 3 patienter [1,2 %]).
The two treatment groups were similar with regard to the overall incidence of all-grade bleeding events (6.3% in the BzmbR-CAP group and 5.0% in the R-CHOP group) as well as Grade 3 and higher bleeding events (BzmbR-CAP: 4 patients [1.7%]; R-CHOP: 3 patients [1.2%]).
Tabel 7: Bivirkninger hos patienter med myelomatose behandlet med bortezomib i kliniske studier samt alle bivirkninger efter markedsføring, uanset indikation#
Table 7: Adverse reactions in patients with Multiple Myeloma treated with bortezomib in clinical trials, and all post-marketing adverse reactions regardless of indication#
Hæmatologisk toksicitet - ≥ Grad 3-neutropeni med feber, grad 4neutropeni, som varer mere end 7 dage, trombocyttal < 10 x 109 celler/l
Haematological toxicity - ≥ Grade 3 neutropenia with fever, Grade 4 neutropenia lasting more than 7 days, a platelet count < 10,000 cells/μl
Thalidomid er et kendt teratogent lægemiddel, der medfører livstruende medfødte misdannelser hos mennesker.
Thalidomide is a known human teratogenic active substance that causes severe life-threatening birth defects.
Bortezomib var ikke genotoksisk i in vitro-analyser af mutagenicitet (Ames' test) og in vivo-analyser af mikronucleus hos mus.
Bortezomib was not genotoxic when tested in the in vitro mutagenicity assay (Ames assay) and in vivo micronucleus assay in mice.
Den rekonstituerede opløsning er klar og farveløs med en pH-værdi på 4-7.
The reconstituted solution is clear and colourless, with a final pH of 4 to 7.
Det Europæiske Lægemiddelagentur har udsat forpligtelsen til at fremlægge resultaterne af studier med bortezomib i alle undergrupper af den pædiatriske population ved myelomatose og ved mantlecelle-lymfom (se pkt.
The European Medicines Agency has waived the obligation to submit the results of studies with bortezomib in all subsets of the paediatric population in multiple myeloma and in mantle cell lymphoma (see section 4.2 for information on paediatric use).