Ibandronate Bluefish
SUMMARYOFPRODUCT CHARACTERISTICS
1. NAMEOFTHEMEDICINALPRODUCT
Ibandronate Bluefish 50 mg film-coated tablets
2. QUALITATIVEANDQUANTITATIVECOMPOSITION
Eachfilm-coatedtabletcontains50mgofibandronicacid(asibandronatesodiummonohydrate).
Excipients:
Each film-coated tablet contains 0.9 mg of lactose monohydrate in the film-coating of the tablet
Forthefulllistofexcipients,seesection6.1.
3. PHARMACEUTICALFORM
Film-coatedtablets.
Whiteround biconvextablets with dimensions: 7.2 mm± 0.1 mm in diameter.
4. CLINICALPARTICULARS
4.1 Therapeuticindications
IbandronateBluefish isindicated in adults forthepreventionofskeletalevents(pathologicalfractures,bonecomplications requiringradiotherapy orsurgery)inpatientswithbreastcancerandbonemetastases.
4.2 Posologyandmethodofadministration
IbandronateBluefish therapyshouldonlybeinitiatedby physiciansexperiencedinthetreatmentofcancer.
Posology
Therecommendeddoseisone50mgfilm-coatedtabletdaily.
Method of administration
For oral use.
Ibandronate Bluefishtabletsshouldbetakenafteranovernightfast(atleast6hours)andbeforethefirstfoodordrink of the day.Medicinalproductsandsupplements(includingcalcium)shouldsimilarly be avoided prior to taking IbandronateBluefish tablets.Fastingshouldbecontinued forat least30 minutesaftertakingthetablet.Watermaybetakenat any timeduringthecourseofIbandronate Bluefishtreatment (see section 4.5).Water with a high concentration of calcium should not be used. If there is concern regarding potentially high levels of calcium in the tap water (hard water), it is advised to use bottled water with a low mineral content..
- Thetabletsshouldbeswallowedwholewithafullglassofwater(180to240ml)whilethepatientis standingorsittinginanuprightposition.
- Patientsshouldnotliedownfor60 minutesaftertakingIbandronate Bluefish.
- Patientsshouldnotchew, suck or crushthetabletbecauseofapotentialfororopharyngealulceration.
- Wateristheonlydrinkthatshouldbetakenwithibandronic acid.
Special populations
Patientswithhepaticimpairment
Nodoseadjustmentisrequired(seesection5.2).
Patientswithrenalimpairment
Nodoseadjustmentisnecessaryforpatientswithmild renal impairment (creatinine clearance ≥50 and <80 mL/min).
Forpatients with moderaterenalimpairment (creatinine clearance ≥30 and <50 mL/min) a dosage adjustment to one 50 mg film-coated tablet every second day is recommended (see section 5.2).
For patients with severe renal impairment (creatinine clearance <30mL/min)therecommendeddoseisone 50mgfilm-coated tablet onceweekly.Seedosing instructions,above.
Elderly population (>65 years)
Nodoseadjustmentisnecessary (see section 5.2).
Paediatric population
The safety and efficacy of IbandronateBluefish in children and adolescents below theageof 18yearshave not been established. Nodata are available. (see section 5.1 and 5.2)_
4.3 Contraindications
-
Hypersensitivity to ibandronic acid or to any of the excipients listed in section 6.1
-
Abnormalities of the oesophagus which delay oesophageal emptying such as stricture or achalasia
-
Inability to stand or sit upright for at least 60 minutes
-
Hypocalcaemia
4.4 Specialwarningsandprecautionsforuse
Patients with disturbances of bone and mineral metabolism
Hypocalcaemiaand otherdisturbancesofboneandmineralmetabolismshouldbeeffectivelytreatedbeforestartingIbandronateBluefish therapy.AdequateintakeofcalciumandvitaminDisimportant inall patients.Patientsshouldreceivesupplementalcalciumand/orvitaminDifdietaryintakeis inadequate.
Gastrointestinal irritation
Orally administered bisphosphonates may cause local irritation of the upper gastrointestinal mucosa. Because of these possible irritant effects and a potential for worsening of the underlying disease, caution should be used when ibandronic acidis given to patients with active upper gastrointestinal problems (e.g. known Barrett’s oesophagus, dysphagia, other oesophageal diseases, gastritis, duodenitis or ulcers).
Adverse experiences such as oesophagitis, oesophageal ulcers and oesophageal erosions, in some cases severe and requiring hospitalization, rarely with bleeding or followed by oesophageal stricture or perforation, have been reported in patients receiving treatment with oral bisphosphonates. The risk of severe oesophageal adverse experiences appears to be greater in patients who do not comply with the dosing instruction and/or who continue to take oral bisphosphonates after developing symptoms suggestive of oesophageal irritation. Patients should pay particular attention and be able to comply with the dosing instructions (see section 4.2).
Physicians should be alert to any signs or symptoms signaling a possible oesophageal reaction and patients should be instructed to discontinue Ibandronate Bluefish and seek medical attention if they develop dysphagia, odynophagia, retrosternal pain or new or worsening heartburn.
While no increased risk was observed in controlled clinical trials there have been post-marketing reports of gastric and duodenal ulcers with oral bisphosphonate use, some severe and with complications.
Acetylsalicylic acid and NSAIDS
SinceAcetylsalicylic acid, Nonsteroidal Anti-Inflammatory medicinal products (NSAIDS) and bisphosphonatesareassociatedwithgastrointestinalirritation,cautionshouldbetakenduring concomitantadministration.
Renal function
Clinicalstudieshavenotshownanyevidenceofdeteriorationinrenal functionwithlongtermibandronic acid therapy.Nevertheless,accordingto clinicalassessmentoftheindividualpatient,it isrecommended thatrenal function,serumcalcium,phosphateandmagnesiumshouldbemonitoredinpatientstreatedwithIbandronate Bluefish.
Rare hereditary problems
Ibandronate Bluefish tablets contain lactose and should not be administered to patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption.
Patients with known hypersensitivity to other bisphosphonates
Caution is to be taken in patients with known hypersensitivity to other bisphosphonates.
Osteonecrosis of the jaw
Osteonecrosis of the jaw, generally associated with tooth extraction and/or local infection (including osteomyelitis) has been reported in patients with cancer receiving treatment regimens including primarily intravenously administered bisphosphonates. Many of these patients were also receiving chemotherapy and corticosteroids. Osteonecrosis of the jaw has also been reported in patients with osteoporosis receiving oral bisphosphonates.
Adentalexaminationwithappropriatepreventivedentistry shouldbeconsideredpriorto treatmentwithbisphosphonatesinpatients withconcomitantriskfactors(e.g.cancer,chemotherapy,radiotherapy,corticosteroids,poororalhygiene).
Whileontreatment,thesepatientsshouldavoidinvasivedentalproceduresifpossible.Forpatients whodeveloposteonecrosisofthejawwhileonbisphosphonatetherapy,dentalsurgerymay exacerbatethe condition.Forpatientsrequiringdentalprocedures,therearenodataavailabletosuggestwhetherdiscontinuation ofbisphosphonatetreatmentreducestheriskofosteonecrosisofthejaw.Clinicaljudgement ofthetreatingphysicianshouldguidethemanagementplanofeachpatientbasedonindividualbenefit/risk assessment.
Atypical fractures of the femur
Atypical subtrochanteric and diaphyseal femoral fractures have been reported with bisphosphonate therapy, primarily in patients receiving long-term treatment for osteoporosis. These transverse or short oblique fractures can occur anywhere along the femur from just below the lesser trochanter to just above the supracondylar flare. These fractures occur after minimal or no trauma and some patients experience thigh or groin pain, often associated with imaging features of stress fractures, weeks to months before presenting with a completed femoral fracture. Fractures are often bilateral; therefore the contralateral femur should be examined in bisphosphonate-treated patients who have sustained a femoral shaft fracture. Poor healing of these fractures has also been reported.
Discontinuation of bisphosphonate therapy in patients suspected to have an atypical femur fracture should be considered pending evaluation of the patient, based on an individual benefit risk assessment.
During bisphosphonate treatment patients should be advised to report any thigh, hip or groin pain and any patient presenting with such symptoms should be evaluated for an incomplete femur fracture.
Osteonecrosis of the external auditory canal
Osteonecrosis of the external auditory canal has been reported with bisphosphonates, mainly in association with long-term therapy. Possible risk factors for osteonecrosis of the external auditory canal include steroid use and chemotherapy and/or local risk factors such as infection or trauma. The possibility of osteonecrosis of the external auditory canal should be considered in patients receiving bisphosphonates who present with ear symptoms including chronic ear infections.
4.5 Interactionwithothermedicinalproductsandotherformsofinteraction
Medicinal product-Food Interactions
Productscontainingcalciumandothermultivalentcations(suchasaluminium,magnesium,iron),includingmilkandfood,arelikelytointerferewithabsorptionofIbandronateBluefish tablets.Therefore,with suchproducts,includingfood,intakemustbedelayedat least30 minutesfollowingoral administration.
Bioavailabilitywasreducedby approximately75%whenibandronic acid tabletswereadministered2hoursafter a standardmeal.Therefore,it isrecommendedthatthetabletsshouldbetakenafteranovernightfast (atleast6 hours)andfastingshouldcontinueforat least30minutesafterthe dosehasbeentaken(see section4.2).
Interactions with other medicinal products
Metabolic interactions are not considered likely, since ibandronic acid does not inhibit the major human hepatic P450 isoenzyme and has been shown not to induce the hepatic cytochrome P450 system in rats (see section 5.2). Ibandronic acid is eliminated by renal excretion only and does not undergo any biotransformation.
H2-antagonists or other medicinal products that increase gastric pH
Inhealthymalevolunteersandpostmenopausalwomen,intravenousranitidinecausedanincreaseinibandronicacidbioavailabilityofabout20%(whichiswithinthenormalvariabilityofthebioavailability ofibandronicacid),probablyasaresultofreducedgastricacidity.However,nodosageadjustment isrequiredwhenIbandronateBluefish is administeredwithH2-antagonistsormedicinal productsthat increasegastricpH.
Acetylsalicylic acid and NSAIDs
Since Acetylsalicylic acid, Nonsteroidal Anti-Inflammatory medicinal products (NSAIDs) and biophosphonates are associated with gastrointestinal irritation, caution should be taken during concomitant administration (see section 4.4).
Aminoglycosides
Cautionisadvisedwhenbisphosphonatesareadministeredwithaminoglycosides,sincebothsubstancescan lower serum calcium levels for prolonged periods. Attention should also be paid to the possible existenceof simultaneous hypomagnesaemia.
4.6 Fertility, pregnancyandlactation
Pregnancy
Therearenoadequatedatafromtheuseofibandronicacidinpregnantwomen.Studiesinratshaveshown reproductivetoxicity(seesection5.3).Thepotentialriskforhumansisunknown.Therefore,IbandronateBluefish should notbeused duringpregnancy.
Brest-feeding
Itisnotknownwhetheribandronicacidisexcretedinhuman milk. Studiesinlactatingratshave demonstratedthepresenceoflowlevelsofibandronicacidinthemilkfollowingintravenous administration.IbandronateBluefish shouldnotbeusedduringlactation.
Fertility
There are no data on the effects of ibandronic acid in humans. In reproductive studies in rats by the oral route, ibandronic acid decreased fertility. In studies in rats using the intravenous route, ibandronic acid decreased fertility at high daily doses (see section 5.3).
4.7 Effectsonabilitytodriveandusemachines
On the basis of the pharmacodynamics and pharmacokinetic profile and reported adverse reactions, it is expected that ibandronic acid has no or negligible influence on theabilityto driveandusemachines.
4.8 Undesirableeffects
Summary of the safety profile
The most serious reported adverse reactions are anaphylactic reaction/shock, atypical fractures of the femur, osteonecrosis of the jaw, gastrointestinal irritation, and ocular inflammation (see paragraph “Description of selected adverse reactions” and section 4.4).
Treatment was most frequently associated with a decrease in serum calcium to below normal range (hypocalcaemia), followed by dyspepsia.
Tabulated list of adverse reactions
Table1listsadversereactions from 2 pivotal phase III studies (Prevention of skeletal events in patients with breast cancer and bone metastases: 286 patient treated with ibandronic acid 50 mg administered orally), and from post-marketing experience.
Adverse reactions are listed according to MedDRA system organ class and frequency category. Frequency categories are defined using the following convention: very common (1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Table1 AdverseDrug Reactions Reportedfor oral administration of ibandronic acid
|
System Organ Class |
Common |
Uncommon |
Rare |
Very rare |
Not Known |
|
Blood and Lymphatic system disorders |
|
Anaemia |
|
|
|
|
Immune system disorders |
|
|
|
Hypersensitivity†, bronchospasm†, angioedema†, Anaphylactic reaction/shock†** |
Asthma exacerbation |
|
Metabolism and nutrition disorders |
Hypocalcaemia** |
|
|
|
|
|
Nervous system disorders |
|
Paraesthesia, dysgeusia (taste perversion) |
|
|
|
|
Eye disorders |
|
|
Ocular inflammation†** |
|
|
|
Gastrointestinal disorders |
Oesophagitis, abdominal pain, dyspepsia, nausea |
Haemorrage, duodenal ulcer, gastritis, dysphagia, dry mouth |
|
|
|
|
Skin and subcutatneous tissue disorders |
|
Pruritus |
|
|
|
|
Musculoskeletal and connective tissue disorders |
|
|
Atypical subtrochanteric and diaphyseal femoral fractures† |
Osteonecrosis of jaw†** Osteonecrosis of the external auditory canal (bisphosphonate class adverse reaction). |
|
|
Renal and urinary disorders |
|
Azotaemia (uraemia) |
|
|
|
|
General disorders and administration site conditions |
Asthenia |
Chest pain, influenza-like illness, malaise, pain |
|
|
|
|
Investigations |
|
Blood parathyroid hormone increased |
|
|
|
**See further information below
†Identified in post-marketing experience.
Description of selected adverse reactions
Hypocalcaemia
Decreased renal calcium excretion may be accompanied by a fall in serum phosphate levels not
requiring therapeutic measures. The serum calcium level may fall to hypocalcaemic values.
Osteonecrosis of jaw
Osteonecrosisofthejawhasbeenreportedinpatientstreatedby bisphosphonates.Themajorityofthereports referto cancerpatients,butsuchcaseshavealsobeenreportedinpatientstreatedforosteoporosis.Osteonecrosis ofthejawisgenerallyassociatedwithtoothextractionand/orlocalinfection(includingosteomyelitis).Diagnosisofcancer,chemotherapy,radiotherapy,corticosteroidsand poororalhygienearealsodeemedasrisk factors(seesection4.4).
Ocular inflammation
Ocular inflammation events such as uveitis, episcleritis and scleritis have been reported with ibandronic acid. In some cases, these events did not resolve until the ibandronic acid was discontinued.
Anaphylactic reaction/shock
Cases of anaphylactic reaction/shock, including fatal events, have been reported in patients treated with intravenous ibandronic acid.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V*.
4.9 Overdose
NospecificinformationisavailableonthetreatmentofoverdosagewithIbandronate Bluefish.However,oraloverdosage mayresultinuppergastrointestinalevents,suchasupsetstomach,heartburn,oesophagitis,gastritisorulcer.Milk orantacidsshouldbegiventobindIbandronate Bluefish.Duetotheriskofoesophagealirritation,vomitingshouldnotbe inducedandthepatientshouldremainfully upright.
5. PHARMACOLOGICALPROPERTIES
5.1 Pharmacodynamicproperties
Pharmaco-therapeuticgroup:Drugs for bone diseases, Bisphosphonate,ATCCode:M05BA06
Ibandronicacidbelongstothebisphosphonategroupofcompoundswhichactspecificallyonbone.Their selectiveactiononbonetissueisbasedonthehighaffinityofbisphosphonatesforbonemineral.Bisphosphonates actbyinhibitingosteoclastactivity,althoughtheprecisemechanismisstillnotclear.
In vivo, ibandronic acid prevents experimentally-induced bone destruction caused by cessation of gonadal function, retinoids, tumours or tumour extracts. 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.
At doses that were considerably higher than the pharmacologically effective doses, ibandronic acid did not have any effect on bone mineralisation.
Bone resorption due to malignant disease is characterized by excessive bone resorption that is not balanced with appropriate bone formation. Ibandronic acid selectively inhibits osteoclast activity, reducing bone resorption and thereby reducing skeletal complications of the malignant disease.
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.
Prevention of skeletal events in patients with breast cancer and bone metastases with ibandronic acid 50 mg tablets was assessed in two randomized placebo controlled phase III trials with duration of 96 weeks. Female patients with breast cancer and radiologically confirmed bone metastases were randomised to receive placebo (277 patients) or 50 mg ibandronic acid (287 patients). The results from these trials are summarised below.
Primaryefficacyendpoints
Theprimaryendpointofthetrialswastheskeletalmorbidityperiodrate(SMPR).Thiswasacomposite endpointwhichhadthefollowingskeletalrelatedevents(SREs)assub-components:
- radiotherapy to bone for treatment of fractures/impending fractures
- surgery to bone for treatment of fractures
- vertebralfractures
- non-vertebral fractures
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 events were therefore, counted only once in any given 12 week period for the purposes of the analysis. Pooled data from these studies demonstrated a significant advantage for ibandronic acid 50 mg p.o. over placebo in the reduction in SREs measured by the SMPR (p=0.041). There was also a 38% reduction in the risk of developing an SRE for ibandronic acid treated patients when compared with placebo (relative risk 0.62, p=0.003). Efficacy results are summarised in Table 2.
Table2 EfficacyResults(BreastCancerPatientswithMetastaticBoneDisease)
|
|
All Skeletal Related Events (SREs) |
||
|
Placebo n=277 |
Ibandronic acid 50 mg n=287 |
p-value |
|
|
SMPR (per patient year) |
1.15 |
0.99 |
p=0.041 |
|
SRE relative risk |
- |
0.62 |
p=0.003 |
Secondaryefficacyendpoints
Astatisticallysignificantimprovementinbonepainscorewasshownforibandronic acid 50mgcomparedto placebo.Thepainreductionwasconsistentlybelowbaselinethroughouttheentirestudy andaccompaniedby a significantlyreduceduseofanalgesicscompared toplacebo.Thedeteriorationin QualityofLifeandWHOperformancestatuswassignificantly lessinibandronic acid treatedpatients comparedwithplacebo.UrinaryconcentrationsoftheboneresorptionmarkerCTx(C-terminaltelopeptidereleasedfromTypeIcollagen)weresignificantlyreducedintheibandronic acidgroupcompared toplacebo.This reductioninurinaryCTxlevelswassignificantlycorrelatedwiththeprimaryefficacyendpointSMPR (Kendall-tau-b(p<0.001)).AtabularsummaryofthesecondaryefficacyresultsispresentedinTable3.
Table3 SecondaryEfficacyResults(BreastCancerPatientswithMetastaticBone
Disease)
|
|
|
|
|
|
|
Placebo n=277 |
Ibandronic acid 50 mg n=287 |
p-value |
|
Bone pain * |
0.20 |
-0.10 |
p=0.001 |
|
Analgesic use * |
0.85 |
0.60 |
p=0.019 |
|
Quality of Life * |
-26.8 |
-8.3 |
p=0.032 |
|
WHO performance score * |
0.54 |
0.33 |
p=0.008 |
|
Urinary CTx ** |
10.95 |
-77.32 |
p=0.001 |
*Meanchangefrombaselinetolastassessment.
**Medianchangefrombaselinetolastassessment
Paediatric population (see section 4.2 and section 5.2)
The safety and efficacy of ibandronic acid in children and adolescents below age 18 years have not been established. No data are available.
5.2 Pharmacokineticproperties
Absorption
Theabsorptionofibandronicacidintheuppergastrointestinaltractisrapidafteroraladministration.Maximumobservedplasmaconcentrationswerereachedwithin0.5to2hours(median1hour)inthe fastedstateandabsolutebioavailabilitywasabout0.6%.Theextentofabsorptionisimpairedwhen takentogetherwithfoodorbeverages(otherthanwater).Bioavailabilityisreducedby about 90%whenibandronicacidisadministeredwithastandardbreakfastincomparisonwithbioavailabilityseeninfastedsubjects.Whentaken30minutesbeforeameal,thereductionin bioavailabilityisapproximately30%.Thereisnomeaningfulreductioninbioavailabilityprovided ibandronic acidistaken60minutesbeforeameal.
Bioavailabilitywasreducedby approximately75%whenibandronic acid tabletswereadministered2hoursafter a standardmeal.Therefore,it isrecommendedthatthetabletsshouldbetakenafteranovernightfast (minimum6 hours)andfastingshouldcontinueforat least30minutesafterthedosehasbeentaken (seeSection4.2).
Distribution
Afterinitialsystemicexposure,ibandronicacidrapidlybindstoboneorisexcretedintourine.Inhumans, the apparentterminalvolumeofdistributionisat least90l andtheamountofdosereachingthe boneisestimatedto be40-50%ofthecirculatingdose.Proteinbindinginhuman plasmaisapproximately 87%at therapeuticconcentrations, andthusdrug-druginteractionduetodisplacementis unlikely.
Biotransformation
Thereisnoevidencethatibandronicacidismetabolizedinanimalsorhumans.
Elimination
Theabsorbedfractionofibandronicacidisremovedfromthecirculationviaboneabsorption(estimatedtobe 40-50%)andtheremainderiseliminated unchangedbythe kidney.The unabsorbedfraction ofibandronicacid iseliminated unchangedinthefaeces.
Therangeofobservedapparenthalf-livesisbroadanddependentondoseandassaysensitivity,butthe apparentterminalhalf-lifeisgenerallyintherangeof10-60hours.However,earlyplasmalevelsfallquickly,reaching10%ofpeakvalueswithin3and8hoursafterintravenousororaladministrationrespectively.
Totalclearanceofibandronicacidislowwithaveragevaluesintherange84-160ml/min.Renalclearance(about60 ml/mininhealthypostmenopausalfemales)accountsfor50-60%oftotalclearance andisrelatedto creatinineclearance.Thedifferencebetweentheapparenttotalandrenalclearances isconsideredto reflect the uptakeby bone.
The secretory pathway of renal elimination does not appear to include known acidic or basic transport systems involved in the excretion of other active substances In addition, ibandronic acid does not inhibit the major human hepatic P450 isoenzymes and does not induce the hepatic cytochrome P450 system in rats.
Pharmacokinetics in Special Populations
Gender
Bioavailabilityandpharmacokineticsofibandronicacidaresimilarinbothmenandwomen.
Race
ThereisnoevidenceforclinicallyrelevantinterethnicdifferencesbetweenAsiansandCaucasians in ibandronicaciddisposition.Thereareonly very fewdataavailableonpatientswithAfricanorigin.
Patients with renal impairment
Exposure toibandronicacidinpatientswithvariousdegreesofrenalimpairmentisrelated to creatinineclearance(CLcr).Subjectswithsevererenalimpairment(CLcr ≤30ml/min)receivingoraladministrationof10mgibandronicaciddailyfor21days,had2-3foldhigher plasmaconcentrationsthansubjectswithnormalrenalfunction (CLcr ≥80 mL/min).Totalclearanceofibandronicacid wasreducedto44mL/mininthesubjectswithsevererenalimpairment compared with 129 mL/min in the subjects with normal renal function. No dosage adjustment is necessary for patients with mild renal impairment (CLcr ≥50 and <80 mL/min). For patients with moderate renal impairment (CLcr ≥30 and <50 mL/min) or severe renal impairment (CLcr <30 mL/min) an adjustment in the dose is recommended (see section 4.2).
Patientswithhepaticimpairment (see section 4.2)
There are no pharmacokinetic data for ibandronic acid in patients who have hepatic impairment. The liver has no significant role in the clearance of ibandronic acid since it is not metabolized but is cleared by renal excretion and by uptake into bone. Therefore dosage adjustment is not necessary in patients with hepatic impairment. Further, as protein binding of ibandronic acid is approximately 87% at therapeutic concentrations, hypoproteinaemia in severe liver disease is unlikely to lead to clinically significant increases in free plasma concentration.
Elderly (see section 4.2)
Inamultivariateanalysis,agewasnotfoundto beanindependentfactorofanyofthepharmacokineticparametersstudied.Asrenalfunctiondecreaseswithage,thisistheonlyfactortotakeintoconsideration(see renalimpairment section).
Paediatric population (see section 4.2 and section 5.1)Therearenodataontheuseofibandronic acid inpatientslessthan18yearsold.
5.3 Preclinicalsafetydata
Effectsinnon-clinicalstudieswereobservedonly atexposuressufficientlyin excessofthe maximumhuman exposureindicatinglittlerelevancetoclinicaluse.Aswithotherbisphosphonates,thekidneywas identifiedtobetheprimary targetorganofsystemictoxicity.
Mutagenicity/Carcinogenicity:
Noindicationofcarcinogenicpotentialwasobserved.Testsforgenotoxicityrevealednoevidenceofgenetic activityforibandronicacid.
Reproductivetoxicity:
Noevidenceofdirectfoetaltoxicityorteratogeniceffectswasobservedforibandronicacidin intravenouslyororallytreatedratsandrabbits.In reproductive studies in rats by the oral route effects on fertility consisted of increased preimplantation losses at dose levels of 1 mg/kg/day and higher. In reproductive studies in rats by the intravenous route, ibandronic acid decreased sperm counts at doses of 0.3 and 1 mg/kg/day and decreased fertility in males at 1 mg/kg/day and in females at 1.2 mg/kg/day. Adverseeffectsofibandronicacidinreproductive toxicitystudiesintheratwerethoseexpectedforthisclassofdrugs(bisphosphonates).Theyincludeadecreasednumberofimplantationsites,interferencewithnaturaldelivery(dystocia),anincreasein visceral variations (renalpelvisuretersyndrome)andteethabnormalitiesinF1offspringinrats.
6. PHARMACEUTICALPARTICULARS
6.1 Listofexcipients
Tablet core:
Povidone
Cellulose,microcrystalline
Crospovidone
Starch pregelatinised (maize)
Glycerol dibehenate
Silica,colloidal anhydrous
Tablet coat:
Opadry OY-LS-28908(White II) consisting of:
Lactose monohydrate
Macrogol
Hypromellose (E464)
Titaniumdioxide(E171)
6.2 Incompatibilities
Notapplicable.
6.3 Shelflife
3 years
6.4 Specialprecautionsforstorage
Storeintheoriginalpackageinordertoprotectfrommoisture.
6.5 Natureandcontentsofcontainer
Ibandronate Bluefish 50mgfilmcoatedtabletsare suppliedin PA/Aluminium/PVC - Aluminum foil(Alu-Alu) blister,whichare presentedaspackscontaining28or84tablets.
Notall packsizesmaybemarketed.
6.6 Specialprecautionsfordisposal
Nospecialrequirements.
7. MARKETINGAUTHORISATION HOLDER
Bluefish Pharmaceuticals AB
Torsgatan 11
111 23 Stockholm
Sweden
8. MARKETINGAUTHORISATION NUMBER(S)
<[To be completed nationally]>
9. DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION
<[To be completed nationally]>
10. DATEOFREVISIONOFTHETEXT
4 February 2016