Safety Information on Serotonin Syndrome for Tapentadol IR and Tapentadol ER Administration

Transcription

1 Sfety Informtion on Serotonin Syndrome for Tpentdol IR nd Tpentdol ER Administrtion # Peter Schmidt, MD Depomed, Inc., Newrk, CA INTROduCTION Serotonin is potentilly life-thretening condition tht typiclly results from exposure to drugs tht increse levels of serotonin in the nervous system, Approprite dignosis of serotonin is often chllenging due to the brod rnge of possible symptoms nd the lck of confirmtory lbortory tests; furthermore, there re severl conditions tht hve similr clinicl fetures to severe serotonin (Tble ) Drugs from number of different clsses, including ntidepressnts, ntiemetics, ntimigrine drugs, nd nlgesics, hve been ssocited with the development of serotonin, Tpentdol is centrlly cting nlgesic with possible mechnisms of ction, µ-opioid receptor gonism nd norepinephrine reuptke inhibition, 6,7 tht my increse serotonin levels 6 Tpentdol is vilble in immedite relese (IR) nd extended relese (ER) formultions ObjECTIvE To evlute the ssocition of tpentdol IR nd tpentdol ER tretment with serotonin using US Food nd Drug Administrtion (FDA) nlyses, post-mrketing dt, nd published cse reports through July 8, Tble. Differentil Dignoses nd Key Clinicl Fetures of Serotonin Syndrome,8 Symptom Anticholinergic poisoning Neuroleptic mlignnt Mlignnt hyperthermi Opioid withdrwl Serotonin Afebrile or low-grde fever Hyperthermi Tchycrdi Mydrisis Shivering Hyperctive bowel sounds Incresed muscle tone (lower limb > upper) Anxiety Agittion nd hypervigilnce Delirium Com Hyperreflexi Spontneous or inducible clonus Oculr clonus methods Anlysis of Clinicl Dt for Serotonin Syndrome nd Relted Adverse Events Dt from nine Phse / clinicl trils in ptients tking tpentdol IR nd nine Phse / clinicl trils in ptients tking tpentdol ER were evluted for reports of serotonin s n dverse event (AE) The s tht were permitted or prohibited in the Phse studies included in these nlyses re summrized in Tble Tble. Permitted nd Prohibited Concomitnt Serotonergic Drugs in Phse Studies Tpentdol IR studies In ddition, results re summrized from integrted dtbse nlyses performed by the Center for Drug Evlution nd Reserch (CDER) t the FDA tht evluted AEs ssocited with serotonin using dt from nine Phse / tpentdol IR studies 9 nd nine Phse / tpentdol ER studies Results re lso summrized from seprte post hoc nlysis of AEs in key system orgn clsses (SOCs) tht re relevnt to serotonin using dt from three Phse tpentdol IR studies Post-mrketing Surveillnce Dt Anlysis for Serotonin Syndrome Post-mrketing surveillnce dt were evluted to identify ny spontneous reports of serotonin Cses of serotonin reported during post-mrketing surveillnce were evluted bsed on the Hunter Serotonin Toxicity Criteri, sensitive nd specific set of dignostic criteri used to define serotonin (Figure ) Biomedicl Literture Anlysis Triptns SSRIs SNRIs TCAs RCT in bunionectomy pin (study ; NCT698) b RCT in bunionectomy pin (study ; NCT6966) b -dy RCT in end-stge joint disese pin (NCT68) c 9-dy RCT in LBP or OA hip or knee pin (NCT66) b b Tpentdol ER studies -week RCT in OA knee pin (study ; NCT98) d -week RCT in OA knee pin (study ; NCT868) d -week RCT in LBP (NCT976) d -week RWT in DPN (NCT) b -yer OL tril in LBP or OA pin (NCT6) b b e -yer OLE tril in LBP or OA pin (NCT87) b b SSRI, selective serotonin reuptke inhibitor; SNRI, serotonin norepinephrine reuptke inhibitor; TCA, tricyclic ntidepressnt; IR, immedite relese; RCT, rndomized controlled tril; LBP, low bck pin; OA, osteorthritis; ER, extended relese; RWT, rndomized-withdrwl tril; DPN, dibetic peripherl neuropthy; OL, open-lbel; OLE, open-lbel extension; MAOI, monomine oxidse inhibitor. MAOIs were not permitted in ny study. b If tken t stble dose for dys prior to screening. c If tken t stble dose for 8 dys prior to screening. d If tken t stble dose for months prior to rndomiztion. e If tken t stble dose for pin mngement. A literture serch of MEDLINE/PubMed using the serch terms tpentdol nd serotonin ws performed to identify ny potentilly relevnt cse reports RESulTS Clinicl Dt for Serotonin Syndrome nd Relted AEs Tpentdol IR Across nine Phse / clinicl studies, 69 ptients received plcebo,,78 ptients received tpentdol IR, nd 67 ptients received oxycodone IR Of the,78 ptients who were exposed to tpentdol IR, there were no reports of serotonin s n AE, despite the permitted concomitnt use of certin s tht re ssocited with risk of serotonin The percentges of ptients experiencing selected AEs potentilly relted to serotonin were <% cross ll tretment groups (Figure ) 9 The mjority of ptients who experienced n AE potentilly ssocited with serotonin experienced only AE 9 Only ptients (plcebo, n = ; tpentdol IR, n = ) experienced AEs potentilly relted to serotonin ; however, these cses were ll considered to be extremely unlikely to be serotonin 9 In seprte post hoc nlysis of dt from three Phse studies of tpentdol IR, the occurrence of AEs in key SOCs relevnt to serotonin were evluted in the following subgroups : Ptients treted with tpentdol IR lone, n =,6 ptients Ptients treted with tpentdol IR concomitntly with, n = Ptients treted with oxycodone IR lone, n = Ptients treted with oxycodone IR concomitntly with, n = 6 In tht nlysis, AEs were reported in of the key SOCs (crdic, gstrointestinl, centrl nervous system, psychitric, vsculr) relevnt to serotonin for similr proportions of ptients tking either tpentdol IR or oxycodone IR lone or with (Figure ) AEs (eg, clonus, hyperreflexi, or hyperthermi) or other signs suggestive of serotonin were identified in ptients receiving tpentdol IR Tpentdol ER SPONTANEOUS CLONUS? INDUCIBLE CLONUS + OCULAR CLONUS + TREMOR + HYPERREFLEXIA? HYPERTONIC + TEMPERATURE >8ºC (.ºF) + OCULAR or INDUCIBLE CLONUS? NO SEROTONIN TOXICITY Any one of the bove criteri would result in dignosis of serotonin. Figure. Hunter Serotonin Toxicity Criteri: decision rules., Across nine Phse / clinicl studies,,98 ptients received plcebo,,6 ptients received tpentdol ER, nd,7 ptients received oxycodone controlled relese (CR) Of the,6 ptients exposed to tpentdol ER, there were no reports of serotonin s n AE SEROTONIN TOXICITY Percentge of ptients Plcebo (n = 69)..9.6 Diphoresis AE, dverse event; IR, immedite relese. Tpentdol IR (n =,78) Fever Hypertension Oxycodone IR (n = 67).6. Tchycrdi Figure. AEs potentilly ssocited with serotonin reported in the Phse / clinicl tril progrm for tpentdol IR. 9 Percentge of ptients Tpentdol IR lone (n =,6) Tpentdol IR + (n = ) Figure. AEs reported in of the key SOCs.,.7 Oxycodone IR lone (n = ) 6. Oxycodone IR + (n = 6) AE, dverse event; SOC, system orgn clss; IR, immedite relese. The SOCs evluted included crdic, gstrointestinl, centrl nervous system, psychitric, nd vsculr events. Percentge of ptients Plcebo (n =,98) 9 AE AE, dverse event; ER, extended relese; CR, controlled relese. Tpentdol ER (n =,6) AEs Oxycodone CR (n =,7) < < < AEs Tble. Post-mrketing Cses of Serotonin Syndrome With Tpentdol ER Tretment Tht Met the Hunter Serotonin Toxicity Criteri Tpentdol ER dose Indiction mg BID Complex regionl pin mg TID Orofcil pin Concomitnt medictions Venlfxine Pregblin Clonidine Levomepromzine Oxycodone Amitriptyline Buprenorphine Gbpentin Prednisolone Nrrtive ER, extended relese; BID, twice dily; CR, controlled relese; TID, three times dily. This dose exceeds the mximum recommended dose in the US prescribing informtion for tpentdol ER. Post-mrketing Reports of Serotonin Syndrome From post-mrketing dt of >. million ptients, only spontneously reported cses of serotonin met the Hunter Serotonin Toxicity Criteri (Tble ) Both of these cses involved ptients in whom tpentdol ER ws dministered concomitntly with potentilly s Published Cse Reports of Serotonin Syndrome Two cse reports, in which tpentdol IR ( cse) nd tpentdol ER ( cse) dministrtion nd serotonin were mentioned, hve been published (Tble ), The cse report tht included tpentdol IR dministrtion nd mention of serotonin described cse of overdose of tpentdol IR (hert blood level of tpentdol IR > times the upper limit of the therpeutic rnge), nd serotonin ws listed s of the possible mechnisms of deth The cse report tht included tpentdol ER dministrtion nd mention of serotonin ws submitted s non peer-reviewed report to sfety compiltion It should lso be noted tht the symptomology presented in tht report does not fulfill the Hunter Serotonin Toxicity Criteri Tble. Published Cse Reports of Possible Serotonin Syndrome Associted With Tpentdol IR or Tpentdol ER Cse : Nrcotic intoxiction with tpentdol IR Subject: -yer-old mle found decesed Cuse of deth: Nrcotic intoxiction with tpentdol IR (hert blood level of tpentdol IR > times the upper limit of the therpeutic rnge) Concomitnt medictions: Diphenhydrmine, mitriptyline, nortriptyline, nd citloprm Findings: The mnner of deth ws undetermined, but serotonin, long with respirtory nd centrl nervous system depression, were listed s possible cuses of deth Cse : Possible serotonin with concomitnt tpentdol ER nd venlfxine ER Ptient: 9-yer-old mle who hd recently switched from oxycodone/cetminophen to tpentdol ER ( mg BID) Indiction: Chronic bck pin Concomitnt medictions: Venlfxine ER (7 mg once dily) Symptoms: Chills, dirrhe, nd severe hedche Findings: Electrocrdiogrm, computerized tomogrphy scn of the hed, chest x-ry, Crdiolite stress test, nd urine nd blood cultures reveled no bnormlities Mngement: The ptient ws dischrged fter dys nd resumed ll prior medictions. The ptient ws redmitted dys lter with body tremors, nxiety, nd excessive sedtion. Due to suspected drug interction, both venlfxine ER nd tpentdol ER were discontinued, nd the ptient improved nd ws dischrged dys lter IR, immedite relese; ER, extended relese; BID, twice dily. A mediclly significnt, serious event of serotonin nd drug interction with venlfxine ws reported for -yer-old femle ptient who hd recently been converted from oxycodone CR to tpentdol ER for complex regionl pin. After strting tpentdol ER, the ptient exhibited the following symptoms potentilly ssocited with serotonin : sweting, dirrhe, elevted blood pressure, trembling, nxiety, confusion, neuromusculr hyperphenomen, utonomic hyperctivity, confirmed bilterl hyperreflexi, nd confirmed tchycrdi. Both serotonin nd drug interction were ssessed s unclssifible to the dministrtion of tpentdol ER. The dose of venlfxine ws tpered nd the dose of tpentdol ER ws reduced to mg BID A mediclly significnt, serious event of serotonin ws reported for -yer-old femle ptient whose dose of tpentdol ER hd recently been incresed to mg TID. After the dose increse, the ptient exhibited the following symptoms potentilly ssocited with serotonin : incresed tendon reflexes nd tchycrdi. Serotonin ws ssessed s unclssifible to the dministrtion of tpentdol ER. The dose of tpentdol ER ws reduced to mg once dily CONCluSIONS Anlyses of dt from,78 ptients exposed to tpentdol IR nd,6 ptients exposed to tpentdol ER in Phse / clinicl studies identified no cses of serotonin reported s n AE 9, Some ptients exhibited AE ssocited with serotonin Nevertheless, the presence of these AEs is not definitive evidence of serotonin ; the Hunter Serotonin Toxicity Criteri should be used to confirm dignosis of serotonin From post-mrketing dt of >. million ptients, only cses of serotonin (both in ptients tking tpentdol ER concomitntly with potentilly s) were identified bsed on the Hunter Serotonin Toxicity Criteri Overll, these nlyses reveled no cses of serotonin in which tpentdol ws the sole custive gent REFERENCES. Pedvlly S, et l. Neurocrit Cre. ;():8-.. Volpi-Abdie J, et l. Ochsner J. ;():-.. Boyer EW, Shnnon M. N Engl J Med. ;():-.. Ables AZ, Ngubilli R. Am Fm Physicin. ;8(9):9-.. Iqbl MM, et l. Ann Clin Psychitry. ;(): Tzschentke TM, et l. J Phrmcol Exp Ther. 7;(): Tzschentke TM, et l. Drugs Future. 6;(): Frnk C. Cn Fm Physicin. 8;(7): US Food nd Drug Administrtion. s_toc.cfm. Accessed July 9,.. US Food nd Drug Administrtion. OrigsTOC.cfm. Accessed July 9,.. Vorsnger G, et l. J Clin Phrmcol. 9;9(9):. Abstrct.. Dunkley EJ, et l. QJM. ;96(9):6-6.. NUCYNTA ER (tpentdol) extended-relese orl tblets C-II Prescribing Informtion... Frnco DM, et l. Am J Forensic Med Pthol. ;():-6.. Mncno MA. Hosp Phrm. ;8(7):-9. ACkNOwlEdgmENTS This nlysis ws sponsored by Depomed, Inc. Editoril ssistnce ws provided by Megn Kngge, PhD, of MedErgy, nd ws funded by Depomed, Inc. The percentges of ptients experiencing,, nd AEs potentilly relted to serotonin re summrized in Figure Figure. Number of AEs potentilly ssocited with serotonin reported in the Phse / clinicl tril progrm for tpentdol ER. Poster presented t the Americn Assocition of Pin medicine (AAPm) nd Annul meeting; Februry 8-, 6; Plm Springs, Cliforni.

2 INTROduCTION Serotonin is potentilly life-thretening condition tht typiclly results from exposure to drugs tht increse levels of serotonin in the nervous system, Approprite dignosis of serotonin is often chllenging due to the brod rnge of possible symptoms nd the lck of confirmtory lbortory tests; furthermore, there re severl conditions tht hve similr clinicl fetures to severe serotonin (Tble ) Drugs from number of different clsses, including ntidepressnts, ntiemetics, ntimigrine drugs, nd nlgesics, hve been ssocited with the development of serotonin, Tpentdol is centrlly cting nlgesic with possible mechnisms of ction, µ-opioid receptor gonism nd norepinephrine reuptke inhibition, 6,7 tht my increse serotonin levels 6 Tpentdol is vilble in immedite relese (IR) nd extended relese (ER) formultions ObjECTIvE To evlute the ssocition of tpentdol IR nd tpentdol ER tretment with serotonin using US Food nd Drug Administrtion (FDA) nlyses, post-mrketing dt, nd published cse reports through July 8, Tble. Differentil Dignoses nd Key Clinicl Fetures of Serotonin Syndrome,8 Symptom Anticholinergic poisoning Neuroleptic mlignnt Mlignnt hyperthermi Opioid withdrwl Serotonin Afebrile or low-grde fever Hyperthermi Tchycrdi Mydrisis Shivering Hyperctive bowel sounds Incresed muscle tone (lower limb > upper) Anxiety Agittion nd hypervigilnce Delirium Com Hyperreflexi Spontneous or inducible clonus Oculr clonus

3 methods Anlysis of Clinicl Dt for Serotonin Syndrome nd Relted Adverse Events Dt from nine Phse / clinicl trils in ptients tking tpentdol IR nd nine Phse / clinicl trils in ptients tking tpentdol ER were evluted for reports of serotonin s n dverse event (AE) The s tht were permitted or prohibited in the Phse studies included in these nlyses re summrized in Tble Tble. Permitted nd Prohibited Concomitnt Serotonergic Drugs in Phse Studies Tpentdol IR studies Triptns SSRIs SNRIs TCAs RCT in bunionectomy pin (study ; NCT698) b RCT in bunionectomy pin (study ; NCT6966) b -dy RCT in end-stge joint disese pin (NCT68) c 9-dy RCT in LBP or OA hip or knee pin (NCT66) b b Tpentdol ER studies -week RCT in OA knee pin (study ; NCT98) d -week RCT in OA knee pin (study ; NCT868) d -week RCT in LBP (NCT976) d -week RWT in DPN (NCT) b -yer OL tril in LBP or OA pin (NCT6) b b e -yer OLE tril in LBP or OA pin (NCT87) b b SSRI, selective serotonin reuptke inhibitor; SNRI, serotonin norepinephrine reuptke inhibitor; TCA, tricyclic ntidepressnt; IR, immedite relese; RCT, rndomized controlled tril; LBP, low bck pin; OA, osteorthritis; ER, extended relese; RWT, rndomized-withdrwl tril; DPN, dibetic peripherl neuropthy; OL, open-lbel; OLE, open-lbel extension; MAOI, monomine oxidse inhibitor. MAOIs were not permitted in ny study. b If tken t stble dose for dys prior to screening. c If tken t stble dose for 8 dys prior to screening. d If tken t stble dose for months prior to rndomiztion. e If tken t stble dose for pin mngement. In ddition, results re summrized from integrted dtbse nlyses performed by the Center for Drug Evlution nd Reserch (CDER) t the FDA tht evluted AEs ssocited with serotonin using dt from nine Phse / tpentdol IR studies 9 nd nine Phse / tpentdol ER studies Results re lso summrized from seprte post hoc nlysis of AEs in key system orgn clsses (SOCs) tht re relevnt to serotonin using dt from three Phse tpentdol IR studies Post-mrketing Surveillnce Dt Anlysis for Serotonin Syndrome Post-mrketing surveillnce dt were evluted to identify ny spontneous reports of serotonin Cses of serotonin reported during post-mrketing surveillnce were evluted bsed on the Hunter Serotonin Toxicity Criteri, sensitive nd specific set of dignostic criteri used to define serotonin (Figure ) Biomedicl Literture Anlysis A literture serch of MEDLINE/PubMed using the serch terms tpentdol nd serotonin ws performed to identify ny potentilly relevnt cse reports

4 SPONTANEOUS CLONUS? INDUCIBLE CLONUS + OCULAR CLONUS + TREMOR + HYPERREFLEXIA? HYPERTONIC + TEMPERATURE >8ºC (.ºF) + OCULAR or INDUCIBLE CLONUS? NO SEROTONIN TOXICITY SEROTONIN TOXICITY Any one of the bove criteri would result in dignosis of serotonin. Figure. Hunter Serotonin Toxicity Criteri: decision rules., RESulTS Clinicl Dt for Serotonin Syndrome nd Relted AEs Tpentdol IR Across nine Phse / clinicl studies, 69 ptients received plcebo,,78 ptients received tpentdol IR, nd 67 ptients received oxycodone IR Of the,78 ptients who were exposed to tpentdol IR, there were no reports of serotonin s n AE, despite the permitted concomitnt use of certin s tht re ssocited with risk of serotonin The percentges of ptients experiencing selected AEs potentilly relted to serotonin were <% cross ll tretment groups (Figure ) 9 The mjority of ptients who experienced n AE potentilly ssocited with serotonin experienced only AE 9 Only ptients (plcebo, n = ; tpentdol IR, n = ) experienced AEs potentilly relted to serotonin ; however, these cses were ll considered to be extremely unlikely to be serotonin 9 In seprte post hoc nlysis of dt from three Phse studies of tpentdol IR, the occurrence of AEs in key SOCs relevnt to serotonin were evluted in the following subgroups : Ptients treted with tpentdol IR lone, n =,6 ptients Ptients treted with tpentdol IR concomitntly with, n = Ptients treted with oxycodone IR lone, n = Ptients treted with oxycodone IR concomitntly with, n = 6 In tht nlysis, AEs were reported in of the key SOCs (crdic, gstrointestinl, centrl nervous system, psychitric, vsculr) relevnt to serotonin for similr proportions of ptients tking either tpentdol IR or oxycodone IR lone or with (Figure ) AEs (eg, clonus, hyperreflexi, or hyperthermi) or other signs suggestive of serotonin were identified in ptients receiving tpentdol IR Tpentdol ER Across nine Phse / clinicl studies,,98 ptients received plcebo,,6 ptients received tpentdol ER, nd,7 ptients received oxycodone controlled relese (CR) Of the,6 ptients exposed to tpentdol ER, there were no reports of serotonin s n AE The percentges of ptients experiencing,, nd AEs potentilly relted to serotonin re summrized in Figure

5 Plcebo (n = 69) Tpentdol IR (n =,78) Oxycodone IR (n = 67) Percentge of ptients.9.6. Diphoresis Fever Hypertension.6. Tchycrdi AE, dverse event; IR, immedite relese. Figure. AEs potentilly ssocited with serotonin reported in the Phse / clinicl tril progrm for tpentdol IR Percentge of ptients.. Tpentdol IR lone (n =,6) Tpentdol IR + (n = ) Oxycodone IR lone (n = ) Oxycodone IR + (n = 6) AE, dverse event; SOC, system orgn clss; IR, immedite relese. The SOCs evluted included crdic, gstrointestinl, centrl nervous system, psychitric, nd vsculr events. Figure. AEs reported in of the key SOCs., Plcebo (n =,98) Tpentdol ER (n =,6) Oxycodone CR (n =,7) Percentge of ptients 9 AE AEs < < < AEs AE, dverse event; ER, extended relese; CR, controlled relese. Figure. Number of AEs potentilly ssocited with serotonin reported in the Phse / clinicl tril progrm for tpentdol ER.

6 Tble. Post-mrketing Cses of Serotonin Syndrome With Tpentdol ER Tretment Tht Met the Hunter Serotonin Toxicity Criteri Tpentdol ER dose Indiction Concomitnt medictions Nrrtive mg BID Complex regionl pin mg TID Orofcil pin Venlfxine Pregblin Clonidine Levomepromzine Oxycodone Amitriptyline Buprenorphine Gbpentin Prednisolone A mediclly significnt, serious event of serotonin nd drug interction with venlfxine ws reported for -yer-old femle ptient who hd recently been converted from oxycodone CR to tpentdol ER for complex regionl pin. After strting tpentdol ER, the ptient exhibited the following symptoms potentilly ssocited with serotonin : sweting, dirrhe, elevted blood pressure, trembling, nxiety, confusion, neuromusculr hyperphenomen, utonomic hyperctivity, confirmed bilterl hyperreflexi, nd confirmed tchycrdi. Both serotonin nd drug interction were ssessed s unclssifible to the dministrtion of tpentdol ER. The dose of venlfxine ws tpered nd the dose of tpentdol ER ws reduced to mg BID A mediclly significnt, serious event of serotonin ws reported for -yer-old femle ptient whose dose of tpentdol ER hd recently been incresed to mg TID. After the dose increse, the ptient exhibited the following symptoms potentilly ssocited with serotonin : incresed tendon reflexes nd tchycrdi. Serotonin ws ssessed s unclssifible to the dministrtion of tpentdol ER. The dose of tpentdol ER ws reduced to mg once dily ER, extended relese; BID, twice dily; CR, controlled relese; TID, three times dily. This dose exceeds the mximum recommended dose in the US prescribing informtion for tpentdol ER. Post-mrketing Reports of Serotonin Syndrome From post-mrketing dt of >. million ptients, only spontneously reported cses of serotonin met the Hunter Serotonin Toxicity Criteri (Tble ) Both of these cses involved ptients in whom tpentdol ER ws dministered concomitntly with potentilly s Published Cse Reports of Serotonin Syndrome Two cse reports, in which tpentdol IR ( cse) nd tpentdol ER ( cse) dministrtion nd serotonin were mentioned, hve been published (Tble ), The cse report tht included tpentdol IR dministrtion nd mention of serotonin described cse of overdose of tpentdol IR (hert blood level of tpentdol IR > times the upper limit of the therpeutic rnge), nd serotonin ws listed s of the possible mechnisms of deth The cse report tht included tpentdol ER dministrtion nd mention of serotonin ws submitted s non peer-reviewed report to sfety compiltion It should lso be noted tht the symptomology presented in tht report does not fulfill the Hunter Serotonin Toxicity Criteri Tble. Published Cse Reports of Possible Serotonin Syndrome Associted With Tpentdol IR or Tpentdol ER Cse : Nrcotic intoxiction with tpentdol IR Subject: -yer-old mle found decesed Cuse of deth: Nrcotic intoxiction with tpentdol IR (hert blood level of tpentdol IR > times the upper limit of the therpeutic rnge) Concomitnt medictions: Diphenhydrmine, mitriptyline, nortriptyline, nd citloprm Findings: The mnner of deth ws undetermined, but serotonin, long with respirtory nd centrl nervous system depression, were listed s possible cuses of deth Cse : Possible serotonin with concomitnt tpentdol ER nd venlfxine ER Ptient: 9-yer-old mle who hd recently switched from oxycodone/cetminophen to tpentdol ER ( mg BID) Indiction: Chronic bck pin Concomitnt medictions: Venlfxine ER (7 mg once dily) Symptoms: Chills, dirrhe, nd severe hedche Findings: Electrocrdiogrm, computerized tomogrphy scn of the hed, chest x-ry, Crdiolite stress test, nd urine nd blood cultures reveled no bnormlities Mngement: The ptient ws dischrged fter dys nd resumed ll prior medictions. The ptient ws redmitted dys lter with body tremors, nxiety, nd excessive sedtion. Due to suspected drug interction, both venlfxine ER nd tpentdol ER were discontinued, nd the ptient improved nd ws dischrged dys lter IR, immedite relese; ER, extended relese; BID, twice dily. CONCluSIONS Anlyses of dt from,78 ptients exposed to tpentdol IR nd,6 ptients exposed to tpentdol ER in Phse / clinicl studies identified no cses of serotonin reported s n AE 9, Some ptients exhibited AE ssocited with serotonin Nevertheless, the presence of these AEs is not definitive evidence of serotonin ; the Hunter Serotonin Toxicity Criteri should be used to confirm dignosis of serotonin From post-mrketing dt of >. million ptients, only cses of serotonin (both in ptients tking tpentdol ER concomitntly with potentilly s) were identified bsed on the Hunter Serotonin Toxicity Criteri Overll, these nlyses reveled no cses of serotonin in which tpentdol ws the sole custive gent REFERENCES. Pedvlly S, et l. Neurocrit Cre. ;():8-.. Volpi-Abdie J, et l. Ochsner J. ;():-.. Boyer EW, Shnnon M. N Engl J Med. ;():-.. Ables AZ, Ngubilli R. Am Fm Physicin. ;8(9):9-.. Iqbl MM, et l. Ann Clin Psychitry. ;(): Tzschentke TM, et l. J Phrmcol Exp Ther. 7;(): Tzschentke TM, et l. Drugs Future. 6;(): Frnk C. Cn Fm Physicin. 8;(7): US Food nd Drug Administrtion. s_toc.cfm. Accessed July 9,.. US Food nd Drug Administrtion. OrigsTOC.cfm. Accessed July 9,.. Vorsnger G, et l. J Clin Phrmcol. 9;9(9):. Abstrct.. Dunkley EJ, et l. QJM. ;96(9):6-6.. NUCYNTA ER (tpentdol) extended-relese orl tblets C-II Prescribing Informtion... Frnco DM, et l. Am J Forensic Med Pthol. ;():-6.. Mncno MA. Hosp Phrm. ;8(7):-9. ACkNOwlEdgmENTS This nlysis ws sponsored by Depomed, Inc. Editoril ssistnce ws provided by Megn Kngge, PhD, of MedErgy, nd ws funded by Depomed, Inc.