Changes t the Prduct infrmatin as apprved by the CHMP n 13 Octber 2016, pending endrsement by the Eurpean Cmmissin Annex III Amendments t relevant sectins f the Prduct Infrmatin Nte: These amendments t the relevant sectins f the Prduct Infrmatin are the utcme f the referral prcedure. The prduct infrmatin may be subsequently updated by the Member State cmpetent authrities, in liaisn with the Reference Member State, as apprpriate, in accrdance with the prcedures laid dwn in Chapter 4 f Title III f Directive 2001/83/EC.
Amendments t relevant sectins f the Prduct Infrmatin The existing prduct infrmatin shall be amended (insertin, replacement r deletin f the text as apprpriate) t reflect the agreed wrding as prvided belw. A. Summary f Prduct Characteristics 4.2 Pslgy and methd f administratin [This sectin shuld be revised as fllws:] Fr prducts cntaining metfrmin as single agent: Pslgy Adults with nrmal renal functin (GFR 90 ml/min) Renal impairment A GFR shuld be assessed befre initiatin f treatment with metfrmin cntaining prducts and at least annually thereafter. In patients at an increased risk f further prgressin f renal impairment and in the elderly, renal functin shuld be assessed mre frequently, e.g. every 3-6 mnths. GFR ml/min Ttal maximum daily dse (t be divided int 2-3 daily dses) Additinal cnsideratins 60-89 3000 mg Dse reductin may be cnsidered in relatin t declining renal functin. 45-59 30-44 2000 mg 1000 mg Factrs that may increase the risk f lactic acidsis (see sectin 4.4) shuld be reviewed befre cnsidering initiatin f metfrmin. The starting dse is at mst half f the maximum dse. <30 - Metfrmin is cntraindicated. [The dsing table abve shuld be adapted fr extended-release prducts cntaining metfrmin as single agent as fllws: - The ttal maximum daily dse fr patients with GFR 60-89 ml/min shuld be the same as the currently apprved dse in adults with nrmal renal functin. - The text: (t be divided int 2-3 daily dses) shuld be mitted.] Fr fixed dse cmbinatin prducts cntaining metfrmin: Pslgy Adults with nrmal renal functin (GFR 90 ml/min)
Renal impairment A GFR shuld be assessed befre initiatin f treatment with metfrmin cntaining prducts and at least annually thereafter. In patients at an increased risk f further prgressin f renal impairment and in the elderly, renal functin shuld be assessed mre frequently, e.g. every 3-6 mnths. The maximum daily dse f metfrmin shuld preferably be divided int 2-3 daily dses. Factrs that may increase the risk f lactic acidsis (see 4.4) shuld be reviewed befre cnsidering initiatin f metfrmin in patients with GFR<60 ml/min. If n adequate strength f [prduct name] is available, individual mncmpnents shuld be used instead f the fixed dse cmbinatin. GFR ml/min Metfrmin [ther mncmpnent] 60-89 Maximum daily dse is 3000 mg Dse reductin may be cnsidered in relatin t declining renal functin. [relevant text] 45-59 Maximum daily dse is 2000 mg The starting dse is at mst half f the maximum dse. 30-44 Maximum daily dse is 1000 mg. The starting dse is at mst half f the maximum dse. <30 Metfrmin is cntraindicated Fr bth prducts cntaining metfrmin as single agent and fr fixed dse cmbinatin prducts cntaining metfrmin: 4.3 Cntraindicatins [This sectin shuld be revised as fllws:] Any type f acute metablic acidsis (such as lactic acidsis, diabetic ketacidsis) Severe renal failure (GFR <30 ml/min) 4.4 Special warnings and precautins fr use [Warnings shuld be revised as fllws:] Lactic acidsis
Lactic acidsis, a very rare but serius metablic cmplicatin, mst ften ccurs at acute wrsening f renal functin r cardirespiratry illness r sepsis. Metfrmin accumulatin ccurs at acute wrsening f renal functin and increases the risk f lactic acidsis. In case f dehydratin (severe diarrhea r vmiting, fever r reduced fluid intake), metfrmin shuld be temprarily discntinued and cntact with a health care prfessinal is recmmended. Medicinal prducts that can acutely impair renal functin (such as antihypertensives, diuretics and NSAIDs) shuld be initiated with cautin in metfrmin-treated patients. Other risk factrs fr lactic acidsis are excessive alchl intake, hepatic insufficiency, inadequately cntrlled diabetes, ketsis, prlnged fasting and any cnditins assciated with hypxia, as well as cncmitant use f medicinal prducts that may cause lactic acidsis (see sectins 4.3 and 4.5). Patients and/r care-givers shuld be infrmed f the risk f lactic acidsis. Lactic acidsis is characterised by acidtic dyspnea, abdminal pain, muscle cramps, asthenia and hypthermia fllwed by cma. In case f suspected symptms, the patient shuld stp taking metfrmin and seek immediate medical attentin. Diagnstic labratry findings are decreased bld ph (< 7.35), increased plasma lactate levels (>5 mml/l) and an increased anin gap and lactate/pyruvate rati. Administratin f idinated cntrast agents Intravascular administratin f idinated cntrast agents may lead t cntrast induced nephrpathy, resulting in metfrmin accumulatin and an increased risk f lactic acidsis. Metfrmin shuld be discntinued prir t r at the time f the imaging prcedure and nt restarted until at least 48 hurs after, prvided that renal functin has been re-evaluated and fund t be stable, see sectins 4.2 and 4.5. Renal functin GFR shuld be assessed befre treatment initiatin and regularly thereafter, see sectin 4.2. Metfrmin is cntraindicated in patients with GFR<30 ml/min and shuld be temprarily discntinued in the presence f cnditins that alter renal functin, see sectin 4.3. Surgery Metfrmin must be discntinued at the time f surgery under general, spinal r epidural anesthesia. Therapy may be restarted n earlier than 48 hurs fllwing surgery r resumptin f ral nutritin and prvided that renal functin has been re-evaluated and fund t be stable. 4.5 Interactin with ther medicinal prducts and ther frms f interactin [The wrding shuld be revised as fllws:] Cncmitant use nt recmmended Alchl Alchl intxicatin is assciated with an increased risk f lactic acidsis, particularly in cases f fasting, malnutritin r hepatic impairment.
Idinated cntrast agents Metfrmin must be discntinued prir t r at the time f the imaging prcedure and nt restarted until at least 48 hurs after, prvided that renal functin has been re-evaluated and fund t be stable, see sectins 4.2 and 4.4. Cmbinatins requiring precautins fr use Sme medicinal prducts can adversely affect renal functin which may increase the risk f lactic acidsis, e.g. NSAIDs, including selective cycl-xygenase (COX) II inhibitrs, ACE inhibitrs, angitensin II receptr antagnists and diuretics, especially lp diuretics. When starting r using such prducts in cmbinatin with metfrmin, clse mnitring f renal functin is necessary. B. Package leaflet [The fllwing texts shuld be added t r replace existing texts, as apprpriate:] Sectin 2: What yu need t knw befre yu <take> <use> <Prduct name> D nt <take> <use> <Prduct name>: If yu have severely reduced kidney functin. if yu have uncntrlled diabetes, with, fr example, severe hyperglycaemia (high bld glucse), nausea, vmiting, diarrhea, rapid weight lss, lactic acidsis (see Risk f lactic acidsis belw) r ketacidsis. Ketacidsis is a cnditin in which substances called 'ketne bdies' accumulate in the bld and which can lead t diabetic pre-cma. Symptms include stmach pain, fast and deep breathing, sleepiness r yur breath develping an unusual fruity smell. Warnings and precautins Risk f lactic acidsis <Prduct name> may cause a very rare, but very serius side effect called lactic acidsis, particularly if yur kidneys are nt wrking prperly. The risk f develping lactic acidsis is als increased with uncntrlled diabetes, serius infectins, prlnged fasting r alchl intake, dehydratin (see further infrmatin belw), liver prblems and any medical cnditins in which a part f the bdy has a reduced supply f xygen (such as acute severe heart disease). If any f the abve apply t yu, talk t yur dctr fr further instructins. Stp taking <Prduct name> fr a shrt time if yu have a cnditin that may be assciated with dehydratin (significant lss f bdy fluids) such as severe vmiting, diarrhea, fever, expsure t heat r if yu drink less fluid than nrmal. Talk t yur dctr fr further instructins. Stp taking <Prduct name> and cntact a dctr r the nearest hspital immediately if yu experience sme f the symptms f lactic acidsis, as this cnditin may lead t cma. Symptms f lactic acidsis include: vmiting stmach ache (abdminal pain) muscle cramps a general feeling f nt being well with severe tiredness difficulty in breathing reduced bdy temperature and heartbeat
Lactic acidsis is a medical emergency and must be treated in a hspital. If yu need t have majr surgery yu must stp taking <Prduct name> during and fr sme time after the prcedure. Yur dctr will decide when yu must stp and when t restart yur treatment with <Prduct name>. During treatment with <Prduct name>, yur dctr will check yur kidney functin at least nce a year r mre frequently if yu are elderly and/r if yu have wrsening kidney functin. Other medicines and <Prduct name> If yu need t have an injectin f a cntrast medium that cntains idine int yur bldstream, fr example in the cntext f an X-ray r scan, yu must stp taking <Prduct name> befre r at the time f the injectin. Yur dctr will decide when yu must stp and when t restart yur treatment with <Prduct name>. Tell yur dctr if yu are taking, have recently taken r might take any ther medicines. Yu may need mre frequent bld glucse and kidney functin tests, r yur dctr may need t adjust the dsage f <Prduct name>. It is especially imprtant t mentin the fllwing: medicines which increase urine prductin (diuretics) medicines used t treat pain and inflammatin (NSAID and COX-2-inhibitrs, such as ibuprfen and celecxib) certain medicines fr the treatment f high bld pressure (ACE inhibitrs and angitensin II receptr antagnists) <Prduct name> with alchl Avid excessive alchl intake while taking <Prduct name> since this may increase the risk f lactic acidsis (see sectin Warnings and precautins ). Sectin 3: Hw t <take> <use> <Prduct name> <If yu have reduced kidney functin, yur dctr may prescribe a lwer dse.> [Text t be included fr prducts where dse reductin is recmmended, nly if the PL prvides specific infrmatin abut the dse] Sectin 4: Pssible side effects [Include amng the mst serius side effects at the tp f sectin 4:] <Prduct name> may cause a very rare (may affect up t 1 user in 10,000), but very serius side effect called lactic acidsis (see sectin Warnings and precautins ). If this happens yu must stp taking <Prduct name> and cntact a dctr r the nearest hspital immediately, as lactic acidsis may lead t cma.