`
`raeg
`
`2 SC%
`ue“wae
`
`FDA CENTER FOR DRUG EVALUATION AND RESEARCH
`DIVISION OF ANESTHETICS, CRITICAL CARE, AND ADDICTION DRUG PRODUCT:Ss
`
`HAFD-170, Room 9B-45, 5600 Fishers Lane, Rockville MD 20857
`Tel:(301) 827-7410
`
`MEMORANDUM
`
`to:
`
`John K. Jenkins, MD
`Director,
`Office ofDrug Evaluation I
`
`Division File: NDA # 21-038
`
`from: CynthiaG.McCormick,MD
`
`. Director, Division ofAnestheticY Critical Care
`Products
`
`ie
`
`dnd Addiction Drug
`
`|
`
`subject: Dexmedetomidine NDA
`
`date: November 30, 1999
`
`-
`
`This memorandum summarizesforthefile the basis for the approval action recommended
`by the Division of Anesthetics, Critical Care, and Addiction Drug Products for NDA #21-
`038, Dexmedetomedine HCIfor Injection, a sedative/hypnotic agent intended foruse in
`the intensivecare setting.
`ee
`
`Background
`Dexmedetomidineis the dextro-enantiomer of the racemic mixture, medetomidine! and a
`selective-2-adrenoreceptor agonist. It has been shown in standard animal models of
`efficacy to have anxiolytic activity (0.3-2.0 jig/kg IV), analgesic activity (3-6 g/kg IV),
`and sedative properties (10-30 g/kg IV) in a dose-related manner in mice, rats and dogs.
`Dexmedetomidine was developed in humans primarily for its sedative properties and was
`studied as a sedative in the intensive care setting, delivered by continuousintravenous
`infusion.
`
`It was anticipated that dexmedetomidine would provide effects similar to those of
`clonidine, also an «-2-adrenergic agonist which has been used as an anesthetic adjuvant
`producing analgesia and sedation, and purported to decrease anesthetic requirements and
`
`* Medetomidineis aveterinary sedativewidely availableinEuropeand approved intheUS
`
`in 1997.
`
`Petition for Inter Partes Review of US 8,242,158
`Amneal Pharmaceuticals LLC — Exhibit 1013 — Page1
`
`

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`
`Petition for Inter Partes Review of US 8,242,158
`Amneal Pharmaceuticals LLC – Exhibit 1013 – Page 2
`
`

`

`Midazolam use as rescue medication during intubation (ITT)
`Study W97-245
`PBO
`Dexmedetomidine
`
`-
`Mean total dose (mg) of midazolam
`
`N=175
`18.6 mg
`
`- .-N=178
`4.8 mg
`
`p-value
`
`0.0011*
`
`Categorized midazolam use
`#ptsused
`ls,
`
`108 (61%)
`43(25%)
`Omg
`36(20%)
`34 (19%)
`0-4 mg
`34 (19%
`98 (56%
`>4m
`* ANOVA model with rx and ctr. **Chi-square( after J.Ma’s table 3.2, review, p.5)
`
`.
`<0.001**
`
`In study W97-246, 198 patients were randomized to the placebo arm and 203patients
`were randomized to receive dexmedetomidine by intravenousinfusion at doses of 0.4
`ukg/hr (with allowed adjustment between 0.2 and 0.7 j:g/kg/hr) following an initial bolus
`of 6 ug/kg IV. Patients were allowed to receive propofol as needed to maintain a
`Ramsay sedation score of 23. In addition, morphinesulfate could be administered as an
`analgesic as needed. The primary outcome measurefor this study was the total amount of
`rescue medication (propofol) needed to maintain sedation as specified while intubated.
`There wasastatistically 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 numberofpatients in the déxmedetomidine group (66%) compared to
`the placebo group (24%) maintained a Ramsay sedation score of 23 without any
`additional propofol rescue.
`
`-
`
`Midazolam use as rescue medication during intubation (ITT)
`Study W97-246
`PBO
`Dexmedetomidine
`
`p-value
`
`Mean total dose (mg) of propofol
`
`.
`
`N=198
`513 mg
`
`N=203
`72 mg
`
`<0.0001*
`
`
`
`Categorized propofol use
`# pts used
`
`122 (60%)
`47(24%)
`Omg
`43 (21%)
`30(15%)
`0-S0mg
`38 (19%)
`__121 (61%)
`>50 mg
`* ANOVA modelwith rx and ctr. **Chi-square (after J.Ma’s table 3.5, review, p.9)
`
`<0.001**
`
`.
`
`For both studies, the time to extubation was measured and analyzed, and foundto be,
`based on a very conservative approach, notsignificantly different between groups. For
`more detail,Dr. Jonathan Ma’s analysis p.10-11 should be referenced.
`In addition the
`
`NDA#21-038-Dexmedetomidine HCl
`
`,
`
`Page 3 of 10
`
`Petition for Inter Partes Review of US 8,242,158
`Amneal Pharmaceuticals LLC — Exhibit 1013 — Page 3
`
`
`

`

`
`
`amount of morphine used for analgesia in both studies was found to besignificantly
`greater in the control group. These are both importantfindings combined with the
`primary analysis, since they establish that the treatment group did not succeed based on
`the sedation afforded by morphinesulfate 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 manycases 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 between the two randomized groupsin both
`studies, the percentage of patients who received only dexmedetomidine and who required
`no rescue medication, confirmingits efficacy as monotherapyin twotrials.
`
`The primary review team and Dr.Rappaport have carefully reviewed thesetrials. Thereis
`nothing to add to the Medical and Statistical analyses and I concur with their conclusions
`that these studies, while somewhat uniquein their design, clearly establish that
`dexmedetomidine is an effective sedative when administered by intravenousinfusion at
`doses of 0.4 i/kg/hr (with allowed adjustment between 0.2 and 0.7 g/kg/hr) following an
`initial bolus of 6 pg/kg IV.
`
`Safety
`Nonclinical
`Nosignificant 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 studies. The genesis of the hepatotoxicity
`has not been characterized as to whetherit is correlated with parent compoundor any
`specific metabolite. While there appears to be an adequate safety margin in dosing, the
`contribution ofa 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 dose.of 80 pg/ke/dose S.C., but after one week oftreatment with 3 19/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 further elaborated concurrently with human trials evaluating the safety oflong-
`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 of imidazole nitrogen) and absent in the
`rat and dog, were neverstudied in animals. Because it is projected that this product will be
`used in ICU for longer than 24 hrs of infusion, the potential toxicity ofthese human
`metabolites should be evaluated. This should be done as a Phase 4 study of long-term
`
`NDA #21-038 Dexmedetomidine HCl
`
`,
`
`Page 4 of 10
`
`-
`
`Petition for Inter Partes Review of US 8,242,158
`Amneal Pharmaceuticals LLC — Exhibit 1013 — Page 4
`
`

`

`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. Howeverfetal
`toxicity was observed in rats, evidenced by increased postimplantation losses and reduced
`numberoflive pupsper litter. Prenatal and postnatal effects included reduced pup body
`weights during andafter nursing and delayed motor development. Placental transfer of
`dexmedetomidine was observed in rats.
`
`Dexmedetomidine was not mutagenic in theAmestest or the mouse lymphomaassay.It
`was shown to be clastogenicin both the in vitro human lymphocytes chromosomal
`aberration assay in the presence of metabolic activation and 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 database 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 andless than 16 hours. The
`dose and duration of exposure provide sufficient experienceto be able to assess the safety
`ofthis product for the proposed duration of up to 24 hours infusion.
`
`
`
`-
`
`There was also limited exposure (78 patients) who received infusion longer than 24 hours
`with the longest infusion lasting between 30-40 hoursin 2 patients.
`
`The deaths and serious adverse events reported were not unexpected for the ICU
`population understudyin this NDAeitherin quality or in quantity.
`
`In the placebo-controlled infusion studies in Phase 2-3, the only commonly reported
`adverse events observed in more than 1% ofpatients treated with dexmedetomidine and
`occurring with a frequency more than 2-fold that of the placebo were predictably
`hypotension (22%) , hypertension (12%) , and bradycardia (5%).
`
`
`
`NDA#21-038-Dexmedetomidine HCI
`
`Page 5 of 10
`
`Petition for Inter Partes Review of US 8,242,158
`Amneal Pharmaceuticals LLC — Exhibit 1013 — Page 5
`
`

`

`Adverse Event
`
`aeee
`Summary ofTreatment-Emergent Adverse Events Occurring in >1% of Dexmedetomidinepatients in
`Phase IVI Continuous Infusion ICU Sedation Studies*
`Placebo
`Randomized dexmedetomidine
`=379
`(N=387)
`16 (4%)
`84 (22%)* - .--
`Hypotension
`24 (6%)
`47 (12%)*
`Hypertension
`6(2%)
`20 (5%)*
`Bradycardia
`4 (1%).
`13 (3%)
`Mouth Dry
`20 (5%)
`16 (4%)
`Nausea
`*Statistically significant difference between randomized dexmedetomidine and placebo patients p<0.05
`Data source 2.2.5.5
`
`-
`
`Abnormal laboratory findings, which might have beenanticipated from thepreclinical
`studies, such as elevated LFTs and glycosuria, were not borne outin laboratory testing.
`
`There are no safety data in pediatric patients. The sponsorwill be required to studythis
`product in children from birth to 16 years of age as a Phase 4 commitment.
`
`Approximately 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 undertakenin an effort to assess whether dosage adjustment may be
`neededin the very elderly patients based on anticipated PD differences associated with
`sedative agents.
`
`
`
`AbusePotential ~
`
`
`
`Dexmedetomidine might be expected, based onits clinical pharmacological effects and its
`similarity to clonidine’, to have some abuse liability. Indeed animal studies indicate that
`there are some reinforcing properties. Reinforcing behaviorin primates was elicited by
`dexmedetomidine 1.0 t1g/kg/dose >saline and equivalentto saline at 0.0625 pg/kg/dose.
`At a dose of 0.25 j1g/kg/dose dexmedetomidine produced reinforcing behavior comparable
`to pentazocine (CIV). Dexmedetomidine also has been shown to attenuate morphine
`withdrawal}suggestive 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.
`
`? Afler Sponsor’s Table 21 ISS 8/10-239-65
`> Clonidineis not currently controlled in the CSA. There have been reports ofabuse with
`clonidine, mostly of reports of opiate addicts using clonidine to suppress withdrawal
`symptoms rather than forits psychotropiceffects.
`
`NDA#21-038Dexmedetomidine HCI
`
`,
`
`Page 6 of 10
`
`Petition for Inter Partes Review of US 8,242,158
`Amneal Pharmaceuticals LLC — Exhibit 1013 — Page 6
`
`

`

`Onbalance, the available studies suggest an abuse potential lower than some products
`controlled in schedule IV or as lowas somenotcontrolled 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 abuse. Furthermoretheclinical setting in whichit will be used, limited to
`hospital intensive care units, reduces that potential. Continued vigilanceis indicated,
`nevertheless, for any actual diversion and abuse that might occur in the post approval
`setting, so that appropriate measurescan be taken to controlthis substance if needed. -
`There have beento date no reports of diversion or abuse ofmedetomidine approved in
`1997.
`
`”
`Biopharmaceutics
`The ADME ofdexmedetomidine has beenfairly 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 of 34%) 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.
`Dexmedetomidineis about 94% protein-bound.
`~
`
`Evaluation of dexmedetomidinein 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 dexmedetomidineis
`infused continuously, particularly for-long periodsof time. The bulk ofelifnination of
`metabolites is thought to be renal. Therefore, this information should be obtained in Phase
`4 in anticipation of more prolongedinfusion 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 impairmentwill be
`included inthe packageinsert.
`
`There was no effect of age on the pharmacokinetics of dexmedetomidine, although only
`20 elderly volunteers, ranging from 66 to 83 years (mean, 72) were evaluated. The
`possibility ofpharmacodynamicdifferences 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 #21-038Dexmedetomidine HCl
`
`-
`
`Page 7 of 10
`
`Petition for Inter Partes Review of US 8,242,158
`Amneal Pharmaceuticals LLC — Exhibit 1013 — Page 7
`
`

`

`
`
`Interaction studies with a spectrum of anesthetics in vivo such as alfentail, midazolam,
`_. propofolandisoflurane did notindicate interactions when added to dexmedetomidine or
`to alfentail, midazolam, propofol or rocuronium when dexmedetomidine was added.
`
`Chemistry and Manufacturing
`Dexmedetomidineis the dextro-enantiomer of medetomidine (4-[1-(2,3-
`dimethylphenyl)ethyl]-1H-imidazole hydrochloride) andit 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-enantiomerlimited to <1%)
`have all been judged acceptable. Stability data on the bulk drug substance and regulatory
`specifications were also deemed acceptable.
`
`_
`
`R=————$—$——
`
`a
`
`
`
`The drug product is a sterile aqueous solution of dexmedetomidine tor intravenous
`infusion uponfurther dilution. The formulation consists of dexmedetomidine HCI (the
`active ingredient) and sodium chloride and waterfor injection. The drug product is
`prepared using standard methods, has undergonestability 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 ofthe drug product is achieved throughaseptic 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 whichit is stable for24 hours.
`
`Compatibility data are provided with commonly used IV solutions, drugs (vasoactive
`agents, musclerelaxants, 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:
`A suitable trade namehas notyet been selected for the drug product to which the Agency
`
`agrees.
`
`Data Integrity
`All questionsrelated 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. DSIinspections were conducted, and aside
`from somereports ofcareless errors in recordkeeping there was no evidence to suggest
`
`
`
`NDA #21-038Dexmedetomidine HCl
`
`Page 8 of 10
`
`Petition for Inter Partes Review of US 8,242,158
`Amneal Pharmaceuticals LLC — Exhibit 1013 — Page 8
`
`
`

`

`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
`approveit for ICU sedation by continuousinfusion for 24 hours. It is anticipated that
`there will be increasing demand for more prolongeduse 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 veryelderly >75 years should also be generated.or existing data analyzed.
`Oncethe 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 DEAreports.
`
`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 sponsorin an effort
`to obtain safety data in more extended ICU infusion, in pediatric patients and in the
`elderly.
`
`~
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`'
`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 HPA axis.
`2. A-second study should evaluate changes in drug metabolism following two
`weeks ofinfusion.
`3:A’third study should evaluate the potential toxicity of human major metabolites
`which are absentin 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 developmentplan 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 dexmedetomidinein very elderly patients, as has been described with
`other sedative/hypnotic drug products.
`3. Lenger-term infusion studies should include safety and pharmacokinetics.
`
`NDA #21-038 Dexmedetomidine HCl
`
`Page 9 of 10
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`Petition for Inter Partes Review of US 8,242,158
`Amneal Pharmaceuticals LLC — Exhibit 1013 — Page 9
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`Petition for Inter Partes Review of US 8,242,158
`Amneal Pharmaceuticals LLC – Exhibit 1013 – Page 10
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