natgillin/translations-raw huggingface dataset:
20% øgning i biotilgængeligheden af ibandronsyre (som ligger inden for den normale variabilitet for biotilgængeligheden af ibandronsyre), formentlig som et resultat af den reducerede gastriske surhedsgrad.
In healthy male volunteers and postmenopausal women, intravenous ranitidine caused an increase in ibandronic acid bioavailability of about 20% (which is within the normal variability of the bioavailability of ibandronic acid), probably as a result of reduced gastric acidity.
Dosisjustering ikke for nødvendig, når Bondronat administreres sammen med H2- antagonister eller andre aktive substanser som øger gastrisk pH.
However, no dosage adjustment is required when Bondronat is administered with H2-antagonists or other drugs that increase gastric pH.
Tilbøjeligheden til klinisk signifikante lægemiddelinteraktioner er ikke stor.
In relation to disposition, no drug interactions of clinical significance are likely.
Udskillesvejen ser ikke ud til at omfatte kendte syre – basetransportsystemer som er involveret i udskillelsen af andre lægemidler.
The secretory pathway does not appear to include known acidic or basic transport systems involved in the excretion of other active substances.
Desuden hæmmer ibandronsyre ikke de vigtigste humane lever P450 isoenzymer og inducerer ikke det hepatiske cytochrom P450 system hos rotter.
In addition, ibandronic acid does not inhibit the major human hepatic P450 isoenzymes and does not induce the hepatic cytochrome P450 system in rats.
Forsigtighed bør udvises når bisphosphonater administreres sammen med aminoglycosider idet begge lægemidler kan bevirke nedsættelse af calciumniveauerne i længere perioder.
Caution is advised when bisphosphonates are administered with aminoglycosides, since both agents can lower serum calcium levels for prolonged periods.
Der foreligger ikke tilstrækkelig data om brugen af ibandronsyre hos gravide kvinder.
There are no adequate data from the use of ibandronic acid in pregnant women.
5. 3).
Studies in rats have shown reproductive toxicity (see section 5.3).
Bondronat bør ikke anvendes ved graviditet.
Therefore, Bondronat should not be used during pregnancy.
16 Det vides ikke om ibandronsyre udskilles i modermælk.
16 It is not known whether ibandronic acid is excreted in human milk.
Sikkerheden af Bondronat er undersøgt i kontrollerede kliniske undersøgelser på den godkendte indikation og efter peroral administration af Bondronat i den anbefalede dosering.
The safety profile of Bondronat is derived from controlled clinical trials in the approved indication and after the oral administration of Bondronat at the recommended dose.
I den sammenfattede database fra de 2 pivotale fase III undersøgelser (286 patienter behandlet med Bondronat 50 mg), havde 27% af patienterne muligt eller sandsynligt relaterede bivirkninger til Bondronat.
In the pooled database from the 2 pivotal phase III trials (286 patients treated with Bondronat 50 mg), the proportion of patients who experienced an adverse reaction with a possible or probable relationship to Bondronat was 27%.
Bivirkningerne er angivet under overskrifter angivende hyppigheden med den hyppigste først under anvendelse af følgende konvention: meget almindelig (≥ 10%), almindelig (≥ 1% og < 10%), ikke almindelig (≥ 0, 1% og < 1%) sjælden (≥ 0, 01% og < 0, 1%, meget sjælden (≤ 0, 01%)
Adverse reactions are ranked under heading of frequency, the most frequent first, using the following convention: very common (≥ 10%), common (≥ 1% and < 10%), uncommon (≥ 0.1% and < 1%), rare (≥ 0.01% and < 0.1%), very rare (≤ 0.01%).
Tabel 1 viser almindelige bivirkninger fra de sammenfattede fase III undersøgelser.
Table 1 lists common adverse reactions from the pooled phase III trials.
Bivirkninger som optrådte med samme frekvens i den aktive - og placebogruppen eller som var hyppigere hos placebo behandlede patienter, er ikke medtaget.
Adverse reactions that are equally frequent in both active and placebo or more frequent in placebo-treated patients are excluded.
Almindelige bivirkninger som er rapporteret hyppigere end placebo
Adverse ReactionsReported Commonly and Greater than Placebo
Bivirkning
p. o. daily
Placebo Bondronat 50 mg dagligt p. o. dagligt p. o. dagligt (n=277 patienter) (n=286 patienter) Antal (%) Antal (%)
Metabolism and Nutrition Disorders
Stofskiftesygdomme og ernæringsbetingede sygdomme
(%)
Hypocalcæmi
(n=286 patients) No.
Dyspepsi Kvalme Abdominalsmerter Oesophagitis
Dyspepsia Nausea Abdominal Pain Oesophagitis General Disorders
Bivirkninger som forekommer med en frekvens på < 1%:
Adverse drug reactions occurring at a frequency < 1%:
Den følgende liste giver information om bivirkninger rapporteret i studierne MF 4414 og MF 4434 og som forekommer hyppigere med Bondronat 50 mg end med placebo:
The following list provides information on adverse drug reactions reported in study MF 4414 and MF 4434 occurring more frequently with Bondronat 50 mg than with placebo:
Ikke almindelig Sygdomme i i blod - og lymfesystem anæmi Sygdomme i nervesystemet Gastrointestinale sygdomme
Blood and Lymphatic System Disorders Nervous System Disorders Gastrointestinal Disorders
paræstesi, dysgeusi (smagsforstyrrelser); hæmoragi, ulcus duodeni, gastritis, dysfagi, abdominalsmerter, mundtørhed,
anaemia paraesthesia, dysgeusia (taste perversion) haemorrage, duodenal ulcer, gastritis, dysphagia, abdominal pain, dry mouth
Sygdomme i hud og subkutane væv
Investigations
pruritus 17
17 Osteonecrosis of the jaw has been reported in patients treated by bisphosphonates.
Knoglenekrose i kæben er normalt ledsaget af tandudtrækning og/ eller lokal infektion (herunder osteomyelitis).
Osteonecrosis of the jaw is generally associated with tooth extraction and / or local infection (including osteomyelitis).
Overdosering kan dog forårsage øvre gastrointestinale bivirkninger som f. eks. mavebesvær, halsbrand, oesophagitis, gastritis eller mavesår.
However, oral overdosage may result in upper gastrointestinal events, such as upset stomach, heartburn, oesophagitis, gastritis or ulcer.
På grund af risikoen for oesophageal irritation, bør opkastning ikke induceres, og patienten bør forblive i oprejst stilling.
Owing to the risk of oesophageal irritation, vomiting should not be induced and the patient should remain fully upright.
Bisphosphonat, ATC- kode:
Bisphosphonate, ATC Code:
M05B A06
M05B A 06
Ibandronsyre hører til bisphosphonatgruppen, som virker specifikt på knoglerne.
Ibandronic acid belongs to the bisphosphonate group of compounds which act specifically on bone.
Bisfosfonater virker ved en hæmning af osteoklast- aktiviteten, men virkningsmekanismen er endnu ikke fuldt ud klarlagt.
Bisphosphonates act by inhibiting osteoclast activity, although the precise mechanism is still not clear.
Hæmning af endogen knogle - resorption er dokumenteret ved 45Ca kinetikstudier og ved frigivelse af radioaktivt tetracyklin, indbygget i skelettet.
The inhibition of endogenous bone resorption has also been documented by 45Ca kinetic studies and by the release of radioactive tetracycline previously incorporated into the skeleton.
Kliniske undersøgelser hos patienter med brystkræft og knoglemetastaser har vist at der er en dosisafhængig hæmmende effekt på knogleosteolysen, udtrykt ved markører for knogleresorption, og en dosisafhængig effekt på de skeletale hændelser.
Clinical studies in patients with breast cancer and bone metastases have shown that there is a dose dependent inhibitory effect on bone osteolysis, expressed by markers of bone resorption, and a dose dependent effect on skeletal events.
Forebyggelse af knoglerelaterede hændelser hos patienter med brystkræft og knoglemetastaser med Bondronat 50 mg tabletter, blev vurderet i to randomiserede, placebokontrollerede, 96 uger varende, fase III undersøgelser.
Prevention of skeletal events in patients with breast cancer and bone metastases with Bondronat 50 mg tablets was assessed in two randomized placebo controlled phase III trials with duration of 96 weeks.
Primære effektparametre Det primære endepunkt i undersøgelsen var skeletal morbidity period rate (SMPR).
Primary Efficacy Endpoints The primary endpoint of the trials was the skeletal morbidity period rate (SMPR).
- non- vertebrale frakturer
- non-vertebral fractures
Analysen af SMPR var tidsjusteret og tog højde for at en eller flere hændelser opstået i en enkelt 12 ugers periode, kunne være potentielt relateret.
18 The analysis of the SMPR was time-adjusted and considered that one or more events occurring in a single 12 week period could be potentially related.
Multiple hændelser blev derfor kun talt én gang til analyseformål.
Multiple events were therefore, counted only once in any given 12 week period for the purposes of the analysis.
Sammenfattende resultater fra disse undersøgelse viste en signifikant fordel for Bondronat 50 mg p. o. frem for placebo, til reduktion af SREs målt ved den tidsjusterede SMPR (p=0, 041).
Pooled data from these studies demonstrated a significant advantage for Bondronat 50 mg p. o. over placebo in the reduction in SREs measured by the SMPR (p=0.041).
Der var en 38% reduktion i risiko for udvikling af en SRE i forhold til placebo (relativ risiko 0, 62, p=0, 003).
There was also a 38% reduction in the risk of developing an SRE for Bondronat treated patients when compared with placebo (relative risk 0.62, p=0.003).
(Brystkræft patienter med metastaserende knoglesygdom)
Efficacy Results (Breast Cancer Patients with Metastatic Bone Disease)
Placebo n=277
All Skeletal Related Events (SREs) Placebo Bondronat 50 mg p-value n=277 n=287
p=0, 041
p=0.041
Sekundære effektparametre Bondronat 50 mg viste i sammenligning med placebo en statistisk signifikant forbedring i knoglesmertescore.
Secondary Efficacy Endpoints A statistically significant improvement in bone pain score was shown for Bondronat 50 mg compared to placebo.
Forringelsen i livskvalitet og WHO performance status var signifikant mindre for Bondronat behandlede patienter i forhold til placebo.
The deterioration in Quality of Life and WHO performance status was significantly less in Bondronat treated patients compared with placebo.
Koncentrationen af urinmarkører for knogleresorption CTx (C- terminaltelopeptid frigjort fra Type I kollagen) blev signifikant reduceret i Bondronat gruppen i forhold til placebo.
Urinary concentrations of the bone resorption marker CTx (C-terminal telopeptide released from Type I collagen) were significantly reduced in the Bondronat group compared to placebo.
Reduktionen i urin CTx niveauet var signifikant korreleret med det primære endepunkt SMPR (Kendall- tau- b, p < 0, 001).
This reduction in urinary CTx levels was significantly correlated with the primary efficacy endpoint SMPR (Kendall-tau-b (p < 0.001)).
En oversigt over de sekundære effektresultater fremgår af Tabel 3.
A tabular summary of the secondary efficacy results is presented in Table 3.
Sekundære effektresultater (brystkræft patienter med metastaserende knoglesygdom)
Cancer Patients with Metastatic Bone
Placebo Bondronat 50 mg p- værdi n=277 n=287
Placebo n=277
0, 20 - 0, 10 P=0, 001
-0.10 p=0.001
WHO performance score *
WHO performance score *
* Middelændring fra baseline til sidste evaluering ** Median ændring fra baseline til sidste evaluering
* Mean change from baseline to last assessment. ** Median change from baseline to last assessment
Absorption Absorptionen af ibandronsyre i den øvre gastrointestinalkanal er hurtig efter peroral administration.
Absorption The absorption of ibandronic acid in the upper gastrointestinal tract is rapid after oral administration.
Biotilgængeligheden reduceres med ca.
The extent of absorption is impaired when taken together with food or beverages (other than plain water).
90% når ibandronsyre indtages sammen med et almindeligt morgenmåltid i forhold til biotilgængeligheden hos personer i fastetilstand.
Bioavailability is reduced by about 90% when ibandronic acid is administered with a standard breakfast in comparison with bioavailability seen in fasted subjects.
30%.
When taken 30 minutes before a meal, the reduction in
Biotilgængeligheden blev reduceret med ca.
There is no meaningful reduction in bioavailability provided ibandronic acid is taken 60 minutes before a meal.
4. 2).
Therefore, it is recommended that the tablets should be taken after an overnight fast (minimum 6 hours) and fasting should continue for at least 30 minutes after the dose has been taken (see Section 4.2).
Lægemiddelinteraktioner på grund af displacering er derfor ikke sandsynlig.
Protein binding in human plasma is approximately 87% at therapeutic concentrations, and thus drug-drug interaction due to displacement is unlikely.
Elimination Den absorberede del af ibandronsyre elimineres fra cirkulationen via knogleresorption (estimeret til 40- 50%) og den resterende del udskilles uændret gennem nyrerne.
Elimination The absorbed fraction of ibandronic acid is removed from the circulation via bone absorption (estimated to be 40-50%) and the remainder is eliminated unchanged by the kidney.
Måleområdet for de tilsyneladende halveringstider er bredt og afhænger af dosis og målefølsomhed, men den tilsyneladende terminale halveringstid er generelt i området 10- 60 timer.
The range of observed apparent half-lives is broad and dependent on dose and assay sensitivity, but the apparent terminal half-life is generally in the range of 10-60 hours.
Race Der er ikke noget der tyder på en klinisk relevant interetnisk forskel i tilstedeværelsen af ibandronsyre mellem asiater og kaukasere.
Race There is no evidence for clinically relevant interethnic differences between Asians and Caucasians in ibandronic acid disposition.
Dosisjustering er ikke nødvendig for patienter med lettere eller moderat nyrefunktionsnedsættelse (CLcr ≥ 30 ml/ min.).
No dosage adjustment is necessary for patients with mild or moderate renal impairment (CLcr > 30 ml/ min).
Patienter med svært nedsat nyrefunktion (CLcr ≤ 30 ml/ min.) som fik 10 mg peroral ibandronsyre dagligt i 21 dage, havde 2- 3 gange højere plasmakoncentrationer end personer med normal nyrefunktion.
Subjects with severe renal impairment (CLcr ≤ 30 ml/ min) receiving oral administration of 10 mg ibandronic acid daily for 21 days, had 2-3 fold higher plasma concentrations than subjects with normal renal function.
Total ibandronsyre clearance var reduceret til 44 ml/ min.
Total clearance of ibandronic acid was reduced to 44 ml/ min in the subjects with severe renal impairment.
Efter intravenøs administration af 0, 5 mg faldt den totale, renale og ikke- renale clearance hos patienter med svær nyrefunktions- nedsættelse, med henholdsvis 67%, 77% og 50%, men der fandtes ikke nedsat tolerabilitet i forbindelse med den øgede eksponering.
However, there was no reduction in tolerability associated with the increase in exposure.
4. 2).
Reduction of the oral dose to one 50 mg tablet once weekly is recommended in patients with severe renal impairment (CLcr < 30 ml/ min) (see Section 4.2).
20 Patienter med nedsat leverfunktion Der er ingen farmakokinetiske data for ibandronsyre hos patienter med nedsat leverfunktion.
Patients with hepatic impairment There are no pharmacokinetic data for ibandronic acid in patients who have hepatic impairment.
Leveren spiller ikke nogen væsentlig rolle ved udskillelsen af ibandronsyre, som ikke metaboliseres, men udskilles gennem nyrerne, samt ved optagelse i knoglerne.
The liver has no significant role in the clearance of ibandronic acid since it is not metabolized but is
Dosisjustering er derfor ikke nødvendig hos patienter med nedsat leverfunktion.
20 cleared by renal excretion and by uptake into bone.
Da proteinbindingen for ibandronsyre desuden er ca.
Therefore dosage adjustment is not necessary in patients with hepatic impairment.
Disse virkninger vurderes derfor til at være af ringe relevans ved klinisk brug.
Effects in non-clinical studies were observed only at exposures sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.
Bivirkningerne af ibandronsyre hos rotter i reproduktions - toksicitets- undersøgelserne var de samme som for bisfosfonatklassen.
Adverse effects of ibandronic acid in reproductive toxicity studies in the rat were those expected for this class of drugs (bisphosphonates).
De omfatter en nedsættelse af implantationssteder, forstyrrelser af den normale fødsel (dystocia), en øgning af viscerale forandringer (nyre pelvis ureter syndrom) og udviklingshændelser på F1 afkommet hos rotter.
They include a decreased number of implantation sites, interference with natural delivery (dystocia), an increase in visceral variations (renal pelvis ureter syndrome) and teeth abnormalities in F1 offspring in rats.
Lactosemonohydrat Povidon Mikrokrystallinsk cellulose Crospovidon Stearinsyre Silica, kolloid, vandfri
Lactose monohydrate Povidone Cellulose, microcrystalline Crospovidone Stearic acid Silica, anhydrous colloidal
Tablet overtræk:
Tablet coat:
Hypromellose Titandioxid E171 Talcum Macrogol 6000
Hypromellose Titanium dioxide E171 Talc Macrogol 6000
21 6. 3 Opbevaringstid
21 6.4 Special precautions for storage
Bondronat 6 mg koncentrat til infusionsvæske, opløsning
Bondronat 6 mg Concentrate for solution for infusion
Et hætteglas med 6 ml koncentrat til infusionsvæske, opløsning indeholder 6 mg ibandronsyre, (som 6, 75 mg ibandronsyre, mononatriumsalt, monohydrat).
One vial with 6 ml concentrate for solution for infusion contains 6 mg ibandronic acid, (as 6.75 mg ibandronic acid monosodium salt, monohydrate)
Bondronat er indiceret til:
Bondronat is indicated for
- Behandling af tumorinduceret hypercalcæmi med eller uden metastaser.
- Treatment of tumour-induced hypercalcaemia with or without metastases.
Bondronat bør kun anvendes af læger med erfaring i behandling af hypercalcæmi.
Bondronat therapy should only be initiated by physicians experienced in the treatment of cancer.
Forebyggelse af knoglerelaterede hændelser hos patienter med brystkræft og knoglemetastaser Den anbefalede dosis ved forebyggelse af knoglerelaterede hændelser hos patienter med brystkræft og knoglemetastaser er 6 mg intravenøs injektion hver 3- 4 uge.
The recommended dose for prevention of skeletal events in patients with breast cancer and bone metastases is 6 mg intravenous injection given every 3-4 weeks.
Ved infusion skal hætteglassets indhold kun tilsættes en 100 ml isotonisk natriumklorid - opløsning eller en 100 ml 5% glucoseopløsning.
For infusion, the contents of the vials(s) should only be added to 100 ml isotonic sodium chloride solution or 100 ml 5% glucose solution.
Forud for behandling med Bondronat, bør patienten være tilfredsstillende hydreret med 9 mg/ ml (0, 9%) NaCl.
Prior to treatment with Bondronat the patient should be adequately rehydrated with 9 mg/ ml (0.9%) sodium chloride.
Hos patienter med moderat
In general patients with osteolytic bone metastases require lower doses than patients with
23 hypercalcæmi (albuminkorrigeret serum calcium < 3 mmol/ l eller < 12 mg/ dl) er 2 mg en effektiv dosis.
In most patients with severe hypercalcaemia (albumin-corrected serum calcium* ≥ 3 mmol/ l or ≥ 12 mg/ dl) 4 mg is an adequate single dosage.
Albuminkorrigeret serum calcium (mmol/ l)
Albumin-corrected Serum calcium (mmol/ l)
Eller Albuminkorrigeret serum calcium (mg/ dl)
Or Albumin-corrected Serum calcium (mg/ dl)
Ældre Dosisjustering er ikke påkrævet
Elderly No dose adjustment is required.
Børn og unge Bondronat bør ikke anvendes til børn under 18 år p. g. a. utilstrækkelig dokumentation for sikkerhed og virkning.
24 Children and adolescents Bondronat is not recommended for patients below age 18 years due to insufficient data on safety and efficacy.
24 Der skal udvises forsigtighed hos patienter med kendt overfølsomhed overfor andre bisphosphonater.
Caution is to be taken in patients with known hypersensitivity to other bisphosphonates.
Tilbøjeligheden til klinisk signifikante lægemiddelinteraktioner er ikke stor.
25 In relation to disposition, no drug interactions of clinical significance are likely.
Udskillesvejen ser ikke ud til at omfatte kendte syre – basetransportsystemer som er involveret i udskillelsen af andreaktive substanser.
The secretory pathway does not appear to include known acidic or basic transport systems involved in the excretion of other active substances.
Desuden hæmmer ibandronsyre ikke de vigtige humane lever P450 isoenzymer og inducerer ikke det hepatiske cytochrom P450 system hos rotter.
In addition, ibandronic acid does not inhibit the major human hepatic P450 isoenzymes and does not induce the hepatic cytochrome P450 system in rats.
Plasma- proteinbindingen er lav ved terapeutiske koncentrationer og ibandronsyre displacering af andre aktive substanser er derfor usandsynlig
Plasma protein binding is low at therapeutic concentrations and ibandronic acid is therefore unlikely to displace other active substances.
25 Forsigtighed tilrådes, når der gives bisphosphonater sammen med aminoglykosider, da begge stoffer kan nedsætte serum calcium i længere perioder.
Caution is advised when bisphosphonates are administered with aminoglycosides, since both agents can lower serum calcium levels for prolonged periods.
Behandlingen var oftest forbundet med en stigning i legemstemperaturen.
Treatment was most commonly associated with a rise in body temperature.
Influenza- lignende symptomer som feber, kulderystelser, knogle - og/ eller muskellignende smerter, kan forekomme.
Occasionally, a flu- like syndrome consisting of fever, chills, bone and/ or muscle ache-like pain was reported.
Tabel 1 viser de bivirkninger, som er registreret i de kliniskeundersøgelser (hændelser blev registreret uanset bestemmelse om årsagssammenhæng).
Table 1 lists adverse reactions recorded in the trials (events were recorded irrespective of a determination of causality).
Frekvens Antal (%) (n=352)
System Organ
Hypocalcæmi
Class / Adverse reaction Frequency Number (%) (n=352)
Sygdomme i bevægeapparatet og bindevæv
Metabolism and nutrition disorders Common:
Almindelig:
Hypocalcaemia
6 (1, 7) 1 (0, 3)
10 (2.8)
26 Systemorganklasse / Bivirkning Almene lidelser og reaktioner på indgivelsesstedet:
26 System Organ Class / Adverse reaction
Frekvens Antal (%) (n=352)
Uncommon:
Meget almindelig:
Bone Pain Myalgia
Pyrexi Ikke almindelig:
Pyrexia Uncommon:
Influenzalignende symptomer Rigor
Influenza-like illness Rigors
Data for både 2 mg og 4 mg doser af ibandronsyre er medtaget.
Data for both the 2 mg and 4 mg doses of ibandronic acid are pooled.
Bivirkninger blev registreret uden afklaring med hensyn til kausalitet
Events were recorded irrespective of a determination of causality.
Andre bivirkninger, som blev rapporteret med lavere frekvens er:
Other reactions reported at lower frequency are as follows:
Sygdomme i hud og subkutane væv Meget sjælden:
Very rare:
Sygdomme i åndedrætsorganer, brysthule og mediastinum Meget sjælden:
Very rare:
bisphosphonater har været forbundet med bronchokonstriktion hos
of other bisphosphonates has been associated with broncho-constriction in
Tabel 2 viser bivirkningerne i den pivotale fase III undersøgelse (152 patienter behandlet med Bondronat 6 mg), det vil sige, bivirkninger med svag, mulig eller sandsynlig sammenhæng med testmedicinen, med en hyppighed på ≥ 5% eller oftere forekommende i den aktive behandlingsgruppe end placebogruppen.
Table 2 lists adverse reactions from the pivotal phase III study (152 patients treated with Bondronat 6 mg), i. e. adverse events with a remote, possible, or probable relationship to study medication, occurring commonly and more frequently in the active treatment group than in placebo.
Relaterede almindelige bivirkninger som er rapporteret hyppigere end placebo hos patienter med metastaserende knoglesygdom ved brystkræft behandlet med Bondronat 6 mg administreret intravenøst
Adverse Reactions Occurring Commonly and Greater than Placebo in Patients with Metastatic Bone Disease due to Breast Cancer Treated with Bondronat 6 mg administered intravenously
Infektion Endokrine sygdomme:
Infection
Forstyrrelser i parathyroidea Sygdomme i nervesystemet:
Parathyroid disorder System disorders:
Hovedpine Svimmelhed Dysgeusi (smagsforstyrrelser) Øjensygdomme:
Headache Dizziness Dysgeusia (taste perversion)
27
27 Adverse Reaction
Hjertesygdomme:
Cataract Cardiac disorders:
Antal (%)
1 (0.6)
Antal (%)
2 (1.3)