FDA CENTER FOR DRUG EVALUATION AND RESEARCH
`DIVISION OF ANES'I'HETICS, CRITICAL CARE, AND ADDICTION DRUG PRODUCTS
`
`HFD-I 70, Room 98-45, 5600 Fishers Lane, Rockville MD 2085 7
`
`Tel:(301) 827-7410
`
`MEMORANDUM
`
`John K. Jenkins, MD
`Director,
`Ofice of Dmg‘Evaluation II
`
`Division File: NDA # 21-038
`
`. CynthiaG. McCormick,MD
`
`. Director, Division ofAnestheticé,’ Critical Care
`Products
`
`d Addiction Drug
`
`
`
`Background
`Dexmedetomidine is the dextro-enantiomer of the racemic mixture, medetomidinel and a
`selectivea-l—adrenoreceptor agonist. It has been shown in standard animal models of
`eficacy to have anxiolytic activity (0.3.2.0 rig/kg IV), analgesic activity (3-6 rig/kg IV),
`and sedative properties (IO-30 ug/kg IV) in a dose-related manner in mice, rats and dogs.
`DemEdetofiiidine was developed in humans primarily for its sedative properties and was
`studied as a sedative in the intensive care setting, delivered by continuous intravenous
`infiision.
`
`subject: Dexmedetomidine NDA
`
`date: November 30, 1999
`
`This memorandum summarizes for the file the basis for the approval action recommended
`by the Division of Anesthetics,'CriticaIl cm," and Addiction Drug Products for NBA #21-
`03 8, Dexmedetomedine HCl for Injection, a sedative/hypnotic agent intended for use in
`the intensive care setting.
`'
`'
`i
`"
`
`It was anticipated that dexmedetomidine would provide efi‘ects similar to those of
`clonidine, also an or-Z-adrenergic agonist which has been used as an anesthetic adjuvant
`producing analgesia and sedation, and purported to decrease anesthetic requirements and
`
`‘ Medetomidine is a veterinary sedative widely available in Europe and approved in the US
`in 1997.
`’
`;
`
`Petition for Inter Partes Review of US 8,242,158
`Amneal Pharmaceuticals LLC — Exhibit 1013 — Page 1
`
`

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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 (I'I'l')
`Stud WSW-245
`
`PBO
`
`Dennedetomidine
`
`p-value
`
`~
`
`N=l75
`
`- - --N=l78
`
`Mean total dose (mg) of midazolam
`
`18.6 mg
`
`4.8 mg
`
`0.0011‘
`
`Categorized midazolarn use
`# pts used
`..
`-.
`.
`
`108 (61%)
`43(25%)
`0mg
`36(20%)
`34 (19%)'
`0-4 mg
`34 99%)
`98 (56%)
`>4 mg
`‘ 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 203 patients
`were randomized to receive dexmedetomidine by intravenous infusion at doses of 0.4
`pkg/hr (with allowed adjustment between 0.2 and 0.7 ug/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, 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 démedetomidine group (66%) compared to
`the placebo group (24%) maintained a Rainsay sedation score of 23 without any
`additional propofol rescue.
`
`
`"
`
`Midazolam use as rescue medication during intubation (ITT)
`Study Win-246
`PBO
`Dexmedetomidine
`
`p-value
`
`Mean total
`
`(mg) of propofol
`
`_
`
`513 mg
`
`N=l98
`
`N-203
`
`72 mg
`
`Categorized propofol use
`# pts used
`
`.
`
`0mg
`0-50 mg
`
`470.4%)
`30 (15%)
`
`122 (60%)
`43 (21%)
`
`<D.0001‘
`
`<0.001“
`
`‘ ANOVA model with m and ctr. “Chi-square (after J.Ma’s table 3.5, review, p.9)
`
`For both studies, the time to extubation was measured and analyzed, and found to be,
`based on a very conservative approach, not significantly difi'erent between groups. For
`more detailipr. Jonathan Ma’s analysis p. 10-11 should be referenced.
`In addition the
`
`NDA azi-oaabmedmmidinc 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 be significantly
`greater in the control group. These are both important findings combined with the
`primary analysis, since they establish that the treatment group did not succeed based on
`the sedation afl'ordcd 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 between the two randomized groups in both
`studies, the percentage‘of patients who received only dexmedetomidine and who required
`no rescue medication, confirming its emcacy as monotherapy in two trials;
`
`The primary review team and DrRappaport 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
`dexrnedetomidine is an efi‘ective sedative when administered by intravenous infusion at
`doses of 0.4 u/kyhr (with allowed adjustment between 0.2 and 0.7 ug/kg/hr) following an
`initial bolus of 6 ug/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 studies. 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 difi'erent human metabolic profile may theoretically alter the toxicity of
`this compound with chronic dosing in humans. This bears further evaluation.
`
`-
`
`Dexmedetomidine had no efi‘ect on ACTH-stimulated cortisol release in dogs given just a
`single dgsesof 80 ug/kg/dose S.C., but after one week of treatment with 3. ug/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
`shouldbe further elaborated concurrently with human trials evaluating the safety of long-
`term infusion.
`-
`
`The nonclinical phamacolcinetics of dexmedetomidine are similar to humans with the
`exception of metabolism, which difi‘crs 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 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 ofthese human
`metabolites should be evaluated. This should be done as a Phase 4 study of long-term
`
`um «21-033 minim nor
`
`‘
`
`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. However fetal
`toxicity was observed in rats, evidenced by increased postimplantation losses and reduced
`number of live pups per litter. Prenatal and postnatal efl‘ects 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 and in in viva mouse micronucleus
`assay. .A
`
`Carcinogenicity testing was considered unnecessary due to the projected short-term use of
`this product.
`
`
`
`gzlinical
`_
`_
`The safety data for this NDA was combined fi'om 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
`infirsion. The bulk of exposure was in the range of 4.6 mg/kg and 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 patients) who received infusion longer than 24 hours
`with the longest infirsion 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 placebo-controlled infusion studies in Phase 2-3, the only commonly reported
`adverse events observed in more than 1% of patients treated with demedetomidine and
`occurring with a fi'equency more than 2-fold that of the placebo were predictably
`hypotension (22%) , hypertension (12%) , and bradycardia (5%).
`
`NDA #2 l-O380exmedetomidine HCl
`
`.
`
`Page 5 of 10
`
`Petition for Inter Partes Review of US 8,242,158
`Amneal Pharmaceuticals LLC — Exhibit 1013 — Page 5
`
`

`

`Summary of Tmunent-Ernergent Adverse Events Occurring in >1% of Dexmedetomidine patients in
`Phase mm Continuous Infusion ICU Sedation Studies’
`Randomized dexmedetomidine
`
`Adverse Event
`
`Placebo
`
`
`
`.
`~
`A _b_use Potentigl
`Dexmedetomidine might be expected, based on its clinical pharmacological efl'ects and its
`similarity to clonidine’, to have some abuse liability. Indeed animal studies indicate that
`there are some reinforcing properties. Reinforcing behavior in primates was elicited by
`demedetomidine 1.0 ug/kg/dose >saline and equivalent to saline at 0.0625 ug/kg/dose.
`At a dose of 0.25 ug/kydose dexmedetomidine produced reinforcing behavior comparable
`to pentazocine (CIV). Dexmedetomidine also has been shown to attenuate morphine
`withdraWalfsuggestive but not conclusive evidence for dependence liability. A mild
`withdrawal syndrome has been described in rodents atter 7 days of treatment.
`
`-’
`
`=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 difi'erence between randomized dexmedetomidine and placebo patients ps0.05
`Data source 2.2.5.5
`
`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.
`
`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 undertaken in an efl‘ort to assess whether dosage adjustment may be
`needed in the very elderly patients based on anticipated PD difi‘erences associated with
`sedative agents.
`
`Extensive receptor binding studies using standard radioligands were presented in the
`NDA, demonstrating very high afinity for the o-adrenergic receptors andmoderate
`afiinity for the serotonergic receptors. Binding at the opiate receptors was negligible.
`Comparative binding to relevant controlled substances was not provided.
`
`'
`
`'
`
`3 After Sponsor’s Table 21 188 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 efi‘ects.
`
`NDA #21-03&Dexinedetornidine HCJ
`
`‘
`
`Page 6 of 10
`
`Petition for Inter Partes Review of US 8,242,158
`Amneal Pharmaceuticals LLc — Exhibit 1013 — Page 6
`
`

`

`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 abuse. Furthermore the clinical setting in which it will be used, limited to
`hospital intensive care units, reduces that potentia'lf 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 been to date no reports of diversion or abuse of medetomidine approved in
`1997.
`"
`
`Evaluation of dcxmedetomidine 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 dexrnedetomidine is
`infiised 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 insuficiency.
`
`Hepatic impairment affected the PK of dexmedetornidine 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 efi‘ect of age on the pharmacokinetics of dexrnedetomidine, although only
`20 elderly volunteers, ranging from 66 to 83 years (mean, 72) were evaluated. The
`possibility of pharmacodynamic difi'erences 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.
`
`' f:
`Biapharmaceua'a
`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. Biotransofonnation 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.
`Dexmedetomidine is about 94% preteinébound.
`‘
`
`
`
`NDA azr-osa- HCI
`
`Page 7 of 10
`
`Petition for Inter Partes Review of US 8,242,158
`Amneal Pharmaceuticals LLC — Exhibit 1013 — Page 7
`
`

`

`The drug product is a sterile aqueous solution of demedetonudine for intravenous
`infusion upon fitrther 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?
`
`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
`
`Interaction studies with a spectrum of anesthetics in viva such as alfentail, midazolam,
`__ propofol and isoflurane did not indicate interactions when added to dexmedetomidine or
`to alfentail, midazolarn, propofol or rocuronium when dexmedetomidine was added.
`
`Chemistry and Manufacturing
`Dexmedetornidine is the dextro-enantiomer of medetornidine (4-[1-(2,3-
`dimethylphenyl)ethyl]-lH-imidazole hydrochloride) 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:
`
`~—
`
`.f
`
`NDA #21-038_Deranedetomidine BC!
`
`'
`
`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.
`‘
`
`_
`Commas:
`There is adequate evidence to support the emcacy and safety of dexrnedetornidine to
`approve it for ICU sedation by continuous infusion for 24 hours. It is anticipated that
`there will be indreasing demand for more prolonged 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 datashould be obtained for safe use at the extremes of age—pediatric dosing,
`pharmacokinetics and safety should be obtained. Geriatric phannacodynamic/safety data
`in the very_elderly >75 years should also be generatedror existing data analyzed.
`
`Once 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.
`‘
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`Phase 4 Commith
`
`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 effort
`to obtain safety data in more extended ICU infusion, in pediatric patients and in the
`elderly.
`
`Nonclinical studie;
`l. A two-week study in dogs with a'2-week recovery phase should evaluate general
`toxicology of prolonged infusion of dexrnedetomidine and the efi‘ect of chronic
`infusion on HPA axis.
`
`2. A second study should evaluate changes in drug metabolism following two
`weeks of infirsion.
`
`37‘A‘t‘third study should evaluate the potential toxicity of human major metabolites
`which are absent in rats and dogs.
`'
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`
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`‘
`gzlinicai hXmaiies
`1. Pediatrics: Studies to obtain an indication for sedation in pediatric patients fiom
`birth to 16 years of age in the ICU setting. The development plan should include
`pharmacoldnetics and safety in pediatric patients fi'om birth to .16 years, and
`eficacy data designed at determining appropriate dosage regimens.
`. Geriatrics: Further studies are needed to evaluate the safety v. difi‘erential
`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 phannacokinetics.
`
`NDA #21-038Deranedetomidine KC]
`
`'
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`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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