SUPPLEMENT - 143 pages 1 17 Oct 1991 0004 S020 c FROM MEDTRONIC INC TODD LANGEVIN ATTN I 7000 CENTRAL AVE NE MINNEAPOLIS SUBJECT SYNCRONED R 3 I MN ILETTER DATE 10 16 91 ILOGIN DATE 10 17 91 I I iDOCUMENT CONTROL PMA i 554323576 INFUSION DATE IDUE I I 0 P860004 S020 AMENDMENT I I I I SYSTEM OFFICE COPIES OF vol use COPIES OF VOLUME I I I I I I I ca gp Mp REFERRED DATE I I I et i I I COPIES OF VOLUME COPIES OF VOLUME I COPIES OF VOLUME I COPIES OF VOLUME I I I I I I I I I I I I I I I COPIES OF VOLUME I COPIES OF VOLUME I COPIES OF VOLUME I COPIES I I OF VOLUME I MEMOTO THE RECORD PROM Chief SUMECT GHDB DATB DIVISIW 10 22 91 DGRD Hedtronic Inc SYNCHRONEDINFUSION SYSTEMFOR THE INTRASPINAL ADMINISTRATION OF PRESERVATIVE PREEMORPHINESULFATEFOR THE TREATNENTOF CHRONICINTRACTABLEPAIN OF NONMALIGNANT ORIGIN This supplement has been submitted to FDA to request approval for the intraspinal and intrathecal epidural administration of preservative free morphine sulfate sterile solution 10 mg mL and 25 mg mL for the treatment of chronic intractable pain of nonmalignant origin via the SynchroMed Infusion System The System includes a programmable pump Models 8611H 8615 programmer Model 8810 catheter access system Model 8500 1 catheter Model 8703 and accessories On October 16 1991 CDRH issued an approvable letter for this supplement pending concurrence vith a post approval study to --------- drug device compatibility data for the life of the pump ----------------------- ----been submitted previously for 25 and 50 mg mL ------------ -------- ---- --------------- ----------- ---- --- ---------- -- ---------------------------------------------- ---- -- ------ -- ------- -- -----------In this amendment the sponsor concurs with this post approval requirement In a phone conversation vith Todd Langevin of yesterday Nedtronic he confirmed that the additional compatibility studies will be performed using the same protocol as previous compatibility testing done by Nedtronic Therefore I recommend approval Amalie C Mattan Page 1 of 1 P860004 S20A P inc Medtronic 7000 Central Avenue N E MN 55432 3576 Minneapolis Telephone 612 574 4000 Telex 29 0598 Cable Medtronic 574 4879 Telecopy 612 Medtronic g C 16 October 1991 3 j Center for Devices and Radiological Food and Drug Administration Oocument Mail Center HFZ 401 1390 Piccard Drive ND 20850 Rockville Amalie Mattan Attention Re v f cd P860004 20 SynchroMed Infusion Administration Health 3 Ci System for Intraspinal Morphine Sulphate a post approval issued 16 October 1991 CDRHrequested sulphate morphine In the approvable letter free of preservative approval study of the long term compatibility for condition with the SynchroNed pump as a solution sterile the results condition and will submit annually duration of Nedtronic hereby concurs with that studies which simulate the expected of extended compatibility exposure please contact the undersigned If you have any questions Sincerely MEDTRONICINC - Todd Langevin Product Regulation Nanager TL 3 I 5 17 may 1993 P860004 8920 DATE ILETTER DATE ILOGIN DATE IDUK FRON 05 14 93 NEVTRGNIC INC 7000 czwvsar ave NINNEAPOLIS NN oocumzm Pea I r4r 554323576 I I 05117 93 lcowTaor 8 z860064 8020 I i REPORT SUBJECT STSTEN SVNCBQNED INFUSION R I COPIE8OF VOLUNE OFFICE I DATE REFERRED l I sJii z COPIES QF VOLUNE COPIES OF VGLUNE CQP1ES OF VOLUNE I II I I COPIES GF VGLUNE COPIES QF VOLUNE COPIES OF VOLUNE l COPIES OF VOLUNE l COPIES OF VOLUNE COPIES OF VOLUNE 7 10 1993 r oi ggi SUBJECT P860004 S20A May 14 1993 Dated Nay 17 1993 Received TO RBC01 6 ------------ July The for 820 requixement tv a post approval a follow up infoxmation compatibility drug pump vas to provide at 25mg ml and 50mg ml morphine the Elkins Sinn that They report Cheek to see if this for 16 veeks found compatible vas initially ----- ----- ----- --- ----- ---- ------- --- ----- --- ---- ------- -------- ------------- ----- ----- ----------- --- ------------ -- --------------------------- ---------- - The time up to --- -------- -- --- --------the contact They expanded data The at that point effect for analyzed vere materials the pump is unaffected that indicate --- --- --- --- --- --- This is condition --- Recommend --- --- --- - First our review at Medtronic with David Nueller this Discuss the for rationale of the a sense 820 to get for evaluation exposure week and the data base on the 16 of approval candition --- - -- - - ---- - - --- --- --- --- --- --- --- --- ----- --- ----- ----- -------- ----- - 7P AT OP HEALTHh59 EWARTSERVICES Pub1ic Health Service Feed and Drug Adeinistratien Ceater for Devices and Radielecrieal eealth 13 8 Piecard Drive Reckville Maryland 20850 Nay 17 1993 DAVID H NUELKER KKQTRQNXC INC 7006 CENTRAL AVE NE NINNEAPQLIS NN 554323576 Dear ket NR P860004 95 14 93 05 17 93 SYNCRONED B INFUSION SYSTEN NUELLER approval Yov vill PNA Number Letter Dated Received Product applicant ion be notified referenced PEA of any need for by you it shall mitted be identified the required number of copies shall directly to above ecfdit ional information When with the ibove PNA number and be submitted as an amended report Food and Drug Administration Center fox Devices and Radiological Health PNA Document Nail Center HFZ 4D1 1390 Piecard Drive Rockville Naryland 20850 concerning this submission may be directed Quest ions at 301 427 ll86 Staff or to the reviewing division of Device Evaluation Office Sincerely to the within PNA the CDRH yours j H Kyper Charles Director Premarket Approval Office of Device Evaluation Center fox Devices and 888l GlO 1 CB1 H881 i Fl Staff Medtronic Neurological 800 53rd Avenue NE P O Box 1250 MN 55440 9087 Minneapolis dtronic gU 572 5000 612 i0 1 800 328 08 572 5078 FAX 6 2 May 14 1993 Food and Drug Administration and Radiological for Devices Center Document Mail Center HFZ 401 Drive 1390 Piccard 20859 ND Rackville RE P860004 S20 SynchroMed4 Nedtronic Post Approval Infusion Health System Requirement Long Term Compatibility Solution Sterile Sulfate Morphine of Preservative free SynchroMed4 the vith pump annual post approval the required This submission provides studies compatibility drug material of extended requirement to response in Nedtronic to by was agreed This requirement 1991 October 16 response letter S20 approvable F860004 commercial confidential This document contains request respectfully and Medtronic information by law Three the maximum protection provided by xegulation as required document are provided Any question 5633 or comments contact the secret and trade that it be given of this copies undersigned at 612 572 Si ncerely EDTRONIC INC - NEUROLOGICALDIVISION ---- -----David H Muell r Affairs Regulatory DHN dm Attachments Manager r 1 Medtronic P860004 SynchroMed Xnfusion Post Approval System Requirement of Preservative free Mozphine Long Term Compatibility with the BynchroMede pump Solution Sterile Sulfate contains the Nedtronic SynchroMed Infusion System This submission of Preservative free Morphine Sulfate Long Term Compatibility vith the SynchroNed8 was Sterile Solution pump This requirement to P860064 S20 approvable agreed to by Medtronic in response 16 Dctober 199ljl letter response morphine formulated at 25 mg ml Elkins Sinn preservat ive free found to be compatible vith the 50 mg ml was originally for up to --- --------SynchroMed System s infusion pathvay and SynchxoNed Infusion System materials t---- ------- nto The Medtronic ------ ---- ----- ---------------- ---- ------ ---------------- ------------ -------- ----------------- --- ----- --- -------- -- ----- -------------- ---------of morphine on the ta see the effects of long term exposure At the end of the incubate on the materials materials periods shows vere analyzed for their The analysis physical properties that all of the materials were within the specified values after the long term exposure show the -------of the The attached figures 1 -----------materials at - --- --- ---- ---- ----- --- -------- --- -------------The ------------------ -------- ------- the curves average standa--std ---tained vere within specific------or each ----------All -------samples - ------------- ------------------------------- --- the - --------------- ----- --- ----- --------- -- ------ samples vere -------The weights of the material --of the weight of the samples exposed to ------- ---- --- --- - --- --------- -------------- ----------one sample at ---- ----- --- -------- ----- ----- --------- -- --- ----- --- --------- These samples were ---- and ---- -------than the water controls respectively None of the materials are affected by long term incubations up to - --- --------- of the SynchroMed Infusion System s fluid pathway mat--------- h high concentrat ions of 25 and 5Q mg ml sulfate free morphine preservative Therefore the Medtronic SynchroNed Infusion System s demonstrates long term compatibility of preservative free morphine sulfate sterile solution winch the SynchroNed fluid materials pathway data System s - -- - ----- -- ----- ---- ------- ----- - - --- ---- -- -------- ------ --- --- - ---- - - ---------- --- ----- ----- -- -- ---- - - --- --- --- - -- -- - - -- -------------------- --- -- - -- --- ----- ---- - --- ----- ----- ---- -- ---- --- ----- --- -- -- ------ ----- --- - -- ------ -------- ----- -- - - - ---- - -- - - - --- --- --- --- ----- --- ------- -- ---- - ---- -- ---------- ---- - ------ -- ----- ---------- --- ---- ----- - - - - - - -- - - - - - --- --------- - - -- -- ----------- ----- ------- -- --- -- -- --- - --- --- II - - - - --- -- -- -- -------- -- - ---- -- - -------- -- ------ ------- ----- - - - --- -- - ------- ----- --- -- -------- - ---- ---- II -- ---- -- -- ---------- ------------------ -------- - ------- -- -------------- ---- - -- -- ------- ---- -- - - - - -- -- ----- -- --- rl - - ----- --- -- -------- ---- ---- - -- - ------ --- ---- -- - ---- -- --- - ------ -- - - - ------- --- - - -- - - ---- II II i I I1 I II Il ---- - ------- ----- -- -------- --- - -- - - --------- ---- - --- - ---- --- ------------- -- ------ ------ ----- -- ----- --- --------- --- p0 P8 I I I l I 04 S020 CD FROM MEDTRONIC INC ATTN TODD LANGEVIN 7000 CENTRAL AVE NE NINNEAPOLIS 29 Aug 1991 RELETTERDATE LOGIN DATE ENDUE DATE 08 28 91 08 29 91 I I I I I CONTROL 0 P860004 S020 I DOCUMENT PMA MN 554323576 I 02 25 92 I I SUBJECT I SYNCROMED R INFUSION SYSTEM I I I I I I I I I I I l I I I I I I I I I COPIES OF VOLUME ca COPIES OF VOLUME I COPIES OF VOLUME I I l l I I I COPIES OF VOLUME COPIES OF VOLUME COPIES OF VOLUME COPIES OF VOLUNE COPIES OF VOLUME COPIES OF VOLUME COPIES OF VOLUME OFFICE I I I I l bQ I I DATE REFERRED I I W 5i LC I I I I I I I I I I I I I I I I I l I 0 CI DATE 10 08 91 MEMOTO THE RECORD FROM Acting SUBJECT Chief Medtronic GHDB DIVISION DGRD Inc ADMINISTRATION INFUSIONSYSTEMFOR THE INTRASPINAL SYNCHROMEIP OF TREATMENT FOR THE SULFATE MORPHINE OF PRESERVATIVE FREE ORIGIN NONMALIGNANT OF PAIN CHRONICINTRACTABLE for the approval to FDA to request has been submitted This supplement of administration and intrathecal preservative intraspinal epidural solution sterile sulfate 10 mg mL and 25 mg mL for the free morphine via the origin intractable of chronic treatment pain of nonmalignant a includes System The System Infusion pump SynchroMed programmable system access catheter 8615 8611H Model 8810 programmer Models and accessories catheter Model 8703 Model 8500 1 PERTINENTBACKGROUND System for the Infusion On March 14 1988 the SynchroMed floxuridine agents of the chemotherapy delivery intravascular have approvals by CDRH Subsequent was approved doxorubicin of cisplatinum delivery intravascular the for granted and clindamycin heparin methotrexate an approvable 30 1991 CDRH issued On January System for the intrathecal Infusion SynchroMed drug baclofen the antispasticity Lioresal NDA by CDER approval of the Lioresal and been for the letter administration to the subject of by System was approved Infusion On March 11 1991 The SynchroMed morphine of preservative free infusion CDRH for the epidural intractable of chronic for the treatment sulfate pain of malignant origin 200 and 500 CII preservative free On July 19 1991 Infumorph by CDER for was approved solution sterile morphine sulfate or epidural for intrathecal devices microinfusion continuous chronic of intractable the treatment infusion in pain use in by System was approved Infusion On July 25 1991 the Synchromed of administration intrathecal CDRH for the preservative free of chronic intractable for the treatment sulfate morphine pain of Amalie C Mattan Page 1 of 6 P860004 S20 g malignant origin of the pump to expand the indications approval is now seeking Medtronic the origin Note that for pain of nonmalignant Infueorph to deliver drug labeling in the approved of pain is not specified origin APPROVAL INFUMORPH microinfusion for use in continuous The drug is approved following the in addressed are portions Implantable pumps labeling of the section Administration and Dosage devices from the OF INFUMORPHIN A ADMINISTRATION FOR NEURAXIAL CANDIDATES TO PROVIDE BE HOSPITALIZED DEVICESHOULD MICROINFUSION CONTINUOUS TO RESPONSE OF DURINGASSESSMENT PATIENTMONITORING ADEQUATE HOSPITALIZATION OR EPIDURALMORPHINE SINGLEDOSESOF INTRATHECAL THE INVOLVING FOR SEVERALDAYSAFTERSURGERY BE NAINTAINED SHOULD OF DAILY ANDADJUSTMENT MONITORING INFUSIONDEVICEFOR ADDITIONAL DOSAGE is device microinfusion with the continuous withdrawn be should amount of morphine The desired from glass risk To minimize a microfilter ampul through a 5 p or through must be filtered the product particles microinfusion into the injecting before microfilter Familiarization essential from the or other smaller device Intrathecal dose must be individualized The starting dosage to serial of the response evaluation based upon in hospital DURANORPH 0 5 regular of injections bolus intrathecal single dose efficacy analgesic of the observation mg mL or 1 mg mL with close continuous the involving to surgery effects and adverse prior device microinfusion based dose must be individualized The starting dosage single dose serial to of the response evaluation upon in hospital Sulfate DURANORPH Morphine of regular injections bolus epidural for observation USP 0 5 mg mL or 1 mg mL with dose Injection involving surgery to effects and adverse efficacy prior analgesic device microinfusion the continuous Epidural POLICYANDGUIDANCE HOSPITALBRANCH GENERAL infusion of implantable the approval pumps and the regarding The policy infusion implantable approved pump was of a drug for an already addition Devices Hospital of the General at a March 5 1991 meeting outlined infusion pumps were reviewed Panel at which two irnplantable Advisory to the Panel at the Branch Chief made a statement Hospital The General Amalie C Mattan Page 2 of 6 P860004 S20 pp3 of each session to manufacturers beginning distributed The policy from those of Hard copies in attendance these can best be summarized and guidance to the Panel statements statements by the were following then excerpts the premarket whether are asked to decide the GH Panel infusion the pumps you will for PMAs applications approval are the devices that assurance reasonable today provide consider of an use The intended use intended for theiz safe and effective for drug an approved is to deliver stated infusion pump simply dosage the and of administration by the route use the intended We are NOT here today to labeling drug in the approved defined The safety of any drug and effectiveness the safety determine or today have been of the drugs encountered and effectiveness established soon will be You FDA sense How do drugs mesh with pumps in a regulatory of pumps are independent for most EXTERNAL infusion approvals specific a to Some external pumps are dedicated drugs specific labeling drug the and drugs specific On the other hand drug with even Still for implantables must alwa s be considered an implantable once Generally is flexibility there implantables of route a for particular qualified pump is clinically of drugs for the same route additional administration clinical without can be added to the pump labeling administration and stability must submit drug and device Manufacturers data must device and for the drug data and the labeling compatibility reprove to have one does not In essence be compatible otherwise of the pump effectiveness and safety the fundamental to simply To reiterate infusion pump is intended the implantable of use the defines that It is the drug labeling a drug infuse the drug as the of capable be must providing The pump the drug the safety We are NOT here to determine directs drug labeling of any drug and effectiveness Panel Meeting Advisory Hospital At the time of the March 5 1991 General to CDRH clear were not totally for the Infumorph indications the exact of for treatment would be indicated Infurnorph that It was anticipated dealt Since the Panel had only previously intractable chronic pain of of drugs for the treatment with implantable pumps for infusion by they were instructed origin intractable pain of malignant chronic drug labeling of the nonspecific the possibility FDA to consider by the General asked was Panel The of the pain the origin regarding issue the following Branch Chief to consider Hospital Amalie C Mattan Page 3 of 6 P860004 S20 - for as defined of the drug indication are the implications benign chronic of for treatment reliability Long term the device from a concern a of less was This pain must be considered pain angle for malignant risk benefit What be 50 patients that by recommending issue to this The Panel responded of an and effectiveness the safety for 24 months to demonstrate followed administration drug intraspinal system for chronic infusion implantable 24 month period that over data the of focus the that The Panel indicated complications be on device REVIEW of the SynchroMed and effectiveness safety Since the fundamental to are necessary following the System has been established Infusion benign or malignant intractable pain to chronic expand the indications origin that evidence intraspinal 2 drug stability pump reservoir 3 drug device 4 data demonstrating drug intraspinal 5 revised The five above is clinically device of administration the route 1 for data the period data compatibility the safety administration for qualified time of the life for the may be stored it of the pump of chronic and effectiveness and labeling issues have been addressed as follows and intrathecal by CDRH for epidural has been approved The device 1 intractable chronic of treatment the for sulfate of morphine delivery that demonstrated has sponsor the Thus origin pain of malignant of route intraspinal the for is clinically qualified device administration 2 for the in data were Stability number one above submitted as part of the supporting the information for 25 and 50 mg mL morphine data were submitted Compatibility 3 ---- number -------------supporting the of for --- -------- as ----sulfate ---- ----------------- ---------------one above - - - ---- ----- --- ------------------ ------ ---- ---- ------ -------------------- ---- ------ ------- ---- --- ------ --- --so 4 years approximately is of the pump life - --- ------- The expected Amalie C Mattan Page 4 of 6 P860004 S20 005 As was data these is required 4 years data for at least compatibility manufacturers implantable to other communicated pump Infumorph study using in a post approval collected may be 50 patients involving data from a study by the Panel As recommended 4 of effectiveness and safety the demonstrate which months 24 for followed are achninistration drug intraspinal for system infusion an implantable that The Panel also indicated reliability to show long term necessary has Medtronic complications device be on data these of the focus of this in support study baclofen intrathecal data from their submitted Infusion SynchroMed of the approval above stated requirement As of the drug by approval is pending baclofen System for intrathecal CDER IDE IND protocols PMA supplement table under several data have been collected The baclofen under a separate been reviewed and have previously in the following is summarized of follow up length 12 FACTOR 24 MONTHS MONTHS 24 Age 16 36 4 years 18 40 1 TOTAL 121 52 69 N 12 38 0 Males 46 29 75 Females 23 23 46 Follow up Mean months SE 16 7 04 42 0 12 23 24 24 81 15 27 6 21 0 36 0 17 0 Median Range The 12 81 recommended meet the time requirements These data more than adequately than 24 for followed been have as 52 patients by the Panel greater months than 24 follow up with both mean and median months greater are System complications are reported for all US studies Complications underinfusion occlusion catheter down into broken port pump stall access dislodgement break occlusion port catheter angulation kink hygroma and pocket kink infection prograrrcner connector contamination reservoir down into are broken complications Procedural disconnection catheter CSF leak headache dislodgment catheter infection erosion revision lacerated catheter programming pocket seroma hematoma error refill reposition catheter error meningitis to catheter break catheter prior angulation catheter puncture wound dehiscence fragment catheter subcutaneous implant pump site Amalie C Mattan Page 5 of 6 P860004 S20 OOS repositioned catheter at implant discomfort pump inverted rates and complication The complications infection incision and its components type of device for this are not unusual These data intraspinal and back reported of chronic System Infusion and effectiveness the safety demonstrate via the SynchroMed drug administration The previous revised labeling adequate has submitted 5 Medtronic specified sulfate of morphine delivery for intraspinal labeling pain for the the device indicates labeling The revised origin malignant and refill The implantation intractable of chronic treatment pain remain the smne procedures of This compatibility in one area is deficient the file In summary I Therefore study in a post approval can be handled deficiency be and approval this time at be issued letter recommend an approvable requirements to the post approval has agreed the sponsor after granted - - ------Amalie C Mattan Page 6 of 6 P860004 S20 007 Public Health Service DEPARTMENTOF HEALTH AND HUMANSERVICES Food and Drug Adainistration and Center f or Devices Radiological Health Drive 1390 Piccard Maryland 20850 Rockville August 29 1991 PMA Number Letter Dated Received Product TODD LANGEVIN MEDTRONIC INC 7000 CENTRAL AVE NE MINNEAPOLIS MN 554323576 Dear F860004 SUP 020 08 28 91 08 29 91 SYNCROMED R INFUSION SYSTEM MR LANGEVIN Health The Center for Devices and Radiological CDRH acknowledges its receipt approval application of the premarket PMA supplement device This PM supple submitted by you for the above referenced ment has been assigned document control number Failure an unique to reference supplement number in further correspondence may this result in processing All further delays correspondence shall be referred to the PMA supplement to as amendments and the required umber of copies bearing number shall be the above PMA supplement submitted directly to Food and Drug Administration for Devices Center and Radiological Health PMA Document Mail Center HFZ 401 1390 Piccard Drive Rockville Maryland 20850 You will be notified of any need for additional information and the CDRH filing decision concerning this submission may be Questions directed to the PMA Staff 427 1186 at 301 or to the reviewing di vision within the CDRH Office of Device Evaluation Sincerely yours Charles H Kyper Director Premarket Approval Office of Device Evaluation Center for Devices and Radiological Health Staff 008 iAedtronic 5l Inc Medtronic 7000 Central Avenue N E Minnesota 55432 3576 Minneapolis Telephone 612 574 4000 Telex 29 0598 Cable Medtronic 0 PMA P860004 S1 Amendment 8 C 28 August 1991 Food and Drug Administration Center for Devices and Radiological Health Document Mail Center HFZ 401 1390 Piccard Drive Rockville MD 20850 Re Amendment 8 to PMA Supplement P860004 S 1 SynchroMed Infusion System for the administration of preservative free morphine sulfate for the treatment of chronic intractable pain of nonmalignant origin Medtronic hereby submits amendment 8 to PMA P860004 S1 for the SynchroMed Infusion System which requests approval for the administration of preservative free morphine sulfate for the treatment of chronic intractable pain of nonmalignant origin This submission contains confidential trade information Medtronic requests that it be given full protection under the law Three copies of this report are provided per regulation Sincerely yeurs - Todd Lan evin Product Regula on Manager OC9 PMA P8600041S1 Amendment 8 Medtronic SynchroMecP Infusion System for the Administration of Preservative Eree Morphine Sulfate Solution for the Treatment of Chronic Intractable Pain of Nonmalignant Origin SUBMITTED 28 AUGUST 1991 010 I 1 I INTRODUCTION 1 A Background 2 B Organization of Clinical Data II CHRONIC CLINCAL DATA SUMMARY 3 A Description of Patient Population 3 B Device Related Complications 9 17 C Summary III COMPREHENSIVE CLINICAL DATA SUMMARY A Description of Studies U S Monitored Studies European Monitored Studies B Comprehensive Summary of System Complications 18 18 20 42 48 1 Summary of U S Monitored Studies 48 2 European Studies 61 3 Comprehensive Summary of U S and European Studies 64 011 LhMR Appendix 1 Appendix 2 Infumorph Drug Package Insert Advisory Panel of the Remarks by Mr Timothy A Ulatowski to the Section of the General General Hospital and Personal Use Device Medical Devices Branch to commercially available spinal catheters Appendix 3 References Appendix 4 SynchroMed draft labeling OlP I INTRODUCTION A Background m en ta tio n Se cti on 6) 200 and 1991 of Infumorph Following FDA approval on 19 July Inc Cherry Hill NJ preservative free 500 Elkins Sinn Infumorph Infusion System was morphine sulfate solutions the Medtronic SynchroMed for Devices and Radiological approved on 25 July 1991 by the Center morphine sulfate for treatment of Health of FDA for the intrathecal infusion of The SynchroMed Infusion chronic intractable pain of malignant origin of for epidural administration System had been previously approved of malignant origin morphine sulfate for treatment of chronic intractable pain route of administration based on clinical data from the intrathecal 500 developed for use in continuous 200 and Infumorph or epidural infusion in the microinfusion devices are indicated for intrathecal etiology is not stipulated treatment of intractable chronic pain The pain insert See Appendix 1 for Infumorph package of malignant origin and a Though approved for the treatment of chronic pain SynchroMed Infusion System suitable drug is commercially available the of nonmalignant origin was not approved for the treatment of chronic pain morphine sulfate with While stability and compatibility of preservative free of use had been the SynchroMed System components under conditions for pain of and served in part as the basis for approval demonstrated of safety and effectiveness malignant origin FDA determined that evidence of chronic pain of for the treatment had not been demonstrated of long term performance nonmalignant origin Specifically documentation and reliability of the pump and catheter had not been presented Yo ur Te xt Co uld Go (S ee Do cu Infumorph On e Pl ac e Hospital and Personal On 5 March 1991 the Advisory Panel of the General Branch recommended Use Device Section of the General Medical Devices demonstrate the safety that 43 patients each be followed for 24 months to chronic of an implantable infusion system for the and effectiveness that the focus of intraspinal delivery of drugs The panel also recommended the data over that 24 month period be on device complications 013 1 submits data which has been In fulfillment of this requirement Medtronic IDE G820002 of the SynchroMed obtained from studies conducted under of baclofen to treat chronic Infusion System for the intrathecal administration chronic pain of nonmalignant origin intractable spasticity Like patients with for extended periods The route of spasticity patients require treatment morphine sulfate solution and administration is the same Preservative free to the intrathecal space Both baclofen solution are both administered the Model 8703 Spinal therapies use Model 8611H SynchroMed pump The implantation Programmer and the 8810 SynchroMed Catheter are identical procedure for both therapies Hospital and Personal Use On 5 March 1991 in remarks to the General Devices Branch Advisory Panel Device Section of the General Medical A Ulatowski Chief General Hospital Devices Appendix 2 Mr Timothy Generally once an implantable pump is clinically qualified Branch stated drugs for the same route of for a particular route of administration additional without clinical data On 30 administration can be added to pump labeling letter to Medtronic for the January 1991 FDA issued an approvable administration of baclofen SynchroMed Infusion System for the intrathecal intrathecal baclofen had been solution pending notification to CDRH that CDRH that the SynchroMed approved by CDER This is an indication by for the intrathecal route of Infusion System has been clinically qualified The The actual approval is contingent on drug approval administration based was subsequently clinical data on which the approvable letter was on 22 August 1991 updated through 1 April 1991 and submitted to CDRH the safety and Medtronic believes that this clinical data demonstrates when used for the chronic effectiveness of the SynchroMed Infusion System delivery of intraspinal medications to consider the data It is on this basis that Medtronic requests CDRH from July 1984 through April collected from intrathecal baclofen studies Infusion System for the 1991 in support of approval of the SynchroMed morphine sulfate solution for the of preservative free administration origin treatment of chronic intractable pain of nonmalignant B Organization of Clinical Data 0l1 2 have been organized to provide The data contained in this amendment of the SynchroMed Infusion evidence of chronic safety and effectiveness Several baclofen studies have been System for intraspinal drug delivery studies are described later in this conducted in the U S and Europe These in followed for greater than 12 months report All patients who have been from evaluated as a cohort The data U S studies have been selected and chronic clinical data summary and these patients are summarized in the numbers length of follow up and serve to satisfy the requirements for patient by the General Hospital and Personal elements of data collection stipulated Devices Advisory Panel Use Device Section of the General Medical U S and in Europe are data from all patients followed in the clinical data summary also provided in the comprehensive For reference II CHRONIC CLIN1CAL DATA SUMMARY A Description of Patient Population from eight U S clinical studies As of 1 April 1991 a total of 121 patients longer Mean follow up for these have been followed for 12 months or 12 81 months and a median of 21 months range 1 5 27 6 is patients of greater than 24 months with months Of these 52 patients have follow up of 36 months a mean of 42 2 4 months and a median Table 1 Summary of Patient Population 12 Months Followed 24m mFgigr Females Follow up Mean Median Range mos SE Tal 121 18 40 1 16 36 4 Age yrs Males nh 52 69 N All Patients 12 38 0 46 29 75 23 23 46 16 7 42 0 04 36 0 24 81 17 0 12 24 23 3 27 6 15 21 0 12 81 015 While the IND sponsor may vary each of the eight U S clinical studies have been conducted under Medtronic s IDE G820002 A listing of each study is shown below 1 Protocol 2 Protocol 3 Protocol 4 Protocol 5 Protocol -- - --------------- ----------------- ------------- -------- - --------------- ------------- ------------ ------------ --- ---------- -- - --------------- ----------------- ------------- ---------------- - ----------------- ------------- ----------- --------------- - --------------- ----------------- ------------- ------------- ------ 6 Protocol -- - --------------- ----------------- ------------- ---------7 Protocol ----- - --------------- ----------------- ------------- ----------- -------- -----8 Protocol --- - ------ --------- ----------------- ------------- ----------- -------- ---------- data is not relied on to demonstrate chronic safety and effectiveness but used rather as supporting information The SynchroMed Infusion System is commercially available in Europe and may be freely purchased by physicians Medtronic is conducting market Though valid information European surveillance activities to collect information on system performance Patients from U S studies selected for follow up of greater than 12 months as of 1 April 1991 are shown in Table 2 016 4 Table 2 Patient Demograhics Protocol N --- - 5 m I n --- 421--- - --- - ul 84 80 1A r A ------ --- 191-- --- - ul 84 81 A ------ --- 531-- --- - ul 84 A ------ --- 351-- --- - ep 84 80 79 ----------- --- 391-- --- Oct 84 78 A --- 221-- --- Dec 84 -------------------------- --- 551--- --- Jul 85 76 68 A A --- 401-- --- 531--- --- Dec 85 --- Apr 86 63 59 A A --- 601-- --- Jul 86 A --- 391-- --- - an 87 56 49 ------ --- 401-- 50 A ---------------------------------------------- --- 441-421--- 50 48 A --- --- - an 87 --- Feb 87 --- Mar 86 --- 251--- --- Mar 87 49 --- 361-- --- Apr 87 --- 101--- --- 411-- --- Jun 87 --- Jun 87 48 45 44 A A A --- 371--- --- Jul 87 44 A --- 451--- --- Aug 87 43 A --- 491--- --- Sep 87 29 D ------ --- 421--- --- Oct 87 40 A ---------------------------------------------- --- 401 --- --- Oct 87 42 A --- 481-- 40 --- 221--- A A --- 591--- --- 291--- --- 311-- Nov 87 --- Dec 87 --- Jan 88 --- Jan 88 --- Feb 88 --- 361--- --- Jan 88 --- 421-- --- 451-- P --- -------- - A II X --- W 35 34 A A A A 38 A A 36 A A --- Apr 88 32 28 --- May 88 35 A 5 1 A 017 --- Praiaaal - Implant Date -- 301--- ------ -- 561-- -------- -- 241--- -------- -- 36 F -------- -- 471--- -------- -- 231--- ------------------------------------------- -- 341--- -- 221 --- -- 251--- -- 251--- -- 411--- -- 391--- -------- -- 401--- -------- -- --------------- - --- I May 88 35 --- Jun 88 --- Apr 89 --- Feb 90 34 A A 22 A 13 A --- Mar 90 --- Apr 89 --- May 89 13 A 23 A 21 A --- Sep 89 --- Dec 89 18 A A --- Jan 90 --- Feb 90 --- Feb 90 15 12 A A A 21 A 321--- --- Aug 89 --- Dec 89 14 A -- 371--- --- Jul 89 20 -- 391-- 13 --------------- -- 491-- --- Mar 90 --- Feb 90 A A 14 A -- 291--- 26 -------------------------------------------------- -- 421-- --- Nov 88 --- Jan 89 24 A A -- 411--- 20 A -- 371--- --- Apr 89 --- Apr 89 21 A -- 311--- --- May 89 22 A -- 331--- --- Jul 89 18 A -- 441-- --- Aug 89 16 A -- 331--- --- Nov 89 17 A -------- -- 301-- --- Jan 90 13 A -------- -- 541-- --- Oct 88 30 A ---------------------- -- 361--- 22 A -- 251--- 15 -- 451 --- --- Jun 89 --- Jan 90 --- Feb 90 14 A A -------- -- 311--- --- Mar 90 13 A -------- -- 62 -- 14 A -------- -- 481--- --- Jan 90 --- Apr 90 12 A ------ 6 14 14 018 nh in - --- ID - - A Data X -- -271--- ----------------------------- -- 521-- -- 441-- -- 411-- -- 651-- --------------- -- ---- Gian 1 II r1 27 A 25 A 19 18 A A 12 A 371--- - an 89 --- Sep 89 --- Aug 89 --- Mar 89 --- Mar 89 --- Dec 89 16 A -- 401-- --- Nov 88 18 A --------------- -- 501--- 27 -- 361--- 26 A A -------- -- 431--- --- Dec 88 --- Feb 89 --- Jun 89 20 A ------------------------------------ -- 281--- --- 19 A -- 301-- Jun 89 --- Oct 89 18 -- 391--- --- Oct 89 16 A A -- 411-- --- Oct 89 16 A -- 431-- 13 -------- -- 521--- 17 A A ----------------------------------------------- -- 271--- 17 A -- 551--- --- Mar 90 --- Sep 89 --- Sep 89 --- Mar 90 12 A -- 351--- 12 --- 541--- --- Jan 90 --- May 88 34 A A --- 571--- 22 A --- 251--- --- Dec 88 --- Nov 88 2B A --- 601--- --- Nov 88 28 A --- 711--- --- Apr 89 24 A ------ --- 461-- --- Apr 89 23 A ---------------------------------------------- --- 181-- --- Jul 89 21 A --- 481-- --- Aug 89 19 --- 411-- --- Aug 89 18 A A --- 391-- --- Aug 89 19 --- 401--- --- Aug 89 20 A A --- 391-- --- Oct 89 15 A --- 501--- --- Oct 89 17 A --- 561-- --- Oct 89 17 A --- 181--- --- Nov 89 13 A -------- 7 019 Erabzal --- 5 Dab Eall --- 661--- --- Nov 89 17 --- 201--- --- Dec 89 16 ------ --- 581-- 13 ----------- --- 211--- --- Jan 90 --- Jan 90 A A A 14 A --- 351--- 12 A -------- -- 321--- 36 A --------------------------------------------------------- -- 441--- 37 -- 591--- --- Apr 90 --- Feb 88 --- Feb 88 --- Mar 88 -- 391--- --- Oct 88 29 -- 401--- --- Mar 89 24 A A A A -- 181--- --- Aug 89 19 A -- 211--- --- Mar 89 25 A -- 531--- --- Sep 89 16 A -- 281--- 13 A -------- -- 361-- 14 A -------- --- 261--- 27 -------------------------------------------------- --- 181--- --- Jan 90 --- Jan 90 --- Feb 89 --- Jun 89 --- 181--- --- Oct 89 19 A A A --- 81--- --- Nov 89 14 T --- 261--- --- Nov 89 14 T --- 91-- --- Jul 89 19 T --- 201-- --- Feb 89 27 A --- 141--- --- Aug 89 21 A ----------- A T D - 34 23 patient still active in study patient terminated from study termination was not related to device patient died from disease OPO 8 B Device Related Complications Device related complications for all U S patients followed for greater than 12 months are listed in Table 3 Complications are divided according to those directly related to procedural events and those directly attributable to device Complications that occurred in patients implanted design or manufacture with a prototype device are indicated Table 4 is a similar table for patients followed 24 months or greater 021 9 Table 3 Summary of Device Related Complications 12 Months Followed All Patients Complications System aiian I r aiisz Pa - Catheter Angulation -------- ------- 15 ------- -------- ------- ----------- ------ -------- -------- ------ --------------------------Catheter Break Catheter Occlusion Catheter Dislodgement 5 4 ------- --------- --------- --------- -------------- ------- ------- --------- -------------- --------- --------- -------- Pump 3 -------- ------ -------- Overinfusion 2 ------ Catheter Disconnect Port Connector Kink 1 Underinfusion Intermittent Alarm 1 ---------------------- Stall 1 Total Procedural 5 ------ -------- 1 38 Complications li i Reservoir Contamination Catheter Dislodgement m r 23 7 i - I ifi i ---------- ------- ------- --------- ------- --------------- ------- -------- ------- ------- ------- ------- ------- ------- ------- ------- -------------- ------- ------- ------- ------------- ------ -------- -------- ---------------- -------- Pocket Infection Erosion Revision 5 Catheter Disconnection Catheter Lacerated 4 4 ------ -------- --------------------------------- ------- -------- ------------- -------- -------- ------ 022 10 Catheter Angulation CSF Leak Refill Error Catheter Puncture 3 2 Catheter Repositioned SeromalHematoma Catheter Break at implant Removal of Subcut Cath 2 Fragement Wound Dehiscence Programming Error 1 Meningitis 1 2 2 2 1 1 1 Total 61 Grand Total 99 - --------- --------- -------- --------- ---------------- -------------- -------------- ------------ ------------------------------------- Directly attributable to device design or manufacture Directly attributable to surgical procedure error Prototype design manufactured prior to October 1985 Reservoirs treated with gentamicin pumps not replaced 023 11 All Patients Table 4 Summary of Device Related Complications Followed 24 Months System Complications Catheter Angulation aiba E iian 14 - ------- ----------------- ------- -------- -------- ------ ------- -------- ------ --- --------- ------Catheter Break Catheter Occlusion Catheter Dislodgement 3 ------- --------- 3 ------- ------- 2 --------- -------- Pump Stall 2 -------- ------ Overinfusion Port Connector Kink Intermittent Alarm 2 -------- -------- ------ -------- Total Procedural -------- -------- 1 28 Complications m Reservoir Contamination 22 i n r - I --------- ------- ------- --------- ------ ------------ ------- -------- ------- ------- ------- Catheter Dislodgement Pocket Infection Erosion 5 ------- ------- ------- ------- ------- -------------- ------- ------- ------------- ------- -------------------------- Revision 2 ------ -------- Catheter Disconnection Catheter Lacerated 4 ----------------------------- 2 -------- -------- 028 12 - Catheter Angulation CSF Leak 2 Refill Error Catheter Puncture Catheter Repositioned 1 SeromalHematoma Catheter Break at implant Removal of Subcut Cath 1 1 --------- -------------------------------------------- Fragement Wound Dehiscence Programming Error 1 ------ 1 -------- 1 ------ 1 1 1 Total 44 Grand Total 72 Directly attributable to device design or manufacture Directly attributable to surgical procedure error Prototype design manufactured prior to October 1985 Reservoirs treated with gentamicin pumps not replaced 025 13 Infusion System complications for various components of the SynchroMed 12 System are summarized in Table 5 for all patients followed greater than months The most common system complication type was that related to the Of the 112 patients catheter These occurred at a rate of about 19 6 implanted with the current system design 22 experienced at least one system complication during the course of their therapy Mean follow up for the 112 evaluable patients is 23 months Table 5 Distribution of Complications By System Component 12 Months Patients Followed All 5 Patients Implanted Patients Implanted With Pump Catheter Prototype Patients Evaluated Patients Reporting System Complications Total System Complications System Component Pump Catheter Access Port Programmer Pocket Total 121 NA 9 NA 112 100 22 19 6 26 23 2 3 22 1 0 27 19 6 09 0 Q 26 Q 232 026 14 Complications are further described in Table 6 according to type of catheter complication and type of pump complication Table 6 Distribution of System Complications 12 Months Followed All Patients R Number of Patients Followed 12 months Number Implanted With Pump Catheter Prototype Number of Patients Evaluated Complication Description Catheter Angulation Catheter Occlusion Catheter Break Catheter Dislodgement Pump Stall Pump Underinfusion Port Connector Kink Catheter Disconnect Total 121 NA 9 NA 112 100 7 5 5 4 2 1 1 62 45 45 36 18 1 26 E2 09 09 23 2 The most common system complications observed have been those A retrospective comparison was related to catheter performance made of Medtronic Model 8703 Spinal Catheter implanted in patients with follow up of 12 months to other commercially available spinal Information for commercially available catheters was catheters obtained from the scientific literature A complete reference listing is provided in Appendix 3 On a per catheter basis complications were slightly higher for Model If one is However 8703 compared to commercial catheters assessing the chronic performance of a spinal catheter it is important to consider months of experience to understand what happens over the implant life of the catheter Total months follow up for Model 8703 is nearly double that of the commercial catheters evaluated while the number of Model 8703 catheters evaluated is less than one third for versus 3 4 Complications per month for Model 8703 is 0 8 15 027 over commercially available catheters In this retrospective analysis time the Model 8703 catheter is superior to commercially available catheters Table 7 Comparison of Spinal Catheter Performance ZG2 Total Catheters Evaluated Total Months Experience I CjgfB 112 383 2590 1379 i Catheter Kink Catheter Occlusion Catheter Break Leak Catheter Dislodgement 5 5 5 4 0 0 Catheter Disconnect Hygroma Total Complications per Catheter Complications per Month Q 5 22 47 19 6 12 3 p 0 05 08 34 p 0 001 Literature References Auld AW Spine 1985 Plummer JL Pain 1991 Shetter AG J Neurosurg 1982 Onofrio BM Mayo Clin Proc 1981 Krames ES Cancer 1985 Greenberg HS J Neurosurg 1982 Coombs DW Can Anesth Soc 1983 Woods WA Anesth 1982 Penn RD J Neurosurg 1987 Leavens ME J Neurosurg 1982 Harbaugh RE J Neurosurg 1982 Delhaas EM Lancet 1984 Cobb CA Surg Neurol 1984 028 16 C Summary for the Medtronic requests approval of the SynchroMed Infusion System the safety and treatment of pain of nonmalignant origin To demonstrate of medications effectiveness of the System for chronic intraspinal infusion 12 for Medtronic has presented clinical data for 121 patients followed Hospital months The data fulfills the requirements set forth by the General Devices Branch and Personal Use Device Section of the General Medical the safety and Advisory Panel who stipulated that to demonstrate intraspinal effectiveness of an implantable infusion system for the chronic 24 months delivery of drugs 43 patients each must be followed for at least Medtronic has presented data from 52 such patients valid and The baclofen clinical data is considered by Medtronic to be drug adequate to support this approval because of the common route of of pain delivery and the similarity of spasticity management and management of nonmalignant origin using an implantable infusion system Both therapies which use the SynchroMed Model 8611H pump and Model 8703 catheter Baclofen solution and are implanted using the same surgical procedure morphine sulfate solution are each delivered by the preservative free intrathecal route of administration for long durations The SynchroMed Infusion System was determined approvable by CDRH of FDA for the intrathecal administration of baclofen to treat chronic spasticity This suggests that the SynchroMed is clinically qualified for the intrathecal route of admini strati on Medtronic considers the clinical data collected for the SynchroMed Infusion System when used for the delivery of intrathecal baclofen to be valid scientific data which support the safety and effectiveness of the device when used to deliver intrathecal preservative free morphine sulfate solution for the treatment of chronic pain of nonmalignant origin The data presented the safety of the device and the absence of demonstrate adequately unreasonable risk when used under the conditions of intended use and in accordance labeling with the final labeling Refer to Appendix 4 for SynchroMed draft OP 0 17 III Comprehensive Clinical Data Summary A Description of Studies clinical experience for all patients The following section summarizes with the enrolled in intrathecal baclofen clinical studies who were implanted was SynchroMed Infusion System through 1 April 1991 This information of PMA reported to CDRH on 22 August 1991 as a clinical data update SynchroMed Infusion System for the Administration of P8600041S11 Intrathecal Baclofen The U S clinical studies are comprised of the eight studies listed earlier for The European studies are comprised of two studies conducted in Europe was which Medtronic is conducting safety surveillance activities Medtronic studies are provided limited access to the data These 1 Protocol ---- - -------------- ------------- multicenter 2 Protocol ---- - --------- ---------------- multicenter An overview of each study is given including patient demograhic information and characteristics of the patients Table 8 summarizes the clinical studies groupings contained in this report 030 18 I CO CV OJ CV C4 t F CD C C c o C C O O CV C 0 0 co n Z Z z z C9 CC CO hi c4 I CD Q CO N m O CV C C Q CO Cu O OJ OJ Co Q C i CV CV O O C O 3 co CD C CV CD CD CO 0 ID CV 0 CD CD n g C9 n OJ l O 0 Q JD 63 - C E E ---- GO CO Q J5 C ------ ----- I D - --- -- --- -- -- -- - - -- ---- --- ---- ---- -- -- 0 Q --- - -- --- - ----- 3- 3- 8e e CD a -- -- --- - ----- O 2 0 ------- - B --- - 0 -- O -- Q ------- -- Q eQ --- D M -- e a O ------ CL --- nfl P Q ---- 65 D C E O -- -- O CO -- --- - --- 0-g -Q --- -- - --- --- ----- 3--0 - 8 -- ------- ---- --- - ------ - -- ---- -- -- -- --- ---- -- D D ------- --- ---- - ---- ---- --------- -- -- - --- -- - ------ ----- -- - - - ------- - U D O 8-B CL 5 O LLJ 03 I Monitored US Studies I A DOUBLE BLIND RANDOMIZED CROSS OVER ----------- OF INTRATHECAL BACLOFEN VERSUS PLACEBO ------ 1 PROTOCOL - --------- Objective in the To evaluate the safety and efficacy of intrathecal baclofen or treatment of severe spasticity caused by spinal cord lesions multiple sclerosis in a randomized double blind cross over study Study Population Twenty adults suffering from severe chronic spasticity due to spinal 10 were enrolled 10 or multiple sclerosis N cord injury N The patients had stable spasticity refractory to oral baclofen or the at effective side effects from oral baclofen were unacceptable doses The patients exhibited adequate CSF flow and must have voluntarily signed informed consent Prior to pump implantation 100 pg single bolus dose of intrathecal patients responded to baclofen Following pump implantation patients were randomized to receive either baclofen or placebo for a period of three days were performed throughout The Safety and efficacy assessments the alternate drug which pump was then emptied and filled with was also administered for three days Table 9 summarizes patients for this study As these patients were of this study enrolled in Protocol - --- following completion of demographic information is included with the demographics Protocol ---- Table 11 032 20 Table 9 Protocol I Summary of Patient Characteristics Easer N Mean Age years Sex Males Females Mean Duration of Spasticity years l M5 10 GCl 10 20 40 0 35 1 37 6 3 7 8 2 44 16 11 9 30 Study Status on 5 May This study was initiated on 7 July 1986 and completed 1988 2 PROTOCOL ---- OPEN LABEL LONG TERM SAFETY BACLOFEN TRIAL OF INTRATHECAL SPASTICITY ------ --------WITH SEVERE EFFICACY AND IN PATIENTS Objective of chronic intrathecal To evaluate the long term safety and efficacy in the treatment baclofen administered via implantable drug pump lesions or multiple of severe spasticity caused by spinal cord study sclerosis in a randomized double blind cross over Study Population due to spinal cord Patients suffering from severe chronic spasticity trial Thirty four injury or multiple sclerosis were enrolled in the were implanted with a pump and are patients were screened 32 to oral The patients had stable spasticity refractory evaluable were unacceptable baclofen or the side effects from oral baclofen CSF flow voluntarily at effective doses The patients had adequate 21 033 and prior to pump implantation signed informed consent 100 pg single bolus dose of intrathecal baclofen responded to Twenty of these patients also participated in Protocol I described for these above Table 10 summarizes patient characteristics patients - Table 11 shows patient demographics ------- ---- ---------- --- Summary of Patient Characteristics Factor Total Patients Mean Age years 34 40 Sex Males Females 17 17 Duration of Spasticity years 30 3 0 41 Diagnosis SCI 4 16 16 2 MS Other Follow up Median Mean Range 48 6 49 5 5 4 81 1 Following screening and pump implant patients returned monthly for reservoir refills and evaluation of safety and efficacy Study Status This study was initiated on 14 June 1984 Enrollment is complete Long term follow u-- ----- ------------- ---- ---------- --- rently active will be rolled over to ---------- ----------------- ---------- which is the -------------- IDE following completion of required follow up and IRB approval 03 22 TABLE 11 PROTOCOL IB PATIENT DEMOGRAPHICS Duration Primary Pt ID - -------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Site of Spasticity Implant yrs Date c Age Sex Ox a Injury b SCI T4 421 -- SCI T4 191-- MS NA 53 F MS NA 351-- MS NA 39 F SCI C6 221-- SCI C7 551--- SCI T5 401 -- MS NA 531--- MS NA 601-- MS NA 391-- MS NA 401-- MS NA 441-- SCI T12 421--- SCI T9 251--- SCI T6 S 361-- 20 30 19 0 80 20 0 20 0 24 0 08 30 30 10 10 20 06 04 25 SCI C1 101--- 21 ---- un 87 SCI C7 411-- C5 371--- SCI C5 451--- SCI T4 5 49 --- MS NA 42 --- MS NA 40 --- MS NA 661--- MS NA 481-- MS NA 481--- 06 20 50 10 20 10 ND 06 ND ---- un 87 SCI SCI T6 221--- MS NA 591--311-- Dystonia NA 361--- SCI C7 251--- Head Inj NA 421-- MS NA 451-- MS designates b Site of Injury T designates thoracic ----- ep 84 --- Oct 84 ----- ec 84 --- Jul 85 ----- ec 85 --- Apr 86 --- Jul 86 ---- an 87 ---- an 87 ----- eb 87 --- Mar 87 --- Mar 87 --- Apr 87 --- Jul 87 ----- ug 87 ----- ep 87 --- Oct S7 --- Oct 87 ---- T IMPL --- Nov 87 ---- T IMPL --- Dec 87 SCI designates 291--- A A A A A A A A A A A A A A A A A A A A D A A Sc A Sc A A A A A D A A --- Jul 84 Multiple Sclerosis C7 NA 80 0 81 1 8 3 78 S 77 5 75 7 68 3 62 7 59 2 55 5 49 1 50 2 4S 6 48 5 48 6 47 6 45 1 44 4 43 9 42 9 29 2 40 3 42 2 ND 40 1 ND 34 9 34 1 37 8 36 5 31 8 54 27 5 35 2 --- Jul 84 --- May 88 SCI Status e Jul 84 19 0 03 80 70 20 36 60 MS a Primary Diagnosis ---- Months Follow up d C designates ---- an 88 ---- an 88 --- Feb 88 --- Jan 88 --- Apr 88 --- Apr SB cervical Spinal Cord Injury NA designates not applicable c Date of SynchroMed pump implant d Duration of long term experience through 4191 or last follow up A D dead due to disease designates active designates e Patient status as of 4191 f Protocol deviation g Patient died due to progressive ND No Data Sc designa disease 23 035 3 PROTOCOL II MULTICENTER OF INTRATHECAL BACLOFEN STUDY RANDOMIZED PLACEBO ------ --------- DOUBLE BLIND VERSUS Objective To evaluate the safety and efficacy of intrathecal baclofen in the treatment of severe spasticity caused by spinal cord lesions or multiple sclerosis in a multicenter randomized double blind study Study Population Ninety three patients have been screened 75 have proceeded to implant Patient selection was based on the following criteria males and females between 18 and 65 years of years patients must have had severe chronic 12 months spasticity as defined by an Ashworth score of three or greater and a spasm frequency score of two or greater spasticity must have been refractory to oral at effective doses baclofen or the side effects unacceptable spasticity must have been stable adequate CSF flow must have been evident patients must have exhibited a response to a single informed dose before implantation bolus 100 pg screening consent must have been given voluntarily All patients were screened in a double blind phase of the study Those who responded proceeded to pump implantation and the long term phase of the study Those who did not respond to screening were not implanted Table 12 is a summary of patient characteristics Table 13 lists patient demographic information 036 24 Table 12 Protocol II Summary of Patient Characteristics r F Total Patients Mean Age years 93 40 2 Sex Males 66 27 Females 79 Duration of Spasticity years 0 1 34 6 Diagnosis SCI 60 MS 31 2 Other Follow up Median 14 0 Mean Range 15 6 4 6 35 3 Study Status This study was initiated in May 2 1988 On March 7 1990 FDA Center for Drug Evaluation and Research authorized Medtronic to proceed with a Treatment Protocol This has been titled Protocol IIB ----------------------- All patients currently enrolled in Protocol II rolled over will be following completion of required follow up and IRB approval at each institution Enrollment in Protocol II is complete and this study will be closed when all - atients have been rolled over to Protocol IIB -------------- ----------- 037 25 TABLE 13 PROTOCOL II PATIENT DEMOGRAPHICS Duration of Primary Pt ID - ------ Dx a MS Injury b NA Implant Spasticity Site of Age Sex SOI-- ------ MS NA 561-- ------ MS NA 62 M yrs 10 0 40 ----- c - Months Follow up d ------- y 88 35 3 ------- 88 34 2 -- A NA ------- 89 46 -------- SCI T4 391--- 66 93 ----------------------------- SCI C2 381--- 84 -- A NA SCI T5 8 241--- 36 ------- r 89 22 4 361--- -- A SCI T6 7 361-- -------- SCI C6 231--- 27 15 5 48 78 54 62 12 ---------------------------------------------------------------------------------------------- ----------------------------- SCI C5 SCI C5 341--- SCI C4 301--- MS NA 261--- SCI T6 221--- SCI T7 331--- SCI T10 251--- 17 5 33 12 ------- c 89 14 4 ------ n 90 15 0 37 27 ------ b 90 13 8 ------ b 90 12 5 ----- pr 90 10 1 ------- g 89 20 7 ------- c 89 13 8 ------- y 90 10 1 A A A A A NA Sc 391--- SCI C4 301--- SCI T6 401--- SCI C4 321--- 10 45 SCI C6 421--- 05 NA 411--- 11 0 SCI C4 5 291--- 93 MS NA 371--- 17 5 251-571--- --------------- SCI T9 291--- MS NA 421-- -------- SCI T10 411--- -------- MS NA 371--- --------------- SCI T7 8 311--- SCI L3 4 331--- -------- MS NA 441-- -------- MS NA 471--- ----------------------------- MS NA 39--- MS NA 49--- MS NA 63--- MS NA 54--- --------------- MS NA 331--- MS NA 56--- ----------------------------- MS NA 30--- MS NA 421--- MS NA 46--- SCI C7 8 54--- --------------- SCI C6 36---- SCI C6 7 34---- -------- SCI C5 6 38---- --------------- SCI C4 5 54---- SCI C4 5 Sc Sc A A A A ------ p 89 C4 T6 21 2 Sc A A A NA SCI C6 23 4 Sc A -- A 411--- SCI ----- pr 89 ------- y 89 Sc W NA C4 SCI ------ b 90 A A -- A SCI NeuroFib NA 12 6 Status -- A 91 a ---- Jul 89 20 4 a Sc D A A ------ n 90 -- A NA ----- ov 89 10 8 53 10 0 ----- ov 88 26 0 ------ n 89 23 7 22 9 10 9 12 9 ----- pr 89 20 5 ----- pr 89 20 6 ------ ay 89 22 0 38 23 39 19 2 57 41 ---- Jul 89 17 6 ----- ug 89 16 0 ------ ar 90 13 4 ------ ar 90 12 7 A A A A A A A ----- eb 90 13 8 80 18 ------ n SO 97 ---- Jul 90 76 A A A 94 81 10 0 18 0 25 3 24 ---- Nov 89 17 0 A ---- Nov 89 11 2 01 21 20 34 0 25 21 9 A A A A A A NA NA Sc NA NA Sc Sc A ---- an 90 13 0 ----- eb 90 50 ------ ar 90 82 ----- ct 88 29 8 ---- un 89 NA ---- an 90 NA 15 2 038 - ------------------------------------ SCI -------- C2 7 631---- SCI T8 38 M 93 SCI C6 451--- 18 5 - NA NA Sc ---- NA Sc -------- 90 14 5 A ------- r 90 13 1 A 89 A SCI C4 5 311--- 72 SCI C4 5 251--- 44 ---- - ul 90 SCI T4 291--- 75 -- A -------- MS NA 62--- -------- SCI C6 7 691--- -------- SCI C6 481--- -------- 13 27 49 NA Sc ------- 90 14 1 A ------- 90 10 0 A -------- 90 11 6 A ---- - ul 90 89 A SCI C3 4 44 M 25 SCI NA 441M 13 5 -- A NA Sc NR 401M 17 9 ------- v 90 47 A 53 ------ n 89 27 1 A A ---------------------------------------------------- Lupus -------- SCI SCI MS C6 271M NA 521F 21 ------- r 89 24 S NA 441-- 15 7 ------- g 89 19 4 A 17 7 A A MS NA 411-- 14 3 ------ p 89 MS NA 651-- 14 2 ------ ar 09 11 9 MS NA 371--- 60 ------- c 89 15 9 A W MS NA 401-- 14 4 ------- v 88 17 5 --------------- SCI L5 501--- 52 ------- c 88 26 8 A SCI C4 5 361--- 38 ------ b 89 26 2 A -------- SCI C6 431--- 08 ------ n 89 20 5 A ----------------------------- SCI C4 5 281--- 13 9 19 2 A ----- ct 89 17 9 A ----- ct 89 15 7 A -------- ---- Jul 89 SCI T10 301-- SCI T7 10 391--- 44 68 SCI C5 411-- 57 ----- ct 89 16 3 A 23 ----- pr 90 10 6 A ------ ar 90 -------- SCI T6 7 241--- -------- SCI T4 5 261--- 16 92 A -------- MS NA 69--- 29 5 -- A NA Sc -------- SCI C5 6 411--- 23 ----- pr 90 97 A ----------------------------- MS NA 531--- 14 2 ------ ar 90 10 6 A NA 431-- 52 ------ ar 90 12 7 A A MS MS NA 621--- 23 ----- pr 90 10 1 MS NA 461--- 20 0 ------ ar 90 11 2 A 17 3 A -------- SCI T5 521--- 30 ------ p 89 --------------- SCI C4 271--- 31 ------ p 89 16 6 A SCI C5 251--- 14 ------- v 89 11 7 A 34 6 ------ ar 90 12 3 A ----- pr 90 81 A 05 ---- an 90 12 2 A ---- un 90 10 5 A -------- MS NA 551--- -------- SCI C4 311--- C4 5 351--- -------- SCI --------- SCI C5 33 --- 22 --------- SCI C6 19---- 15 NA NA NA NA Sc NA Sc --------- SCI NA 481--- 16 NA --------- MS NA 41--- S2 NA SCI designates Multiple Sclerosis a Primary Diagnosis MS designates cervical C Injury T thoracic designates designates Site of b Spinal Cord Injury c Date of SynchroMed pump implant 0 Duration of long term experience through 4191 or last follow up D A dead due to disease designates active designates e Patient status as of 4191 screened only not implanted f Protocol deviation not applicable NA designates 26B Sc designa 03g 4 PROTOCOL IIB TREATMENT PROTOCOL OF INTRATHECAL BACLOFEN VERSUS MULTICENTER STUDY PLACEBO - ------ --------- Objective The objective of this study is to provide chronic Lioresal baclofen USP Injection therapy for patients with severe spasticity of spinal cord origin who meet protocol criteria and to obtain additional data on the safety of intrathecally administered Lioresal Injection Study Population Sixty six patients have been screened 61 have proceeded to implant Patient selection was based on the following criteria patients must have had severe chronic spasticity as defined by an Ashworth score of three or greater or a spasm frequency score of two or greater spasticity must have been refractory to oral baclofen or the side effects unacceptable at effective doses patients must have exhibited a response 100 pg single bolus screening dose before implantation informed consent must have been given voluntarily Table 14 summarizes patient characteristics Table 8 lists patient demographic information to a 040 27 Table 14 Protocol IIB Summary of Patient Characteristics Fager Total Patients Mean Age years 66 39 7 16 71 Sex Males Females 42 23 95 Duration of Spasticity years 0 3 62 0 Diagnosis SCI 42 MS 22 1 Other Follow up Median Mean 45 44 Range 0199 Data for patient - -------- is not available Study Status This study was initiated on 7 March 1990 and remains active Quarterly safety updates are filed with FDA describing results from weekly telephone surveys of newly enrolled patients 041 28 TABLE 15 Primary Pt ID - -------------------------------------------------------------------------------------- PROTOCOL IIB PATIENT DEMOGRAPHICS Implant Duration Site of Dx a Injury b Age S--- SCI T11 12 711--- Date c Spasticity 19 - ---- Jul 90 Months Follow up d Status e 85 A A MS NA 271-- NR ----- ug 90 74 MS NA 641-- 07 ------ p 90 61 51 4 61 A ----- ct 90 A MS NA 23 --- 88 MS NA 36--- 13 9 ----- ov 90 MS NA 551-- NR ----- ov 90 T2 52--- 33 7 ----- ec 90 SCI C6 511--- 43 ---- an 91 SCI T10 431--- 15 ---- an 91 52 ----- pr 91 A A SCI NR SCI C5 171--- 19 ----- pr 91 3 98 3 42 3 45 3 29 07 30 SCI NA 691--- BR ----- ct 90 45 A A SCI 21--- A A A A A 55--- 18 ---- an 91 1 64 NA 44--- 52 ------ ay 90 621--- NR ---- un 90 82 89 A NA MS NA 68--- 20 8 ---- un 90 76 SCI T8 471--- 24 3 ---- un 90 97 A A SCI C3 301--- 53 ------ ay 90 10 9 ----- ep 90 99 46 89 69 60 A A A A A Sc A SCI NR MS Familial A - pastic Disease ------------------------------------------- SCI C4 5 331--- SCI C4 201--- 31 ---- un 90 SCI NR 511--- 13 6 ----- ep 90 -------- SCI C1 2 161--- 24 ----- ep 90 --------------- SCI T4 471--- 10 02 NA NA SCI C5 401--- 31 --- Dec 90 32 ------------------------------------ MS NA 401--- 24 9 --- Dec 90 3 45 SCI T7 8 63--- 10 --- Dec 90 SCI CS 27 --- 35 --- Jan 91 3 68 2 01 NA 95 A A A Sc A MS NA 361--- 12 7 NA SCI T6 251--- 17 --- Mar 91 --------------- SCI C5 6 601--- 26 ----- ug 90 SCI T4 31--- 63 ----- ug 90 --------------- SCI 79 37---- 29 ------ ar 90 SCI C6 461--- 18 --- Dec 90 ------------------ MS NA 481--- 24 8 --- Nov 90 NA NA NA NA NA 11 6 --- Aug 90 --- Sep 90 83 48 Sc A A --- Jan 91 --- Feb 91 1 84 1 51 A A 0 10 4 05 A A 76 76 p --------------- MS NA 601--- MS NA 291--- 48 ------------------------------------------- MS NA 531--- 23 0 MS NA 541-- 17 0 MS NA 531-- 50 ---- an 91 MS NA 451-- 17 9 --- Dec 90 SCI C5 6 211--- 03 --- Aug 90 SCI C3 4 261--- 05 ---- un 90 29A 56 02 3 85 3 88 50 NA A A A A A A 0l - ---------------------------------------------------------- --------------------------------------------------------------------------------- SCI SCI SCI SCI C7 T8 T4 C7 SCI T11 L4 MS MS SCI SCI SCI SCI SCI SCI NA NA T5 C1 2 C2 3 C3 NR NR SCI C6 --37-24---- 25 22--25---- 56 58 98 46--- 12 ---- Nov 90 --- Aug 90 --- Dec 90 --- Jan 90 --- Apr 90 --- Oct 90 --- Oct 90 --- Oct 90 --- Oct 90 --- Jul 90 24---36--27---21--29---- 14 7 53---49---- 09 33--22---- 37 --- Nov 90 --- Mar 91 --- Mar 91 12 --- Dec 91 16 6 21 51 NR 18 SCI C4 5 24---- 06 --- Feb 91 SCI C4 5 49---- 15 2 SCI C2 27---- 01 MS NA 32---- 11 9 --------- MS NA 43--- 10 8 --------------------------------- SCI T6 38---- 23 --- Feb 91 --- Oct 90 --- Feb 91 --- Dec 90 --- Mar 91 MS NA 42---- 24 0 --- Feb 91 MS NA 50--- 13 9 NA SCI C6 34---- 47 NA 46 7 63 3 68 2 17 96 50 57 51 50 83 5 26 62 4 11 3 26 1 74 59 53 59 4 54 66 76 NA NA A A A A A A A A A A A A A A A A A A A A A Sc Sc a Primary Diagnosis MS designates Multiple Sclerosis SCI designates Spinal Cord Injury b Site of Injury T designates thoracic C designates Cervical c Date of SynchroMed pump implant d Duration of experience through last follow up A W designates active designates withdrawal e Patient status not implanted f Protocol deviation g Patient --------- demographic data missing NA signifies not applicable Sc designated screened only Q43 29B 5 PROTOCOL III DOUBLE BLIND RANDOMIZED STUDY OF INTRATHECAL Objective To evaluate treatment disorders BACLOFEN VERSUS PLACEBO ------ --------- the safety and efficacy of intrathecal baclofen in the of severe spasticity caused by various neurological Study Population This study was conducted by Dr Richard Penn at Rush Luke s Medical Center under physician sponsored Presbyterian St ------- --------Patients enrolled in this study are considered deviations from Protocol II Entry criteria were identical to those of Protocol II except the evaluable patients were given a higher initial screening bolus dose than the protocol stipulates Inevaluable patients included those with spasticity of neurological origins other than spinal cord injury and multiple sclerosis Table 16 summarizes patient characteristics demographic information Table 17 lists patient 044 30 Table 16 Protocol Ill Summary of Patient Characteristics EQgi9r Total Patients Mean Age years 32 41 0 12 76 Sex Males 16 Females 16 Duration of Spasticity years 10 6 3 0 31 Diagnosis SCI 11 MS 9 Other 12 Follow up Median Mean 1 16 2 15 1 Range 0 1 34 1 Study Status This study was initiated April 1989 Dr Penn has screened 32 patients and implanted 28 He will continue to enroll patients into this study under his physician sponsored IND Q4 c 31 17 TABLE III INEVALUABLE PROTOCOL PATIENT DEMOGRAPHICS Duration of Primary ox a ---- --- - dystonia --------- SCI ------ ------ SCI cervical --------- Yrs Implant Date c --- --- ay 88 34 14 A ----- ec 88 21 94 A A Spasticity Site of Age Sex Injury b NA 541--- 16 8 T4 5 571--- 12 - Months Follow up d Status e C5 251--- 05 ----- ov 88 28 39 C4 6 601--- 14 ----- ov 88 28 52 A NA 711--- 28 3 --- Apr 89 23 91 A NA 461-- 21 --- Apr 89 23 32 A NA 181-- 13 5 ---- Jul 89 20 79 A myelopathy --------- neurofibroma MS ------ arachnoiditis --------- ------ MS NA 481-- 23 ----- ug 89 18 91 A ------ SCI C5 6 411-- 3 ----- up 89 17 76 A NA 391-- 11 5 ----- ug 89 19 28 A 19 64 ------ MS NA 401--- 22 ----- ug 89 ------ SCI C4 T4 5 121--- 12 1 ----- ep 89 33 W ------ MS NA 441--- 13 ----- ep 89 03 D --------- spondylolithesis A ------ MS NA 391-- 20 ----- ct 89 15 20 A ----------- SCI T6 7 501--- 17 ----- ct 89 17 04 A A MS traumatic --------- NA 561-- 19 6 ----- ct 89 17 04 NA 181--- 05 ----- ov 89 13 39 A TB 12 661--- 12 5 ----- ov 89 16 91 A 17 ----- ec 89 injury brain ------ SCI ------ SCI C5 6 201--- ------ MS NA 411--- NA MS NA SCI --------- spasticity unknown ------------------- 15 56 A 15 2 -- A NA Sc 761-- 71 -- A NA Sc 581-- 31 1 ---- an 90 12 96 A TB 9 211--- 86 ---- an 90 14 21 A NA 401--- 72 ----- pr 90 6 02 A A - origin stiffman syndrome - ------ MS NA 411-- 21 9 --- Apr 90 9 93 ------ SCI CS 351--- 13 9 --- Apr 90 11 78 A --------- dystonia NA 371-- 20 4 NA Sc ------ SCI T4 5 221-- 31 --- Jul 90 86 A ----- ---- head injury NA 181-- 21 --- 1 68 A 391-- 15 ---- un 90 51 A --- Mar 91 NA Sc ------ SCI C3 4 --- --- SCI C4 7 441-- 18 --------- anoxic NA 361--- 03 a Primary Diagnoeie MS designates b Site of Injury T deeignates c Date of SynchroMed throacic Multiple Sclerosis C designates SCI designates cervical -- A Jul 90 NA A Spinal Cord Injury NA designatee not applicable pump implant 4 Duration of long term experience through 3190 or last follow up NA designates not applicable A W Patient etatue as of 3190 designates active designates withdrawal due to pocket infection le f Protocol deviation 4A signifies not applicable 32 Sc designates screened only not implanted 046 7 PROTOCOL V REPORT BACLOFEN INTRATHECAL OF A SINGLE IN PATIENTS CENTER WITH STUDY SPINAL OF CORD INJURY ------- --------- Objective To evaluate the safety and efficacy of intrathecal baclofen in the treatment of severe spasticity in a single center randomized double blind study Study Population Sixteen patients with severe chronic spasticity due to spinal cord injury were screened and implanted Oral baclofen was ineffective or caused intolerable side effects Table 18 summarizes patient characteristics Table 19 lists patient demographic information 047 33 Table 18 Protocol V Summary of Patient Characteristics F or Total Patients Mean Age years 16 35 1 18 59 Sex Males Females 14 2 Duration of Spasticity years 59 051 89 Diagnosis SCI 14 MS 0 Other 1 Follow up Median 13 4 Mean 18 0 Range 1 4 37 0 Study Status This study was initiated 3 February 1988 Dr Loubser continues to enroll patients at the Institute of Rehabilitation and Research Houston Texas under his physician sponsored IND 048 34 TABLE 19 PROTOCOL V EVALUABLE PATIENT DEMOGRAPHICS Duration of Primary Pt ID - Dx a Site of Injury b Age Sex Spasticity Implant yrs Date c -------- CP -------- SCI C2 21---- -------- SCI T121L1 53---- 8 05 05 5 3 18 41 28 281--- -------- SCI T8 32---- -------- SCI C4 44---- C7 59---- -------- SCI -------- SCI T8 39---- -------- SCI T7 40---- NA 18---- -------- SCI C4 5 -------- SCI C7 361-- -------- SCI T12 401-- Status e ------ b 88 36 38 A ------ b 88 37 01 A ------ ar 68 34 28 A ----- ct 88 29 01 A ------ ar 89 24 11 A ----- ug 89 18 88 A ------ ar 89 24 80 A ----- ep 89 16 55 A 13 ---- an 90 13 42 A ---- an 90 13 88 A ----- ug 90 6 38 A ---- Jul 90 8 52 A SCI C5 201--- -------- NR NR NRI--- -------- SCI C5 211--- 6 5 NR 4 -------- - Months Follow up d ----- pr 90 11 12 A ----- ug 90 7 04 A A A -------- SCI C6 40I--- 15 ---- an 91 1 41 -------- SCI C5 6 361--- 5 --- Oct 90 5 39 Spinal Cord Injury Multiple Sclerosis SCI designates a Primary Diagnosis MS designates lumbar cervical L designates thoracic C designates b Site of Injury T designates c Date of SynchroMed pump implant d Duration of long term experience through 4191 or last follow up A active designates e Patient status as of 4191 048 35 7 PROTOCOL VIII DOUBLE BLIND RANDOMI2ED STUDY OF INTRATHECAL BACLOFEN MANAGEMENT OF SPASTIC VERSUS PLACEBO CEREBRAL PALSY I-- ----------- --------- Objective To evaluate the safety and efficacy of intrathecal baclofen in the treatment of severe spasticity caused by cerebral palsy in a single center controlled study Study Population This study is being conducted by Dr Richard Penn at Rush Luke s Medical Center under physician sponsored Presbyterian St ------- --------- Pediatric patients with cerebral palsy are candidates Table for enrollment Table 20 summarizes patient characteristics 21 lists patient demographic information 05o 36 Table 20 Protocol Vill Summary of Patient Characteristics Easier 3 Total Patients Mean Age years 117 11 13 Sex Males Females 2 1 Duration of Spasticity years 11 9 11 1 13 1 Diagnosis SCI 0 MS 0 CP 3 Follow up Median 96 Mean Range 96 8 8 10 3 Study Status This study was initiated April 1989 Dr Penn has enrolled three patients thus far He will continue to enroll patients into this study under his physician sponsored IND 05 37 Pt ID - ---------------- TABLE 21 PROTOCOL VIII PATIENT CHARACTERISTICS Implant Duration of Primary Site of ---- e b Spasticity Age Sex Injury Diagnosis a ----- pr 90 11 1 11---NA CP 11 4 ---- Jul 90 11---NA CP -- A 13 07 13--NA CP Months Follow up c 10 33 8 82 NA Status d A A Sc a Primary Diagnosis CP designates cerebral palsy lb Date of SynchroMed pump implant c Duration of experience through last follow up Sc A designates screened only not implanted designates active d Patient statu NA signifies not applicable 057 38 8 PROTOCOL VI DOUBLE BLIND TRIAL OF INTRATHECAL MANAGEMENT RANDOMIZED BACLOFEN OF SPASTIC VERSUS CEREBRAL CROSS OVER PLACEBO PALSY IN THE -------------- Objective To evaluate the safety and efficacy of intrathecal baclofen in the treatment of severe spasticity caused by cerebral palsy in a single center controlled study Study Population This study is being conducted by Dr Leland Albright at Children s Hospital Pittsburgh PA Thirty six patients have been screened Table 22 summarizes 18 have been implanted patient characteristics Table 23 lists patient demographic information 053 39 Table 22 Protocol Vl Summary of Patient Characteristics F r Total Patients Mean Age years 36 13 4 5 31 Sex Males Females 24 12 Duration of Spasticity years 11 1 0 5 26 Diagnosis CP 32 4 Hl Follow up Median Mean 11 11 1 0 5 27 Range Study Status This study was initiated February 1989 Dr Albright has enrolled 18 patients thus far He will continue to enroll patients into this study under his physician sponsored IND 050 40 TABLE 23 --- ------ - -------- Dx a CP PROTOCOL AGE SEX Vl PATIENT DEMOGRAPHICS MONTHS YEARS IMPLANT SINCE Dx DATE d 25 - ----- eb 89 27 A 23 A 261--- FOLLOW UP e STATUS f -------- CP 181--- 16 -------- CP 181--- 17 ---- un 89 ----- ct 89 19 A 81--- 7 ---- -- ov 89 14 T ----- ov 89 14 T 19 T 27 A -------- CP -------- Hl 261--- 3 -------- CP 91-- 8 ---- Jul 89 -------- HI 201 -- 2 ------ b 89 -------- CP 141--- 13 ----- ug 89 -------- CP 81-- 7 -------- CP 11--- 10 ------ n 90 -------- CP 11--- 10 ------ n 90 -------- CP 151--- 13 -------- CP 51--- 5 -------- CP 14--- 13 -------- CP 7 -- 6 21 A NA Sc ONLY 11 A NA Sc ONLY 3 T NA NA Sc ONLY NA NA Sc ONLY NA NA Sc ONLY NA NA ------ ay 89 A -------- CP 121--- 12 -------- CP 51--- 5 NA NA Sc ONLY -------- CP 91--- 9 05 T -------- CP 15--- 15 --- Aug 90 ----- eb 91 3 A -------- CP 131--- 13 ---- an 91 4 A -------- CP 191--- 19 ------ ar 91 2 A -------- CP 10--- 10 NA NA Sc ONLY -------- CP 12---- 11 NA NA Sc ONLY NA NA Sc ONLY -------- CP 18---- 18 -------- CP 5 5---- 55 NA NA Sc ONLY -------- CP 31--- 26 NA NA Sc ONLY 9 NA NA Sc ONLY -------- CP -------- CP 71-- 7 NA NA Sc ONLY -------- CP 15---- 15 NA NA Sc ONLY 8 A 91--- 9 - ----- ep 90 10---- 1 ----- ec 90 CP 17---- 17 CP 61--- 5 2 A -------- Hl 16 5---- 5 NA NA Sc ONLY -------- CP 12--- 11 na NA Sc ONLY -------- CP 23---- 23 -------- CP 91--- -------- Hi --------------- a Diagnos s CP designates CSA des gnates congenital Cerebral Palsy - NA ------ ar 91 NA Hl designates 5 A NA Sc ONLY NA post traumatic Sc ONLY head injury skull agenesis given prior to study entry to affect functional status medication administered to patients prior to entry Oral anti spasticity c d Date of SynchroMed pump implant b Therapy e Duration of long term experience through 4191 or last follow up Sc A screened designates active designates f Patient status as of 4191 T implanted designates patient terminated study NA Not Applicable NR Not Recorded only not 055 41 European Studies 1 PROTOCOL IV REPORT OF AN OPEN LABEL LONG TERM SAFETY AND EFFICACY TRIAL OF INTRATHECAL BACLOFEN CONDUCTED IN EUROPE Objective To evaluate the safety and efficacy of intrathecal baclofen in the treatment of severe spasticity in a multicenter open label trial conducted in Europe Study Population Twenty eight patients with severe chronic spasticity due to spinal cord injury or multiple sclerosis were enrolled Oral baclofen was ineffective or caused intolerable side effects Table 24 summarizes patient characteristics information Table 25 lists patient demographic 056 42 Table 24 Protocol IV Summary of Patient Characteristics F r 28 Total Patients Mean Age years 46 4 20 64 Sex Males Females 16 12 Duration of Spasticity years NA Diagnosis SCI 18 MS 10 CP 0 Follow u p Median 42 0 Mean 42 5 Range 7 60 Study Status This study was initiated 1 December 1986 and completed 30 1988 Patients are currently being followed in a September European market surveillance program 057 43 TABLE 25 PROTOCOL ---- --- ---------------------------------------------------------------------------------- -------------------------------------------------------------------------------------------- a MS Center 2 2 1 1 IV PATIENT DEMOGRAPHICS Implant Date - ----- ec 86 ----- ep 86 MS Age S--371 ---- SCI 641--- MS MS MS MS 611-461 -261 -591 -- ----- ov 86 SCI SCI MS 33I--431-501 --271 --- ----- ec 86 Diagnosis a ----- pr 86 ---- ul 86 ----- eb 86 ----- pr 87 ----- pr 87 ------ ay 87 ----- pr 87 2 3 4 4 3 1 2 SCI SCI SCI SCI SCI MS MS MS 1 2 3 3 1 MS 561-601 -- SCI SCI SCI 631--501--471--- SCI SCI SCI SCI SCI SCI SCI 571--471 --361 --201 --49-- -48-- -- ---- an 88 ---- an 88 ----- ec 87 ----- ec 87 ----- ec 87 ------ ar 88 ----- eb 88 ---- an 88 ----- eb 88 241--- ----- ov 87 3 4 4 4 Multiple sclerosis SCI 521-391--621-401--561-461 --- ---- ul 87 ---- ul 87 ----- ug 87 ------ ay 87 ----- ep 87 ----- ep 87 ----- ug 87 Follow up mes 50 53 48 58 56 60 50 46 46 46 46 43 43 42 45 41 41 42 37 39 38 38 35 25 37 36 41 spinal cord injury 058 44 VII 2 PROTOCOL SURVEILLANCE REPORT OF A EUROPEAN MARKET Objective To monitor the safety of intrathecal baclofen in the treatment spasticity in actual clinical practice in Europe of Study Population This patient population is derived from several investigators in Europe where baclofen is supplied by several manufacturers the though none are conducting clinical trials In addition Infusion is commercially available in Medtronic SynchroMed infusion of for intraspinal Europe and may be purchased Physicians administering baclofen therapy in this setting did not adhere to a consistent prospective protocol Table Table 27 lists patient 26 summarizes patient characteristics demographic information medications 058 45 Table 26 Protocol VII Summary of Patient Characteristics r F Total Patients Mean Age years 165 40 5 12 72 Sex Males Females 96 69 Duration of Spasticity years NA Diagnosis SCI 49 MS 66 other 45 unknown 5 Follow u p Median 23 5 Mean 22 1 Range 1 59 Age missing for patients CH3 1 and CH3 2 Study Status This study was initiated June 1987 A total of 166 patients have been screened and 164 have been implanted Medtronic continues to monitor activity in Europe 060 46 TABLE 27 Pt ID - ------------------------------------------------------------------------------------------------------------------------------------------------------------- ------------------------------------------------------------------ PROTOCOL Age Sex 151--491-251-201--121--27---241--331 --491--441--451 --491 --341 --201 --201 --231--451-561 --61--62--391 --38----431 --- VII PATIENT DEMOGRAPHICS Primary Diagnosis a NA Encephalitis Brain trauma Cerebral trauma Cerebral trauma Spinal hemiangioma SCI Hydromyely MS MS MS MS Cerebral trauma latrogenic SCI Strumpell Lorrain ------- t 89 Cerebral trauma MS MS ------- g 90 Strumpell Lorrain MS SCI SCI SCI 411-- MS 311--401--521 -- SCI MS 191--401 -531 --351 -631--401-- ------ n 88 ------ n 88 32489 ------- c 88 ------ b 90 Cerebral trauma 381 ---611--681--481--281 --- ---- j ------- g 90 MS 621-241 --121--571 --- 721--- Implant Date dlml b - ------- 89 ------- 90 ------- 90 ------- y 90 ------- y 90 ------- 88 ------ n 88 ------- y 89 ------- c 89 ------ b 90 SCI Cerebral hemiplegia Hemiplegia post Vase accident Cerebral trauma SCI Vascular hemiplegia SCI SCI SCI MS SCI MS ------ p 90 ------ ay 88 ------ n 88 ------ n 88 ------ b 89 ------ b 89 ------ ar 89 ----- pr 89 ---- un 89 ----- ct 89 ------ n 90 ----- eb 90 ------ ar 90 months c 17 12 13 9 9 32 32 21 14 12 NA 6 32 32 26 26 16 11 6 4 33 32 32 24 24 23 22 20 15 13 12 11 ------ ar 90 ----- pr 90 ----- pr 90 ----- ep 88 ---- un 88 ---- an 89 ----- ov 87 ----- ov 87 Strumpell Lorrain ----- eb 89 ---- un 88 MS ----- ov 88 47A Duration of Follow up 10 10 17 32 25 39 39 38 35 27 061 - ---------------------------------------------------------------------------------------------------------------------------------------- 341-351-211-291 --271--561-261--371-511-431--301--431-141 --401 --511-201 --- MS MS Strumpell Lorrain SCI Cerebral palsy NA SCI MS MS ----- eb 86 ---- un 87 Ischemia ---- an 88 SCI MS Myelitis MS MS NA NA NA NA ------- ay 88 SCI SCI SCI SCI MS ---- ul 88 ----- ct 88 351--341-251-491 -- Friedreich s Disease ------------------------------------------- 331 --251 --- SCI ------- 341 -- SCI ------- 341--411--- SCI --------------------------------------------------------------------------------------------------- 231--481 -611-501 -461--481-531-481-- NA NA MS 381--481-231 --261 --601 --381 --381 --- ------------------- - ----- ov 88 ----- eb 89 ---- un 88 NA ----- ep 88 ----- ov 88 ----- ov 88 ----- pr 89 MS ---- an 89 SCI SCI SCI MS MS ------ ay 89 ----- pr 89 SCI Tumor SCI MS MS MS Cerebral trauma MS MS MS MS ----- eb 90 ----- eb 88 ------ ar 88 ----- ec 88 ---- un 88 ----- ep 88 ------ ar 89 --- Apr 89 ----- ep 89 ---- an 89 ----- pr 88 ------ ay 88 - ---- un 88 --- Jul 88 ----- ug 88 ----- ep 88 --- Oct 88 491-- MS 451-451---481 --521 -191--- MS MS MS MS Cerebral trauma ---- an 89 ---- an 89 ------ ar 89 --- Apr 89 331-471 -- MS MS ---- un 89 47B ----- ov 88 ----- pr 89 27 24 32 51 21 26 59 45 37 37 36 34 32 26 33 31 25 29 27 27 23 25 21 10 36 35 26 32 29 26 22 20 34 33 32 31 30 29 28 27 25 11 5 23 22 22 20 062 - --------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- 411F441F MS MS 331--701-- Vase Myelopathy - ---- ul 89 --- Jul 89 --- Jul 89 SCI SCI MS MS ----- ug 89 ----- ct 89 ----- ct 89 311--471--491-591-341-471-521--491-531-471-501-461 --681-521-581 --571-671 -151--621--651--271 -441--331--271-531-501 --- --------------------------------------------- 521-321--321-621-151-581 --321 --- ----------------- 381--291 -281-271--- ----------------------------------------------------------------- 601--421--331--561--591--531 -531--- Spinal meningeoma MS MS MS --- Jul 89 ----- ov 89 ----- ov 89 ----- ec 89 ---- an 90 MS MS MS MS ----- eb 90 --- Mar 90 --- Apr 90 ------ ay 90 MS MS --- Jul 90 --- Jul 90 MS ---- an 90 AV angioma Stiff man Syndrome Brain infarctus Cerebral diplegia SCI MS SCI Spastic paraplegia SCI SCI MS SCI MS ----- ct 90 ----- ec 89 ---- an 89 ---- an 89 --- Mar 88 --- Mar 88 ---- un 87 ----- ov 90 --- Jul 90 ----- ov 87 ----- ec 87 ---- an 88 --- May 88 SCI NA Cerebral trauma --- Aug 88 MS ----- ug 88 ----- ov 88 Cerebral trauma SCI Cerebral trauma Cerebral trauma Cerebral Paralysis ----- ec 88 --- Dec 88 --- Apr 89 MS --- Jun 89 SCI SCI SCI SCI Encephalon euritis MS MS MS 47C ------ ay 89 NA NA NA NA ----- ct 87 ----- ec 87 ---- un 88 ---- an 89 19 19 19 19 18 17 17 16 16 15 13 12 10 9 8 8 13 14 15 25 25 35 35 44 3 8 39 38 37 43 NA 30 30 27 26 26 22 21 20 NC NC NC NC 40 38 32 25 063 - ------------- 531--251--- Idiopathic spastic ---------------------------------------------------------------------------------------------------------------------------------------------------------------- 241--451--- paraparesia Strumpell Lorrain Cervical myelopathy -- ------- ------ 52--26-- -- MS - ----- pr 89 ------- g 89 ----- ov 89 ------ ar 90 ------ ar 88 581--531--311--341-421--441 -431 -- SCI MS SCI MS ------ ay 88 411--291--501--191--- Brain infarctus ------ n 89 ------ n 89 ------ ay 89 371--481--431--- Cerebral trauma Myelopathy 531-421-441 --- - ------471- --- SCI NA NA SCI SCI SCI NA MS MS NA SCI SCI Cerebral vascular infarctus SCI MS ------- v 87 ------- y 88 -- A -- A ------- y 88 ------- v 89 ------ ay 90 ------ ay 88 ---- un 90 ------ ay 89 ------- v 89 ------ ay 90 ----- eb 90 ----- ec 89 ---- un 90 ---- an 91 ----- ec 90 21 18 16 11 35 39 33 NA NA 33 33 25 25 21 15 9 33 9 21 16 9 12 14 8 3 a SCI Spinal cord injury MS Multiple sclerosis 0 Date of SynchroMed pump implant c Duration of long term experience through 8190 or last follow up NA Not Available 665 47D Summary of System Complications B Comprehensive Performance of the SynchroMed Infusion System through 1 April 1991 is reported for studies conducted in the U S and in Europe The data has been summarized for 1 U S monitored studies only and 2 European studies U S studies have been collapsed and reported separately because they is The SynchroMed have been carefully monitored by Medtronic commercially available in Europe and may be purchased by physicians for spinal applications Rigorous methods of data collection was not possible in all cases Performance within each individual study is also presented In October 1985 a device design modification was made to correct a passive leak from the pump Also initial implants used an earlier catheter replaced by the Model 8703 System version which was subsequently complications occurring in the earlier pump design or catheter have been noted in the tables of complications 1 U S Monitored Studies a Comprehensive Summary U S monitored studies are all baclofen studies conducted in the U S with the exception of Protocol Vl Though Protocol Vl A Single Center Study of Intrathecal Baclofen Versus Placebo in the Management of Spastic Cerebral Palsy Dr Albright was conducted in the U S and monitored by Medtronic it is from the comprehensive summary of device complications Table 30 to maintain consistency with the reporting format of Medtronic s pending NDA application --------- --------- Clinical Data Amendment 6 May 1991 Data from this study is reported in Table 35 Table table 28 summarizes the distribution observed in U S Monitored Studies SynchroMed programmer of system complications These are stratified by System component pump catheter access port and Pump pocket complications are also included 065 48 Of 214 patients implanted 205 are evaluable for system performance because they were implanted with the current system configuration Nine patients were implanted prior to October 1985 with prototype have reported at least one complication devices A total of 14 6 related to the system within each stratifies complications component according to description of the complication Table 29 further system Table 30 is a comprehensive summary of all device complications observed in U S monitored studies Table 28 Distribution of System Complications U S Monitored Studies 5 Patients Implanted Patients Implanted With Pump Catheter Patients Evaluated Prototype Patients Reporting System Complications Total System Complications System Component Pump Catheter Access Port Programmer Pocket Total 214 NA 9 NA 205 100 30 14 6 33 16 1 4 27 1 0 19 132 05 0 1 33 16 1 066 49 U S Monitored Table 29 Summary of System Complications Studies Number of Patients Implanted Number Implanted With Pump Catheter Number of Patients Evaluated Prototype Complication Description Catheter Angulation Catheter Occlusion Catheter Break Catheter Dislodgement Pump Stall Pump Catheter Port Occluded Pump Underinfusion Port Connector Kink Catheter Disconnect Pocket Infection Hygroma Total The most common system complications observed A retrospective related to catheter performance H 214 NA 9 NA 205 16 1 10 49 6 5 4 29 24 20 2 1 1 1 1 1 10 05 05 05 05 05 33 kk 16 1 have been those comparison was made of Medtronic Model 8703 Spinal Catheter to other commercially Information for commercially available available spinal catheters catheters was obtained from the scientific literature A complete reference listing is provided in Appendix I The results of this comparision following page are summarized in Table 30 on the 067 50 Table 30 Comparision of Spinal Catheter Performance a Total Catheters Evaluated Total Months Experience 205 383 3711 1379 10 17 6 17 5 4 5 Catheter Kink Catheter Occlusion Catheter Break Leak Catheter Dislodgement 0 0 Catheter Disconnect Hygroma Total Complications per Catheter Complications per Month 1 5 27 47 13 2 12 3 p 0 75 06 34 p 0 001 Literature References Auld AW Spine 1985 Plummer JL Pain 1991 Shetter AG J Neurosurg 1982 Onofrio BM Mayo Clin Proc 1981 Krames ES Cancer 1985 Greenberg HS J Neurosurg 1982 Coombs DW Can Anesth Soc 1983 Woods WA Anesth 1982 Penn RD J Neurosurg 1987 Leavens ME J Neurosurg 1982 Harbaugh RE J Neurosurg 1982 Delhaas EM Lancet 1984 Cobb CA Surg Neurol 1984 51 068 U S Monitored Studies Table 31 Device Related Complications hI QO 5 Iaial R QO H S NA 205 NA 214 NA 0 00 23 11 2 23 10 8 1 22 2 8 39 9 CSF leak headache 0 00 2 10 2 42 09 Catheter disconnection 2 22 2 2 10 4 19 Catheter lacerated 1 11 1 4 5 23 Pocket infectionlerosion revision 1 11 1 6 20 29 Programming 0 00 2 10 2 10 0 00 3 15 3 14 0 00 3 15 3 14 Refill error 0 00 3 15 3 14 Seromalhematoma 0 00 4 4 19 Catheter angulation 0 00 6 20 29 6 28 Catheter puncture break prior to implant 0 00 2 10 2 10 0 00 05 0 00 05 05 05 Wound dehiscence 1 11 1 0 00 05 Pump site discomfort 0 00 1 05 Pump inverted at implant 2 Subtotal 6 66 7 72 35 1 78 36 4 8 88 9 10 49 18 84 11 1 2 10 3 14 0 00 5 24 5 23 Pocket infectionlerosion 0 00 1 05 Catheter 0 6 29 6 28 1 05 1 05 0 00 2 09 05 4 19 Number of patients E3Q Reservoir Catheter evaluated contamination dislodgement error Meningitis Catheter Catheter reposition Subcutaneous Catheter catheter angulation fragment 9 Pump stall Catheter break 1 Pump underinfusion 0 Pump overinfusion 2 22 2 Catheter disconnect 0 00 Catheter dislodgement 05 00 0 00 Pump intermittent alarm Port connector kink 0 00 20 00 05 Occluded 0 00 00 1 20 0 45 catheter port 4 0 Hygroma 2 Subtotal 12 05 1 00 00 occlusion 33 1 133 To 33 05 05 05 1 21 0 maintain consistency with the reporting format in Medtronic s pending NDA application information for Protocol Vl is provided separately in Table 38 52 OGS b Individual Study Summaries Each U S monitored study is presented individually in Tables 32 38 070 53 TABLE 32 PROTOCOL Complications System in m Catheter Angulation 12 f mli Catheter Break Catheter Occlusion Overinfusion Pump Stall Intermittent Alarm Procedural P in r I nifi in - -------- -------- --------------- -------- ----------- ------ -------- -------- ------ -------- 1 ------- ------------- --------------- ------------- 2 2 2 Total ID IB SUMMARY OF DEVICE RELATEO COMPLICATIONS 1 20 Complications i Reservoir Contamination Catheter Disconnection Catheter Dislodgement Catheter Lacerated Catheter Break at implant Removal of Subcut Cath Frag ement Catheter Repositioned Pocket Infection Erosion Revision Seroma Hematoma Wound Dehiscence Programming Error Total Grand Total Pa i 20 - i tion -------- ------- ------- -------- ------- ------ ------- ------- -------- ------- ------- ------- 4 --------------------------------------------------------------- ------ -------- ------ 2 1 1 -------- ------------------ 1 1 ----------- 2 --------------- 1 ------------------ 35 55 Directly attributable to device design or manufacture Directly attributable to surgical procedure error Prototype design manufactured prior to October 1985 Reservoirs treated with gentamicin pumps not replaced 54 071 TABLE 33 System PROTOCOL II SUMMARY COMPLICATIONS OF DEVICE RELATED Complications ID iion Catheter Angulation Catheter Break Catheter Dislodged 4 Catheter Occlusion Catheter Disconnect Port Connector Kink Pocket Infection Pump Stall 2 3 2 - --------- --------- --------- ---------------- --------- ---------------- -------- 1 ------- ---------------------- 1 -------- 1 -------- 1 -------- Pump Underinfusion Total Procedural boa Ea 16 Complications iioa Ea Catheter Dislodgement 6 - --------- --------- --------- --------- --------- -------Catheter Angulation Catheter Lacerated Pocket Infection Erosion 3 2 -------- ---- ---------------- -------- 3 --------- --------- -------- Pocket Seroma Pump Site Discomfort -------- CSF Leak Refill Error --------------- -------- 1 Total 18 Grand Total 34 Directly attributable to device design or manufacture Directly attributable to surgical procedure error 072 55 TABLE 34 PROTOCOL System IIB SUMMARY COMPLICATIONS OF DEVICE RELATED Complications Catheter Angulation Occluded Catheter Port Hygroma Total Procedural iificaiian hbzzhar Ea tion I 1 --------- 1 -------- 1 3 -------- Complications I fTl 6 Catheter Angulation Catheter Repositioned Pocket Infection Erosion 1 -------- 1 -------- 1 -------- Pocket Seroma Pump Placed Inverted At 2 ------- Implant 1 ------ Refill Error Programming 1 -------- Error ifi i I -------- --------- Total 8 Grand Total 11 Directly attributable to device design or manufacture Directly attributable to surgical procedure error 073 56 PROTOCOL TABLE 35 System III SUMMARY COMPLICATIONS OF DEVICE RELATED Complications aiian alii - Catheter Angulation Catheter Occlusion Catheter Dislodgement Total Procedural 1 ------ 1 ------ 1 ------ 3 Complications I I I - I ------- ------- ------ Meningitis Reservoir Contamination Catheter Puncture 3 3 2 ------- ------- ------ Catheter Lacerated Catheter Dislodgement Catheter Reposition 2 ------- ------ ------- ----------- ------ Pocket Infection -----Total 13 Grand Total 16 Directly attributable to device design or manufacture Directly attributable to surgical procedure error 074 57 TABLE 36 PROTOCOL V SUMMARY OF DEVICE RELATED COMPLICATIONS System Complications zelicaiian I Ea hLua lian - Catheter Break Catheter Dislodgement Total Procedural I 1 -------- 1 -------- 2 Complications ation lian 2 Catheter Angulation CSF Leak Headache Refill ErroR - --------- -------- 1 -------- -------- Total 1 4 Grand Total 6 Directly attributable to device design or manufacture Directly attributable to surgical procedure error Pump reservoir not accessed patient lost effect until reservoir refilled 075 58 TABLE 37 PROTOCOL System Ixu VIII SUMMARY OF DEVICE RELATED COMPLICATIONS Complications - ------ Catheter Occlusion Total Procedural 1 Complications his n I None iifimiian Ea aiian I NA aiian NA Directly attributable to device design or manufacture Directly attributable to surgical procedure error 076 59 TABLE 38 System PROTOCOL Vl SUMMARY COMPLICATIONS RELATED Complications sr Ea lian - Catheter Dislodgement Total Procedural OF DEVICE aiian -------- 1 Complications Pai s ilQQ Al CSF Leak Catheter Dislodgement Catheter Punture 3 1 --------------- Wound Dehiscence 1 -------- Pocket Seroma Meningitis 1 1 --------------- Pump Implanted Inverted 1 -------- Infection back incision Total 1 -------- 1 - -------- ---- -------- 11 Directly attributable to device design or manufacture Directly attributable to surgical procedure error 077 60 2 European Studies The SynchroMed Infusion System is commercially available in Europe Medtronic is conducting market surveillance activities to collect information on system performance Tables 39 and 40 summarize complications from Protocols IV and Vll which were conducted in Europe 078 61 PROTOCOL TABLE 39 System OF DEVICE RELATED Complications ID tion R1LQQ pe Catheter Angulation Pump Stall 2 - 2 Total Procedural IV SUMMARY COMPLICATIONS -------- --------- -------- ------ 4 Complications li r Pai i - Catheter Disconnection Catheter Dislodgement 1 1 ------ CSF Leak Pocket Erosion 1 -------- 1 ------ Total 4 Grand Total 8 i tion ------ Directly attributable to device design or manufacture Directly attributable to surgical procedure error Prototype design manufactured prior to October 1985 079 62 TABLE 40 System PROTOCOL RELATED Complications I i n tion Catheter Angulation Catheter Break Catheter Occlusion Pocket Erosion Pocket Infection Catheter Dislodgement - --------- ------ 2 -------- --------- 2 ------ 2 -------- 2 ------ 1 --------- 2 SeromlHematoma ------------------ ------- Total Procedural OF DEVICE VII SUMMARY COMPLICATIONS 12 Complications I I Catheter Dislodgement CSF Leak 5 - -------- --------- ------ 5 -------- -------- -------- Programming Error Catheter Angulation 2 ------- ------ -- 1 --------- ------ -------- -------- --------- ------ Pocket Infection Total 14 Grand Total 26 Directly attributable to device design or manufacture Directly attributable to surgical procedure error 080 63 3 Comprehensive Summary of U S and European Studies Experience from U S monitored studies and from European studies have summary table Table 41 describes been merged into a comprehensive world wide experience from a total of 406 patients implanted Table 41 does not include Protocol Vl 081 64 Table 41 DEVICE RELATED COMPLICATIONS U S AND EUROPEAN STUDIES LK 5 Number of patients evaluated Reservoir contamination Catheter dislodgement CSF leak headache Catheter disconnection Catheter lacerated Pocket infectionlerosionlrevision Programming error Meningitis Catheter reposition Refill error Seromalhematoma Catheter kink Catheter break implant Subcutaneous catheter fragment Pump site discomfort Pump inverted at implant Subtotal QO E2G E5 5 IQIBl QO 24 NA 382 NA 406 NA 0 00 3 0 3 12 5 23 15 60 39 23 18 8 3 5 21 08 13 10 10 08 08 08 8 6 57 44 20 2 0 0 0 0 0 0 0 0 0 00 12 5 42 83 00 00 00 00 00 00 00 00 00 9 4 4 3 3 3 2 2 1 05 05 03 03 03 Q2 1 1 6 6 4 15 15 15 10 a 07 07 07 05 05 02 02 02 k2 3 3 3 2 2 1 1 9 37 5 79 20 7 88 21 7 9 4 0 37 5 16 7 00 17 44 5 7 13 18 26 9 7 64 22 0 0 00 8 7 21 18 8 7 20 3 2 08 05 00 05 05 3 2 2 2 2 1 07 05 I 5 Catheter angulation Pump stall Catheter break Pocket infectionlerosion Catheter occlusion Seromalhematoma Pump underinfusion Pump overinfusion Catheter puncture Catheter dislodgement Pump intermittent alarm Wound dehiscence Hygroma Subtotal Grandtotal 0 0 2 0 0 00 00 00 83 42 42 0 2 2 0 0 1 00 k2 70 8 54 14 1 70 8 133 34 8 00 00 Q 26 65 00 1 1 17 05 05 05 02 02 92 17 5 159 39 2 08Z APPENDIX 1 083 i pl 084 J 1131 a I ELKINS SINN INC INFUMORPH 200 INFUMORPH 500 g Preservative free MorphineSulfate Sterile Solution For Use in Continuous MicroinfusionDevices DESCRIPTION Morphine is the most important alkaloid having the followmg structural formula of opium and is a phenanthrene H derrvative Il is available as the sulfale salt CHp I HE H Hq SOi 5HqO HO 0 OH 7 8 Didehydro 4 5 epoxy 17 methyl 5o 6a morphinan 3 6 diol sullate 2 1f saltl pentahydrale Ct1H oNOsb HaSOi SHOO Molecular Weight is 758 83 INFUMORPH is a sterile nonpyrogenic isobaric high potency aolution et morphia aullale free of antioxidants preservatives or other potentially neurotoxic additives INFUMORPH la intended for uee in continuous microlntualon devices for Inlrasplnal admlnlatratlon In management of pain Each 20 mL ampule of INFUMORPH 200 contains morphine sulfate USP 200 mg or 10 rnglmL habit forming and sodium chloride 8 mglmL Warning May be in Water d or Injecbon USP Each 20 mL ampul ot INFUMORPH contains 500 morphine sulfate USP 500 mg or 25 mglmL May be habit forming Warning and sodium chloride 6 25 mglmL in Water for Injection USP If needed sodium hydroxide andlor sulfuric ac4 are added for to 4 5 Amputs are sealed under nitrogen adjustment pH Each 20 mL DQSETTEe ampul ot INFUMORPH is intended for aingle use only Discard eny unused portion DO NOT HEAT STERILIZE CLINICAL PHARMACOLOGY Morphine produces a wide spectrum of pharmacologic effects including analgesia dysphoria euphoria somnolence resairatory depression diminished gastrointestinal motility and physical dependence Opiate analgesia involves at least three anatomicaf areas ot the central nervous system the penaqueductal periventncular medulla and the spinel cord A systemically gray matter the ventrornedial administered opiate may produce analgesia by acting at any all or combination same of these distinct regions Morphine interacts with the p receptor predominantly The p binding sites of op nids are very discretely distributed in the human brain with high densities of siles found in the hypothalamus amygdala posterior thalamus nucleus caudatus putamen and certain corlicai areas They are also found on the lerminal axans of primary atferents within laminae I and II tsubstantia geladnosa ot the sprnal cord and in the spinal nucleus at Ihe trigeminal nerve Morphine has an apparent volume of distribution ranging from 1 0 to 4 7 Llkg aher intravenous is law about 36 I and muscle tissue dosage Protein b nding binding is reported as 54 A blood brain barrier exists and when morphine is introduced outside of the CNS e g intrevenously plasma concentrations of morphine remain higher than the corresponding CSF morphine levels Conversely when morphine is injected into the intrethecal into the systemic circulation slowly space it diffuses out accounting for the long duration of action of morphirw administered by this route Morphine has a total plasma clearance which ianges from 0 9 to 1 2 Llkglh lilerslkilogramlhourJ in patients but shows considerable postoperative interindividual variation The major of clearance pathway is hepatic morphine 3 glucuronide to which is pharmacologically plucuronidation inactive The major excrebon kidneys with about 10 o in the feces path of the coniugate is through the Morphine is also eliminated by the kidneys 2 to t M being excreted uriah anged in the urine Terminal half life is commonly reported to vary tram 1 5 to 4 5 hours although the longer halt lives were obtained when morphine levels were monitored over protracted periods with very senseve rsdioimmunoassay The accepted methods elimination half lile in normal subjects is 1 5 to 2 hours Selective blockade of pain sensation is by neuraxial applicafion at morphine In addition duration of analgesia may be much longer by this route possible compared to systemic adminislration However CNS effects associated wilh systemic administration are still seen These include respiratory depression sedation nausea and vomiting prunlus and urinary retention tn particular both early late respirator and depression up to 24 hours been reporled following neuraxial administration dosing have Circulation of the spinal fluid may also result in high posl morphine reaching the brain stem directly concentrations of The incidence of unwanted CNS etiects including delayed respiratory depression associated with neuraxial application of morphine is related to the circulatory dynamics of the epidural venous plexus and the spinal tluid The lipid solubly and degree of ionization ot morphine pleys an important pari in both the onset and duralion of analgesia and the CNS elfects Morphine has a pl 7 9 with an octanollwater partition caefhcient of 1 42 at pH 7 4 At this pH the tertiary amino group in each ot the opioids is mostly ionized making the molecule water soluble Morphine with additional hydroxyl groups on the molecule is significantly more water solute than any other opioid in clinical use Morphine injected into the epidural space is rapidly absorbed into the the plasma concentration time general circulation Absorption is so rapid that profiles closely resemble those obtained aher intravenous tration Peak plasma concentrations or intramuscular adminis averaging 33 40 nglmL range 5 62 nglmLJ are achieved within 10 to 15 minutes after admrnistration et 3 mg of morphine Plasma concentra1ens decline in a multiexponential half life is reporled to range from 39 to fashion The terminal 249 minutes mean of 90 2 34 3 min and though somewhat shorter is similar in magnitude as values reported afler intravenous and inVamuscular administration h CSF concentrations morphine after epidural doses at 2 to 6 mg in 1545 at postoperative have patients been reported to be 50 to 250 times higher Ihan corresponding The CSF levels of morphine plasma concentrations exceed those in plasma atler only 15 minutes and are detec1able tor as long as 20 hours aNer the injection o 2 mg of epidural morphine Approximately 4 dose injected epidurally reaches the of the CSF This corresponds to the relative minimum effective epidural doses of 5 mg and 0 25 mg respectively and intrathecal The disposition at morphine in Ihe CSF follows a biphasic pattern with an early half life of 1 5 h and a late phase half lile of about 6 h Morphine crosses the hail lite across the dura averaging dura slowly with an absorption 22 minutes Maximum CSF concentrations are seen 60 90 minutes after injec ion Minimum etlective CSF concentrations for postoperative analgesia average 150 ng mL The intrethecal route of administration range 1 380 nglmL circumvents meningeaI diltusion barriers and therefore lower doses of morphine produce comparable analgesia to that induced by the epidural route Afler intrethecal bolus inieclion of morphine there is a rapid initial distribution phase lasling 15 30 minutes and e hall knife in the CSF of 42 136 min mean 90 Derived from limited data it appears 16 min that the disposition of morphine in the CSF from 15 minutes administration to the end of a six hour pastintrathecai observation period represents a combination of the distribution and elimination phases Morphine concentrations in the CSF averaged 332 2 137 nglmL at 6 hours tollowing a bolus dose morphine The apparent volume o distribution of morphine of 0 3 mg of in the intrathecal space rs about 22 Time to peak 8 rnL concentrations plasma however is similar 5 10 min after either epidural administration or intrall ecal of morphine Maximum plasma morphine concentrations bolus aRer 0 3 mg intrathecal morphine have been 085 reported lrom 1 to 7 8 nglmL The minimum analgesic Analgesia morphine plasma concenlration PCA has been reposed during Patient Controlled as 20 40 ngimL suggesbrg redistribution thai any analgesic would be minimal afler contribution from syslemrc Ihe hrst 30 60 minutes with intrathecal administralion ep dural administration of morphrne and virtually absenl with INDICATION AND USAGE INFUMORPH Preaervative tree Morphine Sulfate Sterile Solution Infusion epidural la Indicated in the treatment only for intrathecal of intractable or chronic microinfusion II waa developed pain devicee and may require for uee In continuous dilution before use as dictated the doaage by requirementa the characterlaliea of tha Individual of the device and patient INFUMORPH IS NOT RECOMMENDED FOR SINGLE DOSE INTRAVENOUS S ADMINISTAATIQN DLlE IMRAMUSCULAR TO TRE VERY LARGE AMOUNT OR OF MORPHINE IN THE AMPUL cony use ot neuraxial analgesia include the prese he coagulant therapy uncontrolled bleeding diathesis ard Ihe presence nti condition which would render of any other concomitant epidural or intrathecal administration Iherapy or medical of medication especially WARNINGS hazardous THIS PRODUCT WAS DEVELOPED FOR USE AFTER APPROPRIATE CONTINUOUS MICROINFUSION DILUTION IF NECESSARY DEVICES FOR INTRATHECAL OA IN CONTROL SEVERE EPIDURAL INFUSION OF CANCER PAIN CHRONIC NEJRAXIAL NARCOTICS TO LESS INVASIVE MEANS OPIOID ANALGESIA IS APPROPRIATE ONLY OF CONTROLLING PAIN WHEN HAVE FAILED AND THOSE WHO ARE SHOULD ONLY BE UNDERTAKEN EXPERIENCED IN APPLYING THIS TREATMENT IN A BY CAN 8E ADEQUATELY SETTING WHERE ITS MANAGED COMPLICATIONS BECAUSE OF THE RISK OF SEVERE AOVERSE EFFECTS EOUIPPED PATIENTS MUS7 BE AND STAFFED ENVIRONMENT OBSERVED IN A FULLY FOR AT LEAST 24 HOURS TES7 DOSE AND AFTER THE INITIAL AS APPROPRIATE fOR THE FIRST SINGLE IMPLANTATION SEVERAL DAYS AFTER CATHETER THE THE FACILITY PERSONNEL MUST BE MUST EQUIPPED TQ RESUSCITAi SE E PATIENTS WITH SEVERE OPIATE FAMILIAA OVERDQSAGE WITH THE ANC ANTAGONISTS USE AND LIMITATIONS NALOXONE NALTREXONE IN OF SPECIFIC NARCOTiC SUCH CASES RESERVOIR FILLING MUST THE DIRECTIONS PROVIDEDBE PERFORMED BY FULI Y TRAINED AND QUALIFIED PERSONNEL BY THE DEVICE MANUFACTURER FOLLOWING THE PROPER REFILL CARE SHOULD BE TAKEN FAEQUENCY TO PREVENT IN SELECTING DEPLETION OF THE EXACERBATION RESERVOIR WHICH OF SEVERE PAIN ANDIOR WOULD RESULT IN REFLUX OF CSF INTO TECHNIQUE IN FILLING IS REQUIRED TO AVOID SOME DEVICES STRICT ASEPTIC BACTEAIAL CONTAMINATION EXTREME CARE MUST BE T1KEN TO ENSURE THAT THE NEEDLE IS PROPERLY ANO SERIOUS INFECTION THE DEVICE BEFORE ATTEMPTING TO REFILL IN THE FILLING PORT TISSUE AROUND THE THE RESERVOIR OF INJECTING THE SOLUTION DEVICE OR IN THE INTO THE CASE OF DEVICES THAT ATTEMPTING TO INJECT HAVE MORE THAN THE REFILL DOSE INTO ONE PORT THE DIRECT INJECTION CLINICALLY SIGNIFICANT PORT WILL RESULT IN A LARGE OVERDOSAGE TO THE PATIENT A PERIOD OF 08SEAVATION APPROPRIATE TO THE OR MANIPULATION CLINICAL SITUATION OF THE DRUG RESERVOIR SHOULD FOLLOW EACH REFILL BEFORE DISCHARGE SHOULD RECEIVE INSTRUCTION THE PATIENT AND IN i HE PROPER HOME ATTENOANT S THE RECQGNITIQN CAAE OF THE DEVICE AND AND PRACTICAL TREATMENT OF AN OVERDOSE OF NEURAXIAL INSERTION SITE AND IN TOLERANCE AND MYOCLONIC MORPHINE ACTIVITY PATIENTS SOMETIMES MANIFEST UNUSUAL ACCELERATION WHICH MAY CAUSE OF NEUAAXIAl MORPHINE CONCERN REGARDING RcQUIREMENTS SYSTEMIC ABSORPTION AND THESE PATIENTS MAY BENEFIT THE HAZARDS OF LARGE FROM HOSPIT4LIZATION MYOCLONIC LIKE DOSES AND DETOXIFICATION SPASM OF THE LOWER TWO EXTREMITIES HAVE SEEN CASES MORE THAN 20 MGI OF REPORTED IN PATIENTS DAY OF INTRATHECAL MORPHINE AFTER RECEIVING RESUME TREATMENT DETOXIFICATION AT LOWEA DOSES IT MIGHT SE POSSIBLE AND SOME PATIENTS HAVE FROM TO CONTINUOUS BEEN SUCCESSFULLY EPIDURAL MORPHINE TO CONTINUOUS CHANGED DETOXIFICATION INTRATHECAL MAY 8E INDICATED MORPHINE AT A LATER DATE REPEAT PATIENT DURING THE UPPER DAILY CONTINUING TREATMENT DOSAGE LIMIT FOR EACH MUST BE INDIVIDUALIZED PRECAUTIONS Control of pain by neuraxial opiate delivery using a continuous considerable risk la the microintusion device is always accompanied these patients must be patients and requires a high level of skill to be successfully by undertaken by expenenced accomplished The task of treating and emerging standards clinical learns well versed in patient selection of care For reasons evolving technology of safety it is recommended and 500 10 and 25 mglmL respectively that administration of INFUMORPH 200 by the intrathecal route USE IN PATIENTS WITH be limited to the lumbar INCREASED INTRACFIANIAL area INFUMORPH PRESSURE OR HEAD Preservative tree INJURY Morphine Sulfate with head injury or Sleriie Solution should increased be used with extreme intracranial caution in patients existence Pupillary changes extent and course of intracranial pressure miosis from morphine may events see WARNINGS obscure the pathology High doses of neuraxial and ADVERSE REACTIONS morphine may drug reactions when Clinicians produce myoclonic sl oufd maintain evaluating altered mental status or movement abnormalities a high index of suspicion for adverse IreatmenL in patients receiving this modality of USE IN CHRONIC PULMONARY DISEASE Care is urged in using this drug in patients who have a decreased kyphoscoliosis respiratory reserve or paralysis of the le g emphysema phrenic nerve INFUMORPH airway obstruction severe obesity should not be or in any other chronic given in cases of chronic asthma respiratory failure following pulmonary disorder withoul due upper consideration morphine administration of the known risk of acute in such patrents USE IN HEPATIC OR RENAL DISEASE The elimination half life of morphine may be renal dysfunction prolonged in paoents with reduced Hence care should metabolic rates and with hepatic and or in adminislering INFUMORPH conditions since high blood morphine be exercised epidurally to patients with levels due la reducecf USE IN SILIARY SURGERY these clearance may take several days OR DISORDERS to develop As significant morphine OF THE BILIARY TRACT is released into the systemic muscle hypertonicity circulation from neuraxial administration may result in biiiary colic the ensuing smooth USE WITH DISORDERS OF THE URINARY SYSTEM Initiation of neuraxial opiate analgesia is frequently associated with disturbances prostatic enlargement Early recognition of of micturition especially difficulty in urination indicated in males with and prompt intervenriarr in cases of urinary retention USE IN AMBULATORY is PATIENTS Patients with reduced circulating blood volume impaired myocardial monitored for the function or on sympatholytic possible occurrence of orthostatic hypolension morphine analgesia drugs should be a frequent complication in single dose USE WITH OTHER neuraxial CENTRAL NERVOUS SYSTEM DEPRESSANTS The depressant effects of morphine are potentialed sedatives by Ihe presence antihistaminrcs of other CNS depressants or psychotropic increase the risk drugs Use of neuroleplics such as alcohol of respiratory depression in conjunction with neuraxial morphine CARCINOGENESIS may MUTAGENESIS IMPAIRMENT OF FERTILITY Morphine is without known carcinogenic or mulagenic effects and animals bul stuches is not known lo impair fertilily of Ihe carcinogenic and mulagenic at non narcotic been conducted doses in potential or the effect on fertility of INFUMORPH have not 2 086 PREGNANCY CATEGORY C Morphine sulfate is not teratogenic in rais at 35 mglkglday thirty five limes the usual human dOse but does result Irl irlcreased puP morlality and growth retardation at doses that narcotize the animal 10 mglkglday ten times the USual human dose INFUMQRPH should only be given to pregnant women when no other method Of corltfollin9 Pain is available and means are at hand to manage the delivery and infant perinatal care of the oPiate dependent LABOR AND DELIVERY INFUMORPH 200 and 500 10 and 25 mg mL respectively are lao highly concentraled for routine use in obstet lc neuraxial analgesia NURSING MOTHERS Morphine is excreted in malernal milk Effects on Ihe nursing infanl are not known PEDIATRIC USE Adequate studies to establish lhe safety and effectiveness of spinal morphine in children have not been performed and usage in this population is not recommended USE IN THE AGED The pharmacodynamic effects of neuraxial morphine in the aged are more variable than in the Patients will vary widely in Ihe younger population effective initial dose rate of developmenl of tolerance and the frequenc Y and maQnitude at associated adverse effects as Ihe dose is increased Initial doses should be based on careful clinical observation following test doses afler making due allowances tor the etlecis at Ihe palienl s age and infirmity on their clear the drug abllitY to parlicularly in palients receiving epidural morphine ADVERSE REACTIONS IMPROPER OR ERRONEOUS SUBSTITUTION OF INFUMORPH 200 or 500 reapectively 10 or 25 mplmL FOR REGULAR DURAMORPH 0 5 or 1 mglmL IS LIKELY TO RESULT IN SERIOUS OVERDOSAGE LEAOING 10 SEIZURES RESPIRATORY DEPRESSION ANO POSSIBLY FATAL OUTCOME The most serious adverse experiences encountered during continuous intrathecal or epidural infusion of INFUMORPH are respiratory depression and myoclonus 1 Single dose neuraxial adminrslralron may result in acute or delayed respiratory depression for long as 24 hours Severe respiratory periods at least as depression life threatening potentially can reault from technical during refill errare g injection of INFUMORPH outside the filling unintentional port injection into the direct bypaas dosinp port featured on aome devices or local Infiltration 2 Tolerance and myoclonus See WARNINGS for discussion of these and relaled hazards While low doses of intravenously administered morphine have little effect on cardiovascular stability high doses are excitafory resulting from sympathetic hyperactivity and increase in circulaling ca echolamines central nervous system Excrtation of the resulting in convulalons may accompany high doses ot morphine Dyephorlc reactlona given intravenously may occur after any size dose and toxic have been reported paychoses Prurltua Single dose epidural or inlrathecal administration is accompanied by a high incidence of dose related but not confined lo the site of administration Ihat is pruritus Pruritus following continuous intrathecal morphine is occasionally infusion of epidural or reported in the literature these reactions are poorly understood as to Iheir cause Urinary retention Urinary retention which may persist 10 to 20 hours following single epidural or intrathecal administration is a frequent side effect and must be anticipated primarily rn male incidence in females patients with a somewhat lower Also frequently reporled in the literature is the occurrence of unnary retention during the first several days of hospitalization for the initiation o continuous intrathecal or epidural morphine develep therapy urinary retention have responded Patients who to cholinomimetic treatment and or judicious use of catheters PRECAUTIONS see Constlpatlon Constipation is IrequenNy encountered during continuous infusion of morphine this can managed by conventional usually be therapy Headache Lumbar puncture type headache is encountered in a significant minority of cases tor several intrathecal catheler implantation days following this generally responds to bed rest andlar other conventional therapy Peripheral edema There are several reporls of penpheral edema including unexplained patients following infusion device genital swelling in male implant surgery Other Other adverse experiences reponed following morphine therapy include Dizzlnesa chpreseion euphoria of cough reflex Interference anxiety with thermal regulation and oligurla Evidence of histamine release as urticaria wheala andlor local tiasue irritation such may occur Pruritus nausealvomiting end urinary retention it associated with continuous infusion therapy intravenous administration may respond to of a low dose of nalaxone 0 2 mg The risks of using narcotic antagonists chronically receiving narcotic therapy in patients should be considered NALOXONE INJECTION AND RESUSCITATIVE EQUIPMENT SHOULD BE IMMEDIATELY FOR USE IN CASE OF LIFE THREATENING AVAILABLE OR INTOLERABLE SIDE EFFECTS INFUMORPH AND WHENEVER THERAPY IS BEING INITIATED THE RESERVOIR IS BEING REFILLED OR ANY MANIPULATION OF THE RESERVOIR SYSTEM IS TAKING PLACE DRUG ABUSE AND DEPENDENCE CONTROLLED SUBSTANCE Morphine sultate is a Schedule ll narcotic under the United Siates Controlled Substance Act 21 U S C 801 886l Morphine is the most commonly cited prototype for narcotic substances that possess an addiction forming sustaining liability A or addiction patient may be at risk for developing a dependence to morphine if used improperly or foi long periods of time As with overly all potent opioids which are w agonists tolerance as well as dependence to morphine may develop irrespective psychological and physical et the route et administration epidural or oral Individuals with intravenous intramuscular intrathecal a prior history of opioid or other substance respond to the euphorogenic abuse or dependence being more apt to and reinforcing properlies of morphine would be considered to be at Care must be taken to avert withdrawal greater risk in patients who have been maintained epidural or intrathecal administration on parenteralloral narcotics when is considered Withdrawal symptoms may occur abruptly or upon administration when morphine is disconbnued of a narcotic antagonist OVERDOSAGE PARENTERAL ADMINISTRATION OF NARCOTICS IN PATIENTS RECEIVING EPIDURAL MORPHINE MAY RESULT IN OVERDOSAGE OR INTRATHECAL Overdosage of morphine is characterized by respiratory depression with respiratory or withoul concomitant arrest may result either through CNS depression Since direct depression ot the respiralory center or as the result primary attention should be given to the establishment of hypoxia of adequate respiratory exchange airway and institution of assisted through provision of a or controlled ventilation The patent narcotic antagonist initial dose of 0 4 to 2 rng naloxone is a specific antidote An of naloxone should be administered intravenously resuscitation If the desired degree of counteraction simultaneously with respirator and improvement in respiratory may be repealed al 2 to 3 minute intervals function is not obtained naloxone If no response is observed after 10 mg of naloxone has been the diagnosis of narcotic induced administered Or partial narcotic induced toxicity should be subcutaneous administration queslioned Intramuscular may be used if the intravenous or route is not available As the duration of effect of naloxone is considerably shorter than that of epidural or administraUon may be necessary intrathecal morphine repeated Palients should be closely observed for evidence of renarcotization DOSAGE AND ADMINISTRATION INFUMORPH 200 AND 500 10 AND 25 MGIML AESPECTIVELYI SHOULD NOT NEURAXIAL INJECTION BECAUSE BE USED FOR SINGLE DOSE LOWER DOSES CAN BE MORE RELIABLY ADMINISTERED WITH STANOARO PREPARATION QF DURAMORPH THE AND 1 MGIML 0 5 CANDIDATES FOR NEURAXIAL ADMINISTRATION OF INFUMORPH DEVICE SHOULD IN A CONTINUOUS MICROINFUSION BE HOSPITALIZED TO PROVIDE FOR ADEQUATE PATIENT MONITORING DURING 3 087 ASSESSMENT OF RESPONSE HOSPITALIZATION SHOULD BE TO SINGLE MAINTAINED DOSES FOR INTRATHECAL OF OAYS 9E rRAL AFTER OR EPIDURAL SURGEAY MORPHINE INVOLVING THE INFUSION OEVICE FOR ADDITIONAL MONITORING AND ADJUSTMENT OF DAILY DOSAGE THE FACILITY MUST BE EQUIPPED WITH RESUSCITATIVE EQUIPMENT OXYGEN NALOXONE INJECTION AND OTHER RESUSCITATIVE DRUGS BECAUSE OF THE RISK OF DELAYED RESPIRATORY DEPRESSION PATIENTS SHOULD BE OBSERVED IN A FULLY EQUIPPED AND STAFFED ENVIRONMENT FOR AT LEAST 24 HOURS AFTER EACH TEST DOSE ANO AS INDICATED FOR THE FIRST SEVERAL DAYS AFTER SURGERY Familiarization with the continuous microinfusion device is essential The desired amount of morphine should be withdrawn from the ampul through a microfilter To minimize riak from the product must glass or other particles be filtered throuph a 5 q or amaller mlcrof liter before injecting into the mletolnfuelon If dilution is device required 0 9 a Sodium Chloride Injection is recommended Intrathecal Dosage The staning dose must 5e individualized based upon in hospital evaluation of the response to serial single dose intrathecal bolus injections of regular DURAMORPH 0 5 mglmL or 1 mglmL wilh close observalion of the analgesic efficacy and adverse effects prior la surgery involving the conlinous microinfusion device The recommended initial lumbar intrathecal dose range in patients with r o tolerance to Opioids is 0 2 1o 1 mglday The publish range of doses for individuals v ho have some degree of opia tolerance varies from 1 to 10 rnglday The upper daily dosage limit for eacl pa isnt must be individualized Limited experience with co tinuous intratharal infusio o morphine has sl own tha the daily doses have to be increased over time Although the rate of increase ovei trme ir the dose required lo sustain analgesia is highly variable an eslrrnate of the expecled ate of increase is shown in the following Figure Fipure Dose Trend Mean in Continuous tntuaiona of Intrathecal and 95 a Confidence Intervals Morphine 40 35 30 25 R 20 o 15 8 C g Q 5 0 0 20 4 8 12 16 20 Infusicn Duration mglday 24 28 32 36 40 weeks is the lowest dose for which regional myoclonus has been reporled The rate ot occurrence cannol be eslirnated Doses above 20 mglday should be employed wilh caution since they may be associated with a higher likelihood of serious side effecls see WARNINGS concerning palenbal r eurological hazards and ADVERSE REACTIONSl Epidural Ooaage The starting dose must be individualized based upon in hospilal evaluation of the response to serial single dose epidural bolus inlec1ions of regular OURAMORPHw Morphine Sulfate Iniection USPI 0 5 mglmL or 1 mglmL with dose observation for ana gesic efficacy and adverse effects prior tc surgery involving the continuous microinfusion device The recommended initial epidural dose in patients who are not tolerant to apioids ranges from 3 5 lo 7 5 mglday The usual starting dose for continuous epidural infusion based upon limited data in patients who have some degree of opiaid tolerance is 4 5 to 10 mglday The dose requirements may increase significantly during treatmenL frequently to 20 30 mglday The upper daily limil for each patient mus1 be individualized SAFETY AND HANDLING INSTRUCTIONS INFUMO4PH is supplied in sealed ampuls Accidental dermal exposure should be treated by the removal of any contaminated clothing and rinsing the aftected area with water Each ampul of INFUMOAPH contains a large amount of a potent narcotic which has been associated with abuse and dependence among health care providers Dw to the limited Indicatlone for this product the risk of overdoaage and the rlak of its dlveralon and abuse It la recommended that apecial measures be taken to control thla proctuct within the haepltal or clinic IIVFllMORPH about br eubjeei to Hyid accounting IfpOPOIIS COlltlOI 0 WJ4tDQO Olid tDOtflCtOd OCCDt4 This paronleral drug producl must be Inapeeted for particulate matter belon opening the amber lmpul and again for color after rwnovlnp contents from the amPul Do nol uae if the solution In the urepened mpul contalne a preclpltate which does not disappear upon shaking Atter removal do not uae unless the solution la coiorlesa or pale yellow HOW SUPPLIED Amber DOSETTE ampuls for epidural or intrathecal administration via a continuous micraintusion device INFUMORPH 200 Preservative free Morphine Sulfate Sisnie Solution 200 mgl20 mL 10 mglmL packaged individually NDC 0641 1131 31 INFUblORPH 500 Preservative free Morphine Sulfate Sterile Solution 500 mgl20 mL 25 mglmLl packaged individually lNDC 0641 1132 31 Also available from Elkins Sinn Inc DURAMORPH Morphine Sulfate Inleciion USP 5 mgl 0 mL 0 5 mglmL and 10 mgl10 mL 1 mglmL See insen J 1113 STORAGE Prolect from light Store in carton at controlled room temperature 15 30 C until ready to use DO NOT 59 86 F FREEZE INFUMORPH contains no preservative or antioxidant DISCARD ANY UNUSED PORTION DO NOT HEA7 STERILIZE Additional package inserts may be obtained by contacting the Prdessional Services Department Issued Manufactured by ELKINS SINN INC Cherry Hill NJ 08003 4099 A subsidiary of A H Robins Company 4 February 1991 J 1131 088 l I ORB APPENDIX 2 090 Statement by Timothy A Ulatowski Chief General Hospital 359 Devices 1 Branch MORNING PRESENTATION Before morning a brief give of the overview implantable with brief Drug delivery are infusion currently approvals and accordance with drugs are and reliability the as medical administered and dosage with device for delivered IV sets ports Center The drug product are Center for together tool and devices by the and device a drug Devices by these or diagnostic delivery devices of the drug depends specific of the the are of the The precise of the and administration the overview presentation The administered determination of devices to evaluatjon this next pre filled sold like provide when used in labeling and drug the the not are therapeutic their to pumps approvals and Research and effectiveness compatibility that the supplement infusion by Drugs interrelated and effectiveness safety regulated effective FDA components of both are regulated Drug Evaluation as that Health currently Although such Id regarding prior syringes are Radiological a safe remarks begins panel I will pumps products and the of FDA s perspective introductory catheters to presentation regulated by separate safety and effectiveness determination of the in part upon the performance delivery system that delivery system depends device with requirements 1 the drug In terms and safety is used in part on the of the The on drug s complexity 091 of product marketed approval devices nev drugs there nev used is consult vith devices and the scientific combinations steps I ve which are operating task before the panel You are asked to effective I want simply pump intended defined in determine the the effectiveness will be most the safety the to route approved of whether the infusion pumps drug use approved today of the consider are safe and of an infusion drug for the NOT here have in approval and of any drug encountered allow scope will devices We are and effectiveness drugs the administration labeling device environment you The intended of and premarket the an and Research process and define deliver and the dosage today to The safety been or and soon established Hov do drugs for by is Since authority regulatory that or Devices drug statutory complex use for with drugs situations to regulatory assurance be used Drug Evaluation to clarify intended to marketed Center FDA s the decide stated use for in the their with related the reasonable for the simplify applications PMAs for provide be used Center illustrated new drugs and many other changes to Now that today to matters Recent take vith authority Health on faced new devices congruent Radiological FDA to we are mesh with pumps in a regulatory EXTERNAL infusion pumps are independent sense FDA approvals of specific drugs 092 2 Some external hand specific considered is pumps are drugs for for the labeling vithout device and and device not have once must to reprove otherwise the must the be compatible there to the submit pump drug labeling and for In essence safety be additional can be added and s clinically administration data fundamental alwa pump is Manufacturers compatibility be other implantables an implantable of On the must with of administration data drug labeling even route clinical stability drug drug Still a particular same route to a specific the Generally qualified for and implantables flexibility drugs dedicated the one does and effectiveness of the pump The determination based upon the vivo data actual progress cause the in the performance flov the concern site must is to deliver of the A second be determined the pump deviation of the manner the and in indicator that desired pump is in vitro and reliability demonstrates in the or inability it PMA including expected vhich patient and an implantable of effectiveness from that to the of drug is the drug was Significant to the whether site anomalies are are failures determination sponsor that drug in flow for device The contained delivered deviations effectiveness One indicator of actually data the documenting and catheter the of must the of identify device and safety all is based complications technique related 3 upon and adverse the same segregate effects data them and The such their 093 causation can be distinguished unrelated to be within In implant acceptable sum the against The the options Device drug effects related or other adverse effects effects should limits known its from risks of the demonstrated benefits to for consider implantable the first pump must device be veighed DEVICE A are as follows 1 The panel in the that there or after based upon the and upon the DEVICE A is FUDR and deficiencies are that application assurance of believes therefore in other the safe should application panel data discussion presented there and effective be identified concerns that based upon the must the delivery There are by the be them is reasonable for approved to no panel resolved nor before approval OR 2 The panel in the believes application assurance that and upon the DEVICE A is of FUDR and therefore deficiencies that or safe should discussion regarding 4 presented there and effective be approved concerns data them is reasonable for However the to the delivery there safety are and 095 effectiveness of DEVICE A that be specified remain concerns must such DEVICE A can be approved that or they can be ansvered The in a post These questions questions or concerns once the conditions approval or are are met format OR 3 The panel in the believes application reasonable delivery of This choice will based and assurance the vote that upon that The deficiencies the therefore discussed in the in data presented discussion DEVICE A is FUDR and be upon the there safe and should not further application to them detail must is no effective be for approved before the be specified 095 5 AFTERNOON PRESENTATION You are now going In this case to consider there and preservative FUDR which background with are free I will from second two drugs morphine not FDA s implantable the that are sulfate discuss and We have for already Let on the once infusion indicated further perspective pumps implantable again use pump use considered me provide of define morphine the some sulfate scope of dxscussxon Duramorph or morphine Astramorph sulfate injection concentrations are intrathecal and relatively lov implantable free flexibility provide such for in use the near Hov do concentrate concentrate only a high infusion supplied morphines they because of for morphine the as in preservative 5mg ml currently have very higher that can provide concentrate almost are hopefully their utility approved physicians free going of for for requirements a decade preservative 1mg ml approved limited dosage for form the ago desired to approved be successful in future physicians morphine morphine manage In patients the without interim individual physicians an lacking and approved an those of Efforts morphine to the free and Because a more concentrated was identified pumps known administration concentration The need preservative dosage the USP epidural pumps many patients generically FUDR approved taking high high part 096 6 in clinical infusion the studies evaluating have pumps used concentrations limited also been use for of a preservative available formulated pharmacy necessary supply management pain concentrate from a pharmaceutical firm NOT approve compatible for approved a device drug A morphine for the of epidural As noted flexibility administration approval a drug has investigational is has by segment pumps for epidural Duramorph current use use administration morphine of for for indicates intractable Duramorph reads the implanted epidural pumps delivery pain of malignant the management of 7 approved of least usage implanted does for not epidural but least The not an Only the a step epidural preservative origin ain and was at forward intended first preservative physician of the of Duramorph of approved the at PMA for that to FDA the for no a PMA infusion approved we recognize now a small implantable an is contrary section continuous administration needed is pumps The dosage there to approve provided infusion by which not that Duramorph implantable currently morphine provide of for we strive of administration pumps for device Likewise of administration epidural infusion delivery a mode of use manufacturer free drug approve route describes a drug Approval to epidural one for labeling opportunity use achieve only FDA will The to management pain high implantable morphine effective free vith free intended responsive t ai 097 non narcotic analgesics defined is Much of based on acute condition that the a drug It A higher what be intended benign to The morphine data pain of both to FDA based limiters vith of for the labeling that drug be capable NOT here to a the for a better implanted intended a deal and pain defines of providing from a pump therapy intractability valid the of preservative Center cannot labeled intended labeling treatment take pain pump simply use to of the the drug as the drug determine the safety and will state use for of free a high the with pending certainty we believe concentrate of it morphine pain of thrust is absolute Still intractable be morphine is that malignant a portion of or the place in malignant on the a drug a pump to implant is This presentation to approved implant not not any drug its origin not should is Obviously pain pump is this for the infusion to anticipate prudent supporting should responsive We are We in will one One concentration approval data etiology pain implantable directs of the obstetrical were The pump must effectiveness that Therefore origin To reiterate is is ratio of maliganant labeling or situation risk benefit drug clinical of view point an infuse the post op risk benefit with Note the PMA sent AND benign information to origin included 8 you for evaluation This in the was PMA not include apparent Nevertheless 098 the manufacturer follov up will submission for you and complicates to the the must be you can use from a device support today and this is in a news to reasonably adjust The decision options when considering morphine use Since alternatives matters The deliberations that use to forego previously of the there of the may be affected the panel for are indicated for for so we wish 9 the risk sound implants intrathecal experience DEVICE A are session record of on a pump panel precedent of and paucity epidural there We will as setting to the same of FUDR and two drugs by the a current clinically administration end of the are the device for from aspects sufficient claim mentioned can be considered at need it benign concern greater we extrapolate DEVICE B for DEVICE B is further the an epidural a relevant is for of chronic of morphine epidural if defined Recognizing to can to All pain as of relatively claim words implants less the ective intrathecal was administration compared other treatment be considered and an epidural In for malignant must ers indication This implants intrathecal Others us Although drug reliability of intrathecal epidural cases of the for placement predominance these for we believe considered angle catheter to matters Long term risk benefit of data FDA evaluation implications device pain the situation What are the clarify are more address necessary in this be as issue definitive 099 as possible 10 100 l 101 e On e ac Pl Yo ur xt Te uld Co Go ee (S ta tio n en m cu Do Se cti on APPENDIX 3 102 6) REFERENCES 1 Auld AW Maki Jokala A Murdoch DM Intraspinal Narcotic Analgesia in the Treatment of Chronic Pain Spine 10 777 781 1985 2 Woods WA Cohen SE High Dose Epidural Morphine in the Terminally Iil Patient Anesthesiolo 56 311 312 1982 3 Shetter AG Administration of Intraspinal Morphine Sutfate for the Treatment of Intractable Cancer Pain J Neurosur 18 740 747 1986 4 Penn RD Paice JA Chronic Intrathecal Morphine for Intractable Pain J Neurosur 67 i 82 186 1987 5 Onofrio BM Continuous Low dose Intrathecal Morphine Administration in the Treatment of Chronic Pain of Malignant Origin Ma Clinic Proc 56 516 520 1981 6 Leavens ME Hill CS Cech DA Weyland JB Weston JS Intrathecal and Intraventricular Morphine for Pain in Cancer Patients Initial Study J Neurosur 56 241 245 7 1982 Krames ES Gershow J et al Continuous Infusion of Spinally Administered Narcotics for the Relief of Pain due to Malignant Disorders Cancer 56 696 702 1985 8 Harbaugh RE Coombs DW Saunders RL Gaylor M Pageau M Implanted Continuous Epidural Morphine Infusion System J Neurosur 56 803 806 1982 9 Greenberg HS Taren J Benefit From and Tolerance to Continuous Intrathecal Infusion of Morphine for Intractable Cancer Pain J Neurosur 57 3 360 364 1982 10 Delhaas EM Lip M Low Dose Epidural Morphine by Infusion Pump Lancet 11 Coombs DW Complications of Continuous Intraspinal Narcotic Analgesia Anesth Soc J 30 315 319 1983 Canad 12 Cobb CA French BN Smith KA Intrathecal Morphine for Pelvic and Sacral Pain Caused by Cancer Sur Neuron 22 63 68 1984 13 Plummer Ji Cherry DA Cousins MJ Gourlay GK Oniey MM Evans KH Long Term Spinal Administration of Morphine in Cancer and Non Cancer Pain A Retrospective Stucfy Pain 44 215 220 1991 8378 690 1984 1G3 l 105 APPENDIX 4 105 Medtronic SynchrolVled Infusion SYSTEM CAUTION Medtronic System DESCRIPTION and use by or on the order Federal law USA restricts this device to sale distribution infusion of floxuridine This device is approved for chronic intravascular of a physician and intraspinal infusion of heparin methotrexate clindamycin cisplatin doxorubicin ARE CONSIDERED ALL OTHER USES morphine sulfate preservative free INVESTIGATIONAL and SynchroMed are trademarks of Medtronic Inc lr ONTENTS PREFACE 1 INDICATIONS 2 CONTR A IN D ICATION SYSTEM 2 S DESCRIPTIONS PUMPS PROGRAMMABLE VASCULAR CATHETERS INTRASPINAL CATHETER Model 8703 ACCESS CATHETER PROGRAMMER TECHNICAL SUPPORT SYSTEM 2 3 3 4 4 5 5 lou PREFACE The Medtronic SynchroMed catheters access system Infusion System and accessories includes a programmable a programmer pump a catheter Q 5g NCwf ciMi D uQ l CJ D 0 E D 0 C3CIOCDDDODGC5OC5 ClOCIOC3C5ClGDC5 GQ 5 NcwPc C3OClt3OC3GQOt5C525 C1 SynchroMed Mf o G Infusion I System The drugs to a specific site and to administer to contain is designed The system parenteral The accessories and catheters system access catheter include the pump implantable devices is to used which Programmer Model 8810 is the SynchroMed external part of the system the implanted pump noninvasively program and interrogate 1 108 INDICATIONS requires the chronic is indicated for use when patient therapy Infusion System The SynchroMed use of bacteriostatic In addition the nontherapeutic infusion of floxuridine or doxorubicin intravascular to support this mode of cancer saline and or heparin is indicated when necessary water physiological therapy infusion The regional intra arterial solid colorectal tumors metastatic of floxuridine to the liver infusion of doxorubicin The systemic intravenous lymphomas and leukemias tumors is used in the palliative is used in the palliative management of unresectable management of various solid infusion of preservative free epidurallintrathecal When patient therapy requires the chronic intraspinal of chronic intractable mglmL in the treatment 25 mglmL pain and morphine sulfate sterile solution 10 Models 8611H and 8615 only A 09 solution of preservative free of preservative free concentration sodium morphine the physician prescribed chloride can be used to achieve sulfate sterile solution the physician prescribed Heparinized physiological catheter patency saline can be used to achieve water or physiological Bacteriostatic or to flush the pump reservoir floxuridine or doxorubicin of concentration in floxuridine therapy to maintain interruption an may used during saline be or doxorubicin Infusion System for use with floxuridine the SynchroMed Physicians prescribing indications with familiar the must be sterile solution morphine sulfate preservative free of Except under approved conditions in the drug labeling and warnings described contraindications to the Infusion System is restricted the use of the SynchroMed Device Exemptions Investigational infusion of the drugs and fluids previously described CONTRAINDICATIONS not be implanted The device should Implantation the surface is contraindicated of the skin and or Patients whose candidates Contraindications SYSTEM body when the pump cannot be implanted less than 2 5 cm one inch medical device when the patient has an implanted programmable size is not sufficient relating of infection in the presence to accept to the use of the prescribed the pump drug should bulk and weight from are not suitable be observed DESCRIPTIONS indications For a complete description contraindications of components manual of component refer to the appropriate sections each please warnings and precautions 2 106 PROGRAMMABLE PUMPS Pumps are implantable 8611H and 8615 Programmable Models 8610H SynchroMed from received to instructions drugs according that store and dispense devices Programmer battery powered the SynchroMed lithium circuitry microprocessor based 18 mL drug reservoir a collapsible The pumps contain with a self sealing fill and port acoustic transducer antenna battery peristaltic pump thionyl chloride Models 8611H and 8615 also contain a bacterial retentive filter through septum and a needle stop an integral Catheter Model 8615 incorporates which the drug passes as it leaves the drug reservoir catheter Access Port with the pump to allow direct access to the the second a hybrid electronic One contains the drug reservoir The pump has three sealed chambers The and the third a peristaltic pump module and battery peristaltic pump forces the drug from the Electronic circuitry site administration into to the a catheter tubing reservoir through elastomeric controls the pumping action entry point via syringe to an implanted catheter The Catheter Access Port provides a transcutaneous The system allows one catheter to deliver infusions and diagnostic for drug administration purposes The access port comes integrally attached to the Pump and an access port from both a SynchroMed Pump SynchroMed The access port housing needle septum self sealing infusion in line valve directs fluid from passing back to the infusion from the pump a and contains silicone rubber and titanium is made of biocompatible The titanium catheter port and an in line valve stop infusion pathway infusion site and prevents flow from the access port toward the catheter When the pressure from the access port injection is removed the pump into the catheter continues its 18 mL drug reservoir is filled with 14 16 Before the pump is sealed in the plastic tray and sterilized The titanium drug reservoir is emptied and refilled through the mL of sterile water for injection silicone septum in the raised fill port self sealing A Dacron pouch included in the pump package serves to fix the pump in the subcutaneous pocket all 8611H 8610H and access system catheter well the optional Models models as to anchor as pump Examine the shipping package carefully do not implant or resterilize the pump To assure subsequent mLlhour If the package is damaged or the Return the pump and its shipping Use Before date is past Inc Medtronic to package limit the reservoir fill volume at implant SynchroMed pump accuracy refill volumes to 18 mL Program the pump to deliver not less than 0 096 modes have not been used in cancer chemotherapy The following programmable for vascular applications modes These are not recommended delay and bolus occlusion increased risk catheter no flow of and the possible periods of VASCULAR to 10 mL and mLlday 0 004 bolus clinical studies due to the intermittent CATHETERS Vascular SynchroMed for drug administration devices designed to provide a fluid pathway Catheters are totally implantable of radiopaque The catheter body is constructed and or diagnostic procedures 3 110 and materials Programmable a strain relief incorporates Pump or Medtronic Catheter assembly connector Access Port for attachment to a SynchroMed use and may be trimmed to The Model 8700 Vascular Catheter is designed for general intravascular with comes packaged The catheter distal to the are attached Fixation rings length portion desired separately rod metal tunneling supplied for a tips and sleeves anchoring a guidewire plastic and small vessel access The Model 8702 Vascular Catheter is designed specifically for intra arterial The to the distal portion Fixation rings are attached introduction may be trimmed to facilitate rod supplied and plastic tips for a metal tunneling sleeves with anchoring is packaged catheter separately use and cannot be trimmed to length The Model 8710 Vascular Catheter is designed for intravenous metal coil and a construction a small inner silicone tubing a high strength because of its trilaminate It is packaged with Therefore the Model 8710 is provided in two lengths large outer silicone tubing sleeves and plastic tips for a metal tunneling rod supplied separately anchoring Catheter occlusions details on methods Refer to the vascular may inhibit drug delivery of clearing an occluded catheter catheters technical the pump should be emptied To maintain catheter patency during periods of nontherapy to a continuous and programmed heparinized solution filled with saline or an appropriate Do not stop the pump during periods of nontherapy not less than 0 096 mL day INTRASPINAL CATHETER intraspinal catheters SynchroMed The catheter drug administration and trimmable manual for of drug and flow rate of Model 8703 and designed to provide a fluid pathway for are totally implantable materials and is elastic flexible of radiopaque body is constructed use The device designed for epidural intrathecal The Model 8703 Intraspinal Catheter is a two piece relieves and to the pump on the proximal section of the catheter segment connects pump connector of the two catheter sections A metal connector assembly facilitates connection strain on the catheter CATHETER ACCESS SYSTEM entry point via Model 8500 1 The SynchroMed Catheter Access System provides a transcutaneous The and or diagnostic purposes Catheter for drug administration syringe to an implanted SynchroMed access Pump and an access port The system allows a catheter to be attached to both a SynchroMed needle stop septum thermoplastic and contains a self sealing port housing is a molded biocompatible is a The connector assembly and a titanium catheter infusion pathway three suture points port in line an a titanium catheter of two silicone connectors T shaped connector consisting port and valve of blood is If the presence The catheter access system is not intended for use in blood withdrawal flush the system with a minimum of 10 mL of saline a in the catheter access system suspected heparinized solution may be used if not contraindicated 111 4 PROGRAMMER program is designed for use by the clinician to noninvasively Model 8810 Programmer The SynchroMed a establishes The Pump Programmable programmer implanted SynchroMed an and interrogate and interrogation transmit programming implanted to with link the radio frequency two way RF pump includes a The programmer from the pump signals to the pump and to receive status information battery rechargeable by a is The wand and powered computer programmer printer programming Medtronic for only used Programmer should be programming The Model 8810 SynchroMed pack which is free best in an environment operates The programmer Pumps Programmable SynchroMed interference from strong electromagnetic TECHNICAL SUPPORT support service is available A toll free technical Telephone Customer infusion System implants 24 hours a day for clinicians 1 800 328 0810 Service at managing SynchroMed 112 5 Medtronic Q Medtronic Neurological 800 53rd Avenue NE PO Box 1250 Minneapolis MN 55440 9087 612 572 5000 1 800 328 081 0 USA 1 991 Copyright All Rights Reserved Printed in USA PN 195XXX 001 August 1991 113 Medtronic SynchroMed Infusion System Model 8703 Intraspinal Catheter TECHNICAL MANUAL NTENTS 2 2 2 3 3 3 4 4 SPECIFICATIONS RESTERILIZATION DESCRIPTION INDI GATI ON S CONTRAINDICATIONS PRECAUTIONS POTENTIAL COMPLICATIONS FOR USE INSTRUCTIONS SPINAL 4 CATHETERIZATIQN Placement Epidural 4 5 6 7 7 Intrathecal Placement CATHETER CONNECTION TECHNICAL DISCLAIMER TO PUMP SUPPORT OF WARRANTIES Back cover and use by or on the Federal law USA restricts this device to sale distribution infusion for intraspinal of preservative free This device is approved of a physician INVESTIGATIONAL morphine ALL OTHER USES ARE CONSIDERED sulfate CAUTION Medtronic TUNNELING and SynchroMed are trademarks of Medtronic Inc order 11 PECIFICATIONS Catheter length Total Distal Proximal cm 41 0 in 104 1 15 0 in 38 1 cm 26 0 in 66 0 cm in 1 2 mm 4 French 0 049 in 0 7 mm 0 027 in 2 2 mm 6 5 French 0 085 in 0 6 mm 0 025 8 08 ullin 3 18 ullcm silicone rubber Radiopaque 1 cm for 20 cm Titanium in 0 6 mm 0 025 Silicone rubber in 9 1 mm 0 360 in 0 053 cm 0 018 needle epidural 16T gauge Tuohy Outer diameter distal Inner diameter distal Outer diameter proximal Inner diameter proximal volume Catheter material Catheter Marker spacing material Tubing connector Inner diameter relief sleeve material Outer diameter maximum Guide wire outer diameter Introducer Percutaneous Strain RESTERILIZATION Do not resterilize the catheter and accessories after exposure oxide have by ethylene are sterilized The catheter and accessories and accessories and the catheter tray has been opened for resterilization radiation or flash autoclaving to body tissues or fluids If the sealed plastic prior to shipment Do not use resterilize not been used when the catheter for resterilization method Ethylene oxide is an acceptable time Allow adequate oxide permeable in an ethylene repackaged package and accessories implanting the catheter A standard method may also be used as a resterilization Steam autoclaving Do not flash autoclave F and 15 psi is recommended 121 C 250 are and accessories for aeration before cycle of 30 minutes at instructions cannot be given here units among sterilizer Due to variations precise sterilization is information If further F C of 60 temperatures 140 should not exceed However the process unit Use the sterilizer manufacturer of contact the to be used regarding necessary procedures unit of the sterilizer method to verify the effectiveness acceptable indicators or another biological DESCRIPTION are made section thicker walled section and a proximal The catheter body sections a distal thin walled on the The connector flexible trimmable rubber is elastic and that radiopaque silicone of pump near the segment to the pump and relieves strain on the catheter facilitates connection section proximal sections catheter of the two facilitates connection assembly The metal connector connection pump The distal section with a guide wire for 20 cm to aid in catheter is marked at 1 cm increments and catheter tip stiffness in the lumen to provide additional 2 It is packaged placement control during placement 115 The catheter percutaneous Tubing may be used in the epidural or intrathecal surgical using the accessories procedures space The catheter can be positioned in the catheter package provided Strain Connector by direct Relief Sleeve Distal Tubing Proximal 1 cm Markings Tubing Guide wire SynchroMed Model 8703 Intraspinal Catheter INDICATIONS The Model 8703 Intraspinal is intended Catheter for use with the Medtronic SynchroMed Infusion System The SynchroMed Infusion System is indicated for use when patient requires therapy the chronic intraspinal infusion of preservative free morphine sulfate sterile solution 10 mglmL and 25 mglmL for the treatment of chronic intractable pain CONTRA INDICATIONS Intraspinal ventriculitis catheterizations skin infection are contraindicated in the presence bacteremia and septicemia Spinal catheterization is contraindicated implantation and fixation of a lumbar of known in the presence of spinal catheter or drug delivery or suspected anomalies that may meningitis complicate the PRECAUTIONS Examine the sealed plastic the catheter and accessories tray carefully with ethylene Do not bend or kink the catheter wire must be withdrawn before and guide connecting If the tray seal is broken oxide Do not sterilize sterility is questionable with radiation or by flash wire either before use or during the catheter sections together 3 implantation Resterilize autoclave The guide 116 catheter placement wall the catheter the guide wire to verify or change When reinserting force could cut or puncture Excessive encountered verify that the catheter implantation or a tortuous position geometries During will not become catheter of damaging are capable instruments Sharp surgical tubing the catheter cut or puncture inadvertently elastomers to the proximal tubing section attached the connector Do not remove and catheter is complete only after placement guide wire is removed before placement DO NOT trim the distal section sleeve anchoring C POTENTIAL tight to not be taken must Care be should due to knots or occluded kinked force no reinsertion Trim the distal tubing section to tissue with an is secured with or guide wire in place MPLICATIONS Infusion SynchroMed of the Medtronic the safety and efficacy to establish A clinical trial was performed associated complications the during this clinical trial potential Based upon the data collected System of therapy Cessation but may not be limited to the following with the use of this device may include infection or erosion hematoma seroma failure component or random pocket depletion due to battery headache lumbar hygroma and angulation puncture type catheter IN FOR TRUCTIONS Examine ethylene SPINAL USE the sealed plastic tray carefully oxide before implantation If contamination is suspected for any reason with resterilize CATKETERIZATION visualization and draped to allow fluoroscopic The patient is placed in a lateral fetal position Under local or regional epidural anesthesia will be placed in the region where the catheter wall Consider position pocket subcutaneous pocket to secure the pump to the abdominal belt lines etc clothing with patient mobility which may interfere locations The catheter needle is most Epidural often placed 16 gauge or intrathecal space using Tuohy a 16 gauge epidural needle until tip is felt embedded Advance in use hanging of epidural space location To aid in determination needle stylet technique a 5 ml glass syringe to needle for loss of resistance or attach Aspirate to ensure proper location neither blood or CSF is obtained Thread epidural catheter epidural to avoid Placement Orient bevel and insert flavum ligamentum Remove method in the lumbar of the spine a prepare of needle bevel in epidural with cm graduations distal tip of catheter marked in advancement A slight increase space pressure reaches the curved point of the epidural needle 4 space Continue procedure drop if the epidural needle into the through will be noted when the tip of the should now The first cm graduation 117 Subsequent needle hub with the end of the epidural space should be minimal into the epidural coincide approximately the catheter to advance required pressure Placement Intrathecal epidural Orient bevel and insert 16 gauge level to desired segment advance fluoroscopy Under needle catheter distal CSF flow until the guide wire slightly to allow retrograde withdraw catheter patency to the drape tubing distal of the end Push the guide wire back in place and clamp the flow of CSF stoppage incision site ensuring To ensure observed above the an incision is made at the spinal region so that the segment of the distal catheter Following placement placement can be made prior to catheter incision subcutaneously this can be secured catheter To the during catheter the procedure or cut not inadvertently puncture care must be taken to Special incision the while keep the Tuohy needle in place while the incision is being made the catheter protect and segment the catheter for securing exposed are is complete tissues incision the made Once is incision at segment point remove the Tuohy needle grasp catheter carefully is confirmed placement and withdraw slowly For added stability wire guide an anchoring place sleeve close entry spinal to the point and suture it to surrounding tissue tubing between catheter pump and spinal the length of proximal Measure the connector that ensuring if necessary Trim the segment the catheter segment distal tubing and trim the Refer to the 1 figure Insert metal catheter the distal connect and tubing connector into to the proximal tubing tubing proximaf large for slack in Unclamp allowing region end is left intact as follows tubing diameter with tubing connector 2 Slide 3 Insert strain relief tubing sleeve connector if used into distal small tubing end first using over care previously not to disrupt placed distal tubing spinal catheter placement 4 and ligate over connection if used Slide strain relief sleeve of tubing as shown ligate both sections not being used Distal and Proximal Catheter Tubing relief sleeve is 4 3 2 Connect If the strain With Sleeve 118 5 Connect Distal 4 3 2 and Proximal Catheter Tubing No Sleeve the pump implant under the skin or tissue and pull toward Place the catheter rod that is provided as an accessory or by using the tunneling tooIs surgical Prevent sleeves tubing tubing catheter in the implanted or angulation tension angulations unusual and to stability additional prevent excessive to provide Suture Ligation Reference anchoring Use catheter that might kink the catheter points Catheter s Anchoring CATHETER site with appropriate Catheter Tunneling see sleeve placements TUNNELING instructions for tunneling procedure in Accessory Kit Model Number 8590 41 11 6 TO PUMP CONNECTION Before connecting infusion parameters the catheter Do not inadvertently CAUTION verify to the pump introduce onto connector Firmly press the silicone rubber ligature placed with a nonabsorbable connector for ligation not use chromium or wire sutures the pump that air bubbles is functioning and set for the desired into the catheter metal fitting of the pump and secure the tapered in the suture groove at the base of the connector the Do ill Push Do not inadvertently CAUTION Place catheter the the connector pump tubing TECHNICAL in the incision pocket will not be punctured tear onto the pump fitting the catheter or puncture and ligate tubing with is not knotted so that the catheter refill the pump used to by needles the metal or kinked pump and fitting so that the SUPPORT service support A toll free technical Telephone implants System Infusion is available Customer 24 hours a day for clinicians Service at 1 800 328 0810 managing SynchroMed 12G 7 DI LAIMER MEDTRONIC INTRASPINAL OF WARRANTIES SYNCHROMED CATHETERS INFUSION SYSTEM WARNING hostile in the extremely are implanted Catheters Catheters Intraspinal Medtronic SynchroMed but including causes variety of for a function fail may to Catheters of the human body environment breakage occlusion or complete by failure Catheters of partial or complications not limited to medical of all due care in design the exercise despite In addition separation or connector dislodgement before may be easily damaged Catheters sale to testing manufacture and selection prior component no Consequently acts intervening other handling or improper insertion by or during after that will not occur of Catheters of function is made that failure or cessation or warranty representation not will medical complications or that of catheters to the implantation the body will not react adversely follow of catheters the implantation AS THE ENTIRE RISK AS TO THE QUALITY AND IN CONDITION ARE SOLD IN AN CATHETERS OR ALL EXPRESS DISCLAIMS MEDTRONIC IS WITH THE BUYER OF CATHETERS PERFORMANCE IMPLIED TO ANY NOT LIMITED BUT INCLUDING CATHETERS REGARDING IMPLIED WARRANTIES MEDTRONIC SHALL PURPOSE OR FITNESS FOR A PARTICULAR WARRANTY OF MERCHANTABILITY CONSEQUENTIAL DIRECT ANY OR OR EXPENSES NOT BE LIABLE TO ANY PERSON FOR ANY MEDICAL OF OR MALFUNCTION FAILURE BY ANY DEFECT FROM OR CAUSED RESULTING DAMAGES TORT CONTRACT WARRANTY IS BASED UPON DAMAGES FOR SUCH A WHETHER CLAIM CATHETERS NO PERSON HAS ANY AUTHORITY TO BIND MEDTRONIC TO ANY REPRESENTATION OR OTHERWISE OR WARRANTY Medtronic WITH RESPECT TO CATHETERS g Medtronic Neurological NE 800 53rd Avenue PO Box 1250 MN 55440 9087 Minneapolis 572 5000 612 328 0810 800 USA 1991 Copyright All Rights Reserved Printed in USA PN 195XXX 001 1991 August 1Z1 Medtronic Synchro Med Infusion System Morphine Sulfate Sterile Solution Preservative Free DRUG CAUTION THERAPY SUPPLEMENT Federal law USA restricts this device to sale distribution and use by or on the order of a physician Medtronic and SynchroMed are registered trademarks of Medtronic Inc NTENTS INTRODUCTION 1 1 INDICATIONS CONTRAINDICATIONS 1 WARNINGS AND PRECAUTIONS 1 POTENTIAL COMPLICATIONS 2 AND ADMINISTRATION 2 DOSAGE 3 OVERDOSAGE TECHNICAL REFERENCES SUPPORT 4 4 122 INTR DUCTION morphine sulfate This supplement gives brief guidelines for the intraspinal infusion of preservative free Pump part of the Programmable 8615 or 8611H Model sterile solution with the Medtronic SynchroMed implantable is an programmable The SynchroMed pump Medtronic SynchroMed Infusion System battery powered infusion device INDICATIONS The SynchroMed infusion System is indicated for use when patient therapy requires the chronic intraspinal infusion of preservative free morphine sulfate sterile solution 10 mg mL and 25 mg mL the treatment of chronic intractable pain in For the indications and instructions for use of Medtronic SynchroMed Models 8611H or 8615 Programmable Pumps refer to the Medtronic SynchroMed Model 8610H 8611H 8615 technical manual CONTRAINDICATIONS The device should not be implanted in the presence of infection Implantation is contraindicated when the pump cannot be implanted less than 2 5 cm one inch from the surface of the skin and or when the patient has an implanted programmable medical device Patients whose body size is not sufficient to accept the pump bulk and weight are not suitable candidates Contraindications WARNINGS relating to the use of the prescribed drug should be observed AND PRECAUTIONS Reservoir filling must be performed by fully trained and qualified personnel following the directions should be provided in the Medtronic SynchroMed Model 8551 Refill Kit Technical Instructions Care result in would which the reservoir of taken in selecting the proper refill frequency to prevent dep1etion 28 not exceed intervals should refill exacerbation of severe pain To ensure adequate drug stability and contamination to bacterial the reservoir avoid days Strict aseptic technique is required while filling reservoir the refills SynchroMed of all pump infection The SynchroMed refill kit must be used during Extreme care must be taken to ensure that the needle is properly placed in the fill port of the Injecting the solution into the tissue around the device before attempting to refill the reservoir the catheter access port will result in a large into device or attempting to inject the refill dose clinically significant overdosage to the patient A period of observation appropriate to the clinical situation should follow each refill or manipulation of the drug reservoir Before discharge the patient and attendant s should receive instruction in the of an proper home care of the device and implant site and in the recognition and practical treatment overdose of intraspinal morphine 123 1 sections of For a complete list of drug warnings and precautions for use please refer to the appropriate the drug labeling Refer to the appropriate Technical Manual for the SynchroMed Programmable cautions and precautions P TENTIAL C Pumps for warnings MPLICATIONS Infusion System Clinical trials were performed to establish the safety and efficacy of the SynchroMed with the Based upon the data collected during these clinical trials the potential complications associated therapy of to Cessation use of the SynchroMed Infusion System may include but may not be limited erosion or due to pump battery depletion or random component failure pocket seroma hematoma headache infection catheter migration angulation or dislodgement lumbar puncture type DOSAGE AND ADMINISTRATION Refer to the package insert for preservative free morphine sulfate sterile solution for dosage instructions for intraspinal infusion in Pumps must be refilled on a prescribed schedule by trained personnel using procedures described Manual the SynchroMed Refill Kit Technical The SynchroMed Refill Kit must be used during all refills of the SynchroMed pump reservoir Preservative free morphine sulfate sterile solution is available commercially in single use ampules in the following concentrations 200mg 20mL 500mg 20mL 1 Omg mL 25mg mL These formulations are stable in the SynchroMed pump reservoir for 90 days exceed 90 days Refill intervals should not The ability to noninvasively program the pump provides flexible control over both the dose and the timing of medication delivery The programming feature allows dose adjustment or titration without changing the drug concentration in the reservoir Dilution is not necessary in most cases SynchroMed pump flow rate Proper dosage may be selected by noninvasively adjusting the Dilution is required for patients who The minimum recommended pump flow rate is 0 096mL day as a diluent chloride of sodium solution Use a 0 9 require less than 1mg day See Table I for sample flow rates and refill intervals 12 2 TABLE I Sample Flow Rates and Refill Intervals Patient Daily Dose mg Morphine Concentration mg mL Recommended Flow Rate mL day Interval daYs a 05 5b 01 90 10 10 01 90 25 10 0 25 64 25 25 01 90 50 10 05 32 50 25 02 80 75 25 03 53 10 0 25 04 40 20 0 25 08 20 25 0 25 10 16 30 0 25 12 13 40 0 25 16 10 50 0 25 20 8 Refill a The refill interval considers the reservoir being filled with 18 mL the low reservoir alarm set at 2 mL and a drug stability in the pump reservoir of 90 days Refill intervals should not exceed 90 days b Dilution is necessary Use a 09 solution of preservative free sodium chloride for diluent OVERDOSAGE Overdosage of morphine is characterized by respiratory depression with or without concomitant CNS depression Since respiratory arrest may result either through direct depression of the respiratory center or as the result of hypoxia primary attention should be given to the establishment of adequate 3 9 g respiratory exchange through provision of a patent airway and institution of assisted or controlled ventilation The narcotic antagonist naloxone is a specific antidote An initial dose of 0 4 to 2 mg of naloxone should be administered intravenously with respiratory resuscitation If the desired degree of counteraction and improvement in respiratory function is not obtained naloxone may be repeated at 2 to 3 minute intervals If no response is observed after 10 mg of naloxone has been administered the diagnosis of narcotic induced or partial narcotic induced toxicity should be questioned Intramuscular or subcutaneous administration may be used if the intravenous route is not available As the duration of effect of naloxone is considerably shorter than that of intrathecal morphine repeated administration may be necessary Patients should be closely observed for evidence of renarcotization TECHNICAL SUPPORT A toll free technical support service is available 24 hours a day for clinicians managing SynchroMed Infusion System implants Telephone Customer Service at 1 800 328 0810 REFERENCES SynchroMed Infusion System Programmable Pumps Technical Manual 2 SynchroMed Infusion System System Description 3 SynchroMed Infusion System Intraspinal Catheter Technical Manual 4 SynchroMed Infusion System Refill Kit Technical Instructions 4 Medtronic g Medtronic Neurological 800 53rd Avenue NE PO Box 1250 Minneapolis MN 55440 9087 USA 612 572 5000 800 328 0810 Copyright 1991 All Rights Reserved Printed in USA PN 186XXX 001 August 1991 127