Drug Use Research & Management Program Phone Fax Generic Bioequivalency Review of Antiepileptic Drugs and Immunosuppressants

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1 Drug Use Research & Management Program DHS Division of Medical Assistance Programs, 500 Summer Street NE, E35; Salem, OR Phone Fax Generic Bioequivalency Review of Antiepileptic Drugs and Immunosuppressants Several single-source antiepileptic drugs and immunosuppressants have recently lost or will soon loose patent protection (Appendix A). Generic substitution of drugs in these drug classes and other narrow therapeutic index classes is controversial The available evidence regarding therapeutic equivalency will be summarized for these two drug classes. The federal and state Medicaid law and Oregon feefor-service Medicaid payment policy for multi-source drugs will also be summarized. This information will be used to make recommendations for changes to the DAW-1 prior authorization criteria. Medicaid Law & Oregon Reimbursement Policy Federal CFR mandates that state Medicaid programs must not pay more than the established Federal Upper Limit (FUL) for multi-source brand name drug unless the physician certifies the a specific brand is medically necessary for a particular patient. 6 Oregon Revised Statutes state the department shall pay only for drugs in the generic form unless an exception has been granted by the department or unless the cost of the particular brand name drug is equal to or less than the cost of the generic version of the drug. 7 These regulations are fulfilled by department policy to reimburse pharmacies at the FUL or State Maximum Allowable Cost (SMAC) for a multi-source brands. SMAC prices are applied only if there are three or more A-rated equivalent products available to Oregon pharmacies. Exceptions to generic pricing of multi-source brands are allowed if the physician indicates Dispense As Written or similar language to the pharmacy (DAW-1) and the prescriber gets prior authorization from the department claim processor. While requests for DAW1 authorizations have increased with the release of three high volume generics since July 2008 (i.e. divalproate, lamotrigine and risperidone), the volume is still extremely low in relation claims processed. Data on DAW1 prior authorization requests from Dec 2007 November 2008 are in Figure 1.

2 Figure 1 DAW-1 Prior Authorization Requests Dec-07 Jan-08 Feb-08 Mar-08 Apr-08 May-08 Jun-08 Jul-08 Aug-08 Sep-08 Oct-08 Nov-08 (partial mth) DAW-1 approvals DAW-1 denials Bioequivalency Background The 1984 Drug Competition and Patent Term Restoration Act (a.k.a. Hatch- Waxman Act) established bioequivalence as the basis for approving generics. The United States (US) Food and Drug Administration (FDA) requires in vivo testing in 24 to 36 healthy adult volunteers to establish average bioequivalence (ABE). 8 The standard ABE study uses a 2-treatment crossover design and measures area under the concentration time curve (AUC), the peak concentration (Cmax) and the time to peak concentration (tmax). Statistically, the geometric mean ratio (e.g. average of the generic Cmax / innovator Cmax) must fall within 90% confidence limits of 80 and 125. These criteria are widely misunderstood and do not allow for -20% to +25% difference in bioavailability between products. These are the statistical parameters in which measures of variance must reside. The FDA has conducted two large surveys to quantify the differences between generic and brand name products The mean differences in pharmacokinetic parameters for most orally administered generic drug products are closer to 3% or 4%. Finally, it is important to emphasize that when the formulation of a brand name innovator drug product is changed by its manufacturer, not an infrequent occurrence; the identical bioequivalence tests are performed to show therapeutic equivalence. The FDA has stated in correspondence with the American Medical Association that it cannot document a single example of therapeutic failure when an FDAdesignated therapeutically equivalent product was substituted for its brand name innovator product and is confident that its methodology for approving generic drugs, including NTI drugs, is adequate to establish therapeutic equivalence. 11

3 The FDA states further in a letter to the National Boards of Pharmacy that; any differences that could exist from substituting an A-rated generic for an innovator product should be no greater than one would expect if one lot of the innovator's product was substituted for another. 12 Antiepileptic evidence: Medline 1998-present was queried using combined search terms anticonvulsants and therapeutic equivalency. Limits of human subjects and English language were applied. This identified 76 articles for review of citations. Citations are available in upon request. Only 9 citations indicated a comparative trial of generic and innovator antiepileptics and were retrieved for abstract review. Data from 7 standard ABE studies in healthy volunteers were collected from abstracts. All but one of these studies were performed abroad and have limited applicability to the US generic market (1 in Korea, 1 in Thailand, 2 in Portugal, 2 in India) Four found bioequivalency (1 for lamotrigine, 1 for levetriacetam, 2 for gabapentin) and a phenytoin study had mixed results and carbamazepine was negative for bioequivalency. The US study found that food significantly impacted bioequivalence of the Mylan generic and innovator Park-Davis phenytoin products. Two comparative studies with clinical outcomes were reviewed in their entirety (Table 1). Table 1 Summary of AED comparison studies Citation Description Results 12 Retrospective claims study comparing switch-back rates of Lamictal, Frisium, and Depakene to Zocor, Prozac and Celexa. Done in Ontario, CA. Identified potential ADEs to Lamictal switch without control as secondary outcome. Control and study groups different at baseline in several respects. Switchback rates significantly higher in AED group. 13 Retrospective review of approximately 200 medical records of patients with seizures who had been mandated to switch from Dilantin Kapseals to an AB-rated generic phenytoin product (Mylan Pharmaceuticals) in State of Minnesota health plans without physician notification. 8 adult patients were identified whose seizures increased such that they were switched back to the brand

4 Immunosuppressant evidence: Medline 1998-present was queried using combined search terms immunosuppressants and therapeutic equivalency. Limits of human subjects and English language were applied. This identified 75 articles for review of citations. Citations are available in upon request. Only 18 citations indicated a comparative trial of generic and innovator immunosuppressants and were retrieved for abstract review. Data from 15 standard ABE studies in healthy volunteers were collected from abstracts. All but one were done outside the US and have limited applicability to the US generic market (1, in US, 1 in Canada, 1 in Mexico, 1 in Australia, 1 in India, 2 in Germany, 4 in Korea, 4 in Brazil). Fourteen studies assessed bioequivalency to Neoral with two finding negative results. The single US study was positive. Two studies assessed bioequivalency to Prograf with positive results in Canada and Korea. There were 2 additional studies assessing the bioequivalency of 5mg tacrolimus compared to 5 x 1mg tacrolimus. The results were mixed. Three comparative studies with clinical outcomes were reviewed in their entirety (Table 2). Citation Study Descriptions Results 15 Unclear randomization; non-blinded. 73 were switched to Gengraf, 9 remained on Neoral (self-selected). 82 s/p >6 mths renal transplant recipients with stable graft function Serum Creatinine and Cyclosporin trough levels at 2wks, and 4 wks. There was no significant difference between the groups. Of the 73 patients switched to Gengraf from Neoral, 13 required a dosage change. 16 Retrospective review of two different CyA formulations. Patients in the Neoral group were transplanted between January 1999 and May 2001; patients in the Gengraf group were transplanted between May 2001 and July Stable kidney transplant patients (Neoral = 100, Gengraf = 88) Gengraf patients were significantly more likely to have a biopsy proven acute rejection episode (39% vs. 25%, P 0.04) 17 Open-label, three-14 day period, cross-over design, 50 renal transplant recipients taking stable doses of Neoral switched 1:1 to Gengraf and then back to Neoral. The pharmacokinetics of Gengraf (Cmax, Tmax, Ctrough, and AUC) were indistinguishable from the corresponding values obtained after administration of Neoral in 50 stable renal allograft recipients when administered under standard conditions.

5 Conclusions: While concerns still persist among some physicians about the therapeutic equivalence of generic narrow therapeutic index drugs to their brand name innovator products, evidence to support these concerns either does not exist or is extremely weak. The evidence for newer antiepileptic drugs did not identify specific bioequivalency problems. Additionally, several of these drugs are used extensively off-label for mood stabilization and neuropathies where targeting a narrow therapeutic drug level is not an established tenet of treatment. The literature did consistently report considerable intra-/inter- patient variability for transplant patients. The two fair studies comparing Neoral to Gengraf had mixed results. There are no approved generics in the US for Prograf, Cellcept, Rapamune or Myfortic to evaluate. Recommendations to DAW1 Criteria: 1) Add cyclosporine to list of DAW exceptions 2) Modify approval criteria to allow patients to remain on branded antiepileptics or immunosuppressants if stabilized. 1 Anonymous. Generic Substitution Raises Questions, Concerns for Some Patient Groups. BP Newsletter. Feb Available at Accessed 3/13/08. 2 Anonymous. FDA s ANDA Review Process Designed to Ensure Safety and Efficacy of New Generic Medications. June-July Available at Accessed 3/13/08. 3 Gidal, BE. Tomson T. Debate: Substitution of generic drugs in epilepsy: is there cause for concern? Epilepsia. 49 Suppl 9:56-62, 2008 Dec. 4 Kahan BD. Considerations Concerning Generic Formulations of Immunosuppressive Drugs. Transplantation Proceedings, 31, Barr WH. Scientific and Professional Concerns Regarding Product Interchange and Subsequent Monitoring of Cyclosporine and Other Critical Dose Drugs. Transplantation Proceedings. 1999: 31: Meyer GF, History and Regulatory Issues of Generic Drugs. Transplantation Proceedings 31(S3A) 10S-12S Nightingale SL, Morrison JC. Generic drugs and the prescribing physician. JAMA. 1987;258: Henney JE. Review of generic bioequivalence studies. JAMA. 1999;282: Anonymous. Generic Substitution Of Narrow Therapeutic Index Drugs. AMA Policy H Updated June Letter from Roger L. Williams, M.D. Deputy Center Director for Pharmaceutical Science FDA Center for Drug Evaluation and Research to Mr. Carmen A. Catizone Executive Director/Secretary National Association of Boards of Pharmacy April 16, Available at 13 Andermann F. Duh. Gosselin A. Paradis PE. Compulsory generic switching of antiepileptic drugs: high switchback rates to branded compounds compared with other drug classes. Epilepsia. 2007: 48(3):464-9.

6 14 Burkhardt RT, Leppik IE, Blesi K, et al. Lower phenytoin serum levels in persons switched from brand to generic phenytoin. Neurology. 2004;63: Qazi YA. Forrest A. Tornatore K. Venuto RC. The clinical impact of 1:1 conversion from Neoral to a generic cyclosporine (Gengraf) in renal transplant recipients with stable graft function. Clinical Transplantation. 2006: 20(3): Taber DJ. Baillie GM. Ashcraft EE. Rogers J. Lin A. Afzal F. Baliga P. Rajagopalan PR. Does bioequivalence between modified cyclosporine formulations translate into equal outcomes?. Transplantation (11): Roza A. Tomlanovich S. Merion R. Pollak R. Wright F. Rajagopalan P. Pruett T. Scandling J. Ryan J. Awni W. Schweitzer S. Greco R. Lam W. Nabulsi A. Hoffman R. Conversion of stable renal allograft recipients to a bioequivalent cyclosporine formulation. Transplantation. 2002: 74(7):

7 Appendix A List of Drugs Date of Patent Expiration* 5/3/2009 4/10/2017 1/10/2010 April 2008 per manufacturer testimony 2/11 3/24/11 Drug Type Name GenericName Total Claim Count Ingredient Cost# Ing Cost / Clm Patient Count Immunosuppressants (66% of patients on s) Generic AZATHIOPRINE AZATHIOPRINE 422 $12,102 $29 82 SANDIMMUNE CYCLOSPORINE 42 $11,108 $264 3 Generic CYCLOSPORINE CYCLOSPORINE 169 $42,134 $ Generic Generic NEORAL GENGRAF CYCLOSPORINE CELLCEPT CYCLOSPORINE, MODIFIED 171 $41,145 $ CYCLOSPORINE, MODIFIED 187 $37,894 $ CYCLOSPORINE, MODIFIED 78 $13,631 $ MYCOPHENOLATE MOFETIL 1,034 $665,707 $ MYFORTIC MYCOPHENOLATE 108 $60,032 $ RAPAMUNE SIROLIMUS 68 $32,632 $ PROGRAF TACROLIMUS ANHYDROUS 1,203 $681,872 $ Immunosuppressant Totals 12/1/07-11/30/08 3,482 $1,598,256 Antiepileptic Drugs (17% of patients on s) TEGRETOL XR CARBAMAZEPINE 864 $87,918 $ CARBATROL CARBAMAZEPINE 734 $87,326 $ TEGRETOL CARBAMAZEPINE 237 $25,096 $ Generic CARBAMAZEPINE CARBAMAZEPINE 2,176 $32,248 $ Generic EPITOL CARBAMAZEPINE 174 $596 $3 48 KLONOPIN CLOZEPAM 64 $9,412 $ Generic CLOZEPAM CLOZEPAM 22,625 $96,436 $4 3,732 DIASTAT DIAZEPAM 444 $248,285 $1, DIVALPROEX DEPAKOTE ^ 12,764 $2,397,622 $188 2,191 DIVALPROEX DIVALPROEX Generic ^ 4,885 $351,339 $72 1,621 DIVALPROEX DEPAKOTE ER ^ 11,222 $2,038,023 $182 1,618 DEPAKOTE DIVALPROEX SPRINKLE ^ 2,484 $432,728 $ Generic ETHOSUXIMIDE ETHOSUXIMIDE 94 $3,916 $42 21 FELBATOL FELBAMATE 147 $49,555 $ CEREBYX FOSPHENYTOIN FOSPHENYTOIN 1 $80 $80 1 FOSPHENYTOIN 2 $12 $6 2 Generic NEURONTIN GABAPENTIN 290 $62,781 $216 52

8 12/30/18 6/10/17 3/26/09 Generic GABAPENTIN GABAPENTIN 6,959 $241,418 $35 1,736 LAMICTAL LAMOTRIGINE^ 19,030 $4,714,317 $248 3,298 Generic LAMOTRIGINE LAMOTRIGINE^ 8,878 $2,056,863 $232 2,668 LAMICTAL (ORANGE) LAMOTRIGINE^ 269 $53,981 $ LAMICTAL (GREEN) LAMOTRIGINE^ 28 $11,123 $ LAMICTAL (BLUE) LAMOTRIGINE^ 31 $4,339 $ KEPPRA LEVETIRACETAM 2,709 $815,599 $ Generic LEVETIRACETAM LEVETIRACETAM 58 $18,064 $ MEBARAL MEPHOBARBITAL 57 $4,060 $71 5 Generic MEPHOBARBITAL MEPHOBARBITAL 68 $4,808 $71 5 CELONTIN METHSUXIMIDE 39 $3,217 $82 4 TRILEPTAL OXCARBAZEPINE 579 $146,633 $ Generic OXCARBAZEPINE OXCARBAZEPINE 1,515 $287,911 $ DILANTIN PHENYTOIN 194 $8,078 $ Generic PHENYTOIN PHENYTOIN 338 $12,926 $38 52 PHENYTOIN EXTENDED 671 $21,136 $ Generic DILANTIN PHENYTOIN EXTENDED PHENYTOIN EXTENDED 1,858 $55,409 $ PHENYTOIN Generic PHENYTEK EXTENDED 54 $2,424 $45 11 LYRICA PREGABALIN 2,727 $428,987 $ Generic PRIMIDONE PRIMIDONE 304 $11,628 $38 57 GABITRIL TIAGABINE HCL 143 $37,243 $ TOPAMAX TOPIRAMATE 4,344 $1,405,444 $ VALPROATE DEPAKENE ^ 14 $2,957 $211 1 VALPROATE Generic VALPROIC ACID ^ 1,340 $34,908 $ Generic VALPROIC ACID VALPROIC ACID^ 546 $24,739 $ ZONEGRAN ZONISAMIDE 94 $22,905 $ Generic ZONISAMIDE ZONISAMIDE 687 $21,367 $31 95 Antiepileptic Totals 12/1/07-11/30/08 112,741 $16,375,857 # Excludes TPL, Copay & Dispense Fee ^ Denotes drug is carved-out of managed care contracts; fee-for-service pays for all patients (enrolled or not). * per