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`IA/kermes·
`t
`
`Patient inspired
`
`VIA HAND DELIVERY
`
`July 11, 2011
`
`Division of Dockets Management (HFA-305)
`Food and Drug Administration
`5630 Fishers Lane, Room 1061
`Rockville, Maryland 20852
`
`Re:
`
`Docket No. FDA-2007-D-0369
`Draft Guidance for Industry Describing Product-Specific Bioequivalence
`Recommendations for Naltrexone Extended Release Suspension/Intramuscular
`
`Dear Sir or Madam:
`
`Alkermes, Inc. ("Alkermes") respectfully submits the following comments on the Food and
`
`Drug Administration's ("FDA") draft product-specific bioequivalence recommendations for naltrexone
`
`extended release intramuscular ("IM") injection. 1 Alkermes developed, manufactures, and markets
`
`Vivitrol® (naltrexone for extended release injectable suspension), the reference listed drug that
`
`serves as the basis for the draft guidance document.
`
`Alkermes is a fully integrated pharmaceutical and biotechnology company that develops
`
`medicines designed to yield better outcomes and improve patients' lives. Our products, which
`
`integrate both novel and well-known molecules and innovative drug delivery technologies, target
`
`widespread diseases including addiction, central nervous system disorders, and diabetes. We
`
`partner with the world's leading pharmaceutical companies to manufacture and market the products
`
`we develop, and also work independently to commercialize our own products.
`
`Alcohol and opioid dependence are chronic, life-threatening diseases that affect a growing
`
`number of Americans - approximately nine million Americans are dependent on alcohol, and
`
`The agency's draft recommendations are available at:
`www.fda.gov/down loads/Drugs/GuidanceComplianceRegulatoryl nformation/Guidances/UC M 179182. pdf.
`
`11\NY - 0871 I 7/000024 - 2325950 v2
`
`ALKERMES EXHIBIT 2011
`Amneal Pharmaceuticals LLC v. Alkermes Pharma Ireland Limited
`IPR2018-00943
`
`Page 1 of 19
`
`

`

`Comment to Bioequivalence Recommendations
`Page 2 of 19
`
`approximately 1.6 million are dependent on opioids. 2 Vivitrol is the first and only non-narcotic, non-
`
`addictive product approved by FDA for the treatment of alcohol dependence and for the prevention
`
`of relapse to opioid dependence, following opioid detoxification. It is designed to deliver therapeutic
`
`levels of naltrexone both quickly and on a sustained basis, to help patients avoid relapse during the
`
`early stages of their therapy and then to provide maintenance levels of naltrexone over a full, 30-day
`
`dosing cycle.
`
`To achieve the release profile on which FDA's approval is based, Vivitrol relies on a precise
`
`formulation of polylactide-co-glycolide ("PLG") microspheres, as well as a delivery system that
`
`essentially deposits the microspheres locally at the IM gluteal injection site. From the local depot
`
`site, the release of the drug is characterized by an initial peak approximately two hours after injection,
`
`followed by a second peak approximately two to three days after injection. Plasma concentration
`
`levels begin a slow decline at or about day 14. The release of the drug is dependent on, among
`
`other factors, the specific composition and formulation of the microspheres and the accompanying
`
`diluent, manufacturing and product quality, and the dynamic interaction between the microspheres
`
`and the conditions at the IM injection and depot site.
`
`Alkermes appreciates this opportunity to comment on FDA's effort to develop in vitro
`
`dissolution and in vivo bioequivalence methodologies for products that reference Vivitrol. As
`
`described below, Vivitrol relies on, and was approved based on, a specific release and absorption
`
`profile. Without dissolution and bioequivalence methodologies tailored to these unique properties,
`
`FDA risks approving a generic product that fails to match Vivitrol's proven safety and efficacy.
`
`2
`See Substance Abuse and Mental Health Services Administration, Office of Applied Studies,
`National Survey on Drug Use and Health (2009) at
`www.oas.samhsa.gov/NSDUH/2k9NSDUH/tabs/Sect5peTabs 1 to56.htm#Tab5. 14A.
`
`Page 2 of 19
`
`

`

`Comment to Bioequivalence Recommendations
`Page 3 of 19
`
`I.
`
`EXECUTIVE SUMMARY
`
`Vivitrol is a long-acting, modified release injectable drug product that delivers its active
`
`ingredient in three, clinically significant phases:
`
`• An "initial phase," during which naltrexone is immediately absorbed from the surface of
`
`the formulation's microspheres into the systemic circulation;
`
`• A "hydration phase," during which physical erosion of the microspheres begins, triggering
`
`the release of subsurface naltrexone; and
`
`• A "sustained release phase," during which the microspheres steadily erode and allow a
`
`constant amount of drug to be absorbed.
`
`Unlike traditional injectable drug products, where pharmacokinetics are driven by the
`
`metabolism and elimination of the drugs, the pharmacokinetics of Vivitrol are "flip-flop," driven by the
`
`multiphasic release of naltrexone from the Vivitrol microspheres. This multiphasic release profile
`
`ensures that circulating naltrexone levels are quickly raised to a therapeutic level and then are
`
`sustained over the course of the month-long dosing interval.
`
`The agency's draft recommendations for Vivitrol lack the specificity needed to ensure that
`
`proposed generics will indeed be therapeutically equivalent to the reference drug. This can be
`
`addressed by improving the guidance in three areas:
`
`First, the draft directs sponsors to an in vitro dissolution methodology that is essentially void
`
`of any direction or limitations.
`
`In contrast, and with the agency's support, Alkermes developed a
`
`specific, multipoint in vitro methodology that tracks the multiphasic release profile of the product.
`
`This unique in vitro methodology, which includes sampling at days 1, 7, 14, and 28, should be
`
`considered the starting point for any generic sponsor that purports to make a comparable version of
`
`Vivitrol.
`
`Page 3 of 19
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`

`

`Comment to Bioequivalence Recommendations
`Page 4 of 19
`
`Second,
`
`the draft should be amended
`
`to
`
`include statistical analysis of additional
`
`pharmacokinetic parameters that are necessary to ensure equivalence to a multiphasic, modified
`
`release product such as Vivitrol. Vivitrol strikes a careful balance between potent early release of
`
`the active drug substance and conserving a sufficient amount of drug to ensure therapeutic
`
`maintenance over the full, 30-day dosing cycle. The guidance should be revised so that a generic
`
`that releases the same amount of total drug, but does so in different phases or with a different
`
`pattern from that of Vivitrol, is not declared bioequivalent.
`
`Third, the guidance should be revised to address the need to show no significant difference
`
`in injection site reactions. Vivitrol deposits a substantial amount of drug product at or about the local
`
`injection site, for a substantial amount of time. The injection site tolerance and safety of the drug is
`
`dependent on local interactions that cannot be characterized solely by analysis of formulation and in
`
`vivo systemic pharmacokinetics. As the agency has done with other local products, including
`
`transdermal systems, FDA should include an in vivo comparative study designed to assess local
`
`injection site safety for any proposed generic drug product.
`
`11.
`
`BACKGROUND
`
`The agency first approved Vivitrol on April 13, 2006, under new drug application ("NOA") 21-
`
`897. Vivitrol is currently approved (a) for the treatment of alcohol dependence in patients who are
`
`able to abstain from alcohol in an outpatient setting prior to the initiation of treatment, and (b) for the
`
`prevention of relapse to avoid opioid dependence, following opioid detoxification.
`
`In both cases,
`
`treatment with Vivitrol should be part of a comprehensive management program that includes
`
`psychosocial support.
`
`The active ingredient in Vivitrol, naltrexone, is microencapsulated in a high molecular weight
`
`75/25 PLG polymer at a concentration of 337 mg of naltrexone per gram of microspheres. The
`
`diluent is a clear, colorless, odorless solution of carboxymethylcellulose sodium salt, polysorbate 20,
`
`Page 4 of 19
`
`

`

`Comment to Bioequivalence Recommendations
`Page 5 of 19
`
`sodium chloride, and water for injection. Each Vivitrol unit is packaged with one, 380 mg vial of
`
`Vivitrol microspheres, one vial containing 4 ml (to deliver 3.4 ml) of diluent, one 5 ml prepackaged
`
`syringe, one 1 inch 20-gauge preparation needle, two 1.5 inch 20-gauge administration needles, and
`
`two 2 inch 20-gauge administration needles. Physicians are instructed to reconstitute the
`
`microsphere suspension using the diluent and the 1 inch preparation needle, and then to administer
`
`the product as an IM gluteal injection, using only the needles provided, alternating sides for
`
`subsequent injections. 3 The recommended dose is one injection every four weeks or once a month.
`
`Naltrexone is an opioid antagonist with affinity for the mu opioid receptor. The competitive
`
`occupation of opioid receptors by naltrexone markedly attenuates or completely blocks the
`
`subjective effects of exogenous opioids. Vivitrol is not associated with the development of tolerance
`
`or dependence. However, in subjects physically dependent on opioids, Vivitrol will precipitate
`
`withdrawal symptoms. The reversible blockade produced by Vivitrol is potentially surmountable, but
`
`overcoming a full blockade by administration of exogenous opioids may result in non-opioid
`
`receptor-mediated symptoms such as histamine release. The mechanisms responsible for the
`
`reduction in alcohol consumption observed in alcohol-dependent patients are not entirely understood.
`
`However, preclinical data suggest the involvement of the endogenous opioid system.
`
`After a single IM injection of Vivitrol, there is an initial drug release phase, which takes place
`
`over the first 24 hours after dosing. During this time, water uptake begins at the injection site and
`
`the Vivitrol microspheres begin to swell. Naltrexone-catalyzed polymer hydrolysis causes a
`
`significant drop in the molecular weight of the microspheres. Naltrexone at or near the surface of the
`
`3
`The different length administration needles are provided to accommodate varying body physiques,
`given the importance of administering the drug as an IM gluteal injection. As discussed below,
`inadvertent subcutaneous injection of Vivitrol increases the likelihood of severe injection site reactions.
`According to Vivitrol's labeling, alternate treatment should be considered for patients whose physiques
`preclude IM injection with one of the provided needles.
`
`Page 5 of 19
`
`

`

`Comment to Bioequivalence Recommendations
`Page 6 of 19
`
`microspheres is released immediately, resulting in a transient, initial peak in plasma concentration
`
`approximately two hours after injection.
`
`This initial phase is followed by a hydration phase, which generally takes place over the first
`
`seven days after dosing. During this time, the microspheres undergo several chemical and physical
`
`changes that begin to define a steady rate of release of naltrexone. After approximately three days,
`
`the molecular weight of the PLG polymer falls below approximately 20 kilodaltons, a threshold level
`
`where physical erosion of the microspheres starts to occur. Some subsurface naltrexone is released,
`
`and the rate of release increases to a maximum at about two to three days after dosing. The
`
`maximum plasma concentration generally occurs at this time. The rate of release of naltrexone from
`
`the Vivitrol microspheres during this phase is carefully engineered to match the rate of release
`
`during the subsequent phase, to provide patients with continuing drug exposure throughout the one
`
`month dosing interval.
`
`During the final, sustained release phase, the majority of the naltrexone encapsulated within
`
`the microspheres is released into the systemic circulation. During this phase, the drug diffuses into
`
`the surrounding tissue as the PLG polymer continues to undergo hydrolysis and erosion. Again,
`
`naltrexone is released at a steady, sustained rate until the microspheres are depleted. Beginning
`
`about 14 days after dosing, plasma concentrations begin to slowly decline, with the concentration
`
`measurable above 1 ng/ml for longer than the one month dosing interval.
`
`In general, the absorption of a drug into the systemic circulation depends on the release of
`
`the drug substance from the drug product or dosage form and the dissolution or solubilization of the
`
`drug under physiological conditions. For this reason, in vitro dissolution testing is critical for virtually
`
`all drug products, but particularly for modified or extended release drugs, such as Vivitrol, whose
`
`safety and efficacy is driven by their dissolution over time.
`
`In the context of generic drugs,
`
`dissolution testing, together with in vivo bioequivalence testing, is used to establish the equivalence
`
`Page 6 of 19
`
`

`

`Comment to Bioequivalence Recommendations
`Page 7 of 19
`
`of a proposed generic to its reference drug, to ensure batch-to-batch consistency, and to make
`
`certain that the product will remain equivalent throughout its shelf life. See generally Guidance for
`
`Industry: Dissolution Testing of Immediate Release Solid Oral Dosage Forms (Aug. 1997) at 3.
`
`With regard to the in vivo bioequivalence of systemically absorbed drugs, FDA generally
`
`recommends that applicants conduct single dose crossover or parallel group pharmacokinetic
`
`studies, measuring the concentrations of the generic and reference drugs in the blood or plasma.
`
`Applicants then calculate a variety of measurements of the resulting drug concentration vs. time
`
`"curve," including the maximum concentration ("Cmax"), the time to maximum concentration ("T max"),
`
`and the area under the curve ("AUC"), both from dosing until the last measured time point ("AUC0.t")
`
`and extrapolated to infinity ("AUC0 ... "). Cmax and T max are believed to reflect the rate of the drug's
`
`absorption into the systemic circulation, and the AUC measures are believed to reflect the extent of
`
`the drug's absorption.
`
`Several significant examples have emerged recently in which FDA has recognized the need
`
`to set additional bioequivalence parameters. Where the clinical performance of a drug product can
`
`be aligned with specific aspects of that drug's pharmacokinetic profile, and where those aspects
`
`cannot be captured by FDA's traditional bioequivalence criteria, FDA has adopted partial AUC
`
`measures or other metrics to ensure that the generic and reference drugs are truly therapeutically
`
`equivalent.4
`
`The efficacy of Vivitrol is driven by a distinct, multiphasic release and absorption profile. This
`
`profile cannot be adequately measured using a standard in vitro dissolution methodology or with
`
`4
`See, e.g., Citizen Petition Response regarding Zolpidem Tartrate, Docket No. FDA-2007-P-0182
`(Oct. 13, 2010) at 4 ("Ambien CR Petition Response"); Citizen Petition Response regarding Morphine
`Sulfate, Docket No. FDA-2010-P-0082 (July 19, 2010) at 7; Citizen Petition Response regarding
`Temazepam, Docket No. FDA-2009-P-0379 (Feb. 2, 2010) at 6-7 n.16 (acknowledging that alternate
`parameters would be required in cases of complex extended or modified release products for which there
`were known and clinically significant connections between release characteristics and performance).
`
`Page 7 of 19
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`

`

`Comment to Bioequivalence Recommendations
`Page 8 of 19
`
`FDA's traditional bioequivalence parameters of Cmax and AUC. For this reason, the agency should
`
`recommend the use of a tailored dissolution methodology and the additional bioequivalence
`
`parameters discussed below.
`
`111.
`
`RECOMMENDED CHANGES TO DRAFT GUIDANCE
`
`(1)
`
`Incorporate into the Bioequivalence Recommendations a Precise In Vitro
`
`Dissolution Methodology that Adequately Characterizes Each of the Clinically
`
`Relevant Release Phases
`
`The agency's draft bioequivalence guidance addresses the in vitro dissolution of prospective
`
`generic products in two ways. First, the guidance references FDA's Dissolution Methods Database
`
`for information on the appropriate dissolution methodology ("Please find the dissolution information
`
`for this product at this website."). Second, the guidance contains a paragraph describing the
`
`apparatus and methodology to be used when conducting dissolution testing on the product.
`
`Neither of these provisions is sufficient; indeed, neither contains any information on the
`
`appropriate dissolution methodology to be used when testing Vivitrol or a proposed generic product.
`
`The Dissolution Methods Database contains no information on injectable naltrexone. It contains only
`
`a brief statement regarding naltrexone hydrochloride tablets and a reference to United States
`
`Pharmacopeia standards for the tablet dosage form. The bioequivalence guidance itself describes a
`
`methodology that appears to be directed to certain modified release tablet products ("Comparative
`
`dissolution profiles should include individual tablet data as well as the mean, range, and standard
`
`deviation at each time point for twelve tablets.").
`
`This lack of meaningful or relevant information regarding an appropriate in vitro dissolution
`
`methodology for proposed generics of Vivitrol is untenable. As noted above, Vivitrol was designed
`
`to exhibit a particular in vitro release profile. This profile begins with the release of surface
`
`naltrexone during the initial phase, continues with hydrolysis and the physical erosion of the
`
`Page 8 of 19
`
`

`

`Comment to Bioequivalence Recommendations
`Page 9 of 19
`
`microspheres during the hydration phase, and ends with the steady depletion of the microspheres
`
`during the sustained release phase. Each of these phases corresponds with Vivitrol's in vivo
`
`absorption, and
`
`thus with
`
`the product's safety and efficacy profile.
`
`See Vivitrol Clinical
`
`Pharmacology Review at 30-31 (demonstrating that the cumulative in vitro release and % in vitro
`
`release per day precisely correspond with the cumulative in vivo AUC and % in vivo AUC per day).
`
`The NOA-approved in vitro dissolution methodology for Vivitrol includes measurement of in
`
`vitro release at days 1, 7, 14, and 28. Each parameter was selected to assess a particular phase of
`
`the release profile. For example, the measurement at day 7 is intended to evaluate the hydration
`
`phase, and to ensure that the drug is releasing from the microspheres at a rate that is sufficient to
`
`provide efficacy, while preventing excess drug from being released, which may raise safety concerns
`
`and prevent sufficient drug from being available for the entire dosing interval. See Medical Review
`
`vol. 2 at 20 ("Higher doses of naltrexone have previously been associated with adverse events, such
`
`as oral toxicity. The drug release specifications should remain as 'tight' as can be reasonably
`
`achieved."). Similarly, the amount of drug released on day 14 and day 28 is measured to define the
`
`sustained release phase. All of these measures are critical to ensure that Vivitrol releases its active
`
`ingredient quickly during the initial phase and steadily during the hydration and sustained release
`
`phases. See Vivitrol Clinical Pharmacology Review at 6 ("consistent product performance over 28
`
`days is pivotal for the safety and effectiveness of this drug").
`
`Alkermes requests that FDA revise its draft bioequivalence guidance to include a rigorous
`
`multipoint in vitro methodology. A specific and sensitive in vitro methodology is essential in this
`
`instance, where the release profile of the drug is both clinically relevant and cannot be assessed
`
`based on a single dissolution point. A test product that purports to be bioequivalent to Vivitrol must
`
`be shown to have a similar dissolution profile at all critical time points, through day 28. Ultimately,
`
`the specifications for the in vitro dissolution of a proposed generic product will be derived from the
`
`Page 9 of 19
`
`

`

`Comment to Bioequivalence Recommendations
`Page 10 of 19
`
`dissolution profile of the product used in a well-conducted bioequivalence study. To ensure
`
`complete characterization of the test product, the in vitro methodology should be biorelevant and
`
`should be as thorough and sensitive as that required for the reference product. Thus, we ask the
`
`agency to amend the guidance to include a multipoint dissolution methodology based on the same
`
`time points (days 1, 7, 14, and 28) specified in the Vivitrol NDA.
`
`(2)
`
`Incorporate
`
`into
`
`the Bioequivalence Recommendations Additional
`
`Pharmacokinetic Parameters, Including Measures to Ensure Bioequivalence
`
`During the Initial and Release Phases
`
`The agency's draft recommendations for Vivitrol state that generic applicants should conduct
`
`one bioequivalence study - a single, 380 mg dose, fasting, parallel group study in healthy subjects.
`
`With regard to the parameters to be used to compare the tested products, the recommendations
`
`state that naltrexone concentrations should be measured in plasma, and that bioequivalence should
`
`be based on FDA's traditional 90% confidence interval approach. To the extent that the guidance
`
`relies solely on FDA's standard bioequivalence measures (including Cmax, AUC 0_1, and AUCo-int), it is
`
`insufficient to ensure the therapeutic equivalence of generic versions of Vivitrol. A proposed generic
`
`product that exhibits a different pharmacokinetic profile may fail to provide an adequate early release
`
`of drug, or may release a different amount of naltrexone than Vivitrol later in the dosing interval.
`
`Either possibility could increase the risk of relapse or other serious consequences.
`
`As noted above, Vivitrol's pharmacokinetic profile - and, thus, the product's safety and
`
`efficacy -
`
`is uniquely driven by the release of the drug substance from the microspheres in a
`
`particular pattern over the course of the entire dosing interval. That pattern is characterized by a
`
`clinically important initial burst of drug into the systemic circulation, followed by a consistent release
`
`over the course of a full month, during which time the Vivitrol microspheres first swell and begin to
`
`Page 10 of 19
`
`

`

`Comment to Bioequivalence Recommendations
`Page 11 of 19
`
`hydrolyze, and then steadily erode. At least two aspects of this multiphasic profile are clinically
`
`relevant, such that FDA's standard bioequivalence measures of AUC and Cmax are inadequate.
`
`First, intensive pharmacokinetic sampling and statistical bioequivalence parameters are
`
`necessary to ensure equivalence at the very beginning of the dosing interval, during the initial phase.
`
`Patients are required for both Vivitrol's alcohol and opioid indications to be drug free before
`
`beginning treatment. Patients then must struggle to remain abstinent prior to receiving their first
`
`Vivitrol injection. See, e.g., D.A. Ciraulo, et al., Early Treatment Response in Alcohol Dependence
`
`with Extended-Release Naltrexone, J. Clin. Psychiatry 2008;69:190-95 ("Although the efficacy of XR-
`
`NTX has been demonstrated over a 6-month period, recovery from alcohol dependence is highly
`
`unstable in the early treatment phase, when most relapses occur.") (attached at Tab 1).
`
`It is,
`
`therefore, critical that any potential generic product bring patients up to a minimum therapeutic level
`
`of naltrexone as quickly as possible.
`
`Vivitrol has been shown to release an adequate amount of drug almost immediately, within
`
`an hour or two. According to a published analysis of the data from Vivitrol's pivotal clinical study in
`
`alcohol-dependent patients, on the first day following injection, the median number of drinks
`
`consumed per day declined in the Vivitrol group to 1.0, vs. 2.0 in the placebo group. See id. On day
`
`2, the Vivitrol group reported consuming significantly fewer drinks per day compared to the placebo
`
`group (p < 0.05). Similarly, with regard to the percentage of patients reporting heavy drinking, 26%
`
`reported in the Vivitrol group on day 1, compared with 35% in the placebo group. Day 3 was the first
`
`day that the percentage of patients reporting a heavy drinking day differed significantly between the
`
`two groups (20% vs. 35%; p < 0.05). Overall, the authors of the study concluded that "[t]his early
`
`clinical effect was consistent with the release characteristics of the formulation, in which plasma
`
`naltrexone levels began to appear on day 1 postinjection." Id.
`
`Page 11 of 19
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`

`

`Comment to Bioequivalence Recommendations
`Page 12 of 19
`
`To ensure equivalent early absorption of naltrexone during the initial phase, FDA should
`
`recommend in its bioequivalence guidance the measurement of "AUCpR," or the AUC truncated to
`
`the population median T max· See Ambien CR Petition Response ("When partial AUC is used to
`
`evaluate early exposure, FDA recommends that the partial area be truncated at the population
`
`median of T max values for the reference formulation"); see also Guidance for Industry: Bioavailability
`
`and Bioequivalence Studies for Orally Administered Drug Products - General Considerations (Mar.
`
`2003) at 8-9. This measure would ensure that sufficient drug is being released early on, to match
`
`the initial phase efficacy of Vivitrol, without releasing so much drug as to raise safety issues or
`
`threaten adequate release of the drug later in the dosing interval. Either may signal a failure in the
`
`generic's manufacturing process, resulting in a different amount of unencapsulated drug on the
`
`surface of the microspheres. Alternatively, the use of a solvent or other substance different from
`
`those used in Vivitrol may result in an injection site reaction, leading to a rapid diffusion of drug out
`
`of the microspheres. In any case, it is critical that FDA's recommended bioequivalence methodology
`
`be able to detect any different drug release during this initial phase.
`
`Statistical bioequivalence parameters are also necessary to ensure equivalence at the end
`
`of the dosing interval, when circulating levels of naltrexone are tailing off. Opioid-tolerant patients
`
`generally require much higher doses of opioids to experience any effect, as compared to opioid-
`
`naive patients. But, after the patients detoxify, their tolerance decreases, and they will respond to
`
`lower doses of drug. Naltrexone protects patients from the effects of opioids, but if a patient goes
`
`back to using the high doses that he or she used to take, at a time when the level of naltrexone in his
`
`or her circulation is dropping, an overdose can result. For this reason, a proposed generic that
`
`releases an excessive amount of naltrexone early during the dosing interval, and thus releases too
`
`little during the final stages, may subject patients to greater risk.
`
`Page 12 of 19
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`

`

`Comment to Bioequivalence Recommendations
`Page 13 of 19
`
`According to Vivitrol's approved labeling, fatal instances of overdose in this context have
`
`been observed:
`
`After opioid detoxification, patients are likely to have reduced tolerance to opioids.
`
`Although VIVITROL blocks the effects of exogenous opioids for 28 days after
`
`administration, cases of opioid overdose with fatal outcomes have been reported in
`
`patients who used opioids at the end of a dosing interval or when missing a dose.
`
`Patients who have been treated with VIVITROL may respond to lower doses of
`
`opioids than previously used. This could result in potentially life-threatening opioid
`
`intoxication (respiratory compromise or arrest, circulatory collapse, etc.). Patients
`
`should be aware that they may be more sensitive to lower doses of opioids after
`
`VIVITROL treatment is discontinued. Reduced tolerance is especially of concern at
`
`the end of a dosing interval, that is, near the end of the month after VIVITROL was
`
`administered, or after a dose of VIVITROL is missed.
`
`It is also possible to overcome the effects of the blockade provided by Vivitrol, even during
`
`the main release phases, by using high enough doses of drug. Thus, the risk of overdose could
`
`be even greater in the context of a patient trying to overcome the naltrexone blockade. If a patient
`
`attempts to overcome the blockade, but has been administered a generic product that releases an
`
`insufficient amount of naltrexone during the hydration or sustained release phases, the result could
`
`be catastrophic. Again, according to Vivitrol's approved labeling:
`
`There is also the possibility that a patient who is treated with VIVITROL could
`
`overcome the opioid blockade effect of VIVITROL. Although VIVITROL is a potent
`
`antagonist with a prolonged pharmacological effect, the blockade produced by
`
`VIVITROL is surmountable. This poses a potential risk to individuals who attempt,
`
`on
`
`their own,
`
`to overcome the blockade by administering large amounts of
`
`Page 13 of 19
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`

`

`Comment to Bioequivalence Recommendations
`Page 14 of 19
`
`exogenous opioids. Any attempt by a patient to overcome the antagonism by taking
`
`opioids is very dangerous and may lead to fatal overdose. Injury may arise because
`
`the plasma concentration of exogenous opioids attained immediately following their
`
`acute administration may be sufficient to overcome the competitive receptor
`
`blockade. As a consequence, the patient may be in immediate danger of suffering
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`life-endangering opioid intoxication (e.g., respiratory arrest, circulatory collapse).
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`Even if a patient does not overdose or experience opioid intoxication, overcoming the blockade in
`
`this manner does mean that the patient will likely suffer from acute withdrawal symptoms upon the
`
`next administration of naltrexone. See M. Fishman, Precipitated Withdrawal During Maintenance
`
`Opioid Blockage with Extended Release Naltrexone, Addiction 2008; 103:1399-1403 ("This case
`
`suggests that, in some circumstances, the opioid blockade may be overcome when naltrexone levels
`
`drop toward the end of the dosing interval, producing vulnerability to subsequent naltrexone-induced
`
`withdrawal.") (attached at Tab 2).
`
`Potential generics must have the same therapeutic effect as Vivitrol throughout the dosing
`
`interval. A potential generic product that, by virtue of a different manufacturing process, or different
`
`intermediates or solvents, releases a different amount of naltrexone during the hydration and
`
`sustained release phases will have a different efficacy profile from that of Vivitrol. This is particularly
`
`evident with regard to the opioid indication, where unlike with the alcohol indication, there is no one
`
`minimum effective dose - efficacy is dictated by competitive occupancy of the opioid receptors, and
`
`can depend on the amount of exogenous opioids in, the systemic circulation. See id.; see also N.
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`Kun0e, et al., Challenges to Antagonist Blockade During Sustained-Re/ease Naltrexone Treatment,
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`Addition 2010;105(9): 1633-39 (attached at Tab 3).
`
`To assess equivalence during the hydration and sustained release phases, FDA should
`
`recommend the use of a partial AUG measurement directed toward those phases, such as partial
`
`Page 14 of 19
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`Comment to Bioequivalence Recommendations
`Page 15 of 19
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`AUC from the population median T max until the last measured time point.
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`If a proposed generic of
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`Vivitrol releases naltrexone at a different rate, or to a different extent, during either of these release
`
`phases, the risk of patients suffering relapse, life-threatening opioid intoxication, overdose, or
`
`withdrawal symptoms will be different.
`
`In summary, Alkermes recommends that guidance naltrexone IM injection specify the use of
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`the following additional parameters in a single dose study:
`
`• The partial AUC from dosing until the population median T max of the reference drug. This
`
`will ensure that any proposed generic product releases a sufficient amount of drug during
`
`the initial phase to provide adequate efficacy during what is a critical time for patients. It
`
`will also protect against an excessive drug release that may put patients at risk of
`
`adverse events or reduce the amount of drug available during the subsequent release
`
`phases.
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`• The partial AUC from the population median T max of the reference drug until the last
`
`measured time point. This will ensure that any proposed generic product does not
`
`release a different amount of drug than Vivitrol during the hydration and sustained
`
`release phases, putting patients at risk of relaps