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`
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`
`FDA CENTER FOR DRUG Ev ALUATION AND RESEARCH
`m
`DIVISION OF .A,rIBSTIIETICS, CRITICAL CARE, AND ADDICTION DRUG PRODUCTS
`
`HFD-170, Room 9B-45, 5600 Fishers Lane, Rockville MD 20857
`Tel:(301) 827-7410
`
`:MEMORANDUM
`John K. Jenkins, MD
`to:
`_ . Director,
`Office of Drug Evaluation Il
`
`...
`
`Division File: NOA# 21-038
`
`. \ C:, \
`from: Cynthia G. McCormick, MD
`Director, Division of Anestheticf. Critical Care dnd Addiction Drug
`Products
`
`subject: Dexmedetomidine NDA
`
`date: November 30, 1999
`
`This memorandum summarizes for the file the basis for the approval actiop recommended
`by the Division of Anesthetics,.Critical.Care, and Addiction Drug Products for NOA #21-
`03 8, Dexmedetomedine HCl for Injection, a sedative/hypnotic agent intended for use in
`the intensive care setting.
`· ·
`·
`·
`
`Background
`Dexmedetomidine is the dextro-enantiomer of the racemic mixture, medetomidine1 and a
`selectivo-.s.-.2.-adrenoreceptor agonist. It has been shown in standard animal models of
`efficacy to have anxiolytic activity (0.3-2.0 µg/kg IV), analgesic activity (3-6 µg/kg IV),
`and :;edativeproperties (10.-30 µg/kg IV) in a dose-related manner in mice, rats and dogs.
`Dexmedetoriiidine was developed in humans primarily for its sedative properties and was
`studied as a sedative in the intensive care setting, delivered by continuous intravenous
`infusion.
`
`It was anticipated that dexmedetomidine would provide effects similar to those of
`clonidine, also an cx-2-adrenergic agonist which has been used as an anesthetic adjuvant
`producing analgesia and sedation, ar.d purported to decrease anesthetic requirements and
`
`1 Medetomigµie is a veterinary sedative widely available in Europe and approved in the US
`in 1997.
`
`Petition for Inter Partes Review of US 8,648,106
`Amneal Pharmaceuticals LLC – Exhibit 1013 – Page 1
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`

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`improve hemodynamic stability. The theoretical basis for the use of the cx-2-adrenergic
`-agonists as adjunctive medications is that they are thought to act as neuromodulators,
`regulating central (medullary) cardiovascular or peripheral vasomotor responses such as
`those to anesthetics, thus producing an anesthetic-sparing effect. These effects were not
`specifically characterized for approval purposes, although some exploratory studies were
`undertaken during early development.
`
`A unique feature of dexmedetomidine as a sedative which was observed in phase I studies
`was its property of providing adequate sedation but with ease of alerting and without
`persisting central effects, once the patient is _aroused.
`
`Efficacy
`The Sponsor submitted two adequate and well-controliCd studies of similar design in
`support of the proposed indication for sedation. The studies were randomized, double
`blind, double-dummy parallel group multicenter trials comparing the effects of
`dexmedetomidine infusion with placebo. The trials evaluated the sedative· properties of
`dexmedetomidine and control by inference, that is, they compared the amount of rescue
`medication (midazolam in one trial and propofol in the second) required to achieve a
`specified level of sedation (by the standardized Ramsay sedation scale) between the
`placebo and treatment group from onset to extubation. There were a number of
`potentially confounding variables that were assessed as secondary outcome measures,
`particularly time to extubation and amount of morphine used for analgesia.
`
`In study W97-245, 175 patients were randomized to the placebo arm and 178 patients
`were randomized to receive dexmedetomidine by intravenous infusion at doses of0.4
`µ/kg/hr (with allowed adjustment between 0.2 ll!ld 0. 7 µg/kg/hr) following an initial bolus
`of 6 µg/kg IV. Patients were allowed to receive midazolam as needed to maintain a
`Ramsay sedation score of~- In addition, .morphine sulfate could be administered as an
`analgesic as needed. The primary outcome measure for this study was the total amount of
`rescue medication (midazolam) needed to maintain sedation as specified while intubated.
`There was a statistically significantly greater use of midazolam in patients randomized to
`placebo than to dexmedetomidine during treatment.
`.--....:.::.
`·_>.._
`A second prospective primary analysis was undertaken at the request of the division to
`obtain a direet assessment of the sedative effects of dexmedetomidine, that is, a
`companso~·t,f the percentage of patients who were able to achieve a Ramsay sedation
`score of~ during intubation, without the use of additional rescue medication, between
`the dexmedetomidine and the placebo groups. It can be seen from the results reported in
`the table on the following page that a significantly greater number of patients in the
`dexmedetomidine group (61%) compared to the placebo group (25%) maintained a
`Ramsay sedation score of~ without any additional midazolam rescue.
`
`NDA #21..038-Dexmedetomidine HO
`
`Pagel of 10
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`Petition for Inter Partes Review of US 8,648,106
`Amneal Pharmaceuticals LLC – Exhibit 1013 – Page 2
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`

`

`Midazolam use as rescue medication during intubation (lT1')
`Study W97-245
`Dexmedetomidine
`PBO
`
`p-value
`
`Mean total dose (mg) of midazolam
`
`N=l75
`18.6 mg
`
`- . ·N=l78
`4.8mg
`
`Categorized midazolam use
`# pts used
`
`Omg
`108 (61%)
`43(25%)
`0-4 mg
`36(20%)
`34 (19%Y
`34 (19%)
`98 (56%)
`>4 mg
`• ANOVA model with rx and ctr ... Chi-square (after I.Ma's table 3.2, review, p.5)
`
`<0.001 ..
`
`In study W97-246, 198 patients were randomized to the placebo arm and 203 patients
`were randomized to receive dexmedetomidine by intravenous infusion at doses of0.4
`µkg/hr (with allowed adjustment between 0.2 and 0. 7 µg/kg/hr) following an initial bolus
`of6 µg/kg IV. Patients were allowed to receive propofol as needed to maintain a
`Ramsay sedation score of~. In addition, morphine sulfate could be administered as an
`analgesic as needed. The primary outcome measure for this study was the total amount of
`rescue medication (propofol) needed to maintain sedation as specified while intubated.
`There was a statistically significantly greater use of propofol in patients randomized to
`placebo than to dexmedetomidine during treatment.
`
`The same prospective primary analysis that was performed in study W97-245 was also
`performed in this study. It can be seen from the results reported in the table below that a
`significantly greater number of patients in the dexmedetomidine group ( 60%) compared to
`the placebo group (24%) maintained a Ramsay sedation score of~ without any
`additional propofol rescue.
`·
`
`Midazolam use as rescue medication during intubation (lT1')
`Study W97-246
`PBO
`Dexmedetomidine
`
`p-value
`
`N=l98
`513 mg
`
`N=203
`72mg
`
`<0.0001*
`
`Mean total~~ (mg) ofpropofol
`-
`Categorized propofol :use
`# pts used
`
`Omg
`122 (60%)
`47(24%)
`0-50 mg
`43 (21 %)
`30 (15%)
`>50 mg
`38 (190/o)
`121 (61%)
`• ANOVA model with rx and ctr ... Chi-square (after I.Ma's table 3.5, review, p.9)
`
`<0.001••
`
`For both studies, the time to extubation was measured and analyzed, and found to be,
`based on a yery conservative approach, not significantly different between groups. For
`In addition the
`more detail;Dr. Jonathan Ma's analysis p.10-11 should be referenced.
`
`NDA #21--038-Dexmedetomidine HO
`
`Pagel of 10
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`Petition for Inter Partes Review of US 8,648,106
`Amneal Pharmaceuticals LLC – Exhibit 1013 – Page 3
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`

`

`amount of morphine used for analgesia in both studies was found to be significantly
`greater in the control group. These are both impo.rtant findings combined with the
`primary analysis, since they establish that the treatment group did not succeed based on
`the sedation afforded by morphine sulfate or because of a longer time and therefore
`greater access to more medication.
`
`Dexmedetomidine is said to have been studied as adjunctive therapy insofar as rescue with
`a second agent was required in many cases to achieve the specified sedation, rather than
`increasing the infusion (and thus the dose) of dexmedetomidine as needed. Clearly it was
`the primary agent. The sponsor compared ~etween the two randomized groups in both
`studies, the percentage·ofpatients who received only dexmedetomidine and who required
`no rescue medication, confirming its efficacy as monotherapy in two trials:
`·
`....
`-
`The primary review team and Dr.Rappaport have carefully reviewed these trials. There is
`nothing to add to the Medical and Statistical analyses and I concur with their conclusions
`that these studies, while somewhat unique in their design, clearly establish that
`dexmedetomidine is an effective sedative when administered by intravenous infusion at
`doses of0.4 µ/kg/hr (with allowed adjustment between 0.2 and 0.7 µg/kg/hr) following an
`initial bolus of 6 µg/kg IV.
`
`Safety
`Nonclinical
`No significant animal toxicity was described in acute studies in rats or dogs. However,
`chronic dosing of up to 28 days in dogs and rats was associated with hepatic toxicity,
`specifically enlarged livers, eosinophilic inclusions in hepatocytes, and elevated LFTs.
`These changes were not observed in the acute ~dies. The genesis of the hepatotoxicity
`has not been characterized as to whether it is correlated with parent compound or any
`specific metabolite. While there appears to be an adequate safety margin in dosing, the
`contribution of a different human metabolic profile may theoretically alter the toxicity of
`this compound with chronic dosing in humans. This bears further evaluation.
`
`Dexmedetomidine had no effect on ACTH-stimulated cortisol release in dogs given just a
`single do_§~>9f80 µg/kg/dose S.C., but after one week of treatment with 3. µg/kg/hr, the
`ACTH-stimulated release of cortisol was reduced by 40%. This has implications on the
`hypothalamic-pituitary-adrenal axis with prolonged ICU treatment with this agent, and
`should "be farther elaborated concurrently with human trials evaluating the safety of long(cid:173)
`term infusion.
`
`The nonclinical pharmacokinetics of dexmedetomidine are similar to humans with the
`exception of metabolism, which differs by two major metabolites. The two major
`metabolites found in human (the 2 glucuronides ofimidazole nitrogen) and absent in the
`rat and dog, were never studied in animals. Because it is projected that this product will be
`used in ICU for longer than 24 hrs of infusion, the potential toxicity of these human
`metabolites should be evaluated. This should be done as a Phase 4 study of long-term
`
`NDA #21-038 Dexmedetomidine HO
`
`Page4 oflO
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`Amneal Pharmaceuticals LLC – Exhibit 1013 – Page 4
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`

`

`infusion in an appropriate animal species, either indirectly by administration to an animal
`species that does not produce these metabolites or in an animal species which produces
`the same metabolites.
`
`Dexmedetomidine was not shown to be teratogenic in rats ·or rabbits. However fetal
`toxicity was observed in rats, evidenced by increased postimplantation losses and reduced
`number of live pups per litter. Prenatal and postnatal effects included reduced pup body
`weights during and after nursing and delayed motor development. Placental transfer of
`dexmedetomidine was observed in rats.
`
`Dexmedetomidine was not mutagenic in the-Ames test or the mouse lymphoma assay. It
`was shown to be clastogenic in both the in vitro human lymphocytes chromosomal
`aberration assay in the presence of metabolic activation·~d in in vivo mouse micronucleus
`assay.-·
`
`Carcinogenicity testing was considered unnecessary due to the projected short-term use of
`this product.
`
`Clinical
`.
`.
`The safety data for this NDA was combined from two sources,·--
`Japanese original development program, and subsequent Abbott Laboratories data from
`· the more recent development. The safety databa5e of dexmedetomidine exposure includes
`3038 subjects, of whom 1473 were ICU patients who received the drug by continuous
`infusion. The bulk of exposure was in the range of 4-6 mg/kg ancl less than 16 hours. The
`dose and duration of exposure provide sufficient experience to be able to assess the safety
`of this product for the proposed duration of up to 24 hours infusion.
`
`There was also limited exposure (78 patie~ts) who received infusion longer than 24 hours
`with the longest infusion lasting between 30-40 hours in 2 patients.
`
`The deaths and serious adverse events reported were not unexpected for the ICU
`population under study in this NDA either in quality or in quantity.
`
`In the piace'5o-controlled infusion studies in Phase 2-3, the only commonly reported
`adverse events observed in more than 1 % of patients treated with dexmedetomidine and
`occufri.og with a frequency more than 2-fold that of the placebo were predictably
`hypotension (22%), hypertension (12%), and bradycardia (5%).
`
`NDA #21~3S-Dexmedetomidine HO
`
`Page 5of10
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`Amneal Pharmaceuticals LLC – Exhibit 1013 – Page 5
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`

`

`Adverse Event
`
`Summary of Treatment-Emergent Adverse Events Occurring in> 1% ofDexmedetomidine patients in
`Phase II/IIl Continuous Infusion ICU Sedation Studies2
`Placebo
`Randomized dexmedetomidine
`N=379
`(N=387)
`84 (22%)•
`16 (4%)
`Hypotension
`24 (6%)
`47 (12%)•
`Hypertension
`6(2%)
`20 (5%)•
`Bradycardia
`4 (1%).
`13 (3%)
`Mouth Dry
`.
`Nausea
`20 (5%)
`16 (4%)
`•Statistically sigrtmcant difrerence between randomiz.ed dexmedetomidine and placebo patients p:S;0.05
`Data source 2.2.S.S
`
`...
`Abnonnal laboratory findings, which might have been anticipated from the preclinical
`studies, such as elevated LFTs and glycosuria, were not borne out in laboratory testing.
`
`There are no safety data in pediatric patients. The sponsor will be required to study this
`product in children from birth to 16 years of age as a Phase 4 commitment.
`
`Appro~tely 500 patients over 65 years of age have been studied in this NDA An
`additional analysis of patients over 75 years has been requested of the sponsor with
`comparison of adverse events by age, separating the elderly by >65 to 75 and >75 years of
`age. This will be undertaken in an effort to assess whether dosage adjustment may be
`needed in the very elderly patients based on anticipated PD differences associated with
`sedative agents.
`
`Abuse Potential
`Dexmedetomidine might be expected, based on its clinical pharmacological effects and its
`
`similarity to clonidine3, to have some abuse liability. Indeed animal studies indicate that
`there are some reinforcing properties. Reinforcing behavior in primates was elicited by
`dexmedetomidine 1.0 µg/kg/dose >saline and equivalent to saline at 0.0625 µg/kg/dose.
`At a dose of0.25 µg/kg/dose dexmedetomidine produced reinforcing behavior comparable
`to pentazocine (CIV}. Dexmedetomidine also has been shown to attenuate morphine
`withdrawaP,~ggestive but not conclusive evidence for dependence liability. A mild
`withdrawal syndrome has been described in rodents after 7 days of treatment.
`-· ~,.:: .
`Extensive receptor binding studies using standard radioligands were presented in the
`NDA, demonstrating very high affinity for the a-adrenergic receptors and-moderate
`affinity for the serotonergic receptors. Binding at the opiate receptors was negligible.
`Comparative binding to relevant controlled substances was not provided.
`
`2 After Sponsor's Table 21 ISS 8/10-239-65
`3 Clonidine is not currently controlled in the CSA There have been reports of abuse with
`clonidine, mostly of reports of opiate addicts using clonidine to suppress withdrawal
`symptoms rather than for its psychotropic effects.
`
`NDA #21-038-Dexmcdetomidine HQ
`
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`'
`
`On balance, the available studies suggest an abuse potential lower than some products
`controlled in schedule IV or as low· as some not controlled at all. I do not agree with the
`controlled substances evaluation team that this product should not be scheduled due to
`lack of information, but rather that the available information suggests a rather low
`potential for abµse. Furthermore the clinical setting in which it will be used, limited to
`hospital intensive care units, reduces that potential.- Continued vigilance is indicated,
`nevertheless, for any actual diversion and abuse that might occur in the post approval
`setting, so that appropriate measures can be taken to control this substance if needed. ·
`There have b_een to date no reports of diversion or abuse of medetomidine approved in
`1997.
`
`. ..
`. _
`Biopharmaceutics
`The ADME of dexmedetomidine has been fairly well studied, but some unanswered
`questions remain that may be very relevant to long term infusion. For example, it is has
`been demonstrated that there is almost no accumulation of parent drug, following IV bolus
`administration, and that there is nearly complete biotransoformation. The fate of the
`metabolites, however, has not been well characterized. Biotransoformation includes direct
`N-glucuronidation (two major metabolites, total of34%) and CYP 2A6-mediated
`metabolism (three additional metabolites, 14%), and N-methylation (three metabolites,
`18% ). There are additional urinary metabolites that have not been identified yet.
`Dexmedetomidine is about 94% protein~bound. ·
`
`Evaluation of dexmedetomidine in patients with renal failure demonstrated no change in
`dexmedetomidine PK with severe renal failure following a single dose, but there is no
`information about the possible accumulation of metabolites when dexmedetomidine is
`infused continuously, particularly for-long periods of time. The bulk of elimination of
`metabolites is thought to be renal. Therefore, this information should be obtained in Phase
`4 in anticipation of more prolonged infusion in patients with renal insufficiency.
`
`Hepatic impairment affected the PK of dexmedetomidine as expected, and the appropriate
`adjustments for patients with mild, moderate and severe hepatic impairment will be
`included in the package insert.
`_ .... ~ -~>~ ..
`
`There was no effect of age on the pharmacokinetics of dexmedetomidine, although only
`20 eldes:Jy volunteers, ranging from 66 to 83 years (mean, 72) were evaluated. The
`possibility of pharmacodynamic differences increasing with increasing age were not
`examined, but should be looked at more closely in Phase 4, as sedative/hypnotics have a
`tendency to result in more significant safety problems (hypotension, confusion, respiratory
`depression) in the elderly. Dexmedetomidine has not been evaluated in the pediatric
`population.
`
`NDA #21-038'Dexmedetomidinc HO
`
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`- - - - - - - - - - - - - - - - - - - - - - - - -
`
`Interaction studies with a spectrum of anesthetics in vivo such as alfentail, midazolam,
`__ propofol and isoflurane did not indicate interactions when added to dexmedetomidine or
`to alfentail, midazolam, propofol or rocuronium when dexmedetomidine was added.
`
`Chemistry and Manufacturing
`Dexmedetomidine is the dextro-enantiomer ofmedetomidine (4-[1-(2,3-
`dimethylphenyl)ethyl]-lH-imidazole hydrochlonde) and it is manufactured by separation
`of the isomers from the racemic mixture. Preparation and characterization of the drug
`substance, levels of impurities including optical purity (levo-enantiomer limited to s 1 % )
`have all been. judged acceptable. Stability data on the bulk drug substance and regulatory
`specifications were also deemed acceptable:
`
`---------
`
`The drug product is a sterile aqueous solution of dexm~detomidine tor intravenous
`infusion upon further dilution. The formulation consists of dexmedetomidine HCl (the
`active ingredient) and sodium chloride and water for injection. The drug product is
`prepared using standard methods, has undergone stability testing (undiluted) under ICH
`storage conditions generating data to support a 2-year shelf life, and has been shown to be
`stable in light. Sterility of the drug product is achieved through aseptic fill and terminal
`sterilization by autoclave. The process and data have been reviewed by microbiology and
`found to be acceptable.
`
`The drug product is prepared for use by diluting it with sterile 0.9% sodium chloride
`solution for injection after which it is stable for ·24 hours.
`
`Compatibility data are provided with commonly used IV solutions, drugs (vasoactive
`agents, muscle relaxants, sedatives, narcotics and plasma substitute), tubing, and syringes
`commonly used for administration of IV drugs. It was observed that dexmedetomidine
`has the potential for adsorption onto certain types of natural rubber. This will be noted in
`the package insert, advising use with synthetic components or coated natural rubber -
`components:
`
`-·-~ • :i
`
`A suitable trade name has not yet been selected for the drug product to which the Agency
`agrees.
`
`Data Integrity
`All questions related to data integrity were resolved during the course of review and
`inspection, including questions about some unreported deaths, randomization errors and
`protocol violations that were not reported. DSI inspections were conducted, and aside
`from some reports of careless errors in recordkeeping there was no evidence to suggest
`
`NDA #21--038_Dexmedetomidine HCI
`
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`

`that the data on which the conclusions and recommendations for this NDA will be based
`have significant problems. ·
`
`Comments:
`There is adequate evidence to support the efficacy and safety of dexmedetomidine to
`approve it for ICU sedation by continuous infusion for 24 hours. It is anticipated that
`there will be increasing demand for more prolongea use of this product once it is
`approved. In addition to collecting additional safety data on prolonged use, there should
`be a better characterization of the activity, toxicity and fate of the metabolites ..
`
`Additional data should be obtained for safe use at the extremes of age-pediatric dosing,
`pharmacokinetics and safety should be obtained. Geriatric pharmacodynamic/safety data
`in the very elderly >75 years should also be generated-or existing data analyzed.
`
`Once the metabolic profile is better established with multiple dosing, its safety should be
`evaluated in patients with renal failure.
`
`Surveillance for possible diversion and abuse can be done through the existing mechanisms
`such as Medwatch, SAMHSA's DAWN database, and DEA reports.
`
`Phase 4 Commitments
`The focus of the dexmedetomidine development plan was short-term ICU sedation in
`adults. It is quite clear that this product will not have use limited to this population, and
`therefore the following phase 4 commitments will be requested of the sponsor in an effon
`to obtain safety data in more extended ICU infusion, in pediatric patients and in the
`elderly.
`
`Nonclinical studies
`1. A two-week study in dogs with a ·2-week recovery phase should evaluate general
`toxicology of prolonged infusion of dexmedetomidine and the effect of chronic
`infusion on HP A axis.
`2. A second study should evaluate changes in drug metabolism following two
`weeks of infusion.
`3:-.:..::.A~third study should evaluate the potential toxicity of human major metabolites
`whi~h are absent in rats and dogs.
`·
`-·.
`.
`Clinical Studies
`1. Pediatrics: Studies to obtain an indication for sedation in pediatric patients from
`birth to 16 years of age in the ICU setting. The development plan should include
`pharmacokinetics and safety in pediatric patients from birth to .16 years, and
`efficacy data designed at determining appropriate dosage regimens.
`2. Geriatrics: Further studies are needed to evaluate the safety v. differential
`toxicity of dexmedetomidine in very elderly patients, as has been described with
`other sedative/hypnotic drug products.
`3. Longer-term infusion studies should include safety and pharmacokinetics.
`
`NDA #21..038Dexmedetomicline HCI
`
`Page 9ofl0
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`Amneal Pharmaceuticals LLC – Exhibit 1013 – Page 9
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`

`4. Renal Impairment: Additional data are needed to examine the potential
`accumulation of dexmedetomidine metabolites upon continuous infusion in
`patients with renal impairment.
`
`It is expected that a reasonable timeline for submission of the protocols might be
`approximately.6 months from approval; and co~~~etion of these studies, approximately 2
`years.
`
`Recommended Action: Approval of dexmedetomidine HCl as an adjunctive _J1ledication
`for ICU sedation.
`
`. ..
`
`APPEARS THIS WAY
`ON ORIGINAL
`
`-..
`
`.........
`
`- -.:
`
`-
`NOA #21~38 Dexmedetomidine HO
`
`Page 10 oflO
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`Petition for Inter Partes Review of US 8,648,106
`Amneal Pharmaceuticals LLC – Exhibit 1013 – Page 10
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`