natgillin/translations-raw huggingface dataset:
Hvis en patient kræver en længere behandling end 5 måneder for behandling af perifere neurogene smerter, bør den behandlende læge vurdere patientens kliniske status og fastsætte behovet for yderligere behandling.
If a patient requires dosing longer than 5 months for the treatment of peripheral neuropathic pain, the treating physician should assess the patient’ s clinical status and determine the need for additional therapy.
Hos patienter med generelt dårlig helbredstilstand, f. eks. med lav legemsvægt, efter organtransplantation eller lignende, bør dosistitrering ske langsommere enten ved at anvende en lavere styrke eller længere interval mellem dosisøgningerne.
In patients with poor general health, i. e., low body weight, after organ transplantation etc., the dose should be titrated more slowly, either by using smaller dosage strengths or longer intervals between dosage increases.
Nedsat nyrefunktion
Use in patients with renal impairment
Dette er beskrevet i tabel 2.
Dosage adjustment is recommended in patients with compromised renal function as described in Table 2 and/ or those undergoing haemodialysis.
Tabel 2 DOSERING AF GABAPENTIN HOS VOKSNE BASERET PÅ NYREFUNKTIONEN
Table 2 DOSAGE OF GABAPENTIN IN ADULTS BASED ON RENAL FUNCTION Creatinine Clearance (ml/ min) ≥ 80 50-79 30-49 15-29 < 15c a
Total daglig dosisa (mg/ dag) 900- 3600 600- 1800 300- 900 150b- 600
Total Daily Dosea (mg/ day) 900-3600 600-1800 300-900 150b-600 150b-300
Den totale daglige dosis bør fordeles på 3 doser.
Reduced dosages are for patients with renal
Nedsat dosis anbefales hos patienter med nedsat nyrefunktion (kreatininclearance < 79 ml/ min). b Gives som 300 mg hver 2. dag. c Hos patienter med kreatininclearance < 15 ml/ min, bør den daglige dosis nedsættes i forhold til kreatininclearance (f. eks. bør patienter med kreatininclearance på 7, 5 ml/ min have halv så stor daglig dosis, som patienter med kreatininclearance på 15 ml/ min får).
For patients with creatinine clearance < 15 ml/ min, the daily dose should be reduced in proportion to creatinine clearance (e. g., patients with a creatinine clearance of 7.5 ml/ min should receive one-half the daily dose that patients with a creatinine clearance of 15 ml/ min receive).
Patienter i hæmodialysebehandling
28 Use in patients undergoing haemodialysis
Anuripatienter, der er i hæmodialysebehandling, og som ikke tidligere har været i behandling med gabapentin, gives initialt en dosis på 300- 400 mg gabapentin, derefter 200- 300 mg gabapentin efter hver 4 timers hæmodialyse.
For anuric patients undergoing haemodialysis who have never received gabapentin, a loading dose of 300 to 400 mg, then 200 to 300 mg of gabapentin following each 4 hours of haemodialysis, is recommended.
I tillæg til vedligeholdelsesdosis anbefales en dosis på yderligere 200- 300 mg efter hver 4 timers hæmodialyse.
In addition to the maintenance dose, an additional 200 to 300 mg dose following each 4-hour haemodialysis treatment is recommended.
30 4. 3 Kontraindikationer
4.3 Contraindications
4. 8).
If a patient develops acute pancreatitis under treatment with gabapentin, discontinuation of gabapentin should be considered (see section 4.8).
4. 2).
Although there is no evidence of rebound seizures with gabapentin, abrupt withdrawal of anticonvulsants in epileptic patients may precipitate status epilepticus (see section 4.2).
Som for andre antiepileptika vil forsøg på seponering af andre samtidige antepileptika hos refraktære patienter, der behandles med mere end et antiepileptikum for at opnå gabapentin monoterapi, have en lav succesrate.
As with other antiepileptic medicinal products, some patients may experience an increase in seizure frequency or the onset of new types of seizures with gabapentin.
Som for andre antiepileptika kan visse patienter opleve en stigning i antallet af anfald, eller der opstår nye typer af anfald med gabapentin.
As with other anti-epileptics, attempts to withdraw concomitant anti-epileptics in treatment refractory patients on more than one anti-epileptic, in order to reach gabapentin monotherapy have a low success rate.
Gabapentin betragtes ikke som effektivt i behandlingen af generaliserede anfald som f. eks. absencer og kan forværre disse anfald hos nogle patienter.
Gabapentin is not considered effective against primary generalized seizures such as absences and may aggravate these seizures in some patients.
I en dobbelt- blind undersøgelse hos patienter med neurogene smerter forekom søvnighed, perifert ødem og asteni hos en større procentdel af patienterne på 65 år eller derover end hos yngre patienter.
In one double blind study in patients with neuropathic pain, somnolence, peripheral oedema and asthenia occurred in a somewhat higher percentage in patients aged 65 years or above, than in younger patients.
Laboratorieundersøgelser Der er rapporteret om falsk- positive resultater ved brug af indikatorpapir/ teststrimler til semi - kvantitativ bestemmelse af proteinindholdet i urinen.
Laboratory tests False positive readings may be obtained in the semi-quantitative determination of total urine protein by dipstick tests.
Biuret- metoden, turbidimetri eller farvestofbindingsmetoder eller at anvende disse alternative metoder fra starten.
It is therefore recommended to verify such a positive dipstick test result by methods based on a different analytical principle such as the Biuret method, turbidimetric or dye-binding methods, or to use these alternative methods from the beginning.
Denne medicin bør ikke anvendes til patienter med arvelig galactoseintolerans, en særlig form af hereditær lactasemangel (Lapp Lactase deficiency) eller glucose/ galactosemalabsorption [denne tekst vil kun indgå i produktresumeet for kapslerne].
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose- galactose malabsorption should not take this medicine [this text will only be included in the capsules SPC].
4. 5 Interaktion med andre lægemidler og andre former for interaktion
29 4.5 Interaction with other medicinal products and other forms of interaction
Derfor bør disse patienter omhyggeligt observeres for tegn på CNS depression, som f. eks. søvnighed, og dosis af gabapentin eller morfin bør reduceres på passende vis.
Therefore, patients should be carefully observed for signs of CNS depression, such as somnolence, and the dose of gabapentin or morphine should be reduced appropriately.
31 Samtidig administration af gabapentin og orale kontraceptiva, der indeholder norethindron og/ eller ethinyl østradiol, påvirker ikke disse stoffers steady state farmakokinetik.
Coadministration of gabapentin with oral contraceptives containing norethindrone and/ or ethinyl estradiol, does not influence the steady-state pharmacokinetics of either component.
2 timer efter administration af antacida.
It is recommended that gabapentin be taken at the earliest two hours following antacid administration.
Risikoen for misdannelser hos børn af mødre behandlet med antiepileptika øges med en faktor på 2- 3.
The risk of birth defects is increased by a factor of 2 – 3 in the offspring of mothers treated with an antiepileptic medicinal product.
Derfor er det vigtigt, at monoterapi anvendes, når det er praktisk muligt.
Multiple antiepileptic drug therapy may be associated with a higher risk of congenital malformations than monotherapy, therefore it is important that monotherapy is practised whenever possible.
Antiepileptisk behandling bør ikke seponeres pludseligt, da dette kan føre til gennembrudsanfald, der kan få alvorlige konsekvenser for både moder og barn.
No sudden discontinuation of antiepileptic therapy should be undertaken as this may lead to breakthrough seizures, which could have serious consequences for both mother and child.
Forsinket psykisk udvikling hos børn af mødre med epilepsi er set i sjældne tilfælde.
Developmental delay in children of mothers with epilepsy has been observed rarely.
Dette skyldes, at epilepsi alene samt anden samtidig antiepileptisk medicin optræder under hver rapporteret graviditet.
No definite conclusion can be made as to whether gabapentin is associated with an increased risk of congenital malformations when taken during pregnancy, because of epilepsy itself and the presence of concomitant antiepileptic medicinal products during each reported pregnancy.
Gabapentin udskilles i modermælk.
30 Gabapentin is excreted in human milk.
32 (meget almindelig (≥1/ 10), almindelig (≥1/ 100, < 1/ 10), ikke almindelig (≥1/ 1000 og < 1/ 100), sjælden (≥1/ 10. 000 og < 1/ 1000).
The adverse reactions observed during clinical studies conducted in epilepsy (adjunctive and monotherapy) and neuropathic pain have been provided in a single list below by class and frequency (very common (> 1/ 10), common (> 1/ 100 ,< 1/10), uncommon (> 1/ 1000 ,< 1/100) and rare (> 1/10 ,000; < 1/1,000).
Infektioner og infestationer Meget almindelig:
Infections and infestations Very Common:
Almindelig:
Viral infection Common:
viral infektion pneumoni, luftvejsinfektion, urinvejsinfektion, infektion, otitis media
Pneumonia, respiratory infection, urinary tract infection, infection, otitis media
Almindelig:
Blood and the lymphatic system disorders Common:
leukopeni thrombocytopeni
leucopenia thrombocytopenia
Sjælden:
Immune system disorders Rare: allergic reactions (e. g. urticaria)
Stofskiftesygdomme og ernæringsbetingede sygdomme Almindelig:
Metabolism and Nutrition Disorders Common:
appetitmangel, øget appetit
anorexia, increased appetite
Almindelig:
Psychiatric disorders Common:
Almindelig:
Nervous system disorders Very Common: somnolence, dizziness, ataxia, Common:
søvnighed, svimmelhed, ataksi konvulsioner, hyperkinesi, dysartri, amnesi, tremor, søvnløshed, hovedpine, berøringsfølelse som f. eks. paræstesi, hypæstesi, koordinationsforstyrrelser, nystagmus, forstærkede, nedsatte eller fraværende reflekser
convulsions, hyperkinesias, dysarthria, amnesia, tremor, insomnia, headache, sensations such as paresthesia, hypaesthesia, coordination abnormal, nystagmus, increased, decreased, or absent reflexes
forstyrrelser i bevægeapparatet (f. eks. choreoatetose, dyskinesi, dystoni)
movement disorders (e. g. choreoathetosis, dyskinesia, dystonia)
synsforstyrrelser, som f. eks. amblyopi, diplopi
visual disturbances such as amblyopia, diplopia
Sygdomme i det ydre og det indre øre Almindelig:
Ear and Labyrinth disorders Common:
Sjælden:
31 Cardiac disorders Rare: palpitations
Karsygdomme Almindelig:
Vascular disorder Common:
hypertension, vasodilatation
hypertension, vasodilatation
dyspnø, bronkitis, pharyngitis, hoste, rhinitis
dyspnoea, bronchitis, pharyngitis, cough, rhinitis
33 Lever - og galdevejslidelser Sjælden:
Hepatobiliary disorders Rare: hepatitis, jaundice
Almindelig:
Skin and subcutaneous tissue disorders Common:
Stevens- Johnsons syndrom, angioødem, erythema multiforme, alopeci
Stevens-Johnson syndrome, angioedema, erythema multiforme, alopecia
Sygdomme i bevægeapparatet, bindevæv og knogler Almindelig:
Musculoskeletal, Common:
arthralgi, myalgi, rygsmerter, muskeltrækninger
connective tissue and bone disorders arthralgia, myalgia, back pain, twitching
Almindelig:
Renal and urinary disorders Common:
inkontinens akut nyresvigt
incontinence acute renal failure
Almene lidelser og reaktioner på indgivelsesstedet Meget almindelig:
and administration site conditions
Almindelig:
Very Common: fatigue, fever Common:
træthed, feber perifere eller generaliserede ødemer, gangforstyrrelser, asteni, smerter, utilpashed, influenzalignende symptomer
peripheral or generalized oedema, abnormal gait, asthenia, pain, malaise, flu syndrome
nedsat antal hvide blodlegemer, vægtøgning, Svingende blodsukkerniveau hos diabetikere, forhøjede levertal
WBC (white blood cell count) decreased, weight gain Blood glucose fluctuations in patients with diabetes, elevated liver function tests
Skader, forgiftninger og komplikationer ved medicinske procedurer Almindelig:
Injury and poisoning Common:
4. 4).
Causality with gabapentin is unclear (see section 4.4).
4. 9 Overdosering
32 4.9 Overdose
Akut livstruende toksicitet er ikke observeret med gabapentin ved overdosering på op til 49 g.
Acute, life-threatening toxicity has not been observed with gabapentin overdoses of up to 49 g.
Symptomer ved overdosering er svimmelhed, dobbeltsyn, talebesvær, døsighed, letargi og mild diarré.
Symptoms of the overdoses included dizziness, double vision, slurred speech, drowsiness, lethargy and mild diarrhoea.
En oral letaldosis af gabapentin er ikke identificeret hos mus og rotter ved doser på op til 8000 mg/ kg.
An oral lethal dose of gabapentin was not identified in mice and rats given doses as high as 8000 mg/ kg.
34 5. 1 Farmakodynamiske egenskaber
5.1 Pharmacodynamic properties
Farmakoterapeutisk klassifikation:
Pharmacotherapeutic groups:
Andre antiepileptika, ATC- kode:
Other antiepileptics ATC code:
Gabapentin ligner strukturmæssigt neurotransmitteren GABA (gammaaminosmørsyre), men dets virkningsmekanisme er forskellig fra den mekanisme, som flere andre aktive stoffer interagerer med GABA- synapser på, herunder valproat, barbiturater, benzodiazepiner, GABA- transaminase- hæmmere, GABA- uptake- hæmmere, GABA- agonister og GABA- prodrugs.
Gabapentin is structurally related to the neurotransmitter GABA (gamma-aminobutyric acid) but its mechanism of action is different from that of several other active substances that interact with GABA synapses including valproate, barbiturates, benzodiazepines, GABA transaminase inhibitors, GABA uptake inhibitors, GABA agonists, and GABA prodrugs.
In vitro forsøg med radioaktivt mærket gabapentin har karakteriseret et nyt peptid- bindingssted i rottehjernevæv, herunder neocortex og hippocampus, der kan relateres til den antikonvulsive og analgetiske virkning af gabapentin og dets strukturmæssige derivater.
In vitro studies with radiolabeled gabapentin have characterized a novel peptide binding site in rat brain tissues including neocortex and hippocampus that may relate to anticonvulsant and analgesic activity of gabapentin and its structural derivatives.
Gabapentins bindingssted er identificeret som alfa2 – delta underenhed af de spændingsafhængige calciumkanaler.
The binding site for gabapentin has been identified as the alpha2-delta subunit of voltage-gated calcium channels.
I klinisk relevante koncentrationer bindes gabapentin ikke til andre almindelige lægemidler eller neurotransmittere i hjernen, herunder receptorer for GABAA, GABAB, benzodiazepin, glutamat, glycin eller N- metyl- d- aspartat.
Gabapentin at relevant clinical concentrations does not bind to other common drug or neurotransmitter receptors of the brain including GABAA, GABAB, benzodiazepine, glutamate, glycine or N-methyl-d- aspartate receptors.
Gabapentin nedsætter delvist virkningen af glutamatagonisten N- metyl- d- aspartat (NMDA) i nogle in vitro testsystemer, men kun ved koncentrationer højere end 100 µM.
Gabapentin partially reduces responses to the glutamate agonist N-methyl-D-aspartate (NMDA) in some test systems in vitro, but only at concentrations greater than 100 µM, which are not achieved in vivo.
Gabapentin nedsætter svagt frigivelsen af monoamin- neurotransmittere in vitro.
Gabapentin slightly reduces the release of monoamine neurotransmitters in vitro.
Gabapentin administreret til rotter øger GABA - omsætningen i flere hjerneregioner på samme måde som natriumvalproat, om end i andre hjerneregioner.
Gabapentin administration to rats increases GABA turnover in several brain regions in a manner similar to valproate sodium, although in different regions of brain.
Hos dyr trænger gabapentin uhindret ind i hjernen og modvirker krampeanfald fremkaldt af elektrochok, af kemiske konvulsiva, herunder GABA- syntese- hæmmere, samt i genetiske krampemodeller.
In animals, gabapentin readily enters the brain and prevents seizures from maximal electroshock, from chemical convulsants including inhibitors of GABA synthesis, and in genetic models of seizures.
En klinisk undersøgelse af supplerende behandling af partiel epilepsi hos børn i alderen 3- 12 år, viser en nummerisk, men ikke statistisk signifikant forskel i den 50% responderrate til fordel for gabapentingruppen sammenlignet med placebo.
A clinical trial of adjunctive treatment of partial seizures in paediatric subjects, ranging in age from 3 to 12 years, showed a numerical but not statistically significant difference in the 50% responder rate in favour of the gabapentin group compared to placebo.
Derudover afslører post- hoc analyser af responderrater efter alder ikke en statistisk effekt efter alder, hverken som vedvarende eller dikotomisk variabel (aldersgruppe 3- 5 år og 6- 12 år).
Additional post-hoc analyses of the responder rates by age did not reveal a statistically significant effect of age, either as a continuous or dichotomous variable (age groups 3-5 and 6-12 years).
Data fra denne ekstra post- hoc analyse er opsummeret i tabellen nedenfor:
The data from this additional post-hoc analysis are summarised in the table below:
Respons (≥ 50% forbedring) ved behandling og alder MITT * population
33 Response (≥ 50% Improved) by Treatment and Age MITT* Population
Alder
Age Category
P- Value
P-Value
< 6 år
< 6 Years Old
6- 12 år
6 to 12 Years Old
* Den modificerede ” intent to treat ” population er defineret som alle patienter, der er randomiseret til forsøgsmedicin, og som også har evaluerbar dagbog over anfald tilgængelig i alle 28 dage under både baseline og dobbelt- blind faserne.
*The modified intent to treat population was defined as all patients randomised to study medication who also had evaluable seizure diaries available for 28 days during both the baseline and double-blind phases.
Gabapentins maksimale plasmakoncentration opnås inden for 2- 3 timer efter oral administration.
Following oral administration, peak plasma gabapentin concentrations are observed within 2 to 3 hours.
60%.
Absolute bioavailability of a 300 mg capsule is approximately 60%.
35 Gabapentins farmakokinetik påvirkes ikke af gentagen indgift.
Gabapentin pharmacokinetics are not affected by repeated administration.
Selvom gabapentins plasmakoncentration i kliniske undersøgelser generelt var 2– 20 µg/ ml, er disse koncentrationer ikke prædikative for sikkerhed eller effekt.
Although plasma gabapentin concentrations were generally between 2 µg/ ml and 20 µg/ ml in clinical studies, such concentrations were not predictive of safety or efficacy.
Tabel 3 Resumé af gennemsnitlig gabapentin (% CV) steady state farmakokinetiske parametre efter administration hver 8. time
Table 3 Summary of gabapentin mean (%CV) steady-state pharmacokinetic parameters following every eight hours administration
Farmakokinetisk parameter 300 mg (N = 7)
Pharmacokinetic parameter
400 mg (N = 14)
400 mg (N = 14)
800 mg (N=14)
800 mg (N=14)
gennemsnit
Mean
% CV gennemsnit% CV gennemsnit% CV
%CV
Cmax (µg/ ml) tmax (time) T1/ 2 (time) AUC (0- 8) µg• time/ ml) Ae% (%)
Cmax (µg/ ml) tmax (hr) T1/ 2 (hr) AUC (0-8) µg• hr/ ml)
4, 02 2, 7 5, 2 24, 8 NA
(24) (18) (12) (24)
(24) 5, 74 (38) (18) 2, 1 (54) (12) 10, 8 (89) (24) 34, 5 (34) NA 47, 2 (25)
(38) (54) (89) (34)
8, 71 1, 6 10, 6 51, 4 34, 4
8.71 1.6 10.6 51.4
(29) (76) (41) (27) (37)
(29) (76) (41) (27)
Cmax = Maksimalt steady state plasmakoncentration tmax = Tid for Cmax T1/ 2 = Eliminationshalveringstid AUC( 0- 8) = Steady state arealet under plasmakoncentrations- tidskurven fra tid 0- 8 timer efter indgift af dosis Ae% = Procent af dosis udskilt uforandret i urinen fra tid 0- 8 timer efter dosis NA = Ikke tilgængelig
Cmax = Maximum steady state plasma concentration tmax = Time for Cmax T1/ 2 = Elimination half-life AUC(0-8) = Steady state area under plasma concentration-time curve from time 0 to 8 hours postdose Ae% = Percent of dose excreted unchanged into the urine from time 0 to 8 hours postdose NA = Not available
Gabapentin bindes ikke til plasmaproteiner, og har et fordelingsvolumen på 57, 7 liter.
Gabapentin is not bound to plasma proteins and has a volume of distribution equal to 57.7 litres.
20% af den tilsvarende laveste plasma - koncentration ved steady state.
In patients with epilepsy, gabapentin concentrations in cerebrospinal fluid (CSF) are approximately 20% of
Gabapentin inducerer ikke hepatisk blandet funktionsoxidase- enzymer ansvarlig for lægemiddelmetabolisme.
Gabapentin does not induce hepatic mixed function oxidase enzymes responsible for drug metabolism.
Gabapentins eliminationshastighed er dosisuafhængig og er gennemsnitlig 5- 7 timer.
The elimination half-life of gabapentin is independent of dose and averages 5 to 7 hours.
Gabapentins eliminationshastighedskonstant, plasmaclearance og renal- clearance er direkte proportionel med kreatininclearance.
Gabapentin elimination-rate constant, plasma clearance, and renal clearance are directly proportional to creatinine clearance.
4. 2).
Dosage adjustment in patients with compromised renal function or undergoing haemodialysis is recommended (see section 4.2).
Gabapentins plasmakoncentration hos børn > 5 år er den samme som hos voksne, når dosis er beregnet i mg/ kg.
In general, plasma gabapentin concentrations in children > 5 years of age are similar to those in adults when dosed on a mg/ kg basis.
Linearitet / non- linearitet:
Linearity/ Non-linearity
Gabapentins biotilgængelighed (fraktion af absorberet dosis) falder, når dosis stiger, hvilket overfører non - linearitet til farmakokinetiske parametre, som omfatter biotilgængeligheds- parameter (F) dvs.
Gabapentin bioavailability (fraction of dose absorbed) decreases with increasing dose which imparts non-linearity to pharmacokinetic parameters which include the bioavailability parameter (F) e. g.
CLr og 36 T1/ 2) er bedst beskrevet som lineær farmakokinetik.
Elimination pharmacokinetics (pharmacokinetic parameters which do not include F such as CLr and T1/ 2), are best described by linear pharmacokinetics.
Gabapentin blev givet gennem føden til mus i doser på 200, 600 og 2000 mg/ kg/ dag og til rotter i doser på 250, 1000 og 2000 mg/ kg/ dag i 2 år.
Gabapentin was given in the diet to mice at 200, 600, and 2000 mg/ kg/ day and to rats at 250, 1000, and 2000 mg/ kg/ day for two years.
Hos rotter, der fik 2000 mg/ kg/ dag, var den maksimale plasmakoncentration 10 gange højere end plasmakoncentrationen hos mennesker, der fik 3600 mg/ dag.
Peak plasma drug concentrations in rats at 2000 mg/ kg/ day are 10 times higher than plasma concentrations in humans given 3600 mg/ day.
5 gange den maksimale daglige dosis til mennesker omregnet til mg/ m2 på basis af kroppens overfladeareal).
No adverse effects on fertility or reproduction were observed in rats at doses up to 2000 mg/ kg (approximately five times the maximum daily human dose on a mg/ m2 of body surface area basis).
Teratogenicitet
35 Teratogenesis
Gabapentin øger ikke forekomsten af misdannelser, sammenlignet med kontrolgruppen, hos afkom af mus, rotter eller kaniner ved doser op til henholdsvis 50, 30 og 25 gange den daglige dosis til mennesker på 3600 mg (henholdsvis 4, 5 og 8 gange dosis til mennesker omregnet til mg/ m2 på basis af kroppens overfladeareal).
Gabapentin did not increase the incidence of malformations, compared to controls, in the offspring of mice, rats, or rabbits at doses up to 50, 30 and 25 times respectively, the daily human dose of 3600 mg, (four, five or eight times, respectively, the human daily dose on a mg/ m2 basis).
Gabapentin medfører forsinket ossifikation i kraniet, ryghvirvler, forbens - og bagbensknogler hos gnavere, hvilket indikerer føtal vækstretardering.
Gabapentin induced delayed ossification in the skull, vertebrae, forelimbs, and hindlimbs in rodents, indicative of fetal growth retardation.
Disse doser svarer til ca.
These effects occurred when pregnant mice received oral doses of 1000 or 3000 mg/ kg/ day during organogenesis and in rats given 500, 1000, or 2000 mg/ kg prior to and during mating and throughout gestation.
1- 5 gange dosis til mennesker på 3600 mg omregnet til mg/ m2 på basis af kroppens overfladeareal).
These doses are approximately 1 to 5 times the human dose of 3600 mg on a mg/ m2 basis.