I. BACKGROUND. Docket No. FDA-2009-P Dear Dr. Aikman:

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1 DEPARTMENT OF HEALTH &. HUMAN SERVICES Food and Drug Administration Rockville MD Mark S. Aikman, Pharm.D. Vice President, Regulatory Affairs and Quality Assurance Osmotica Pharmaceutical Corp Culbreth Drive, Suite 200 Wilmington, NC Re: Docket No. FDA-2009-P-0403 Dear Dr. Aikman: This responds to your citizen petition dated August 20,2009 (Third Venlafaxine Petition or petition) regarding venlafaxine hydrochloride (HC1) extended-release tablets. I Your petition requests that the Food and Drug Administration (FDA or the Agency) require that any company with a pending abbreviated new drug application (ANDA) for a venlafaxine HCI extendedrelease drug product, or that submits an ANDA for a venlafaxine HCl extended-release drug product in the future, conduct appropriate in vitro testing to assess the effect of alcohol on the extended-release dosage form to ensure that there is no "dose dumping" if the drug is consumed with alcohol. We have reviewed your Third Venlafaxine Petition and have determined, for the reasons stated in section II of this response, that your petition is granted in part and denied in part. I. BACKGROUND A. Venlafaxine Products On October 20, 1997, Wyeth Pharmaceuticals, Inc. (Wyeth) obtained approval for Effexor XR (venlafaxine HCl) Extended-Release Capsules, 37.5 milligram (mg), 75 mg, 100 mg,2 and 150 mg, for the treatment of major depressive disorder. Effexor XR subsequently was approved for the treatment of generalized anxiety disorder in 1999, treatment of social anxiety disorder in 2003, and treatment ofpanic disorder in On April 16,2003, Lachman Consultant Services, Inc. (Lachman) submitted a suitability petition requesting permission to file an ANDA for a drug product, venlafaxine HCl extended-release tablets, 37.5 mg, 75 mg, and 150 mg, that differed from Effexor XR, the RLD, in dosage form (see section 505Q)(2)(C) of the Federal Food, Drug, and Cosmetic Act (the Act) (21 U.S.C. I Osmotica's First and Second Venlafaxine Petitions are described in section LA of this response. 2 The IOO-mg strength of Effexor XR (venlafaxine hydrochloride) extended-release capsules has been discontinued from marketing.

2 3SS(j)(2)(c)) and 21 CFR ).3 FDA determined that Lachman's request for a change in dosage form (from extended-release capsules to extended-release tablets) was a type of change authorized by section SOS(j)(2)(C) of the Act, and granted Lachman's suitability petition on March 30, 200S.4 The approval ofthe suitability petition would permit an ANDA to be submitted for venlafaxine BCI extended-release tablets, 37.S mg, 7S mg, and iso mg, that referred to the corresponding strengths of Effexor XR extended-release capsules as the basis for AND A submission (see 21 CFR ( a )(3)). Prior to the approval of any ANDA submitted based upon the approved suitabilty petition, a new drug application (NDA) submitted through the approval pathway described by section SOS(b )(2) ofthe Act (SOS(b)(2) application) was approved for venlafaxine Bei extended-release tablets. On May 20, 2008, your SOS(b)(2) application for 37.S-mg, 7S-mg, IS0-mg, and 22S-mg venlafaxine BCI extended-release tablets (NDA ) was approved for treatment of major depressive disorder and social anxiety disorder. On May 30, 2008, you submitted a citizen petition requesting that FDA refrain from approving any pending ANDA for venlafaxine BCI extended-release tablets that cites Effexor ER capsules as the RLD and that was submitted based on the March 30, 200S, approved suitability petition (First Venlafaxine Petition). You also requested that any applicant with such a pending ANDA reference instead your approved venlafaxine BCI extended-release tablets as the RLD and, as required by section SOS(j)(2)(D)(i) of the Act, submit a new ANDA to make that change. In addition, you requested that FDA require any such applicant to conduct new bioequivalence studies comparing its proposed product to your approved drug product. FDA granted your First Venlafaxine Petition on November 2S, In a citizen petition.dated July 24, 2009, you requested that FDA clarify the patent certification requirements for an ANDA that relies upon a RLD approved through the pathway described by section SOS(b)(2) ofthe Act (21 U.S.c. 3SS(b)(2)) (Second Venlafaxine Petition). Specifically, you requested that when an ANDA relies upon an RLD approved through the SOS(b)(2) pathway (SOS(b)(2) application) and the SOS(b)(2) application relied upon FDA's finding of safety and effectiveness for a listed drug, FDA require the ANDA applicant to provide an appropriate patent certification or statement to patents listed for the RLD (e.g., Osmotica's venlafaxine BCI extended-release tablets (NDA )) and for the listed drug upon which the RLD relied (e.g., Effexor XR (venlafaxine BCI) extended-release capsules (NDA )). You asserted that if Sun Pharmaceutical Industries, Ltd's ANDA for venlafaxine BCI extended-release tablets did not contain such patent certification(s) or statement(s), the ANDA should not have been received by FDA because it was deficient on its face. Accordingly, you requested that FDA require Sun to submit a new ANDA with appr~riate patent certifications. On January 21, 2010, FDA denied your Second Venlafaxine Petition. 3 See Docket No. FDA-2003-P The original docket number for this suitability petition, 2003P-0 159, was changed to FDA-2003-P-0351 as a result of FDA's transition to its new docketing system (Regulations.gov) in January See FDA-2003-P (March 2005). 5 See FDA-2008-P-0329 (November 2008). 6 See FDA-2009-P-0356 (January 2010). 2

3 B. Statutory and Regulatory Basis for Bioequivalence The Drug Price Competition and Patent Term Restoration Act of 1984 (the Batch-Waxman Amendments) created section SOS(j) of the Act, which established the current ANDA approval process. To obtain approval, an ANDA applicant is not required to submit evidence to establish the clinical safety and effectiveness of the drug product; instead, an ANDA relies on FDA's previous finding that the RLD is safe and effective. To rely on a previous finding of safety and effectiveness, an ANDA applicant must demonstrate, among other things, that its drug product is bioequivalent to the RLD (section SOS(j)(2)(A)(iv) ofthe Act). In addition, an ANDA must contain, with certain exceptions not relevant here, information to show that the proposed drug has the same active ingredient(s), conditions of use, route of administration, dosage form, strength, and labeling as the RLD (section SOS(j)(2)(A) ofthe Act). FDA must approve an ANDA unless the information submitted in the ANDA is insufficient to meet the requirements delineated in section SOS(j)(2)(A) of the Act, including a demonstration ofbioequivalence (section SOSG)(4) ofthe Act). Section SOSG)(2)(A)(v) of the Act requires that an ANDA contain information to show that the labeling proposed for the new (generic) drug is the same as the labeling approved for the listed drug... except for changes required because of differences approved under a petition fied under (section 505U)(2)(C) of the Act) or because the new drug and the listed drug are produced or distributed by different manufacturers. A parallel provision appears in section SOSG)(4)(G) of the Act.7 FDA's regulations in 21 CFR part 320 list acceptable methodologies for determining the bioequivalence of drug products. These methodologies include pharmacokinetic studies, pharmacodynamic studies, comparative clinical trials, and in vitro studies. The choice of which study design to use is based on the ability of the design to compare the drug delivered by the two products at the particular site of action of the drug. The cours have expressly upheld FDA's regulatory implementation of the Act's bioequivalence requirements (see, e.g., Schering Corp. v. FDA, SI F.3d 390 at (3rd Cir. 1995); Fisons Corp. v. Shalala, 860 F. Supp. 8S9 (D.D.C. 1994)). Drug products that meet the approval requirements under section SOS(j) of the Act generally wil be considered by FDA to be "therapeutically equivalent" to the RLD.8 Drug products are considered to be therapeutic equivalents only if they are "pharmaceutical equivalents" and if they 7 Section 5050)(4)(0) of the Act provides that FDA must approve an ANDA unless, among other things, "the information submitted in the application is insuffcient to show that the labeling proposed for the drug is the same as the labeling approved for (the reference listed drug) except for changes required because of differences approved under (an ANDA suitabilty petition) or because the drug and the listed drug are produced or distributed by different manufacturers. " 8 Drug products approved in ANDAs submitted pursuant to the suitability petition provisions of section 5050)(2)(C) of the Act wil not be therapeutically equivalent to the RLD that serves as the basis for the petition. 3

4 can be expected to have the same clinical effect and safety profie when administered to patients under the conditions specified in the labeling (which would include the demonstration of bioequivalence). (See Approved Drug Products with Therapeutic Equivalence Evaluations (the Orange Book), 29th ed., at vii.) Pharmaceutical equivalents have the same dosage form, strength, and route of administration. They contain the same amounts of the same active drug ingredient and meet the same compendial or other applicable standard of identity, strength, quality, and purity, including potency and, where applicable, content uniformity, disintegration times, and/or dissolution rates. Pharmaceutical equivalents do not necessarily contain the same inactive ingredients and may also differ in characteristics such as shape, scoring, release mechanism, and, within certain narrow limits, labeling (see 21 CFR and the Orange Book, at vi, et seq.). Products classified as therapeutically equivalent can be substituted with the expectation that the substituted product wil produce the same clinical effect and safety profie as the prescribed product. (See the Orange Book at vii.) C. Alcohol Induced Dose Dumping Dose dumping is a term that describes the unintended, rapid release in a short period of time of the entire amount or a significant fraction ofthe drug contained in a modified-release dosage form. Depending on the therapeutic indication and other characteristics of the drug, dose dumping can pose a significant risk to patients, either because of safety issues or diminished effcacy or both. Generally dose dumping is observed as a result of a compromise of the releaserate-controllng mechanism. Some modified-release oral dosage forms contain drugs and excipients that exhibit higher solubility in ethanolic solutions compared to water. Such products can be expected to exhibit a more rapid drug dissolution and release rate in the presence of ethanol. Therefore, when a modified-release product is consumed with alcohol, the modifiedrelease mechanism could be adversely affected, which could lead to dose dumping. Where appropriate, based on the risk of dose dumping when a modified-release drug product is consumed with alcohol, the modified-release drug product's labeling includes warnings against the consumption of alcohol while taking the drug product. Even with significant warnings in the labeling, the consequences of concomitant alcohol use need to be considered for certain drug products because alcohol use may stil be likely, and such alcohol use may lead to dose dumping, which could result in serious adverse events. The problem of dose dumping led to the withdrawal of Palla done (hydromorphone BCI) extended-release capsules from the market in 200S. In 200S, FDA acquired new information that serious and potentially fatal adverse reactions can occur when Palladone extended-release capsules are taken together with alcohol. The labeling for Palladone already included a warning against the use of alcohol and Palladone. Because Palladone contained significant amounts of a very potent narcotic, even at its lowest marketed strength, the FDA did not believe that the risk of serious and potentially fatal adverse events could be effectively managed by label warnings and a risk management plan.9 FDA asked Purdue Phara L.P. to withdraw Palladone from the market. Purdue agreed, and Palladone was withdrawn in July 200S. 9 "FDA Asks Purdue Pharma to Withdraw Palladone for Safety Reasons," July 13,2005, available at htt:// 4

5 Since Palladone's withdrawal from the market, FDA has considered whether other products are affected by similar concerns about dose dumping. The risks of dose dumping for other products were discussed at a meeting ofthe Advisory Committee for Pharmaceutical Science in October 200S. FDA has conducted a comprehensive evaluation of its policies and taken various actions to address the issue ofthe potential for alcohol-induced dose dumping in modified-release drug products. FDA has invested resources to better understand and predict alcohol-induced dose dumping. D. Section 505( q) of the Act Your petition is subject to section 914 of the Food and Drug Administration Amendments Act of 2007 (FDAAA), which amended section SOS ofthe Act (21 U.S.c. 3SS) by adding new subsection (q). Section SOS( q) of the Act applies to certain citizen petitions and petitions for stay of Agency action that request that FDA take any form of action relating to a pending application submitted under section SOS(b)(2) or (j) of the Act (21 U.S.C. 3SS(b)(2) or (j)) and governs the manner in which these petitions are treated. Among other things, section SOS(q)(I)(F) ofthe Act governs the time frame for final Agency action ona petition subject to section SOS( q). Under this provision, FDA must take final Agency action on a petition not later than 180 days after the date on which the petition is submitted. The 1 80-day period is not to be extended for any reason. II. DISCUSSION A. Require ANDA Applicants for Venlafaxine Extended-Release Drug Products to Conduct In Vitro Alcohol-Induced Dose Dumping Studies In your Third Venlafaxine Petition, you request that FDA refrain from approving any ANDAs for venlafaxine extended-release drug products unless the application includes the results of in vitro testing that ensures a lack of any dose dumping if the drug product is consumed with alcohol. As you note in your petition, FDA required you to perform ethanol dissolution studies to rule out dose dumping as part of your phase iv postapproval commitments. lo As you state in your petition, you completed the required in vitro dissolution testing and submitted your results to the Agency on October 6, You state in your petition that your data demonstrated that no effect of alcohol was noted on the rate of release of the drug from the tablet until the dissolution medium contained at least 20 percent ethanol. You state in your petition that your data were made public as a poster presentation at the April 20, 2009, Annual Meeting of the College of Psychiatric and Neurologic Pharmacists. FDA Response Your request that FDA refrain from approving any ANDAs for venlafaxine extended-release drug products unless the application includes the results of in vitro testing that ensures a lack of any dose dumping ifthe drug product is consumed with alcohol is granted. FDA recognizes the potential for alcohol-induced dose dumping in modified-release drug products. We have thus adopted a policy of considering information on dose dumping in our review of applications for these drug products. FDA's current draft bioequivalence guidance on venlafaxine BCI extendedio See FDA NDA approval letter, NDA (May 20,2008). S

6 release capsule/oral contains recommendations for in vitro dissolution testing using various 11 We plan to issue a draft bioequivalence concentrations of ethanol in the dissolution medium. guidance on venlafaxine BCI extended-release tablets that wil describe in vitro dissolution testing in alcohol for the tablet dosage form as well. B. Assign a "BX" Rating to Any Venlafaxine HCL Extended-Release Drug Product Approved Without Data to Demonstrate a Lack of Alcohol-Induced Dose Dumping In your petition, you request that if any ANDAs for venlafaxine BCI extended-release drug products are approved absent data that demonstrate a lack of dose dumping in alcohol, those products should not be designated as therapeutically equivalent to the listed drug, but instead should be assigned a "BX" rating.. FDA Response The Orange Book provides FDA's therapeutic equivalence evaluations for approved multi source prescription drug products and facilitates knowledge about the availability of generic drugs that are substitutable at the pharmacy level. Drug products are classified as therapeutically equivalent ifthey are approved as safe and effective, pharaceutically equivalent, bioequivalent, adequately labeled, and manufactured in compliance with Current Good Manufacturing Practice regulations (see Orange Book at vii). As noted in the Preface to the Orange Book, "FDA believes-that products classified as therapeutically equivalent can be substituted with the full expectation that the substituted product wil produce the same clinical effect and safety profile as the prescribed product" when administered to patients under the conditions specified in the labeling (Orange Book at vii). 12 The coding system for therapeutic equivalence evaluations allows users to determine quickly whether we have evaluated an approved product as therapeutically equivalent to other pharmaceutically equivalent products (the first letter) and to provide additional information on the basis of FDA's evaluations (the second letter) (Orange Book at xiii). An "A" category drug code applies to products that have been determined to be therapeutically equivalent to other pharmaceutically equivalent products (Orange Book at xiii). A "B" category drug code indicates that the approved drug product has actual or potential bioequivalence problems not resolved by adequate evidence of bioequivalence and thus would not be considered therapeutically 11 See FDA's draft guidance for industr on Individual Product Bioequivalence Recommendations, Draft Guidance on Venlafaxine Hydrochloride (December 2008) at page 2 (available on the Internet at htt:// ). 12 As defined at 21 CFR 320.1(c): Pharmaceutical equivalents means drug products in identical dosage forms that contain identical amounts of the identical active drug ingredient, i.e., the same salt or ester of the same therapeutic moiety, or, in the case of modified release dosage forms that require a reservoir or overage or such forms as prefilled syringes where residual volume may vary, that deliver identical amounts of the active drug ingredient over the identical dosing period; do not necessarily contain the same inactive ingredients; and meet the identical compendial or other applicable standard of identity, strength, quality, and purity, including potency and, where applicable, content uniformity, disintegration times, and/or dissolution rates. 6

7 equivalent to other pharmaceutically equivalent products (Orange Book at xii,i). These products often have a problem with specific dosage forms rather than with the active ingredients (Orange Book at xvii). A BX rating is assigned to specific drug products for which the data are insuffcient to determine therapeutic equivalence to the reference listed drug. A "BX" drug product is presumed therapeutically inequivalent until the Agency determines there is adequate information to make a full evaluation of therapeutic equivalence (Orange Book at xix-xx). As we are requiring applicants for venlafaxine BCI extended-release products to conduct in vitro alcohol-induced dose-dumping studies, your request that any future ANDAs be rated BX in the absence of such data is moot, and your request is denied. As described in section LB of this response, drug products that meet the approval requirements under section SOS(j) of the Act generally wil be considered by FDA to be "therapeutically equivalent" to the RLD. Therefore a venlafaxine BeL extended-release product that meets the ANDA approval requirements can be expected to receive an "A" therapeutic equivalence code. III. CONCLUSION For the reasons discussed in this response, your Third Venlafaxine Petition is granted in part and denied in part. FDA is requiring applicants to conduct alcohol-induced dose-dumping studies for all approved venlafaxine BCI extended-release products. We plan to issue a draft bioequivalence guidance for venlafaxine BCI extended-release tablets to recommend in vitro dissolution testing in alcohol. Therefore, your request that we assign a BX rating to any approved venlafaxine BCI extended-release product absent such data is moot, and your request is denied. Sincerely, Janet Woodcock, M.D. Director Center for Drug Evaluation and Research 7