natgillin/translations-raw huggingface dataset:
30%, men der observeredes ingen åbenbar ændring i distributionsvolumen.
Topotecan half-life was increased by about 30% but no clear change in volume of distribution was observed.
10% sammenlignet med kontrolgruppen.
Plasma clearance of total topotecan (active and inactive form) in patients with hepatic impairment only decreased by about 10% compared with the control group of patients.
67% sammenlignet med kontrolgruppen.
Plasma clearance in patients with renal impairment (creatinine clearance 41-60 ml/ min.) decreased to about 67% compared with control patients.
Distributionsvolumen faldt en anelse, hvorved halveringstiden kun steg 14%.
Volume of distribution was slightly decreased and thus half-life only increased by 14%.
Hos patienter med moderat nedsat nyrefunktion faldt topotecan plasmaclearance til 34% af værdien for kontrolgruppens patienter.
In patients with moderate renal impairment topotecan plasma clearance was reduced to 34% of the value in control patients.
Den gennemsnitlige halveringstid steg fra 1, 9 time til 4, 9 time.
Mean half-life increased from 1.9 hours to 4.9 hours.
Et studie med et doseringsinterval på 1, 4 mg/ m2 – 2, 4 mg/ m2/ dag til børn (fra 2 år og op til 12 år; n = 18), til unge (fra 12 år op til 16 år; n = 9) og yngre voksne (fra 16 år op til 21 år; n = 9) med refraktære solide tumorer.
One study included a dose range of 1.4 mg/ m2 to 2.4 mg/ m2 in children (aged 2 up to 12 years, n = 18), adolescents (aged 12 up to 16 years, n = 9), and young adults (aged 16 to 21 years, n = 9) with
Det andet studie med et doseringsinterval på 2, 0 mg/ m2 - 5, 2 mg/ m2 til børn (n = 8), unge (n = 3) og yngre voksne (n = 3) med leukæmi.
The second study included a dose range of 2.0 mg/ m2 to 5.2 mg/ m2 in children (n = 8), adolescents (n = 3), and young adults (n = 3) with leukaemia.
Topotecan har også vist sig at forårsage embryo - og fosterdødelighed, når det gives til rotter og kaniner.
Topotecan was also shown to cause embryo-foetal lethality when given to rats and rabbits.
Hos hunnerne blev dog set super- ovulation og let forhøjet præimplantationstab
In reproductive toxicity studies with topotecan in rats there was no effect on male or female fertility; however, in females super-ovulation and slightly increased pre-implantation loss were observed.
Rekonstituerede og fortyndede opløsninger Produktet skal bruges umiddelbart efter rekonstituering, da det ikke indeholder noget antibakterielt konserveringsmiddel.
Reconstituted and diluted solutions The product should be used immediately after reconstitution as it contains no antibacterial preservative.
Hvis opløsning og fortynding udføres under strikt aseptisk teknik (f. ex i LAF - bænk), skal produktet anvendes (infusion afsluttes) inden for 12 timer ved opbevaring i stuetemperatur eller inden for 24 timer, hvis det opbevares ved 2 - 8 oC efter, at hætteglasset er punkteret første gang.
If reconstitution and dilution is performed under strict aseptic conditions (e. g. an LAF bench) the product should be used (infusion completed) within 12 hours at room temperature or 24 hours if stored at 2-8 0C after the first puncture of the vial.
HYCAMTIN 1 mg leveres i 5 ml hætteglas af type I flintglas sammen med 13 mm grå butylgummipropper og 13 mm aluminiumsforseglinger med plastik flip- off låg.
HYCAMTIN 1 mg is supplied in 5 ml type I flint glass vials, together with 13 mm grey butyl rubber stoppers and 13 mm aluminium seals with plastic flip-off caps.
6. 6 Regler for destruktion og anden håndtering
Not all pack sizes may be marketed.
HYCAMTIN 1 mg i injektionsflaske skal opløses med 1, 1 ml vand til injektionsvæske.
6.6 Special precautions for disposal and other handling 12 HYCAMTIN 1 mg vials must be reconstituted with 1.1 ml water for injections.
Eftersom HYCAMTIN indeholder et overskud på 10%, indeholder den klare rekonstituerede opløsning, hvis farve er gul til gulgrøn, 1 mg/ ml topotecan.
Since HYCAMTIN contains a 10% overage, the clear, reconstituted solution is yellow to yellow-green in colour and provides 1 mg per ml of topotecan.
Yderligere fortynding af den rekonstituerede opløsning med enten 0, 9% vægt/ volumen natriumchlorid til intravenøs infusion eller 5% vægt/ volumen glucose til intravenøs infusion er påkrævet for at opnå den endelige koncentration på mellem 25 og 50 mikrogram/ ml.
Further dilution of the appropriate volume of the reconstituted solution with either 0.9% w/ v sodium chloride intravenous infusion or 5% w/ v glucose intravenous infusion is required to a final concentration of between 25 and 50 microgram/ ml.
12 De normale procedurer for korrekt håndtering og bortskaffelse af anticancermedicin skal overholdes, dvs.: − Personale skal oplæres i rekonstitution af medikamentet. − Gravide kvinder blandt personalet må ikke arbejde med dette medikament. − Personale, som håndterer dette medikament under rekonstitution skal bære beskyttelsesdragt, herunder maske, beskyttelsesbriller og handsker. − Alle genstande brugt under håndtering eller rengøring, herunder handsker, skal anbringes i højrisikoaffaldsposer beregnet til forbrænding ved høj temperatur.
The normal procedures for proper handling and disposal of anticancer medicinal products should be adopted, namely: − Personnel should be trained to reconstitute the medicinal product. − Pregnant staff should be excluded from working with this medicinal product. − Personnel handling this medicinal product during reconstitution should wear protective clothing including mask, goggles and gloves. − All items for administration or cleaning, including gloves, should be placed in high-risk, waste disposal bags for high-temperature incineration.
Flydende affaldsmateriale kan skylles ud i vasken med rigelige mængder vand. − Hvis man ved et uheld får medikamentet på huden eller i øjnene, skal der straks skylles med rigelige mængder vand.
Liquid waste may be flushed with large amounts of water. − Accidental contact with the skin or eyes should be treated immediately with copious amounts of water.
SmithKline Beecham plc, 980 Great West Road, Brentford, Middlesex, TW8 9GS, Storbritannien
SmithKline Beecham plc, 980 Great West Road, Brentford, Middlesex, TW8 9GS, United Kingdom.
5 hætteglas 1 hætteglas
5 vials 1 vial
Dato for første tilladelse 12/ 11/ 1996 Dato for seneste forlængelse 12/ 11/ 2006
12/ 11/ 2006
HYCAMTIN 4 mg pulver til koncentrat till infusionsvæske, opløsning
HYCAMTIN 4 mg powder for concentrate for solution for infusion
Pulver til koncentrat till infusionsvæske, opløsning Lysegult til grønligt pulver
Powder for concentrate for solution for infusion.
14 Efterfølgende doser Topotecan bør ikke gives igen, medmindre neutrofiltallet er ≥ 1 x 109/ l, trombocyttallet er ≥ 100 x 109/ l og hæmoglobinniveauet er ≥ 9g/ dl (om nødvendigt efter transfusion).
14 Subsequent doses Topotecan should not be re-administered unless the neutrophil count is ≥ 1 x 109/ l, the platelet count is ≥ 100 x 109/ l, and the haemoglobin level is ≥ 9g/ dl (after transfusion if necessary).
Ved dosisreduktion hos patienter, som oplever alvorlig neutropeni (neutrofiltal < 0, 5 x 109/ l) i 7 dage eller mere, eller alvorlig neutropeni forbundet med feber eller infektion, eller hvis behandling er blevet udskudt på grund af neutropeni, bør dosis reduceres med 0, 25 mg/ m2/ dag til 1, 25 mg/ m2/ dag (eller derefter om nødvendigt ned til 1, 0 mg/ m2 / dag).
If dose reduction is chosen for patients who experience severe neutropenia (neutrophil count < 0.5 x 109/ l) for 7 days or more, or severe neutropenia associated with fever or infection, or who have had treatment delayed due to neutropenia, the dose should be reduced by 0.25 mg/ m2/ day to 1.25 mg/ m2/ day (or subsequently down to 1.0 mg/ m2/ day if necessary)
Den rekommenderede topotecandosis ved monoterapi hos patienter med ovariecarcinom eller småcellet lungecancer og en kreatinin clearance mellen 20 og 39 ml/ min er 0, 75 mg/ m2/ dag i 5 sammenhængende dage.
The recommended monotherapy dose of topotecan in patients with ovarian or small cell lung cancer and a creatinine clearance between 20 and 39 ml/ min is 0.75 mg/ m2 / day for 5 consecutive days.
5. 1 og 5. 2).
15 Paediatrics The experience in children is limited, therefore no recommendation for treatment of paediatric patients with HYCAMTIN can be given (see sections 5.1 and 5.2).
Dette bør overvejes ved valg af terapi til f. eks. patienter med øget risiko for tumorblødning.
This should be taken into account, e. g. in case patients at increased risk for tumour bleeds are considered for therapy.
Topotecan er ikke rekommanderet till anvendelse i disse patientgrupper.
Topotecan is not recommended to be used in these patient groups.
16 Topotecan hæmmer ikke humane P450- enzymer (se afsnit 5. 2).
Topotecan does not inhibit human P450 enzymes (see Section 5.2).
I en populationsundersøgelse påvistes, ved samtidig administration af granisetron, ondansetron, morfin eller kortikosteroider, ingen signifikant påvirkning af farmakokinetikken af total topotecan (aktiv og inaktiv form).
In a population study, the co- 16 administration of granisetron, ondansetron, morphine or corticosteroids did not appear to have a significant effect on the pharmacokinetics of total topotecan (active and inactive form).
Når topotecan gives sammen med andre kemoterapeutika kan det være nødvendigt at reducere doseringen af hver af de enkelte lægemidler for at forbedre stoffernes tolerabilitet.
In combining topotecan with other chemotherapy agents, reduction of the doses of each medicinal product may be required to improve tolerability.
Hvis topotecan anvendes under graviditet, eller hvis graviditet indtræder under behandling med topotecan, skal patientern advares om den potentielle riskiko for barnet.
If topotecan is used during pregnancy, or if the patient becomes pregnant during therapy with topotecan, the patient must be warned of the potential hazards to the foetus.
17 De samlede sikkerhedsdata for topotecan- monoterapi fremgår herunder.
17 The integrated safety data of topotecan monotherapy are presented below.
18 Hæmatologiske Neutropeni:
The frequencies associated with the haematological and non-haematological adverse events listed below represent the adverse event reports considered to be related/ possibly related to topotecan 18 therapy.
19 replikationsgaffel.
19 The anti-tumour activity of topotecan involves the inhibition of topoisomerase-I, an enzyme intimately involved in DNA replication as it relieves the torsional strain introduced ahead of the moving replication fork.
Recidiverende ovariacancer
Relapsed Ovarian Cancer
(se afsnit 4. 8).
These data should be evaluated in the context of the overall safety profile of the medicinal product, in particular to the important haematological toxicity (see section 4.8).
84 dage for oral topotecan + BSC, 90 dage for BSC] og for hvem gentagelse af behandling med i. v. kemoterapi ikke var hensigtsmæssig.
84 days for oral topotecan + BSC, 90 days for BSC] and for whom retreatment with i. v. chemotherapy was not considered appropriate.
11, 1; 18, 6] for patienter, der modtog BSC alene [p = 0. 0104].
11.1, 18.6] for patients receiving BSC alone [p=0.0104].
Et fase II- forsøg (forsøg 065) og et fase III- forsøg (forsøg 396) blev gennemført til vurdering af effekten af oral topotecan versus intravenøs topotecan til patienter, der havde oplevet tilbagefald > 90 dage efter afslutningen af et tidligere behandlingsforløb med kemoterapi (se tabel 1).
One Phase 2 study (Study 065) and one Phase 3 study (Study 396) were conducted to evaluate the efficacy of oral topotecan versus intravenous topotecan in patients who had relapsed ≥ 90 days after completion of one prior regimen of chemotherapy. (see Table 1).
20 Tabel 1.
20 Table 1.
I en population af patienter med refraktær SCLC (dem, som ikke responderer på førstebehandling) var responsraten 4, 0%.
In a population of patients with refractory SCLC (those not responding to first line therapy), the response rate to topotecan was 4.0%.
21 Resultater Studie GOG- 0179 ITT- population
21 Study results Study GOG-0179 ITT population
Topotecan havde ligeledes et højt
Following intravenous administration of topotecan at doses of 0.5 to 1.5 mg/ m2 as a 30 minute infusion daily for five days, topotecan demonstrated a high plasma clearance of 62 l/ h (SD 22), corresponding to approximately 2/ 3 of liver blood flow.
22 distributionsvolumen på omkring 132 l (SD 57), samt en relativ kort halveringstid på 2 - 3 timer.
Topotecan also had a high volume of 22 distribution, about 132 l, (SD 57) and a relatively short half-life of 2-3 hours.
Der ses ringe eller ingen akkumulering af topotecan ved gentagen daglig dosering, og der er ingen tegn på ændring i PK efter multiple doser.
There is little or no accumulation of topotecan with repeated daily dosing and there is no evidence of a change in the PK after multiple doses.
Samlet set, bidrog N - desmethyl metabolitten i gennemsnit mindre end 7% (interval 4- 9%) til det lægemiddelstofrelateret materiale i urin og fæces, som der kunne gøres rede for.
Overall, the N-desmethyl metabolite contributed a mean of less than 7% (range 4-9%) of the total medicinal product related material accounted for in the urine and faeces.
23 5. 3 Prækliniske sikkerhedsdata
23 Paediatrics
Hos hunnerne blev dog set super- ovulation og let forhøjet præimplantationstab.
In reproductive toxicity studies with topotecan in rats there was no effect on male or female fertility; however, in females super-ovulation and slightly increased pre-implantation loss were observed.
HYCAMTIN 4 mg leveres i 17 ml hætteglas af type I flintglas sammen med 20 mm grå butylgummipropper og 20 mm aluminiumsforseglinger med plastik flip- off låg.
HYCAMTIN 4 mg is supplied in 17 ml type I flint glass vials, together with 20 mm grey butyl rubber stoppers and 20 mm aluminium seals with plastic flip-off caps.
HYCAMTIN 4 mg kan leveres i æsker indeholdende 1 hætteglas og 5 hætteglas.
24 HYCAMTIN 4 mg is available in cartons containing 1 vial and 5 vials.
HYCAMTIN 4 mg i injektionsflaske skal opløses med 4 ml vand til injektionsvæske.
HYCAMTIN 4 mg vials must be reconstituted with 4 ml water for injections.
Den klare rekonstituerede opløsning, hvis farve er gul til gulgrøn, indeholder 1 mg/ ml topotecan.
The clear, reconstituted solution is yellow to yellow-green in colour and provides 1 mg per ml of topotecan.
24 De normale procedurer for korrekt håndtering og bortskaffelse af anticancermedicin skal overholdes, dvs.: − Personale skal oplæres i rekonstitution af medikamentet. − Gravide kvinder blandt personalet må ikke arbejde med dette medikament. − Personale, som håndterer dette medikament under rekonstitution skal bære beskyttelsesdragt, herunder maske, beskyttelsesbriller og handsker. − Alle genstande brugt under håndtering eller rengøring, herunder handsker, skal anbringes i højrisikoaffaldsposer beregnet til forbrænding ved høj temperatur.
The normal procedures for proper handling and disposal of anticancer medicinal products should be adopted, namely: − Personnel should be trained to reconstitute the medicinal product. − Pregnant staff should be excluded from working with this medicinal product. − Personnel handling this medicinal product during reconstitution should wear protective clothing including mask, goggles and gloves. − All items for administration or cleaning, including gloves, should be placed in high-risk, waste disposal bags for high-temperature incineration.
4 mg hætteglas:
4 mg vials:
HYCAMTIN 0, 25 mg kapsler, hård
HYCAMTIN 0.25 mg hard capsules
En kapsel indeholder topotecanhydrochlorid svarende til 0, 25 mg topotecan.
Each capsule contains topotecan hydrochloride equivalent to 0.25 mg of topotecan.
Kapslerne er uigennemsigtige hvide til gullig- hvide og præget med ” HYCAMTIN ” og ” 0. 25 mg ”.
The capsules are opaque white to yellowish white and imprinted with ‘ HYCAMTIN’ and ‘ 0.25 mg’.
5. 1).
HYCAMTIN capsules are indicated as monotherapy for the treatment of adult patients with relapsed small cell lung cancer (SCLC) for whom re-treatment with the first-line regimen is not considered appropriate (see section 5.1).
Brug af Hycamtin kapsler bør kun udskrives og administreres under overvågning af en læge, der har erfaring i brugen af kemoterapeutiske midler.
HYCAMTIN capsules should only be prescribed and therapy supervised by a physician experienced in the use of chemotherapeutic agents.
Første dosis Den anbefalede dosis af HYCAMTIN kapsler er 2, 3 mg/ m2 legemsoverflade/ dag administreret hver dag 5 dage i træk, med et interval på 3 uger mellem begyndelsen af hver behandling.
Initial dose The recommended dose of HYCAMTIN capsules is 2.3 mg/ m2 body surface area/ day administered for 5 consecutive days with a 3 week interval between the start of each course.
4. 8 og 5. 1).
If well tolerated, treatment may continue until disease progression (see sections 4.8 and 5.1).
5. 2).
Hycamtin capsules may be taken with or without food (see section 5.2).
Før administration af første topotecan- behandling skal patienterne have et baseline- neutrofiltal på ≥ 1, 5 x 109/ l, et trombocyttal på ≥ 100 x 109/ l og et hæmoglobinniveau på ≥ 9 g/ dl (om nødvendigt efter transfusion).
Prior to administration of the first course of topotecan, patients must have a baseline neutrophil count of ≥ 1.5 x 109/ l, a platelet count of ≥ 100 x 109/ l and a haemoglobin level of ≥ 9 g/ dl (after transfusion if necessary)..
Efterfølgende doser Topotecan bør ikke gives igen, medmindre neutrofiltallet er ≥ 1 x 109/ l, trombocyttallet er ≥ 100 x 109/ l og hæmoglobinniveauet er ≥ 9 g/ dl (om nødvendigt efter transfusion).
Subsequent doses Topotecan should not be re-administered unless the neutrophil count is ≥ 1 x 109/ l, the platelet count is ≥ 100 x 109/ l, and the haemoglobin level is ≥ 9 g/ dl (after transfusion if necessary).
Ved dosisreduktion hos patienter, som oplever alvorlig neutropeni (neutrofiltal < 0, 5 x 109/ l) i 7 dage eller mere, eller alvorlig neutropeni forbundet med feber eller infektion, eller hvis behandling er blevet udskudt pga. neutropeni, bør dosis reduceres med 0, 4 mg/ m2/ dag til 1, 9 mg/ m2/ dag (eller derefter om nødvendigt ned til 1, 5 mg/ m2/ dag).
If dose reduction is chosen for patients who experience severe neutropenia (neutrophil count < 0.5 x 109/ l) for 7 days or more, or severe neutropenia associated with fever or infection, or who have had treatment delayed due to neutropenia, the dose should be reduced by 0.4 mg/ m2/ day to 1.9 mg/ m2/ day (or subsequently down to 1.5 mg/ m2/ day if necessary).
26 Doserne skal ligeledes reduceres, hvis trombocyttallet falder til under 25 x 109/ l.
26 Doses should be similarly reduced if the platelet count falls below 25 x 109/ l.
I kliniske forsøg blev topotecan- behandlingen stoppet, hvis dosis var blevet reduceret til 1, 5 mg/ m2.
In clinical trials, topotecan was discontinued if the dose needed to be reduced below 1.5 mg/ m2.
4. 4).
For patients who experience Grade 3 or 4 diarrhoea, the dose should be reduced by 0.4 mg/ m2/ day for subsequent courses (see section 4.4).
Dosering til patienter med nedsat nyrefunktion Patienter med småcellet lungekarcinom, som deltog i kliniske forsøg med oral topotecan, havde et serumkreatinin, der var mindre end eller lig med 1, 5 mg/ dl (133 µmol/ l) eller en kreatinin- clearance større end eller lig med 60 ml/ min.
Dosage in renally impaired patients Patients with small cell lung carcinoma who participated in oral topotecan clinical trials had a serum creatinine less than or equal to 1.5 mg/ dl (133 µmol/ l) or a creatinine clearance of greater than or equal to 60 ml/ min.
4. 4).
Dosing recommendations for patients receiving oral topotecan with Clcr less than 60 ml/ min have not been established (see section 4.4).
Dosering til patienter med nedsat leverfunktion Farmakokinetikken for HYCANTIN kapsler er ikke undersøgt specifikt hos patienter med nedsat leverfunktion.
Dosage in hepatically impaired patients Pharmacokinetics of HYCAMTIN capsules have not been specifically studied in patients with impaired hepatic function.
4. 4).
There are insufficient data available with HYCAMTIN capsules to make a dose recommendation for this patient group (see section 4.4).
5. 1).
Paediatrics The experience in children is limited, therefore no recommendation for treatment of paediatric patients with HYCAMTIN can be given (see section 5.1).
Ældre Der sås ingen generelle forskelle i effektivitet hos patienter over 65 år i forhold til yngre voksne patienter.
Elderly No overall differences in effectiveness were observed between patients over 65 years and younger adult patients.
4. 4 og 4. 8).
However in the two studies administering both oral and intravenous topotecan, patients older than 65 years old receiving oral topotecan experienced an increase in drug related diarrhoea compared to those younger than 65 years of age (see section 4.4 and 4.8).
4. 6) − før den første serie indledes, lider af alvorlig knoglemarvssuppression defineret som et baseline - neutrofiltal på < 1, 5 x 109/ l og/ eller et trombocyttal på ≤ 100 x 109/ l
HYCAMTIN is contraindicated in patients who − have a history of hypersensitivity to the active substance or to any of the excipients − are breast feeding (see section 4.6) − already have severe bone marrow depression prior to starting first course, as evidenced by baseline neutrophils < 1.5 x 109/ l and/ or a platelet count of < 100 x 109/ l.
Topotecan- induceret neutropeni kan medføre neutropen colitis.
Topotecan-induced neutropenia can cause neutropenic colitis.
I kliniske forsøg med topotecan har man set dødsfald på grund af neutropen colitis.
Fatalities due to neutropenic colitis have been reported in clinical trials with topotecan.
Patienter bør monitoreres for pulmonale symptomer, der indikerer interstitiel lungesygdom (f. eks. hoste, feber, dyspnø og/ eller hypoxia), og topotecan bør seponeres, hvis en ny diagnose af ILD er bekræftet.
Patients should be monitored for pulmonary symptoms indicative of interstitial lung disease (e. g. cough, fever, dyspnoea and/ or hypoxia), and topotecan should be discontinued if a new diagnosis of 27 ILD is confirmed.
27 Topotecan og topotecan i kombination med cisplatin er i almindelighed associeret med klinisk relevant trombocytopeni.
Topotecan and topotecan in combination with cisplatin are commonly associated with clinically relevant thrombocytopenia.
Dette bør overvejes ved valg af terapi til f. eks patienter med øget risiko for tumorblødning.
This should be taken into account, e. g. in case patients at increased risk of tumour bleeds are considered for therapy.
4. 8).
As expected, patients with poor performance status (PS > 1) have a lower response rate and an increased incidence of complications such as fever, infection and sepsis (see section 4.8).
Topotecan udskilles delvis via nyrerne, og nedsat nyrefunktion kan føre til øget eksponering af topotecan.
Topotecan is partly eliminated via renal excretion and renal impairment might lead to increased exposure to topotecan.
Der er ikke fastlagt en rekommandation for dosering til patienter, der får oral topotecan og har en Clcr mindre end 60 ml/ min.
Dosing recommendations for patients receiving oral topotecan with Clcr less than 60 ml/ min have not been established.
Der er utilstrækkelig erfaring med brugen af oral eller intravenøs topotecan til patienter med alvorlig nedsat nyrefunktion (kreatininclearance < 20 ml/ min).
There is insufficient experience of the use of oral or intravenous topotecan in patients with severely impaired renal function (creatinine clearance < 20 ml/ min).
Topotecan anbefales ikke anvendt til disse patienter.
Topotecan is not recommended to be used in these patients.
Et lille antal patienter med nedsat leverfunktion (serum bilirubin mellem 1, 5 og 10 mg/ dl) fik 1, 5 mg / m2 intravenøs topotecan i 5 dage hver tredje uge.
A small number of hepatically impaired patients (serum bilirubin between 1.5 and 10 mg/ dl) were given intravenous topotecan at 1.5 mg/ m2 for five days every three weeks.
En reduktion i topotecan- clearance blev observeret, men der er ikke tilstrækkelige tilgængelige data til at kunne lave en dosisrekommendation til denne patientgruppe.
A reduction in topotecan clearance was observed however there are insufficient data available to make a dose recommendation for this patient group.