natgillin/translations-raw huggingface dataset:
Det firma, der fremstiller Siklos, skal sørge for, at læger og patienter får udleveret oplysninger om sikkerheden ved lægemidlet.
The company that makes Siklos will provide information packs for doctors and for patients describing the safety information on the medicine.
Andre oplysninger om Siklos:
Other information about Siklos:
Europa- Kommissionen udstedte en markedsføringstilladelse med gyldighed i hele Den Europæiske Union for Siklos til Addmedica den 29. juni 2007.
The European Commission granted a marketing authorisation valid throughout the EU for Siklos to Addmedica on 29 June 2007.
Sammendraget af udtalelsen om Siklos fra Udvalget for Lægemidler til Sjældne Sygdomme findes her.
The summary of opinion of the Committee for Orphan Medicinal Products for Siklos is available here.
Den fuldstændige EPAR for Siklos findes her.
The full EPAR for Siklos can be found here.
EU- nummer EU/ 1/ 07/ 397/ 001
EU Number EU/ 1/ 07/ 397/ 001
Særnavn Siklos
Invented name Siklos
Styrke 1000 mg
Strength 1000 mg
Lægemiddelform Filmovertrukket tablet
Pharmaceutical Form Film-coated tablet
Indgivelsesvej Oral anvendelse
Route of Administration Oral use
Emballage Blister (PVC/ PVDC- aluminiumsfolie)
Packaging blister (PVC/ PVDC/ alu)
Paknings- størrelse 30 filmovertrukne tabletter
Package size 30 film-coated tablets
Hver tablet indeholder 1000 mg hydroxycarbamid.
Each tablet contains 1000 mg of hydroxycarbamide.
En råhvid, kapselformet, filmovertrukket tablet med tredobbelt delekærv på begge sider.
An off-white, capsule-shaped, film-coated tablet with triple scoring on both sides.
Siklos er indiceret til forebyggelse af recidiverende smertefulde vasookklusive kriser og akut lungesvigt (acute chest syndrome) hos pædiatriske og voksne patienter, der lider af symptomatisk seglcellesygdom.
Siklos is indicated for the prevention of recurrent painful vaso-occlusive crises including acute chest syndrome in paediatric and adult patients suffering from symptomatic Sickle Cell Syndrome.
Dosering Til voksne, unge og børn over 2 år:
Posology In adults, adolescents and children older than 2 years:
Doseringen skal baseres på patientens legemsvægt (lv.).
The posology should be based on the patient’ s body weight (b. w.).
Initialdosis af hydroxycarbamid er 15 mg/ kg legemsvægt, og den normale dosis er mellem 15 mg og 30 mg/ kg legemsvægt/ dag.
The starting dose of hydroxycarbamide is 15 mg/ kg b. w. and the usual dose is between 15 and 30 mg/ kg b. w. / day.
4. 4).
Under exceptional circumstances a maximum dose of 35 mg/ kg b. w. / day might be justified under close haematological monitoring (see section 4.4).
Doseringen af Siklos kan justeres efter legemsvægten i trin á 250 mg med anvendelse af en kvart tablet.
The dosage of Siklos can be adjusted to body weight by increments of 250 mg by using a quarter of a tablet.
Dosis af Siklos bør opretholdes, så længe patienten reagerer på behandlingen – enten klinisk eller hæmatologisk (fx stigning i hæmoglobin F (HbF), Mean Corpuscular Volume (MCV), neutrofiltælling).
As long as the patient responds to therapy either clinically or haematologically (e. g. increase of haemoglobin F (HbF), Mean Corpuscular Volume (MCV), neutrophil count) the dose of Siklos should be maintained.
Den daglige dosis kan øges i trin á 250 mg i tilfælde af manglende respons (hvis kriserne genopstår, eller der ikke er fald i frekvensen af kriser).
In case of non-response (re-occurrence of crises or no decrease in crisis rate) the daily dose may be increased by 250 mg steps.
Permanent seponering af Siklos bør overvejes, hvis en patient stadig ikke reagerer efter behandling med maksimumdosis af hydroxycarbamid (35 mg/ kg legemsvægt/ dag) i et tidsrum på tre til seks måneder.
In the event a patient does still not respond when treated with the maximum dose of hydroxycarbamide (35 mg/ kg b. w. / day) over three to six months, permanent discontinuation of Siklos should be considered.
Hvis blodtællingerne er inden for det toksiske område, bør Siklos seponeres midlertidigt, indtil blodtællingerne er normaliserede.
If blood counts are within the toxic range Siklos should be temporarily discontinued until blood counts recover.
2 Behandlingen kan derefter genoptages med reduceret dosis.
2 at a reduced dose.
Det toksiske område kan karakteriseres af følgende blodprøveresultater:
The toxic range may be characterised by the following results of blood tests:
Neutrofiler Thrombocytter < Hæmoglobin
Neutrophils Platelets Haemoglobin Reticulocytes
Retikulocytter < 80. 000/ mm3 hvis hæmoglobinkoncentrationen < 9 g/ dl
< 2000 / mm3 < 80,000/ mm3 < 4.5 g/ dl < 80,000/ mm3 if the haemoglobin concentration < 9 g/ dl
Langtidsdata vedrørende den fortsatte brug af hydroxycarbamid til patienter med seglcellesygdom findes for børn og unge med 12 års opfølgning af unge og mere end 13 års opfølgning af voksne.
Long-term data on the continued use of hydroxycarbamide in patients with Sickle Cell Syndrome are available in children and adolescents, with a follow-up of 12 years in adolescents and over 13 years in adults.
Børn under 2 år På grund af manglende data vedrørende behandling med hydroxycarbamid til børn under 2 år er der ikke fastlagt nogen doseringsregimer, og hydroxycarbamid bør derfor ikke bruges til denne population.
Children less than 2 years of age Because of the rarity of data on treatment with hydroxycarbamide in children less than 2 years of age, dosage regimens have not been established and thus, in this population, the treatment with hydroxycarbamide is not recommended.
Børn og unge (2- 18 år) Den systemiske eksponering for hydroxycarbamid er for børn og unge den samme som for voksne patienter.
Children and adolescents (2-18 years old) In children and adolescents with Sickle Cell Syndrome, systemic exposure to hydroxycarbamide is similar to adult patients.
Dosisjusteringer er derfor ikke nødvendige til yngre patienter.
Hence, no dose-adjustments are necessary in younger patients.
Nyreinsufficiens Da eliminering hovedsageligt sker via nyrerne, bør en reduktion af dosis af Siklos overvejes for patienter med nedsat nyrefunktion.
As renal excretion is a main pathway of elimination, dosage reduction of Siklos should be considered in patients with renal impairment.
For patienter med en kreatininclearance på ≤ 60 ml/ min bør initialdosis af Siklos reduceres med 50%.
In patients with a creatinine clearance ≤ 60 ml/ min the initial Siklos dose should be decreased by 50%.
Hos disse patienter tilrådes nøje overvågning af de hæmatologiske parametre.
Close monitoring of haematologic parameters is advised in these patients.
4. 3, 4. 4 og 5. 2).
Siklos should not be administered to patients with severe renal impairment (creatinine clearance < 30 ml/ min) (see sections 4.3, 4.4 and 5.2).
Leverinsufficiens Der findes ingen data, som understøtter særlige dosisjusteringer til patienter med nedsat leverfunktion.
There are no data that support specific dosage adjustments in patients with hepatic impairment.
4. 3 og 4. 4).
Due to safety considerations, Siklos is contraindicated in patients with severe hepatic impairment (see sections 4.3 and 4.4).
Indgivelsesmåde Tabletten eller den halve eller kvarte tablet skal alt efter den individuelle dosis tages én gang om dagen – helst om morgenen inden morgenmaden, sammen med et glas vand eller en meget lille portion mad.
Method of administration Conforming with the individual dosage, the tablet or the halves or quarters of the tablet should be taken once daily, preferably in the morning before breakfast and, where necessary, with a glass of water or a very small amount of food.
Svær leverinsufficiens (Child- Pugh- klasse C) eller svær nyreinsufficiens (kreatininclearance < 30ml/ min).
Severe hepatic (Child-Pugh classification C) or severe renal impairment (creatinine clearance < 30ml/ min).
4. 2.
Toxic ranges of myelosuppression as described under section 4.2.
4. 6).
Breast-feeding must be discontinued while taking Siklos (see section 4.6).
3 Behandling med Siklos kræver nøje klinisk overvågning.
3 Treatment with Siklos requires close clinical monitoring.
Patientens hæmatologiske status samt nyre - og leverfunktion skal fastlægges inden behandlingen og gentagne gange under behandlingen.
The haematological status of the patient, as well as renal and hepatic functions should be determined prior to, and repeatedly during treatment.
Under behandlingen med Siklos skal blodtællingerne kontrolleres hver anden uge ved behandlingens start (dvs. i de første to måneder), og hvis den daglige dosis hydroxycarbamid er på op til 35 mg/ kg legemsvægt.
During treatment with Siklos, blood counts must be monitored every two weeks at treatment initiation (i. e. for the first two months) and if the daily dose of hydroxycarbamide is up to 35 mg/ kg b. w.
4. 2).
Siklos therapy can then be re-initiated at a slightly lower dose (see section 4.2).
4. 2).
Siklos should be used with caution in patients with mild to moderate renal or hepatic impairment (see section 4.2).
På grund af de potentielt alvorlige kliniske udfald af de kutane vaskulære ulcerationer, der blev indberettet for patienter med myeloproliferativ sygdom, skal hydroxycarbamid seponeres og/ eller dosis reduceres, hvis der opstår kutane vaskulære ulcerationer.
Due to potentially severe clinical outcomes for the cutaneous vasculitic ulcers reported in patients with myeloproliferative disease, hydroxycarbamide should be discontinued and/ or its dose reduced if cutaneous vasculitic ulcerations develop.
Ulcera er i sjældne tilfælde forårsaget af leukocytoklastisk vaskulit.
Rarely, ulcers are caused by leukocytoclastic vasculitis
Kontinuerlig opfølgning af behandlede børns vækst anbefales.
Continuous follow-up of the growth of treated children is recommended.
Hydroxycarbamid forårsager makrocytose, som kan skjule den medfølgende udvikling af folinsyre - og vitamin B12- mangel.
Hydroxycarbamide causes macrocytosis, which may mask the incidental development of folic acid and vitamin B12 deficiency.
Patienterne og/ eller forældrene eller den juridisk ansvarlige person skal være i stand til at følge anvisningerne vedrørende indgivelse af dette lægemiddel samt overvågningen og plejen af patienterne.
Patients and/ or parents or the legal responsible person must be able to follow directions regarding the administration of this medicinal product, their monitoring and care.
Det vides ikke, om denne leukæmogene effekt er sekundær til hydroxycarbamid eller forbundet med patientens bagvedliggende sygdom.
It is unknown whether this leukemogenic effect is secondary to hydroxycarbamide or is associated with the patient’ s underlying disease.
Potentielt fatal pancreatitis og hepatotoksicitet og svær perifer neuropati er blevet indberettet for HIV - inficerede patienter, som fik hydroxycarbamid i kombination med antiretrovirale midler, herunder især didanosin plus stavudin.
Potentially fatal pancreatitis and hepatotoxicity, and severe peripheral neuropathy have been reported in HIV-infected patients who received hydroxycarbamide in combination with antiretroviral agents particularly didanosine plus stavudine.
Patienter, der blev behandlet med hydroxycarbamid i kombination med didanosin, stavudin og indinavir, udviste et gennemsnitligt fald i CD4- celler på cirka 100/ mm3.
Patients treated with hydroxycarbamide in combination with didanosine, stavudine, and indinavir showed a median decline in CD4 cells of approximately 100/ mm3.
4 Samtidig anvendelse af hydroxycarbamid og andre myelosuppressive præparater eller strålebehandling kan forværre en allerede eksisterende myelosuppression (knoglemarvshæmning), gastrointestinale forstyrrelser eller mucositis.
4 Concurrent use of hydroxycarbamide and other myelosuppressive medicinal products or radiation therapy may increase bone marrow depression, gastro-intestinal disturbances or mucositis.
Samtidig anvendelse af hydroxycarbamid med en levende virusvaccine kan forstærke vaccinevirussens replikation og/ eller øge vaccinevirussens bivirkning, da de normale forsvarsmekanismer kan være undertrykkede af behandlingen med hydroxycarbamid.
Concomitant use of hydroxycarbamide with a live virus vaccine may potentiate the replication of the vaccine virus and/ or may increase the adverse reaction of the vaccine virus, because normal defence mechanisms may be suppressed by hydroxycarbamide therapy.
Patienter i behandling med hydroxycarbamid skal være opmærksomme på den teoretiske risiko for fosteret, og patienter, der ønsker at blive gravide, skal om muligt seponere behandlingen 3- 6 måneder inden graviditeten.
Patients on hydroxycarbamide should be made aware of the theoretical risks to the foetus and those wishing to conceive should stop treatment 3 to 6 months before pregnancy if possible.
Evalueringen af risici kontra fordele skal foretages på individuel basis, hvor risikoen ved behandling med hydroxycarbamid opvejes mod et skift til et blodtransfusionsprogram.
The evaluation of the risk- benefit ratio should be made on an individual basis outweighing the respective risk of hydroxycarbamide therapy against the switch to a blood transfusion programme.
Som følge af den begrænsede mængde information, der er til rådighed, skal en nøje opfølgning med fyldestgørende kliniske og biologiske undersøgelser og ultralydsundersøgelser overvejes i tilfælde af, at en patient eksponeres for hydroxycarbamid under graviditet.
Based on the limited amount of available information, in case of an exposure to hydroxycarbamide during pregnancy, a careful follow-up with adequate clinical, biological and ultrasonographic examinations should be considered.
Kvinder i den fødedygtige alder skal tilrådes at anvende effektive antikonceptionsmetoder under behandlingen med hydroxycarbamid.
Women of child-bearing potential should be advised to use adequate birth-control measures during treatment with hydroxycarbamide.
Hvis en patient bliver gravid, mens hun får Siklos, skal hun vejledes om den mulige risiko for fosteret.
If the patient becomes pregnant while taking Siklos, she should be advised of the potential risk to the foetus.
Hydroxycarbamid udskilles i human modermælk.
Hydroxycarbamide is excreted in human milk.
Amning skal ophøre under behandling med Siklos på grund af risikoen for alvorlige bivirkninger på spædbørn.
Because of the potential for serious adverse reactions in infants, breast-feeding must be discontinued while taking Siklos.
Patienterne skal dog informeres om, at svimmelhed tidligere er indberettet, om end det ikke er almindeligt.
However, patients should be informed that dizziness has been reported from literature, but not commonly.
Patienterne skal frarådes at føre motorkøretøj og betjene maskiner, hvis de oplever svimmelhed, mens de er i behandling med Siklos.
Patients should be advised not to drive or operate machines, if dizziness is experienced while taking Siklos.
Sikkerheden ved hydroxycarbamid er specifikt blevet undersøgt retroaktivt i kohorter med 123 voksne (13 år eller derover) patienter og 352 pædiatriske (op til 12 år) patienter.
Specifically the safety of hydroxycarbamide had been examined retroactively from cohorts of 123 adults and 352 paediatric patients, over 13 years and up to 12 years respectively.
Hvis den maksimalt tolererede dosis ikke nås, opstår der normalt forbigående myelotoksicitet hos mindre end 10% af patienterne, mens mere end 50% kan opleve reversibel knoglemarvshæmning under den maksimalt tolererede dosis.
When the maximum tolerated dose is not reached transient myelotoxicity usually occurs in less than 10% of patients, while under the maximum tolerated dose more than 50% can experience reversible bone marrow suppression.
4. 2).
Gradual dose titration may help to diminish these effects (see section 4.2).
5 De bivirkninger, der anses for som et minimum at kunne være forbundet med behandlingen, er angivet på nedenstående liste, inddelt efter systemorganklasse og absolut hyppighed.
Frequencies are defined as very common (> 1/ 10), common
Hyppighed defineres som meget almindelig (> 1/ 10); almindelig (> 1/ 100, < 1/ 10); usædvanlig (> 1/ 1. 000, < 1/ 100); sjælden (> 1/ 10. 000, < 1/ 1. 000); meget sjælden (< 1/ 10. 000), ikke kendt (kan ikke estimeres ud fra forhåndenværende data).
5 (> 1/ 100 ,< 1/10), uncommon (> 1/ 1,000 ,< 1/100), rare (> 1/ 10,000, < 1/ 1,000), very rare (< 1/ 10,000), not known (cannot be estimated from the available data).
Knoglemarvshæmning1 herunder neutropeni (< 2, 0 x 109/ l), retikulocytopeni (< 80 x 109/ l), makrocytose2
Bone marrow depression1 including neutropenia (< 2.0 x 109/ l), reticulocytopenia (< 80 x 109/ l), macrocytosis2
Almindelig:
Nervous system
Sygdomme i nervesystemet:
Common: disorders:
Hovedpine Svimmelhed
Thrombocytopenia (< 80 x 109/ l), anaemia (haemoglobin < 4.5 g/ dl)3 Headache Dizziness
Kvalme Gastrointestinale forstyrrelser, opkastning, gastrointestinal ulceration, svær hypomagnesaemia
Nausea Gastrointestinal disturbances, vomiting, gastrointestinal ulcer, severe hypomagnesaemia
Hudreaktioner (for eksempel oral, negle - og kutan pigmentering) samt oral mucositis.
Skin reactions (for example oral, ungual and cutaneous pigmentation) and oral mucositis.
Udslæt, melanonychia, alopecia Bensår Hudtørhed
Rash, melanonychia, alopecia Leg ulcers Cutaneous dryness Parvovirus B19 infection
Infektioner og parasitære sygdomme:
Neoplasms, benign, malignant and unspecified
Benigne, maligne og uspecificerede tumorer (inkl. cyster og polypper)
Leukaemia and in elderly patients, skin cancers
Lever og galdeveje:
Hepathobiliary
Sjælden:
Not known: disorders Rare:
Forhøjede leverenzymer
Fever Elevated liver enzymes
Azoospermia, oligozoospermia4 Amenorré
Azoospermia, oligospermia4 Amenorrhea
Hæmatologisk genoprettelse sker normalt inden for to uger efter seponering af hydroxycarbamid.
Haematological recovery usually occurs within two weeks of withdrawal of hydroxycarbamide.
5. 3).
4 Oligospermia and azoospermia are in general reversible, but have to be taken into account when fatherhood is desired (see section 5.3).
5 Som kan være et resultat af en forbedret generel tilstand.
5 Which may be an effect of improved general conditions.
De kliniske data, der er indsamlet fra patienter med seglcellesygdom, har ikke vist tegn på bivirkninger af hydroxycarbamid på lever - og nyrefunktionen.
The clinical data obtained in patients with Sickle Cell Syndrome have not shown evidence of adverse effects of hydroxycarbamide on hepatic and renal function.
6 Akut mucokutan toksicitet er blevet indberettet for patienter, der fik hydroxycarbamid i doseringer, som var flere gange højere end den terapeutiske dosis.
Soreness, violet erythema, oedema on palms and soles
Ømhed, blåviolet erythem, ødem på håndflader og fodsåler efterfulgt af skældannelse på hænder og fødder, svær generaliseret hyperpigmentering af huden samt stomatitis er blevet observeret.
6 followed by scaling of hand and feet, severe generalised hyperpigmentation of the skin and stomatitis have been observed.
Hos patienter med seglcellesygdom blev neutropeni indberettet i isolerede tilfælde af overdosering med hydroxycarbamid (1, 43 gange og 8, 57 gange den anbefalede maksimumdosis på 35 mg/ kg legemsvægt/ dag).
In patients with Sickle Cell Syndrome, neutropenia was reported in isolated cases of hydroxycarbamide overdose (1.43 times and 8.57 times of the maximum recommended dose of 35 mg/ kg b. w. / day).
Andre antineoplastiske midler, ATC- kode:
Other antineoplastic agents, ATC code:
I næsten alle de kliniske studier, der er gennemført af seglcellesygdom, reducerede hydroxycarbamid hyppigheden af vasookklusive episoder med 66% til 80% hos børn og voksne.
In nearly all clinical studies conducted in Sickle Cell Syndrome, hydroxycarbamide reduced the frequency of vaso-occlusive episodes by 66% to 80%, in children and in adults.
Den årlige hyppighed af akut lungesvigt blev også reduceret med 25% til 33% ved behandling med hydroxycarbamid i adskillige studier.
The yearly frequency of acute chest syndrome was also reduced by 25 to 33% under hydroxycarbamide in several studies.
Akut lungesvigt er en hyppig, livstruende komplikation ved seglcellesygdom og er kendetegnet af brystsmerter eller feber eller dyspnø med nyere infiltrat på thoraxrøntgen.
Acute chest syndrome is a frequent life-threatening complication of Sickle Cell Syndrome and is characterized by chest pain or fever or dyspnoea with recent infiltrate on chest X-ray.
HbF bryder ind i polymeriseringen af HbS og hindrer dermed ” sickling ” af røde blodlegemer.
HbF interferes with the polymerisation of HbS and thus impedes the sickling of red blood cell.
Andre kendte farmakologiske effekter af hydroxycarbamid, som kan bidrage til midlets fordelagtige virkninger på seglcellesygdom, omfatter reduktion af neutrofiler, forøgelse af eythrocytters vandindhold, forøgelse af seglcellers deformabilitet samt ændret vedhæftning af røde blodlegemer til endotelet.
Other known pharmacological effects of hydroxycarbamide which may contribute to its beneficial effects in Sickle Cell Syndrome include decrease of neutrophils, increase of the water content of erythrocytes, increase of the deformability of sickled cells, and altered adhesion of red blood cells to the endothelium.
Desuden medfører hydroxycarbamid en direkte hæmning af DNA- syntesen ved at fungere som en hæmmer af ribonukleotidreduktase uden at forstyrre syntesen for ribonukleinsyre eller - protein.
In addition hydroxycarbamide causes an immediate inhibition of DNA synthesis by acting as a ribonucleotide reductase inhibitor, without interfering with the synthesis of ribonucleic acid or protein.
Den samlede eksponering indtil 24 timer efter dosering er 124
After oral administration of 20 mg/ kg of hydroxycarbamide, a rapid absorption is observed with peak plasma levels of about 30 mg/ l occurring after 0.75 and 1.2 h in children and adult patients with Sickle Cell Syndrome, respectively.
7 mg* t/ l for børn og unge og 135 mg* t/ l for voksne patienter.
The total exposure up to 24 h post-dose is 124 mg*h/ l in children and adolescents and 135 mg*h/ l in adult patients.
Distribution:
7 Distribution:
Distributionsvolumen ved steady state justeret for biotilgængelighed er 0, 57 l/ kg for patienter med seglcellesygdom (i alt cirka 72 l og 90 l for henholdsvis børn og voksne).
The volume of distribution at steady state adjusted for bioavailability is 0.57 l/ kg in patients with Sickle Cell Syndrome (amounting to approximately 72 and 90 l in children and adults, respectively).
Hydroxycarbamid som 30, 100 og 300µM metaboliseres ikke in vitro af cytochrom P450 i humane levermikrosomer.
Hydroxycarbamide at 30, 100 and 300µM is not metabolised in vitro by cytochrome P450s of human liver microsomes.
I koncentrationer inden for området 10 til 300 µM stimulerer hydroxycarbamid ikke adenosintriphosphatase- aktiviteten in vitro af rekombinant human P- glykoprotein (PGP), hvilket indikerer, at hydroxycarbamid ikke er et PGP- substrat.
At concentrations ranging from 10 to 300 µM, hydroxycarbamide does not stimulate the in vitro ATPase activity of recombinant human P glycoprotein (PGP), indicating that hydroxycarbamide is not a PGP substrate.
Der forventes derfor ingen interaktion i tilfælde af ledsagende indgivelse af stoffer, som er substrater af cytochrom P450 eller P- glykoprotein.
Hence, no interaction is to be expected in case of concomitant administration with substances being substrates of cytochromes P450 or P-glycoprotein.
I en undersøgelse med gentagne doser på voksne patienter med seglcellesygdom blev cirka 60% af hydroxycarbamid- dosis konstateret i urin ved steady state.
In a repeated dose study in adult patients with Sickle Cell Syndrome approximately 60% of the hydroxycarbamide dose was detected in urine at steady state.
Den samlede clearance justeret for biotilgængelighed var hos voksne 9, 89 l/ t (0, 16 l/ t/ kg), heraf 5, 64 og 4, 25 l/ t ved henholdsvis renal og ikke- renal clearance.
In adults the total clearance adjusted for bioavailability was 9.89 l/ h (0.16 l/ h/ kg) thereof 5.64 and 4.25 l/ h by renal and non-renal clearance, respectively.
Den tilsvarende værdi for den samlede clearance for børn var 7, 25 l/ t (0, 20 l/ t/ kg) med 2, 91 og 4, 34 l/ t ved renal og ikke- renal clearance.
The respective value for total clearance in children was 7.25 l/ h (0.20 l/ h/ kg) with 2.91 and 4.34 l/ h by renal and non-renal pathways.