Recall Recommendation Review 30007825 . 8 To. . DOE A can Re: Recall Enterprise System (RES) Event Number: 46685 Subj: Please classify the above Recommendation using one of the three modes below: Panel Product code: (ex. Verify Marketing Status: 510(k) P860004 Pre- -amendmenUExempt (Circle One) Consider Warning Letter il firm has no and th in a pre- -amendment or exempt device What CFR andlor THE ACT violation does this Recommendation support 7 Misbranding - 5020) of Act (21CFR . USC . Misbranciing etc.) Precedent recall with comparable health risk: . MD concurrence Was a Precedent or Policy selected by the district? Yes NO If Yes, is the district selected Precedent recall appropriate? Yes NO If No, search RES for a Precedent Recall with the same Risk to Health. Precedent recalls can be found on the Search page of RES. below the blue line. Or search top section for similar recall and verify ill-IE was used. 2. CDRH recall policy that applies: 1. Latex surgical glove fails leak test 5. Intended use not in 510(k) or PMA 2. Latex exam glove fails leak test 6. Sterility (package integrity) compromised 3. Latex condom tails leak test 7. Labeled latex free. contains latex 4. Marketed without a 510(k) or PMA 8. Needle stick risk 9. Fails to comply with performance standard These recalls can be directly classified as Class ll alter verilying that no deaths or serious injuries are associated with the problem. 3. [x A completed Health Hazard Evaluation (attached), wl Medical Officer?s signatun Also e-mail corn leted electronic HHE form to CDRH Recall Group, with RES in subject 6 OCIOIVD MD concurrence II Safety Alert. Market Withdrawal. Stock Recovery, Non-Concur (Circle one) (if Class I. a new HHE is required) The Recall Class is: If Recall, assign: Depth (W=Wholesale. U=Consumerlpalienu Effectiveness Level A Audit Level c=10%. e=oi Risk Quigg- glass l: NB or 100-300 consignee visits. Class ll: CID or 2-80 consignee visits. Class DIE (audit/effectiveness levels) -User level -Relail level -Wholesale level Compare RES _t_g Firm?s Recall Letter f_o_r accuracy 1 1(Producl Names. LolNumbers. Reason fOrRecallelc Classified w/o letter Center Comments" Classified w/o Revise Recall Letter 1 Request CAPA for review before termination Revise Firm's Press statement Revise No changes needed *(ll comments. corrections or changes are needed. please check box above and send (3- mail to CDRH Recall/62?: with RES in subject.) Printed name Kenneth C. Millen Signature 3/11 logy . .. Branch: Date: Februagy 29. 2008 Supervisor approval: faded/t Date: This form MUST BE RETURNED TO Recall Team for rocessin/ I ?a ?300?? RES by__ 61/ Ely]. e- mail to 080 by?C?M/ to Internet {?cleg OCTR125.051 02121I2006 by Root Cause Code [Vi/Scanned by by . MAR 2 Please submit comments. concerns or suggestions to Please save as a different l'IlentInIe before ?lling out this form. j. . . HHEVersion 3-1 01/12/2007 . Health Hazard Evaluation or Health Risk Assessment Center for Devices and Radiological Health Date: February 29. W: 16685 Safety Of?cer: Kenneth C. Millen 2008 -- I. Product Data - . . . . Panel Code: 80 El. SyneliroMed II and lsoMed implantable infusion Product Code: LKK Deuce t\.tme. pump 5) stems SyneltroMed EL Models 8626-10, 8626L-l0. 3626-] 8. 8626L-l8, 8627-! 0. 8627L-l0. 8627-!8. Models: g?illirliitled II Lot/Serial Numbers: All Models 8637-20, 8637-40; and IsoMed Models 8472-20, 8472-35, ?3 8472-60 Marketing Status (Include Or PMA Number, Specify IfClass I Exempt From 5l0(K) 1? PMA P860004 Total Number Of Devices In Distribution: 403.792 pumps U.S.: 90,330 pumps Foreign: H.462 pumps Number OfDevices Subject To Recall or Review: 102,792 pumps U.S.: 90.330 pumps 1 Foreign: 12.462 pumps Manufacturer/ Recalling Firm, Address: Medtronic Neuromodulation soo 53'd Ave NE Minneapolis, Minnesom 5542 Product Description (Include Intended Use From Labeling): I The and lsoMed pumps are implantable, programmable, batter-powered devices that store and deliver medication according to insuuetions received front a programmer. EL Indications: Chronic intraspinai (intratheeal or epidural) infusion of preservative-free momhine sulfate for treatment of chronic, intractable pain. Chronic intrathecal infusion of presets?atiI-?c-free ziconotide Sterile solution for the management of severe chronic pain. Chronic intralhecal infusion of Lioresal" Intratheeal (baclofen injection) for severe spaslieity. Chronic intravascular infusion of Iloxuridinc (FUDR), or melhotrexale for the treatment of primary or metastatic cancer. II Indications: Chronic intraspinal (epidural and intrathecal) infusion of preservative-free morphine sulfate Sterile solution in the treatment of chronic intractable pain. chronic intratliccal infusion of preservative-free ziconmide sterile solution for the management of severe chronic pain, and chronic intrathecal infusion of Lioresalg' lntrathecal (baclofen injection) for the management ol'severe spasticity; chronic intravascular infusion of?oxuridine (FUDR) or methotrcxate for the treatment ol?primary or metastatic cancer. Outside of US: Chronic infusion of drugs or ?uids tested as compatible and listed in the product labeling. lsuMed Indications: To deliver the chemotherapy agent ?oxuridine (FUDR) for use in hepatic arterial infusion therapy, a treatment for patients with coloreeta] liver cancer, and to deliver morphine to the spinal ?uid as a treatment for patients with chronic intractable pain. a -. . 'iCIa'ss:'t i . i" 552:: a . Health Hazard Evaluation or Health Risk Assessment Center for Devices and Radiological Health one: February 29, 2008 RES 46685 11. Problem DefinitiOn and Analysis Reason for Recall or Risk Assessment Description of the Defect, Malfunction or Error in Use of the Dex ice: In?ammatory Mass Lesions (primarily intrathecal granulomas) presenting as a chronic inflammatory or granulomatous mass lesion at the tip at the intrathecal drug delivery catheters. Unrecognized and/or untreated inflammatory mass lesions may result In serious neurological de?cits complete or partial spinal cord injury). lliere have been anecdotal reports of a drug eprIt'Ite forming with the use of compounded Baclofen (at high concentrations) which resembles the granulomatous mass with Magnetic Resonance Imaging. Root Cause ofthe Problem (If Known): Mass formation at or near the distal tip ol'the intratliccal catheter has been reported with the intrathecal infusion of opioids, baclofcn, pharmacy-compounded baclol?en and other drugs, as well as with other pharmacological admixtures. Factors That May Contribute to Product Risk (Le. Device Design, Manufacturing Problems or User Error): Device design. device interaction with drug therapy Design Factors That Might Mitigate Risk? The number and orientation of holes in the catheter and the material used in construction might influence the formation ofmasses within the intrathccal space. The concentration, dosage. rate of drug infusion and placement ofcatheter may also influence the formation of masses within the intrathecal space. If Device Failure Occurs [s It Easily Recognized by User?.? The presence ol'a developing mass may not be known to patient or physician until appear and diagnostic imaging is perforated. Inspection ol?the device does not indicate whether a mass will develop with use. Typically. prodromal and signs that could indicate presence ol?a mass in the intrathecal space, include: Change in the character, quality or intensity of pain New radicular pain, especially at or near the dennatomal level of the catheter tip Frequent or large escalations of the daily drug dose are required to maintain the analgesic effect - Dose escalations may alleviate the patient's increasing pain only temporarily. - Early of mass in the thoracic spinal canal may also include thoracic radicular pain in the lumbar region sometimes simulate root compression from a herniated disc or spinal stcnosis Additionally if the patient has pain that responds to the level oi the catheter tip during Catheter Access Port (CAP) injections or programmed boluses, this may indicate p1 escnce of a mass. Manufacturer?s CAPA Investigation (If Available): Summary: Taken from ?rm?s investigation report 1 19-95024 and associated reconunended corrective action: The ?rm believes that masses could occur with any serial munber for any of the device models listed above however the rate of occurrence may be related to the speci?c therapy, concentration and rate being infused. This can present itself as a chronic in?ammatory or granulomatous mass lesion at the distal end (delivery hole area) of intrathecal drug delivery catheters. Unrecognized and/or untreated in?ammatory mass lesions may result in serious neurological de?cits complete or partial spinal cord injury). Affects all models of EL, II and IsoMed, intrathecal catheters, and re?ll kits. The ?rm also states in their Investigative Report that their assessment shows in?ammatory mass is a drug-induced phenomenon. It is not a product/device failure.? (page 27 of 149, 1 19-95024) however ?ndings ?'orn the MIN-DO 1 1/2112006?1124/2007 inspection noted the following regarding root cause: - The ?rm has used different catheter designs - 6 side holes (8709, 8709M, 8711, 8731, 8598) versus the open tip (8703, 8703W) thinking that hole size or orientation might have an impact. A FMEA was performed by Medtronic in September 2003 (Model 8731 Design FMEA, 8731-70145, Version 2.0), regarding the growth issues in their inn'athecal catheters. In that FMEA analysis, the ?rm cites ?Contributes to in?ammatory mass" as an effect of the Cause of Failure, ?Holes are not ideal size or have incorrect orientation?. The ?Failure Mode? is, ?Fluid ?ow out of catheter causes bodily reaction?. (As of the date of the inspection, the ?rm has not de?nitively determined whether hole size or numbers have an impact.) - In a discussion with Dr. Jeffrey W. Allen Senior Scientist, Emerging Therapies Research, who supports the Medtronic engineering groups and helps to develop in?vivo testing and animal models, Dr. Allen mentioned a new catheter that is in deveIOpment that has a permeable membrane along its length to provide better mixing in the CSF. Dr. Allen said that catheter design may help, and that current catheters are not designed to be anti-mass-forming (Page 13 of 33, FDA EIR from Inspection However, a preliminary study ?nalized in November, 2007 by the ?rm has concluded that the current permeable membrane catheter (PMC), as designed, did not prevent or reduce the incidence of morphine-induced intrathecal mass formation in the hound model (Page 289, Medtronic Neuromodulation Investigation Report- NDFHI 1 19-95024). These ?ndings indicate catheter design may play a role in the formation of intrathecal in?ammatory mass formation a?er infusion of opioids, baclofen, pharmacy-compounded baclofen and other drugs, as well as with other pharmacological admixtures, the risk of in?ammatory mass formation appears to increase in the ?rst 3-4 years a?er implant. A medical consultant to the ?rm has said based on his experience that granulomatous mass lesions do not occur with use of the brand of baclofen recommended in product labeling. They may occur with the use of generic or compounded versions of the drug but are not frequent. He also indicated that a participate from generic versions of the drug may occur around the catheter tip creating an image on MRI that is similar to a granulomatous mass. The ?rm indicated that they have received some MDR reports for granulomatous masses with baclofen use and lack suf?cient information to support or disprove this expert?s view. The ?rm initially said it does not believe that granulomatous masses are a device issue, rather they believed them to be a drug therapy issue. However, a voluntary recall has been initiated. Corrective Action: Update labeling appropriately to include risk information. Customer communication - Physician Letter sent January 28, 2008 reminding of 1M, and details on recognition, treatment and mitigation. Preventive Action: Continue to monitor the rate of in?ammatory mass at a minimum on an annual basis. I Date of Analysis: August 13, 2007 Finn?s Estimate of Number of Devices that will Develop the Defect and/or Fail How Many Devices from the Affected Lots Are Expected to Have or Develop the Defect? All intrathecal catheters could potentially be affected by the problem. 0 How Many Devices with the Defect are Likely to Exhibit the Failure Over the Lifetime of the Device? All intrathecal catheters could potentially be affected by the mass problem. 0 Of Those Devices that Fail, How Many are Likely to Cause Injury if Used? There is a potential for further complications, if the I is not diagnosed and treated. 0 Any Comments on How these Estimates were Reached: Firm?s Conclusion About Health Risk. (Attach a Copy of Firm?s HHEs or HHAs): See attached ?rm Any FDA Comments: Adverse Events, Complaints and Problems or Incidents that may be Related to the Device Defect: Number of Complaints 603 as of Malfunction Reports At least February 6, 18" 2008 MAUDE search Injuries Reported U.S. 396* International Deaths Reported U.S. 14* International Sources: Manufacturer Inspection Explanation: ?Analysis ofMDR?s after May 7, 2007 is not complete so the malfunction, injury and death numbers could be higher. Describe the Complaints and Injuries Reported to Date: Inspectional Findings: The following list shows typical that were reported in the ?rm?s complaint system: PCR Number Description PCR 60377 Discovered granulema via MRI. Patient experienced subarachmoid hemorrhage and paralysis. PCR 183288 Patient reports granuloma following paralysis of left leg. Surgery to remove distal end of catheter with granuloma. Post op: Patient reports still paralyzed. PCR 191620 Patient reported ?fell over backwards", burning/numbing pain in abdominal, back, legs and feet. MR1 found granuloma. PCR 278679 Rep reports: Granuloma at catheter tip. Doctor states that this is the largest or 2mi largest he has ever seen. PCR 95901 Continued intraspinal mass. Patient reports ?pain at catheter site for three months, numbness/tingling in hands and feet, had two MRl?s showing suspected granuloma.? PCR 171432 Patient reports six months of excellent relief following implant in 2000, however began to return including increased Granuloma in September 2003 and surgery was performed.? Health Hazard Evaluationor Health Risk Assessment - . . - Center for Devices and RadiOlogical Health Date: February 29. 2003 I RES 46685 3 Health Risks 7 q, a . TO BE COMPLETED BY MEDICAL OFFICER OR COMMITTEE THE FOLLOWING ASSESSMENT IS BASED ON CURRENTLY AVAILABLE INFORMATION. CONCLUSIONS MAY CHANGE IF ADDITIONAL INFORMATION BECOMES AVAILABLE IN THE FUTURE. Immediate and Long Range Health Consequences: A. Describe the Immediate and Long Range Health Consequences (Injuries or Illnesses) That May Result from Use of or Exposure to the Defective Device. (Include Known Ofl? Label Uses) If an in?ammatory mass, ?brosis or granuloma develops, it could initially be Over time, the mass can enlarge to compress the subaraehnoid space and/or spinal cord. thus impinging on the exiting nerves. This could lead to temporary or permanent sensory de?cit and progress to motor de?cit and potential paralysis. As the mass grows in size. the flow of medication can be interrupted, thus the patient may not receive all or a portion of the desired therapy, medication could also be delivered outside ol'tlte intended area (cg, intrathccal space). If patient experiences consistent with underdose Of medication tlte patient may receive therapy via alternative routes or from an increased pump dosage. this may result in over-dosing of medication. Overdose of therapies such as morphine could result in respiratory depression and possibly respiratory arrest; an underdose may result in inadequate therapy. Underdose of therapies such as baclofen could result in baelofcn withdrawal which can encompass neuroleptic malignant which may re5ult in cardiac andfor rhabdomyolysis, all of which could potentially lead to deatlt. If the mass is large enough, it could obstruct the flow of cerebral spinal fluid (C SF) thus resulting in increased intracranial pressure (ICP). Inflammatory mass, granuloma. and ?brosis catt itself be a seed for sepsis. These complications may require ntedical or surgical intervention (with the associated risks). There have been anecdotal reports of a drug precipitate mass forming in the intrathccal space with the use of phannacy-compounded. high concentration Baelofen. This may have initial which are similar to in?ammatory mass however it is unknown if the long-term will differ. Diagnostic images of a precipitous mass may be dif?cult to distinguish from a mass. B. Describe Any Clinical Factors That May Mitigate the Risk: Follow-up other diagnostic procedures, and/or neurological assessments that lead to early identi?cation Ol'a granuloma. Changing therapy, adjusting the concentration of the medication, dose, and/or ?ow rates might mitigate the formation of the granuloma. Monitoring of dosage administration to assure that the calculated residual matches the measured residual of drug therapy. C. What Segment of the Population is Most at Risk? infants, Elderly, Pregnant Women, Critically Patients, Immunocomprontiscd, etc.) Higher risk of granuloma formation may occur in patients receiving a higlt concentration of opioid therapy. After the formation of the granuloma, itnmuric-compromised patients, and the elderly population may be at higher risk of infections secondary to the D. Does the Health Consequence Have Signi?cant Public Health Impact Beyond Users Spread of Serious Infection to Others)? No Assess the hazards associated with use of the defective product Check All that Might Occur: Population at Greatest Overall Population Risk Using Device >14 >14 >14 >14 12Explanation: Life-threatening (death has or could occur) Results in permanent impairment of body function or permanent damage to a body structure. Necessitates medical or surgical intervention. Temporary or reversible (without medical intervention). Limited (transient, minor impairment or complaints). No adverse health consequences. Hazard cannot be assessed with the data currently available. Assess the Probability that Use of, or Exposure to, Product under Recall will Cause Adverse Health Medically Reversible or Transient Adverse Health Conseguences Consequences Every Time Reasonable Probability that Use will Cause Remote Probability that Use will Cause Not Likely that Use will Cause Any Adverse Events Serious Adverse Health Conseguences (Death, Life Threatening, Results in Permanent Impairment) Overall Population Using Device El Population at Overall Greatest Risk Population Using Device 13 El El EL >14 13 Population at Greatest Risk Explanation I Comments: The reported incidence of patients who have developed in?ammatory mass is approximately ?ve times higher than was reported in 2001 The ?rm states that no dose and/or concentration of morphine sulfate can be considered completely free of risk of in?ammatory mass. By the ?rm?s admission there is known under-reporting. The rate of occurrence is expected to increase with use over time. The committee concluded that there is a reasonable probability of mass formation and related risk even for patients who have not received the higher drug concentrations. SIGNATURE PAGE ATTACHED BELOW "Contributed to HHE via teleconference and concurred with risk but were not available for signatures. Sionaturcs Date Printed Name /4 78/3/6513, Murray Malia. K. XL 02 r-R?i?o? KimberC. Richter. MD. Lana Shiu. MD. Ha - I George 'Kroehling 73 Claudia Gaffey. Audrey Morrison? 9:5? 2'6? 9/9755? Daniel B. Lyle ?gage, ?aw 49/29/61" Valerie A. Floumoy 0 Nikhil Thakur Io Kenneth C. Millen x/hwd 21 (7er!) T7 25-" 1-77?) 223/! ,1 \0 II 23%ng