Annex II. Scientific conclusions and grounds for. Variation to the terms of the Marketing Authorisations (oral formulations) and

Transcription

1 Annex II Scientific cnclusins and grunds fr Variatin t the terms f the Marketing Authrisatins (ral frmulatins) and Revcatin f the Marketing Authrisatins (parenteral frmulatins)

2 Scientific cnclusins Overall summary f the scientific evaluatin f tlperisne-cntaining prducts (see Annex I) Tlperisne is a centrally acting muscle relaxant first synthesized in 1956, and used in clinical practice since the 1960 s. The precise mechanism f actin is nt fully knwn. It pssesses high affinity fr nervus tissue, reaching the highest cncentratins in the brain stem, spinal crd and peripheral nerve tissue. The chemical structure f tlperisne is similar t that f lidcaine and, similarly t lidcaine, tlperisne has membrane stabilising effects. Tlperisne reduces the sdium influx thrugh the islated nerve membrane in a dse dependent way, thus amplitude and frequency f actin ptentials are reduced. Furthermre, inhibitry effects n vltage dependent Ca 2+ channels have been demnstrated, suggesting that tlperisne might als reduce the transmitter release in additin t its membrane stabilising effect. Tlperisne exerts its actin at 3 levels: Peripheral level stabilises the membrane f neurns, and cnsequently supresses the amplitude and frequency f the actin ptentials. It is capable f inhibiting the pathlgical peripheral impulse cnditin induced by pain, which culd start varius mtric r vegetative reflexes that wuld lead t increased muscular tne. Central-spinal level tlperisne reduces the increased mn- and plysynaptic reflex activity in a dse-dependent manner t the physilgical level. This effect is well demnstrated in several animal mdels. Central-reticular level An imbalance between supraspinal facilitatry and inhibitry cntrl can als lead t an enhanced reflex activity and an increased muscle tne. Tlperisne reduces the reticul-spinal facilitatin in the brainstem and has been shwn t be effective in alleviating experimental gamma-rigr f reticular rigin. Tlperisne-cntaining prducts are currently apprved in the fllwing EU cuntries: Bulgaria, Cyprus, Czech Republic, Germany, Hungary, Latvia, Lithuania, Pland, Rmania and Slvak Republic. The fllwing indicatins have been apprved in at least ne Member State (specific wrding f the indicatin may vary frm prduct t prduct): Acute r chrnic treatment f pathlgically elevated skeletal muscle tne in rganic neurlgical disrders Treatment f muscular hypertnicity and muscle spasms assciated with lcmtr diseases (e.g. spndylsis, spndylarthrsis, cervical and lumbar syndrmes, arthrsis f large jints) Rehabilitatin after rthpaedic and trauma surgery Treatment f bliterative vascular diseases as well as syndrmes due t impaired vascular innervatin (e.g. acrcyansis, dysbasia angineurtica intermittens) Little s disease (infantile diplegia spastica) and ther encephalpaties accmpanied by dystnia On 15 July 2011, Germany triggered a referral under Article 31 f Directive 2001/83/EC. Germany cnsidered that the numerus reprts f hypersensitivity reactins received in the pst authrisatin phase are indicative f a safety cncern which is nt balanced by the limited evidence f efficacy. The CHMP was therefre requested t give its pinin n whether the marketing authrisatins fr medicinal prducts cntaining tlperisne, and assciated names shuld be maintained, varied, suspended r withdrawn. Clinical Efficacy

3 Treatment f pathlgically elevated skeletal muscle tne in rganic neurlgical disrders This indicatin is mainly supprted by the Stamenva (2005) study, which is f acceptable quality. In this randmised, duble-blind, placeb cntrlled, multicentre study efficacy f tlperisne has been shwn in the symptmatic treatment f patients with spasticity fllwing cerebral strke. The Ashwrth scale used in this study is a validated instrument generally accepted fr the clinical evaluatin f degree f spasticity. The mean imprvement in the Ashwrth scre fund in the Stamenva study was 32% in the verall ITT (intentin-t-treat) ppulatin and 42% in the subgrup f patients receiving mg/day). Van Denburg et al. (2008) have fund a 33% change in the Ashwrth Scale t crrelate with a 1-pint change in the Physician s glbal assessment scre in patients with pst-strke spasticity, indicating clinical relevance. The imprvement in Ashwrth scale was accmpanied by a statistically significant difference in the investigatr s verall assessment f efficacy in favur f tlperisne. Further functinal secndary parameters (i.e. the mdified Barthel Index (assessing activities f daily living), capacity t perfrm rutine activities and walking endurance) cnsistently favured tlperisne ver placeb. Mean maximum walking distance per 2 minutes at final visit was apprx. 70 meters in the tlperisne and 40 meters in the placeb grup. In the Stamenva study, patients culd be titrated up t 900 mg per day, thus nly a subgrup (35%) f tlperisne patients was treated within the dse range currently apprved in the SPC ( mg). Hwever, efficacy results f the subgrup treated with a daily tlperisne dse f up t 450 mg/day were cnsistent with the results f the whle ITT ppulatin. In cnclusin the Stamenva study can be regarded as a psitive study, the results f which are indicative f a clinically relevant effect f tlperisne in the treatment f patients with pst-strke spasticity. In cntrast, the prematurely terminated Avigen study AV (2007) failed t demnstrate any effect in the multiple sclersis ppulatin. The interim analysis results indicated that it failed t achieve statistical significance in any evaluated efficacy endpint. The Feher study (1985) used the Rivermead scale, which has shwn high validity and reliability in assessment f mtr functin in strke patients. While the results are difficult t interpret due t the lack f a placeb cntrl grup t verify assay integrity, this randmised, duble-blind actively cntrlled study prvides supprting evidence f efficacy f tlperisne in terms f imprvement f mbility in patients with spasticity caused by neurlgical disrders. In the Melka study (1997), the reductin in muscle tne (as measured by the Ashwrth scale) was accmpanied by a cnsistent imprvement in functinal parameters indicative f clinical relevance. Hwever, it nly included patients with spasticity caused by neurlathyrism. Neurlahyrism affects predminantly yung adult males at time f famine and generally des nt ccur in Eurpean cuntries, therefre generalisatin f the study results t the existing indicatin is questinable. The Melka study can nly be cnsidered as prviding supprtive evidence f efficacy in the treatment f spasticity caused by neurlgical diseases. Taken tgether, the existing dataset is indicative f a mdest effect f tlperisne in the treatment f spasticity caused by neurlgical disrders. It is imprtant t nte that the evidence f efficacy is mainly based n the results f the Stamenva study, which nly included patients with pst-strke spasticity. Treatment f muscular hypertnicity and muscle spasms assciated with lcmtr diseases In the nly study in this indicatin where superirity f tlperisne ver placeb in the primary utcme was shwn (Pratzel 1995), this was achieved using a new parameter in the frmula fr calculatin which was nt pre-determined but rather intrduced in pst-hc efficacy analysis. Validatin f new parameters needs t be dne befrehand if prf f efficacy is t be derived frm a study. In additin, the imprvement in PPT was nt accmpanied by a crrespnding imprvement in

4 the mbility f patients. It is therefre nt plausible hw the reductin f a triggered PPT culd have been translated int a clinically relevant effect in patients with painful reflex muscle spasm. The Struck 2002 study failed t demnstrate a significant imprvement in the primary endpint, and the tw secndary parameters fr which a statistically significant imprvement culd be seen are subjective, and nt cnsidered clinically meaningful given that they were nt accmpanied by cmmensurate imprvements in clinically relevant parameters such as pain intensity, pain at mvement and mtility. The Struck 2004 study als failed t demnstrate a significant imprvement in the primary endpint. In additin, all patients started by receiving dses abve the apprved dse. Finally, the Hdinka 2001 study als failed t demnstrate a relevant difference in the primary endpint, and the nly transient significant difference bserved was in the Rland-Mrris Disability Scale at day 7, having disappeared at day 14. It can therefre be cncluded that f the fur main studies in this indicatin, which became available after the initial marketing authrisatin was granted, ne suffers frm substantial deficiencies and the remaining 3 failed t demnstrate an effect n the efficacy utcme. Rehabilitatin after rthpaedic and trauma surgery The data available n this indicatin cmes frm tw bservatinal studies (1986 and 1989) with a ttal f 166 patients, where 450 mg tlperisne were given daily fr a few weeks. In bth studies, tlperisne is given t a very hetergeneus ppulatin as part f a rehabilitatin prgram, s it is nt pssible t islate the effect f tlperisne frm the effect f ther interventins and therefre this data des nt supprt the evidence f efficacy in this particular indicatin. Treatment f bliterative vascular diseases as well as syndrmes due t impaired vascular innervatin Very limited infrmatin exists n the efficacy f tlperisne in this indicatin. There are n GCPcmpliant studies, there is 1 actively-cntrlled trial and a few bservatinal studies. The actively cntrlled study was pen label, used pentxyphyllin as cntrl and invlved a ttal f 70 patients. Little s disease and ther encephalpaties accmpanied by dystnia Very limited infrmatin exists n the efficacy f tlperisne in this indicatin. The nly studies that exist are f bservatinal nature, were cnducted in a hetergeneus ppulatin and cntain extremely limited infrmatin. Parenteral frmulatin There are a few studies where a parenteral frmulatin was used. These are mstly bservatinal and extremely limited dcumentatin is available. The nly duble-blind, placeb-cntrlled studies identified where parenteral tlperisne was used and that have acceptable methdlgical standards were cnducted in indicatins where efficacy has nt been demnstrated, that have never been apprved fr the prduct r included nly a very small number f patients in the indicatin f interest.. N data was submitted in supprt f the dsing recmmendatins. Clinical safety While n fatal case f hypersensitivity was reprted, arund 10% f all cases reprted with tlperisne were cnsidered t be life-threatening. Hypersensitivity reactins accunt fr mre than half f the spntaneus reprts in the riginatrs database, fllwed by adverse events (AEs) frm the SOCs (System Organ Class) Gastrintestinal disrders, General disrders and administratin site cnditins and Nervus system disrders. Analysis f spntaneus reprts suggests that hypersensitivity reactins are mre frequent in wmen, patients with previus r current allergic disease r thse using NSAIDs r ther analgesics cncmitantly. A causal relatinship with tlperisne was assessed as at least pssible in 90% f all hypersensitivity reactins.

5 There is a discrepancy between the patterns f spntaneus reprts and the reprts frm studies. While nly a small number f reprts f hypersensitivity reactins were bserved in the studies submitted, they represent mre than half f all spntaneus reprts. Hypersensitivity can be a significant event and cases f anaphylactic reactins/anaphylactic shck have been reprted. The currently apprved prduct infrmatin des nt seem t adequately reflect the risk r cmmunicate it t patients in rder t allw early identificatin f signs f hypersensitivity. It is als nted that the reprting rates in Germany appear t be significantly higher than thse calculated thrugh the MAH s database. The mechanism f tlperisne-related hypersensitivity is unknwn. Hyptheses include tlperisne metablites as hapten frmatins activating the patient s immune system thrugh cvalent mdificatin f prteins, r structural similarity t the lcal anaesthetic lidcaine. Due t lack f adequate data, n firm cnclusins n the influence f renal r hepatic functin can be drawn, althugh the existing data des nt raise cause fr cncern. It was nted that infrmatin in the Summary f Prduct Characteristics regarding interactins, effects n ability t drive and use machines and effect f fd n pharmackinetic parameters was nt reflecting the latest available data. It was als nted that nt all prducts mentined the adverse events cnfusin and hyperhidrsis in the prduct infrmatin and that this shuld be harmnised. It is well knwn that the safety prfile f a prduct may vary depending n the frmulatin. Hwever, as hypersensitivity is a characteristic f the active substance rather than f the frmulatin, the cncerns identified with the ral frmulatins are als relevant fr the parenteral frmulatin. The cmpany that hlds these marketing authrisatins was asked t submit any existing data in supprt f its safety and dsing recmmendatins, but n relevant data was submitted fr assessment as the marketing authrisatin hlder cncluded itself that the data is insufficient t cnclude that the benefits utweigh the risks and prpsed that the marketing authrisatins fr the parenteral frmulatins be revked. Overall cnclusin The CHMP has cnsidered the ttality f the available data n the safety and efficacy f tlperisne. While n fatal case f hypersensitivity was reprted, arund 10% f all cases reprted with tlperisne were cnsidered t be life-threatening. Hypersensitivity reactins accunt fr mre than half f the spntaneus reprts in the riginatrs database, fllwed by adverse events (AEs) frm the SOCs Gastrintestinal disrders, General disrders and administratin site cnditins and Nervus system disrders. Analysis f spntaneus reprts suggests that hypersensitivity reactins are mre frequent in wmen, patients with previus r current allergic disease r thse using NSAIDs r ther analgesics cncmitantly. A causal relatinship with tlperisne was assessed as at least pssible in 90% f all hypersensitivity reactins. There is a discrepancy between the patterns f spntaneus reprts and the reprts frm studies. While nly a small number f reprts f hypersensitivity reactins were bserved in the studies submitted, they represent mre than half f all spntaneus reprts. Hypersensitivity can be a significant event and cases f anaphylactic reactins/anaphylactic shck have been reprted. The currently apprved prduct infrmatin des nt seem t adequately reflect the risk r cmmunicate it t patients in rder t allw early identificatin f signs f hypersensitivity. It is als nted that the reprting rates in Germany appear t be significantly higher than thse calculated thrugh the MAH s database. Due t lack f adequate data, n firm cnclusins n the influence f renal r hepatic functin can be drawn, althugh the existing data des nt raise cause fr cncern. The mechanism f tlperisne-related hypersensitivity is unknwn. Hyptheses include structural similarity t the lcal anaesthetic lidcaine, s the risk fr crss-reactins needs t be cnsistently described in the prduct infrmatin. The prduct infrmatin shuld als be updated s that all prducts cntain cnsistent and updated infrmatin n interactins, effects n ability t drive and use

6 machines, the effect f fd n biavailability, influence f renal r hepatic functin and adverse reactins. On the efficacy side, the existing dataset is indicative f a mdest effect f tlperisne in the treatment f spasticity caused by neurlgical disrders, but it is imprtant t nte that the evidence is mainly based n the results f the Stamenva study - which nly included patients with pst-strke spasticity. Relevant studies als exist in the lcmtr indicatin, the majrity f which failed t demnstrate the efficacy f the prduct. The nly study in this indicatin with a psitive utcme cntains significant methdlgical deficiencies which preclude any cnclusin n the efficacy f the prduct. Fr the remaining indicatins (rehabilitatin after rthpaedic and trauma surgery, treatment f bliterative vascular diseases as well as syndrmes due t impaired vascular innervatin, and Little s disease and ther encephalpaties accmpanied by dystnia) there is extremely limited evidence f efficacy, mainly based n small studies with inadequate design and including a hetergeneus ppulatin. It is therefre cnsidered that efficacy in these indicatins has nt been demnstrated. In this respect, the CHMP tk nte f the fact that the marketing authrisatin hlder f the prducts fr which these indicatins are apprved cncluded that the evidence f efficacy is insufficient t balance the risks assciated t the prduct and prpsed that the indicatins be deleted. Based n the ttality f the data made available n the safety and the efficacy f tlperisne, the CHMP cnsidered that the risk f hypersensitivity is mre significant than previusly identified, and that as a cnsequence the demnstrated clinical benefits nly utweigh the risks in the restricted indicatin symptmatic treatment f pst-strke spasticity in adults. It is well knwn that the safety prfile f a prduct may vary depending n the frmulatin. Hwever, as hypersensitivity is a characteristic f the active substance rather than f the frmulatin, the cncerns identified with the ral frmulatins are als relevant fr the parenteral frmulatin. The cmpany that hlds these marketing authrisatins was asked t submit any existing data in supprt f its safety and dsing recmmendatins, but n relevant data was submitted fr assessment as the marketing authrisatin hlder cncluded itself that the data is insufficient t cnclude that the benefits utweigh the risks and prpsed that the marketing authrisatins fr the parenteral frmulatins be revked. The CHMP endrsed a cmmunicatin i.e. Dear Healthcare Prfessinal Cmmunicatin (DHPC) t cmmunicate the utcme f the present review. Benefit risk balance The Cmmittee cncluded that the benefit-risk balance f tlperisne-cntaining ral frmulatins is psitive under nrmal cnditins f use nly in the symptmatic treatment f pst-strke spasticity in adults, subject t the changes t the prduct infrmatin agreed. The Cmmittee als cncluded that the benefit-risk balance f tlperisne-cntaining parenteral frmulatins is nt psitive, and recmmends the revcatin f the crrespnding marketing authrisatins. Re-examinatin prcedure Fllwing the adptin f the CHMP pinin and recmmendatins during the June 2012 CHMP meeting, re-examinatin requests were received frm Geden Richter PLC and PP Nature Balance Lizenz GmbH, as they cnsidered that there is adequate data supprting the efficacy f tlperisne in the treatment f muscular hypertnicity and muscle spasms assciated with lcmtr diseases indicatin. The MAHs als disagreed with the CHMP assessment f the safety prfile f tlperisne. Geden Richter PLC prpsed t restrict the indicatin t Shrt-term treatment f muscle spasms in adult patients with acute nn-specific lw back pain, with a maximum duratin f treatment f 7 days.

7 The CHMP therefre carried ut a new assessment f the available efficacy data in the cncerned indicatin. In particular, the CHMP re-assessed 4 pled analyses (Alken-2005, Farkas-2011, Varga- 2011a and Varga-2011b) f randmised clinical trials (Pratzel 1995, Struck 2002 and Struck 2004) and requested the Bistatistics Wrking Party (BSWP) t give its view n the pled analyses data. Having nted the BSWP assessment, the CHMP cncluded that there are serius cncerns regarding the apprpriateness f the statistical methdlgy used fr the pled analyses, mainly because they have been based n fixed effects mdels in the presence f evident hetergeneity but in particular because the main grunds fr the refusal f the evidence relate t the lack f cmpliance with the key criteria detailed in the CHMP Pints t cnsider dcument (CPMP/EWP/2330/99). As a result, the CHMP cnsidered that nne f the prvided pled analyses culd be cnsidered as supprtive t demnstrate the efficacy f tlperisne in the treatment f muscular hypertnicity and muscle spasms assciated with lcmtr diseases indicatin, nr in the prpsed restricted indicatin. The CHMP als cnsulted its Neurlgy Scientific Advisry Grup (SAG). The SAG stated that it did nt cnsider the results f the 4 pled analyses t be supprtive f the efficacy f tlperisne. Overall, the SAG cnsidered that the analyses has nt been perfrmed apprpriately and that the prvided data did nt allw an assessment f hw the varius ppulatin and treatment characteristics were taken int accunt fr the analyses. The SAG was als f the pinin that it is nt pssible t derive any cnclusin regarding the efficacy f tlperisne, nr was it pssible t identify any specific patient subgrups that culd benefit frm treatment with tlperisne cmpared t ther treatments. The CHMP als cnsidered a recently cnducted meta-analysis presented during the Octber 2012 ral explanatin but raised cncerns with regard t the methdlgy f the analysis and the quality f the included individual studies and therefre cncluded that this meta-analysis did prvide any additinal supprt f the efficacy f tlperisne. The CHMP als nted the MAH prpsal t cnduct a clinical study t cllect additinal evidence f the efficacy f tlperisne in the prpsed restricted lw back pain indicatin, as a pst-referral cmmitment, as well as the related draft study synpsis. Hwever, the Cmmittee cnsidered the prpsed study t be inadequate t prvide cnclusive evidence regarding the ptential efficacy f tlperisne in the prpsed indicatin, in particular due t the shrt treatment duratin prpsed. With regard t the safety f tlperisne, the CHMP reviewed the available safety data and retained its previus cnclusins that there is a risk f hypersensitivity reactins assciated with tlperisne, with data shwing that 10% f all reprted cases f hypersensitivity were cnsidered t be life-threatening. A causal relatinship with tlperisne was assessed as at least pssible in 90% f all hypersensitivity reactins. Based n the ttality f the data available n the safety and the efficacy f tlperisne and having nted the pinins f the BSWP and the SAG, the CHMP cnfirmed its initial cnclusin that the risk f hypersensitivity is mre significant than previusly identified at the time f the initial marketing authrisatin, and that as a cnsequence the benefits f tlperisne are utweighed by the risks in the indicatin treatment f muscular hypertnicity and muscle spasms assciated with lcmtr diseases as well as in the prpsed restricted indicatin shrt-term treatment f muscle spasms in adult patients with acute nn-specific lw back pain. The Cmmittee therefre cncluded that the benefit-risk balance f tlperisne-cntaining ral frmulatins is psitive under nrmal cnditins f use nly in the symptmatic treatment f pststrke spasticity in adults, subject t the changes t the prduct infrmatin agreed. Grunds fr the variatin/revcatin t the terms f the marketing authrisatin Whereas The Cmmittee cnsidered that the risk f hypersensitivity reactins is mre significant than previusly identified.

8 The Cmmittee is f the pinin that the evidence fr clinically significant efficacy f tlperisne in the currently apprved indicatins is extremely limited, and therefre the ptential benefit fr patients in these indicatins is utweighed by the identified risk. The Cmmittee is als f the pinin that there is evidence f clinically significant efficacy f tlperisne in the symptmatic treatment f pst-strke spasticity in adults. The Cmmittee therefre cnsidered that the benefit-risk balance f tlperisne-cntaining ral frmulatins under nrmal cnditins f use: Is psitive fr symptmatic treatment f pst-strke spasticity in adults. Is nt psitive fr treatment f muscular hypertnicity and muscle spasms assciated with lcmtr disease. Is nt psitive fr rehabilitatin after rthpaedic and trauma surgery. Is nt psitive fr treatment f bliterative vascular diseases as well as syndrmes due t impaired vascular innervatin. Is nt psitive fr Little s disease and ther encephalpaties accmpanied by dystnia. The Cmmittee als cncluded that, in the absence f relevant data t supprt the efficacy in the dsing recmmendatins apprved, the ptential benefit f tlperisne-cntaining parenteral frmulatins is utweighed by the identified risk f hypersensitivity. The Cmmittee, as a cnsequence, cncluded that the benefit-risk balance f tlperisne-cntaining ral frmulatins is psitive under nrmal cnditins f use nly in the symptmatic treatment f pst-strke spasticity in adults, taking int accunt the changes t the prduct infrmatin agreed. The Cmmittee als cncluded that the benefit-risk balance f tlperisne-cntaining parenteral frmulatins is nt psitive, and recmmends the revcatin f the crrespnding marketing authrisatins. Therefre, in accrdance with Article 32(4)(d) f Directive 2001/83/EC, the CHMP recmmended: The variatin t the terms f the marketing authrisatin fr the ral frmulatins f medicinal prducts referred t in Annex I, fr which the relevant sectins f the summary f prduct characteristics and package leaflet are set ut in Annex III t the pinin. The revcatin f the marketing authrisatin fr the parenteral frmulatins f medicinal prducts referred t in annex I. The cnditins affecting the marketing authrisatins are set ut in Annex IV. The divergent psitins are appended t this pinin.