Idaho Medicaid Drug Utilization Review Program

1. Idaho Medicaid Drug Utilization Review Program 21 July 2011

2. Follow-up to Previous Reviews • Tramadol with SSRI’s or SNRI’s • Potential for Serotonin Syndrome • Thiazolidinedione (TZD) Safety • Proton Pump Inhibitors • Long Term Continuous Use

3. Tramadol with SSRI’s or SNRI’s: Potential for Serotonin Syndrome • Patients were selected if they had more than one tramadol fill, at least a 30 day overlap with the SSRI or SNRI, and had both a tramadol and an antidepressant claim within the most recent six weeks of data. • 179 patient profiles were evaluated. • Letters were sent to 174 prescribers about 94 patients on 2/21/2011. • Only prescribers of tramadol, SSRI, or SNRI received letters. • As of 7/5/2011, 42 responses have been received (24% response rate.) • See packet for copy of the letter and the Serotonin Syndrome Informational sheet.

4. Tramadol with SSRIs or SNRIsPotential for Serotonin Syndrome Response detail as of 7/5/2011 • Note that providers may choose more than one selection per response. • Reviewed and do not believe adjustment is needed 15 • Reviewed and have or will modify the treatment 6 • Information clinically useful: plan to monitor 11 • I will use this information in the care of future pts 10 • No longer my patient 6 • My patient, but I did not prescribe this 3 • Somewhat useful to my practice 5 • Not useful to my practice 4 • Very useful to my practice 9

5. Tramadol with SSRIs or SNRIsPotential for Serotonin Syndrome Response detail as of 7/5/2011 • “We are actually tapering the tramadol. Used it as a way to stop opioid use.” • “I was not aware that the patient was on tramadol.” • “Thank You” • “This patient did not report to me that she was on tramadol to the best of my memory. She has since been fired from my office for med seeking behavior.” • “Defer long term considerations to patient’s primary provider. I am an ER provider only for this patient.” • “tramadol has been discontinued” • “Have already started taper and will be off in 30-60 days” • “she is only taking tramadol 2 to 3 times a week and we are going to try to stop completely. She is trying to take Excedrin for migraines. No new order for tramadol was given at last visit.” • “Review with supervising physician. Historically before I started seeing this patient. I only provide follow up care at the facility this report is referring to. Often the patients have been stable on their meds for quite some time and to make any changes could cause decompensation. When possible I attempt to make reductions when appropriate. I will still use the information provided as appropriate.”

6. Thiazolidinediones (TZD’s) • Patients were selected for evaluation if there was a paid claim for a TZD within the last three months. • 83 patient profiles were evaluated. • Letters were sent to 65 prescribers about 63 patients on 3/22/2011. • As of 7/5/2011, 16 responses have been received (25% response rate.) • See packet for copy of the letter and FDA Drug Safety Communication Insert.

7. Thiazolidinedione Safety Response detail as of 7/5/2011 • Note that providers may choose more than one selection per response. • Reviewed and do not believe adjustment is needed 2 • Reviewed and have or will modify the treatment 5 • Attempted to modify therapy unsuccessfully 1 • Information clinically useful: plan to monitor 5 • I will use this information in the care of future pts 3 • Previously saw this pt, but no longer in my care 2 • My patient, but I did not prescribe this 1 • Under my care, but have not seen recently 1 • Extremely useful to my practice 1 • Very useful to my practice 2 • Somewhat useful to my practice 3 • Not useful to my practice 1 • Will discontinue medication 1

8. Thiazolidinedione SafetyResponse detail as of 7/5/2011 • “Patient was already on Avandia® and doing well prior to the drug label change and guidelines state ok to use in patients already on this med. Patient did not want to change then I will approach him again to consider change to Actos®” • “I am already complying with the above and am no longer prescribing Avandia®”. Note that prescriber also wrote in next to #8 that medication was reordered. • “Control is poor with metformin. Patient is reluctant to try insulin at this time. Her diabetes control is poor.” • “Plan to modify therapy. Actos ®15mg every day” • “NO CHANGE” • “Patient has been informed of risks and wishes to continue Avandia®” • “Review with supervising physician. Historically before I started seeing this patient. I only provide follow up care at the facility this report is referring to. Often the patients have been stable on their meds for quite some time and to make any changes could cause decompensation. When possible I attempt to make reductions when appropriate. I will still use the information provided as appropriate.” • “Will start Actos®”

9. Thiazolidinediones (TZD’s) • Risk Evaluation and Mitigation Strategy (REMS) • Rosiglitazone REMS Program • Approved 05/2011 • Goals • To restrict access to rosiglitazone-containing medicines so that only prescribers who acknowledge the potential increased risk of myocardial infarction associated with the use of rosiglitazone are prescribing rosiglitazone. • To restrict access to patients who have been advised by a healthcare provider about the potential increased risk of myocardial infarction associated with the use of rosiglitazone and are one of the following: • Either already taking rosiglitazone or • If not already taking rosiglitazone, they are unable to achieve glycemic control on other medications and, in consultation with their healthcare provider, have decided not to take pioglitazone for medical reasons

10. Thiazolidinediones (TZD’s) • Risk Evaluation and Mitigation Strategy (REMS) • Rosiglitazone REMS Program • Elements to Assure Safe Use • Healthcare providers who prescribe rosiglitazone-containing medicines for outpatient or long-term care use are specifically certified • Rosiglitazone will be dispensed only by specially certified pharmacies • Medication will be mailed to the patient • Rosiglitazone will only be dispensed to patients with evidence or other documentation of safe-use conditions • Patient must review the Medication Guide and sign the Patient Enrollment Form with their prescriber • Distributors will become certified and all rosiglitazone medicines will be withdrawn from uncertified pharmacies within 6 months after initial approval of the REMS

11. Thiazolidinediones (TZD’s) • Risk Evaluation and Mitigation Strategy (REMS) • Rosiglitazone REMS Program (Avandia-Rosiglitazone Medicines Access Program™) • www.avandia.com or • Phone: 1-800-AVANDIA (1-800-282-6342) • Fax: 1-888-772-9404 http://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/UCM255624.pdf

12. Proton Pump Inhibitors: Long Term Continuous Use Patients were selected for evaluation if they had at least 8 claims for a PPI over the six month period. 167 patient profiles were evaluated. Letters were sent to 473 prescribers about 92 patients on 4/11/2011 (19% lettering rate.) As of 7/5/2011, 113 responses have been received (24% response rate.) See packet for copy of the letter and informational sheet.

13. Proton Pump Inhibitors: Long Term Continuous UseResponse detail as of 7/5/2011 • Note that providers may choose more than one selection per response. • Reviewed and do not believe adjustment is needed 27 • Reviewed and have or will modify the treatment 19 • Attempted to modify therapy unsuccessfully 10 • Information clinically useful: plan to monitor 21 • Previously saw this pt, but no longer in my care 23 • Very useful to my practice 16 • Somewhat useful to my practice 16 • Not useful to my practice 17 • Will discontinue medication 3 • I am not the provider for this patient 14 • The information regarding this patient appears to be incorrect 6

14. Proton Pump Inhibitors: Long Term Continuous UseResponse detail as of 7/5/2011 • “I agreed to refills but did not know how she had done eight refills in six months” • “Patient has seen gastroenterologist and otolaryngologist who recommended the higher dose.” • “I was on call and covering for another provider” • “The procedure ID on December 28 2010 is not mine. I never prescribed Omeprazole to this patient. Please correct error” • “Will review in closer detail her symptoms and discontinue of her PPI” • “Prescribed this medication for this patient” • “Previous NP saw this patient and she has left office” • “Try to taper and use H2 blockers for breakthrough symptoms. Patient is intellectually disabled and lives in a residential treatment center.” • “Taper dose and uses H2 blockers for breakthrough. This patient has a diagnosis of eosinophilic gastritis and is being monitored closely. He can purposely vomit if he is upset for whatever reason possible anxiety. Very complex patient is intellectually disabled and lives in a residential treatment center.”

15. Proton Pump Inhibitors: Long Term Continuous UseResponse detail as of 7/5/2011 • “Chronic GERD” • “Loves the medication and does not want to stop. Wonders if she can take medication less often but continues. She will call back after receiving more information.” • “Patient dismissed from clinic and care.” • “I cared for this patient in the hospital but not as an outpatient.” • “Getting to be annoying.” • “I am not the prescriber.” • “Increase GERD when off PPI.” • “Someone else wrote Nexium”

16. Colchicine DUR • Historical Perspective • In June 2006, the FDA announced a new drug safety initiative to remove unapproved drugs from the market, including a final guidance entitled “Marketed Unapproved Drugs-Compliance Policy Guide (CPG)”. • Notice that any illegally marketed product is subject to FDA enforcement at any time • Clarified that the FDA intends to use a risk-based approach to enforcement • July 29, 2009: Colcrys® approved for Familial Mediterranean Fever (FMF) • July 30, 2009: Colcrys® approved for Acute Gout Flares • October 16, 2009: Colcrys® approved for Chronic Gout

17. Colchicine DUR • “Outraged Politicians Demand Gout Drug Price Probe” • Article written June 10, 2011 for Medscape Medical News • Colcrys® granted 3 years marketing exclusivity • At time of approval, 21 companies were making oral colchicine with costs as low as $0.04 per tablet. After approval Colcrys® raised the price to $5 per tablet. • 2 US Senators and 3 US Representatives are charging the company with price gouging and are demanding an investigation. • Concerns that this may be a new model for drug companies.

18. Colchicine DUR • October 1, 2010: FDA sent out a notice that it intends to initiate enforcement action against any marketed and listed unapproved single-ingredient oral colchicine product that is manufactured on or after November 15, 2010, or that is shipped on or after December 30, 2010. • Use of Colcrys®

19. Colchicine DUR • Cost Avoidance Calculations • 34 less colchicine prescriptions per month • 34 x $241.82 per Rx = $8221.88 per month • Total cost avoidance of $98,662.56 per year

20. Colchicine DUR • Definitions • Gout is defined as an inflammatory arthritis induced by the deposition of monosodium urate crystals in synovial fluid and other tissues • Hyperuricemia is defined as a serum urate level ≥ 6.8mg/dl, which is the limit of urate solubility at physiologic temperature and pH

21. Colchicine DUR • Epidemiology of Gout • 6.1 million adults in the US • Prevalence increases with age • Incidence higher in men than women (3-4:1 overall) although decreases at older ages (at least partially due to declining levels of estrogen which has uricosuric effects in women) • Risk Factors: thiazide diuretics, cyclosporine, low dose aspirin (<1000 mg/day), insulin resistance, metabolic syndrome, obesity, renal insufficiency, hypertension, congestive heart failure • Dietary Risk Factors: meat, seafood, ethanol, soft drinks

22. Colchicine DUR • Acute Gout Attack • Sudden onset of severe debilitating pain with progressive worsening over the first 24 hours • Erythema and swelling in a joint • Most attacks resolve within 3-10 days • Management of Acute Gout • Non-pharmacologic: joint rest and icing the affected site • Pharmacologic – NSAIDS, corticosteroids, colchicine

23. Colchicine DUR • Pharmacologic Treatment of Acute Gout Attack • First line – NSAIDS, colchicine • Relative efficacy of colchicine as compared with NSAIDS is unknown • In head-to-head studies between various NSAIDS, they had similar benefits • Alternative Agent – corticosteroids (all routes including oral and intra-articular)

24. Colchicine DUR • Treatment of Acute Gout Attack – NSAIDS • Relative Contra-Indications: renal impairment, risk factors for GI bleeding, congestive heart failure, concomitant anticoagulant therapy • Commonly used agents: indomethacin, naproxen, sulindac • Dose: Start as soon as possible (within 12-24 hours of pain onset). High dose therapy for 2-3 days, then decrease dose. Continue for at least 48 hours after resolution of symptoms

25. Colchicine DUR • Treatment of Acute Gout Attack – Colcrys® • Dosage • First Day – 1.2mg at first sign of gout flare, followed by 0.6mg one hour later • Subsequent Days – 0.6mg twice daily until flare subsides (typically 3-10 days) • For mild (CrCl 50-80ml/min) to moderate (CrCl 30-50ml/min) renal impairment, no dosage adjustment is needed, but the patient should be monitored for adverse effects. • For severe (CrCl < 30ml/min) renal impairment, a treatment course should be repeated no more than once every 2 weeks. For patients with gout flares requiring repeated courses, consideration should be given to alternate therapy. For patients undergoing dialysis, the total recommended dose for the treatment of gout flares should be reduced to a single dose of 0.6mg (1 tablet).

26. Colchicine DUR • Treatment of Acute Gout Attack – Corticosteroids • Can be given orally, intravenously, intramuscularly, intra-articularly • e.g. prednisone 20mg daily until symptoms resolve, generally within 5-7 days (taper not necessary after short-term treatment) • Monoarticular attacks are often managed with the use of intra-articular glucocorticoids.

27. Colchicine DUR • Chronic Gout • Chronic tophaceous gout • Polyarticular attacks • Symptoms between attacks • Crystal deposition (tophi) in soft tissues or joints • Who to treat? • Patients with hyperuricemia who have at least two attacks per year or tophi as determined by either clinical or radiographic methods • When to treat? • Wait 1-2 weeks after the acute attack has subsided to begin chronic treatment • Goal of therapy • Uric Acid Level < 6mg/dl • Some patients may require Uric Acid level < 5mg/dl for resolution of tophi

28. Colchicine DUR • Management of Chronic Gout – Allopurinol • Allopurinol is the drug of choice to lower serum uric acid • Mechanism of action • Xanthine oxidase inhibitor which blocks the synthesis of uric acid • Prior Authorization is not needed • Dosage range is 100-800 mg daily (assess renal function) • Mild gout: 200-300 mg daily • Moderate gout: 400-600 mg daily • Severe gout: 700-800 mg daily

29. Colchicine DUR • Management of Chronic Gout – Allopurinol, con’t. • Patient has not failed allopurinol therapy if only on 300mg daily with normal renal function for severe gout • Allopurinol dosing in renal impairment: • If CrCl 10-20ml/min, 200mg daily • If CrCl 3-10ml/min, 100mg daily • If CrCl <3ml/min, 100mg every other day

30. Colchicine DUR • Management of Chronic Gout – Uloric® • Uloric requires prior authorization • Mechanism of Action – also a xanthine oxidase inhibitor • No comparative studies done on efficacy between Uloric and allopurinol • Cost Comparison to allopurinol • #30 allopurinol 300mg - $7.16 • #30 Uloric® 80mg - $168.24 • Therapeutic criteria for Uloric® • Continuation of gout attacks after three months of allopurinol therapy at a therapeutic dose (includes assessment of renal function) • Serum urate levels > 6mg/dl after three months of allopurinol therapy at a therapeutic dose • Documented intolerance or allergy to allopurinol

31. Colchicine DUR • Management of Chronic Gout – Colcrys® • To prevent an acute attack as a result of starting allopurinol, low dose NSAID (e.g. naproxen 250mg twice daily) or prophylactic Colcrys® can be used. • Duration of therapy: • Without tophi, prophylaxis with Colcrys® for 6 months • With tophi, optimal duration of therapy is unknown

32. Colchicine DUR • Management of Chronic Gout – Colcrys®, con’t. • Dose: Colcrys® 0.6mg orally once or twice daily • For mild (CrCl 50-80ml/min) to moderate (CrCl 30-50ml/min) renal impairment, no dosage adjustment is needed, but the patient should be monitored for adverse effects. • For severe (CrCl < 30ml/min) renal impairment, the starting doses should be 0.3mg per day and any increase in dose should be done with close monitoring. For the prophylaxis of gout flares in patients undergoing dialysis, the starting dose should be 0.3mg given twice a week with close monitoring.

33. Colchicine DUR • Management of Chronic Gout – Probenecid • Mechanism of action – increases uric acid excretion by blocking urate reabsorption • Prior authorization is not needed • Management of Chronic Gout – Krystexxa® • Not covered by Idaho Medicaid outpatient prescription drug program • Pegylated urate oxidase enzyme – administered IV every 2 weeks by a healthcare professional due to the risk of infusion reactions and anaphylaxis. • Cost is $20,000 annually.

34. Colchicine DUR • Pseudogout • Deposition of calcium pyrophosphate crystals in joints (rather than uric acid crystals). • Causes arthritis characterized by sudden, painful swelling in one or more joints, especially the knee. • Drug of choice – NSAIDs • Alternate drug – colchicine (if cannot use NSAID) • Other treatments • Joint aspiration • Intra-articular corticosteroid • Joint rest

35. Colcrys’® Place in Therapy • Utilization Overview All information based on Idaho Medicaid Pharmacy Data 2ndQuarter 2011 (4/1/11-6/30/11).

36. Colchicine DUR • Colcrys® • Patients were selected for evaluation if there was a paid claim for Colcrys® over the six month period 11/1/2010-4/30/2011. A total of 21 patient profiles were evaluated. • 2 additional profiles were reviewed which had denied PA requests for Colcrys®, but no paid claims.

37. Colchicine DURPatient Profiles Reviewed

38. Colchicine DUR • Colcrys® • Prior Authorization approved for 8 patients with acute gout (*one patient failed both NSAID & corticosteroid)

39. Colchicine DUR • Colcrys® • 3 Prior Authorizations approved for Chronic Gout • Patients were already on allopurinol • 2 Prior Authorization approved for other Diagnosis • 1 : vasculitis (approved for 3 month trial) • 1 : Familial Mediterranean Fever (patient has been on colchicine for years)

40. Colchicine DUR • Colcrys® • 5 Prior Authorizations Denied • 3 patients with paid Colcrys® claims previously (Colcrys® would pay if there was a previous paid claim for colchicine in the past 90 days. This AutoPA rule has since been removed.) • 2 patients with paid Colcrys® claims had chronic constipation • 1 patient has been on generic colchicine since 2005 • 1 patient has been on generic colchicine since 2008 (please refer to profile #16 in packet for further review) • 1 patient had diagnosis of pseudogout on prior authorization form, but no other information was provided by the prescriber.

41. Colchicine DUR • Colcrys® • 5 Prior Authorizations Denied (con’t.) • 2 patients had no paid Colcrys® claims • 1 patient had “possible gout” with uric acid level of 6.6 mg/dl and no contraindications to NSAIDS/corticosteroids • 1 patient was subsequently approved the following day when the prescriber phoned into the call center with additional information.

42. Colchicine DUR • Colcrys® • 5 patients had at least one paid Colcrys® claim, but a Prior Authorization request was never submitted • 3 patients have no paid claims for any other gout medications (NSAIDs, corticosteroids, allopurinol) • Assumption would be off-label use • 2 patients also on allopurinol • Assumption would be gout diagnosis

43. Colcrys® - Summary • 72.2% (13/18) of the Prior Authorization requests received were approved. • Continue to require Prior Authorization for Colcrys® with the current therapeutic criteria (listed on next slide) • Off-label use for treatment of chronic constipation was discovered • Turned off Auto Pay rule which approved Colcrys® at point of sale if there was a paid colchicine claim in the past 90 days.

44. Therapeutic Criteria for Colcrys® • Acute Gout • Contra-indication and/or failure to NSAIDS or corticosteroids • Chronic Gout • Adjunct to allopurinol AND contra-indication or failure to NSAIDS

45. Colchicine DUR • References • Neogi, T. NEJM 2011;364(5):443-452. • Management of Gout. Pharmacist’s Letter/Prescriber’s Letter November 2010, Volume 26, Number 261102. • Kelly, J. (2011, June 10). Outraged Politicians Demand Gout Drug Price Probe. Retrieved from http://www.medscape.com/viewarticle/744408 • Federal Register/ Vol.75, No. 190/ Friday, October 1, 2010/ Notices:60768-60771. • http://fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm227796.htm • http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/EnforcementActivitiesbyFDA/SelectedEnforcementActionsonUnapprovedDrugs/ucm118990.htm

46. Ketorolac DUR • Historical Perspective: • Discovered that in the drug profiles the Maximum Quantity was set at 10 tablets per day. • The Maximum Quantity was immediately changed to 4 tablets per day as recommended by the package insert. • Report was generated to see how many patients have actually received doses higher than the recommended amount and based on this report it was felt that a Retrospective DUR would be appropriate.

47. Ketorolac DUR • Black Box Warnings: • WARNING • TORADOL ORAL (ketorolac tromethamine), a nonsteroidal anti-inflammatory drug (NSAID), is indicated for the short-term (up to 5 days in adults) management of moderately severe acute pain that requires analgesia at the opioid level and only as continuation treatment following IV or IM dosing of ketorolac tromethamine, if necessary. The total combined duration of use of TORADOL ORAL and ketorolac tromethamine should not exceed 5 days. • TORADOL ORAL is not indicated for use in pediatric patients and it is NOT indicated for minor or chronic painful conditions. Increasing the dose of TORADOL ORAL beyond a daily maximum of 40 mg in adults will not provide better efficacy but will increase the risk of developing serious adverse events. • GASTROINTESTINAL RISK • Ketorolac tromethamine, including TORADOL, can cause peptic ulcers, gastrointestinal bleeding and/or perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Therefore, TORADOL is CONTRAINDICATED in patients with active peptic ulcer disease, in patients with recent gastrointestinal bleeding or perforation, and in patients with a history of peptic ulcer disease or gastrointestinal bleeding. Elderly patients are at greater risk for serious gastrointestinal events.

48. Ketorolac DUR • Black Box Warnings con’t. • CARDIOVASCULAR RISK • NSAIDs may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk. • TORADOL is CONTRAINDICATED for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery. • RENAL RISK • TORADOL is CONTRAINDICATED in patients with advanced renal impairment and in patients at risk for renal failure due to volume depletion. • RISK OF BLEEDING • TORADOL inhibits platelet function and is, therefore, CONTRAINDICATED in patients with suspected or confirmed cerebrovascular bleeding, patients with hemorrhagic diathesis, incomplete hemostasis and those at high risk of bleeding. • TORADOL is CONTRAINDICATED as prophylactic analgesic before any major surgery.

49. Ketorolac DUR • Black Box Warnings con’t. • RISK DURING LABOR AND DELIVERY • The use of TORADOL in labor and delivery is contraindicated because it may adversely affect fetal circulation and inhibit uterine contractions. The use of TORADOL is contraindicated in nursing mothers because of the potential adverse effects of prostaglandin-inhibiting drugs on neonates. • CONCOMITANT USE WITH NSAIDS • TORADOL is CONTRAINDICATED in patients currently receiving aspirin or NSAIDs because of the cumulative risk of inducing serious NSAID-related side effects. • SPECIAL POPULATIONS • Dosage should be adjusted for patients 65 years or older, for patients under 50 kg (110 lbs) of body weight and for patients with moderately elevated serum creatinine. • http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=c0336606-7366-41ce-9cef-aa6524b92b11

50. Ketorolac DUR • Patients were selected for evaluation if there was a paid claim for ketorolac > 40mg total daily dose over the 3 month period 3/1/2011-5/31/2011. • A total of 29 patient profiles were evaluated • Letters were sent to 9 prescribers about 9 patients on 6/20/2011. • As of 7/7/2011, 3 responses have been received (33% response rate)