rFNTF.R FOR nunc FVAT TTATTON AND RFSFARPH
`
`Application Number
`
`£1-038
`
`FINAL PRTNTRD T ABFI TNC
`
`Petition for Inter Partes Review of US 8,338,470
`Amneal Pharmaceuticals LLC – Exhibit 1009 – Page i
`
`

`

`Dexmedetomidine HC1
`Draft Labeling
`PRECEDEX™
`DEXMEDETOMIDINE HYDROCHLORIDE Injection
`
`DEC 1 7 1999
`
`December 17, 1999
`1
`
`DESCRIPTION
`PRECEDEX™ (dexmedetomidine hydrochloride injection) is a sterile, nonpyrogenic
`solution suitable for intravenous infusion following dilution. Dexmedetomidine
`hydrochloride is the S-enantiomer of medetomidine and is chemically described as (+)-4-
`. (S)-[l-(2,3-dimethylphenyl)ethyl]-lH-imidazole monohydrochloride. Dexmedetomidine
`has a molecular weight of 236.7. The empirical formula is
`• HC1 and the
`structural formula is:
`
`CH3
`
`CH3
`
`<
`NH
`
`H
`
`CHj
`
`•HCI
`
`Dexmedetomidine hydrochloride is a white or almost white powder that is freely soluble
`in water and has a pKa of 7.1. Its partition coefficient in-octanol:water at pH 7.4 is 2.89.
`PRECEDEX is supplied as a clear, colorless, isotonic solution with a pH of 4.5 to 7.0.
`Each 1 mL of PRECEDEX contains 118 meg of dexmedetomidine HCI (equivalent to _
`100 meg dexmedetomidine base) and 9 mg of sodium chloride in water. The solution is
`preservative-free and contains no additives or chemical stabilizers.
`
`CLINICAL PHARMACOLOGY
`General
`Dexmedetomidine is a relatively selective alpha2-adrenoceptor agonist with sedative
`properties. Alpha2-selectivity was observed in animals following slow intravenous (IV)
`infusion of low and medium doses (10-300 mcg/kg). Both alpha, and alpha2 activity was
`observed following slow IV infusion of high doses (>1000 mcg/kg) or with rapid IV
`adminisiration.
`~
`-jr.
`In a study in healthy volunteers (N=10), respiratory rate and oxygen saturation remained
`within normal limits and there was no evidence of respiratory depression when
`PRECEDEX was administered by IV infusion at doses within the recommended dose
`range (0.2-0.7 mcg/kg).
`
`Pharmacokinetics
`Following intravenous administration, dexmedetomidine exhibits the following
`pharmacokinetic parameters: a rapid distribution phase with a distribution half-life (ti/3) of
`approximately 6 minutes; a terminal elimination half-life (t|/z) of approximately 2 hours;
`and steady-state" volume of distribution (Vss) of approximately 118 liters. Clearance is
`
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`Amneal Pharmaceuticals LLC – Exhibit 1009 – Page 1
`
`

`

`Dexmedetomidine HC1
`Draft Labeling
`estimated to be approximately 39 L/h. The mean body weight associated with this
`clearance estimate was 72 kg.
`
`December 17, 1999
`
`Dexmedetomidine exhibits linear kinetics in the dosage range of 0.2 to 0.7 jag/kg/hr when
`administered by IV infusion for up to 24 hours. Table 1 shows the main pharmacokinetic
`parameters when PRECEDEX was infused (after appropriate loading doses) at
`maintenance infusion rates of 0.17 ng/kg/hr (target concentration of 0.3 ng/mL) for 12
`and 24 hours, 0.33 ^ig/kg/hr (target concentration of 0.6 ng/mL) for 24 hours, and 0.70
`Hg/kg/hr (target concentration of 1.25 ng/mL) for 24 hours.
`
`Table 1:
`Parameter
`
`Mean ± SD Pharmacokinetic Paramet'ers.
`Loading Infusion (min)/T6tal infusion duration (hrs)
`10 min/12 hrs
`10 min/24hrs
`10 niin/24 hrs
`35 min/24 hrs
`Dexmedetomidine Target Concentration (ng/mL) /Dose (mcg/kg/hr)
`0.3/0.17
`0.3/0.17
`0.6/0.33
`1.25/0.70
`1.78 ±0.30
`2.22 ± 0.59
`hour
`2.23 ± 0.21
`2.50 ± 0.61
`46.3 ± 8.3
`CL, liter/hour
`43.1 ±6.5
`35.3 ± 6.8
`36.5 ± 7.5
`88.7 ±22.9
`V,s, liter
`102.4 ±20.3
`93.6 ± 17.0
`99.6 ± 17.8
`0.27 ± 0.05
`Avg Css#, ng/mL
`0.27 ±0.05
`0.67 ± 0.10
`1.37 ±0.20
`""Presented as harmonic mean and pseudo standard deviation.
`#Avg Css = Average steady-state concentration of dexmedetomidine. (2.5 - 9 hour
`samples for 12 hour infusion and 2.5 -18 hour samples for 24 hour infusions.).
`
`Distribution
`The steady-state volume of distribution (Vss) of dexmedetomidine is approximately 118
`liters. Dexmedetomidine protein binding was assessed in the plasma of normal healthy
`male and female volunteers. The average protein binding was 94% and was constant
`across the different concentrations tested. Protein binding was similar in males and
`females. The fraction of dexmedetomidine that was bound to plasma proteins was
`statistically significantly decreased in subjects with hepatic impairment compared to
`healthy subjeetSi-.
`
`The potential for protein binding displacement of dexmedetomidine by fentanyl,
`ketorolac,IhtopHy'lline, digoxin, and lidocaine was explored in vitro, and negligible
`changes in the plasma protein binding of dexmedetomidine were observed. The potential
`for protein binding displacement of phenytoin, warfarin, ibuprofen, propranolol,
`theophylline, and digoxin by dexmedetomidine was explored in vitro and none of these
`compounds appeared to be significantly displaced by dexmedetomidine.
`
`Metabolism
`Dexmedetomidine undergoes almost complete biotransoformation with very little
`unchanged dexmedetomidine excreted in urine and feces. Biotransformation involves
`
`Petition for Inter Partes Review of US 8,338,470
`Amneal Pharmaceuticals LLC – Exhibit 1009 – Page 2
`
`

`

`Dexmedetomidine HC1
`December 17, 1999
`Draft Labeling
`3
`both direct glucuronidation as well as cytochrome P450-mediated metabolism. The major
`metabolic pathways of dexmedetomidine are: direct N-glucuronidation to inactive
`metabolites; aliphatic' hydroxylation
`(mediated
`primarily
`by CYP2A6) of
`dexmedetomidine to generate 3-hydroxy dexmedetomidine, the glucuronide of 3-hydroxy
`dexmedetomidine,-
`and
`3-carboxy
`dexmedefomidine;
`and N-methylation
`of
`dexmedetomidine to generate 3-hydroxy N-methyl dexmedetomidine, 3-carboxy N-
`methyl dexmedetomidine, and N-methyl O-glucuronide dexmedetomidine.
`
`Elimination
`The terminal elimination half-life (t]/2) of dexmedetomidine is approximately 2 hours and
`clearance is estimated to be approximately 39 L/h. A mass balance study demonstrated
`that after nine days an average of 95% of the radioactivity, following IV administration of
`radiolabeled dexmedetomidine, was recovered in the urine and 4% in the feces. No
`unchanged dexmedetomidine was detected in the urine. Approximately 85% of the
`radioactivity recovered in the urine was excreted within 24 hours after the infusion.
`Fractionation of the radioactivity excreted in urine demonstrated that products of N-
`glucoronidation accounted for approximately 34% of the cumulative urinary excretion.
`In addition, aliphatic hydroxylation of parent drug to form 3-hydroxy dexmedetomidine.
`the glucuronide of 3-hydroxy dexmedetomidine, and 3-carboxylic acid dexmedetomidine
`together represented approximately 14% of the dose in urine. N-methylation of
`dexmedetomidine to form 3-hydroxy N-methyl dexmedetomidine, 3-carboxy N-methyl
`dexmedetomidine, and N-methyl O-glucuronide dexmedetomidine accounted for
`approximately 18% of the dose in urine. The N-methyl metabolite itself was a minor
`circulating component and was undetected in urine. Approximately 28% of the urinary
`metabolites have not been identified.
`
`Gender
`There was no observed difference in dexmedetomidine pharmacokinetics due to gender.
`
`Geriatrics
`The pharmacokinetic profile of dexmedetomidine was not altered by age. There were no
`differences in the pharmacokinetics of dexmedetomidine in young (18-40 years),
`middle-age (41-65 years), and elderly (>65 years) subjects.
`
`Pediatrics
`The pharmacokinetic profile of dexmedetomidine has not been studied in pediatric
`patients.
`
`Renal Impairment
`Dexmedetomidine pharmacokinetics (Cm„, Tm„, AUC, t,Q, CL, and Vss) were not
`significantly different in subjects with severe renal impairment (creatinine clearance <30
`mL/min) compared to healthy subjects. However, the pharmacokinetics of the
`
`Petition for Inter Partes Review of US 8,338,470
`Amneal Pharmaceuticals LLC – Exhibit 1009 – Page 3
`
`

`

`Dexmedetomidine HC1
`Draft Labeling
`metabolites of dexmedetomidine have not been evaluated in patients with impaired renal
`function. Since the majority of metabolites are excreted in the urine, it is possible that the
`metabolites may accumulate upon long-term infusions in patients with impaired renal
`function (See PRECAUTIONS, Geriatrics, DOSAGE AND ADMINISTRATION).
`
`December 17, 1999
`4
`
`Hepatic Impairment
`In subjects with varying degrees of hepatic impairment (Child-Pugh Class A, B, or C),
`clearance values for dexmedetomidine were lower than in healthy subjects. The mean
`clearance values for subjects with mild, moderate, and severe hepatic impairment were
`74%, 64%, and 53% of those observed in the normal healthy subjects, respectively.
`Mean clearances for free drug were 59%, 51%, and 32% of those observed in the normal
`healthy subjects, respectively.
`"
`
`Although PRECEDEX is dosed to effect, it may be necessary to consider dose reduction
`in patients with hepatic impairment (see PRECAUTIONS, Hepatic Impairment and
`DOSAGE AND ADMINISTRATION).
`
`Clinical Trials
`The safety and efficacy of PRECEDEX has been evaluated in two randomized,
`double-blind, parallel-group, placebo-controlled multicenter clinical trials in 754 patients
`being treated in a surgical intensive care unit (ICU). All patients were initially intubated
`and received mechanical ventilation. These trials evaluated the sedative properties of
`dexmedetomidine by comparing the amount of rescue medication (midazolam in one trial
`and propofol in the second) required to achieve a specified level of sedation (using the
`standardized Ramsay sedation scale) between PRECEDEX and placebo from onset of
`treatment to extubation or to a total treatment duration of 24 hours. The Ramsay Level
`of Sedation Scale is displayed in Table 2.
`"
`
`Table 2: Ramsay Level of Sedation Scale
`Clinical Score I Level of Sedation Achieved
`6
`Asleep, no response
`5
`Asleep, sluggish response to light glabellar tap or loud auditory
`stimulus
`Asleep, but with brisk response to light glabellar tap or loud
`auditory stimulus
`Patient responds to commands
`Patient cooperative, oriented, and tranquil
`Patient anxious, agitated, or restless
`
`4
`
`3
`
`I
`
`In the first study, 175 patients were randomized to receive placebo and 178 to receive
`dexmedetomidine by intravenous infusion at a dose of 0.4 mcg/kg/hr (with allowed
`adjustment between 0.2 and 0.7 mcg/kg/hr) following an initial loading infusion of 1
`(one) mcg/kg over 10 minutes. The study drug infusion rate was adjusted to maintain a
`Ramsay sedation score of >3. Patients were allowed to receive "rescue" midazolam as
`
`Petition for Inter Partes Review of US 8,338,470
`Amneal Pharmaceuticals LLC – Exhibit 1009 – Page 4
`
`

`

`Dexmedetomidine HC1
`Draft Labeling
`needed to augment the study drug infusion. In addition, morphine sulfate was
`administered for pain 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. Patients randomized to placebo received significantly more midazolam
`than patients randomized to dexmedetomidine (see'Ta'ble 3).
`
`December 17, 1999
`5
`
`A second prospective primary analysis assessed the sedative effects of dexmedetomidine
`by comparing the percentage of patients who achieved a Ramsay sedation score of >3
`during intubation without the use of additional'rescue medication. A significantly greater
`percentage of patients in the dexmedetomidine group maintained a Ramsay sedation
`score of >3 without receiving any midazolam rescue compared to the placebo group (see
`Table 3)
`Table 3: Midazolam Use As Rescue Medication During Intubation (ITT)*
`Study One
`Placebo
`
`p-value
`
`Mean total dose of
`midazolam
`Standard deviation
`Categorized midazolam use
`
`N=175
`19 mg
`
`S3 mg
`
`Dexmedetomidine
`N=178
`
`5 mg
`
`19 mg
`
`0.0011**
`
`<0.001***
`
`108 (61%)
`43(25%)
`Omg
`36(20%)
`34(19%)
`0-4 mg
`>4 mg
`34(19%)
`98 (56%) -
`*1TT (intent-to-treat) population includes al randomized patients.
`**ANOVA model with treatment and Center ***Chi-Square
`
`A prospective secondary analysis assessed the dose of morphine sulfate administered to
`patients in the dexmedetomidine and placebo groups. On average, dexmedetomidine-
`treated patients received less morphine sulfate for pain than placebo-treated patients (0.47
`versus 0.83 mg/h). In addition 44% (79 of 178 patients) of dexmedetomidine patients
`received no morphine sulfate for pain versus 19% (33 of 175 patients) in the placebo
`group. - r
`-
`
`In a second study, 198 patients were randomized to receive placebo and 203 to receive
`dexmedetomidine by intravenous infusion at a dose of 0.4 mcg/kg/hr (with allowed
`adjustment between 0.2 and 0.7 meg /kg/hr) following an initial loading infusion of 1
`(one) mcg/kg IV over 10 minutes. The study drug infusion was adjusted to maintain a
`Ramsay sedation score of >3. Patients were allowed to receive "rescue" propofol as
`needed to augment the study drug infusion. In addition, morphine sulfate was
`administered as needed for pain. The primary outcome measure for this study was the
`total amount ofrescue medication (propofol) needed to maintain sedation as specified
`
`Petition for Inter Partes Review of US 8,338,470
`Amneal Pharmaceuticals LLC – Exhibit 1009 – Page 5
`
`

`

`Dexmedetomidine HC1
`Draft Labeling
`while intubated. Patients randomized to placebo received significantly more propofol
`than patients randomized to dexmedetomidine (see Table 4).
`
`December 17, 1999
`6
`
`A significantly greater percentage of patients in the dexmedetomidine group compared to
`the placebo group maintained a Ramsay sedation score of >3 without receiving any
`propofol rescue (see Table 4).
`
`Table 4: . Propofol Use As Rescue Medication During Intubation (ITT)
`Study Two
`"
`Placebo
`
`Dexmedetomidine
`
`N=198
`
`N=203
`
`513 mg
`
`782 mg
`
`Mean total dose (mg) of
`propofol
`Standard deviation
`Categorized propofol use
`47(24%)
`Omg
`122 (60%)
`30(15%)
`43 (21%)
`0-50 mg
`>50 mg
`38 (19%)
`121 (61%)
`* ANOVA model with treatment and center **Chi-square
`
`72 mg
`
`249 mg
`
`p-value
`
`<0.0001*
`
`<0.001**
`
`A prospective secondary analysis assessed the dose of morphine sulfate administered to
`patients in the dexmedetomidine and placebo groups. On average, dexmedetQmidine-
`treated patients received less morphine sulfate for pain than placebo-treated patients (0.43
`versus 0.89 mg/h). In addition 41% (83 of 203-patients) of dexmedetomidine patients
`received no morphine sulfate for pain versus 15% (30 of 198 patients) in the placebo
`group.
`
`INDICATIONS AND USAGE
`PRECEDEXjsindicated for sedation of initially intubated and mechanically ventilated
`patients during treatment in an intensive care setting. PRECEDEX should be
`administered by continuous infusion not to exceed 24 hours.
`
`WARNINGS
`PRECEDEX should be administered only by persons skilled in the management of
`patients in the intensive care setting. Due to the known pharmacological effects of
`PRECEDEX, patients should be continuously monitored while receiving PRECEDEX.
`
`Petition for Inter Partes Review of US 8,338,470
`Amneal Pharmaceuticals LLC – Exhibit 1009 – Page 6
`
`

`

`Dexmedetomidine HC1
`Draft Labeling
`Clinically significant episodes of bradycardia and sinus arrest have been associated with
`PRECEDEX administration in young, healthy volunteers with high vagal tone or with
`different routes of administration, including rapid intravenous or bolus administration.
`
`December 17, 1999
`7
`
`PRECAUTIONS
`General
`Some patients receiving PRECEDEX have been observed to be arousable and alert when
`stimulated. This alone should not be considered an evidence of lack of efficacy in the
`absence of other clinical signs and symptoms.
`.
`
`Reports of hypotension and bradycardia have been associated with PRECEDEX infusion.
`If medical intervention is required, treatment may include decreasing or stopping the
`infusion of PRECEDEX, increasing the rate of IV fluid administration, elevation of the
`lower extremities, and use of pressor agents. Because PRECEDEX has the potential to
`augment bradycardia induced by vagal stimuli, clinicians should be prepared to intervene.
`The intravenous administration of anticholinergic agents (eg, atropine) should be
`considered to modify vagal tone. In clinical trials, atropine or glycopyrrolate were
`effective in the treatment of most episodes of PRECEDEX-induced bradycardia.
`However, in some patients with significant cardiovascular dysfunction, more advanced
`resuscitative measures were required. Caution should be exercised when administering
`PRECEDEX to patients with advanced heart block.
`
`Transient hypertension has been observed primarily during the loading dose in
`association with the initial peripheral vasoconstrictive effects of PRECEDEX. Treatment
`of the transient hypertension has generally not been necessary, although reduction of the
`loading infusion rate may be desirable.
`
`PRECEDEX infusion should not be coadministered through the same IV catheter with
`blood or plasma since physical compatibility has not been established. Safety and
`effectiveness of dexmedetomidine have not been evaluated in infusions over 24 hours.
`Dexmedetomidine is not indicated for infusions lasting over 24 hours (see
`INDICATIONS AND USAGE, DOSAGE AND ADMINISTRATION).
`
`Withdrawal
`Although not specifically studied, if PRECEDEX is administered chronically and stopped
`abruptly, withdrawal symptoms similar to those reported for another alpha-2-adrenergic
`agent, clonidine, may result. These symptoms may include nervousness, agitation, and
`headaches, accompanied or followed by a rapid rise in blood pressure and elevated
`catecholamine concentrations in the plasma. PRECEDEX should not be administered for
`greater than 24 hours (see INDICATIONS AND USAGE, DOSAGE AND
`ADMINISTRATION).
`
`Petition for Inter Partes Review of US 8,338,470
`Amneal Pharmaceuticals LLC – Exhibit 1009 – Page 7
`
`

`

`Dexmedetomidine HCI
`Draft Labeling
`
`December 17, 1999
`8
`
`-
`Adrenallnsufficiency
`Dexmedetomidine had no effect on ACTH-stimulated Cortisol release in dogs after a
`single dose; however, after the subcutaneous infusion of dexmedetomidine for one week,
`the Cortisol response to ACTH was diminished by approximately 40%.
`
`Hepatic Impairment
`Since dexmedetomidine clearance decreases with severity of hepatic impairment, dose
`reduction should be considered in patients with impaired hepatic function (see
`CLINICAL PHARMACOLOGY, Pharmacokinetics, DOSAGE AND
`ADMINISTRATION).
`
`Drug Interactions
`General
`In vitro studies in human liver microsomes demonstrated no evidence of cytochrome
`P450-mediated drug interactions that are likely to be of clinical relevance.
`
`Anesthetics/Sedatives/Hvpnotics/Qpioids
`Co-administration of PRECEDEX with anesthetics, sedatives, hypnotics, and opioids is
`likely to lead to an enhancement of effects. Specific studies have confirmed these effects
`with sevoflurane, isoflurane, propofol, alfentanil, and midazolam. No pharmacokinetic
`interactions between dexmedetomidine and isoflurane, propofol, alfentanil, arid
`midazolam have been demonstrated. However, due to possible pharmacodynamic
`interactions, when co-administered with PRECEDEX, a reduction in dosage of
`PRECEDEX on the concomitant anesthetic, sedative, hypnotic or opioid may be required.
`
`Neuromuscular Blockers
`In one study of 10 healthy volunteers, administration of PRECEDEX for 45 minutes at a
`plasma concentration of 1 (one) ng/mL resulted in no clinically meaningful increases in
`the magnitude or neuromuscular blockade associated with rocuronium administration.
`
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`Animal carcinogenicity studies have not been performed with dexmedetomidine.
`
`Dexmedetomidine was not mutagenic in vitro, in either the bacterial reverse mutation
`assay (£. coli and Salmonella typhimurium) or the mammalian cell forward mutation
`assay (mouse lymphoma). Dexmedetomidine was clastogenic in the in vitro human
`lymphocyte chromosome aberration test with, but not without, metabolic activation.
`Dexmedetomidine was also clastogenic in the in vivo mouse micronucleus test.
`
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`
`

`

`Dexmedetomidine HC1
`Draft Labeling
`Fertility in male or female rats was not affected after daily subcutaneous injections at
`doses up to 54 mcg/kg (less than the maximum recommended human intravenous dose on
`a mcg/m: basis). Dexmedetomidine was dosed from 10 weeks prior to mating in males
`and 3 weeks prior to mating and during mating in females.
`
`December 17, 1999
`9
`
`Pregnancy: Teratogenic Effects. Pregnancy Category C
`Teratogenic effects were not observed following administration of dexmedetomidine at
`subcutaneous doses up to 200 mcg/kg in rats from day 5 to day 16 of gestation arid
`intravenous doses up to 96 mcg/kg in rabbits from day 6 to day 18 of gestation. The dose
`in rats is approximately 2 times the maximum recommended human intravenous dose on
`a mcg/m2 basis. The exposure in rabbits is approximately equal to that in humans at the
`maximum,recommended intravenous dose based on plasma'area-under-the-curve values.
`However, fetal toxicity, as evidenced by increased postimplantation losses and reduced
`live pups, was observed in rats at a subcutaneous dose of 200 mcg/kg. The no-effect dose
`was 20 mcg/kg (less than the maximum recommended human intravenous dose on a
`mcg/m2 basis). In another reproductive study when dexmedetomidine was administered
`subcutaneously to pregnant rats from gestation day 16 through nursing, it caused lower
`pup weights at doses of 8 and 32 mcg/kg as well as fetal and embryocidal toxicity of
`second generation offspring at a dose of 32 mcg/kg (less than the maximum
`recommended human intravenous dose on a mcg/m2 basis). Dexmedetomidine also
`produced delayed motor development in pups at a dose of 32 mcg/kg (less than the
`maximum recommended human intravenous dose on a mcg/m2 basis). No such effects
`were observed at a dose of 2 mcg/kg (less than the maximum recommended intravenous
`dose on a mcg/m2 basis).
`
`Placental transfer of dexmedetomidine was observed when radiolabeled
`dexmedetomidine was administered subcutaneously to pregnant rats.
`
`There are no adequate and well-controlled studies in pregnant women.
`Dexmedetomidine should be used during pregnancy only if the potential benefits justify
`the potential risk to the fetus.
`
`Labor and Delivery
`The safety of PRECEDEX during labor and delivery has not been studied. Therefore,
`PRECEDEX is not recommended during labor and delivery, including cesarean section
`deliveries.
`
`Nursing Mothers
`It is not known whether PRECEDEX is excreted in human milk. Radiolabeled
`dexmedetomidine administered subcutaneously to lactating female rats was excreted in
`milk. Because many drugs are excreted in human milk, caution should be exercised when
`PRECEDEX is administered to a nursing woman.
`
`Petition for Inter Partes Review of US 8,338,470
`Amneal Pharmaceuticals LLC – Exhibit 1009 – Page 9
`
`

`

`Dexmedetomidine HC1
`Draft Labeling
`Pediatrics
`There have been no clinical studies to establish the safety and efficacy of PRECEDEX in
`pediatric patients below 18 years of age. Therefore, PRECEDEX is not recommended for
`use in this population.
`
`December 17, 1999
`10
`
`Geriatrics
`A total of 531 subjects in the clinical studies were 65 years of age and over. A total of
`129 subjects in the clinical studies were 75 years of age and over. In patients greater than
`65 years of age, a higher incidence of bradycardia and hypotension was observed
`following administration of PRECEDEX. Therefore a dose reduction may be
`considered in patients over 65 years of age.
`
`Dexmedetomidine is known to be substantially excreted by the kidney, and the risk of
`adverse reactions to this drug may be greater in patients with impaired renal function.
`Because elderly patients are more likely to have decreased renal function, care should be
`taken in dose selection in elderly patients, and it may be useful to monitor renal function.
`
`ADVERSE REACTIONS
`Adverse event information is derived from the placebo-controlled, continuous infusion
`trials of dexmedetomidine for sedation in the ICU setting in which 387 patients received
`PRECEDEX. Overall, the most frequently observed treatment-emergent adverse events
`included hypotension, hypertension, nausea, bradycardia, fever, vomiting hypoxia,
`tachycardia and anemia (see Table 5).
`
`Adverse Event
`
`Table 5: Treatment-Emergent Adverse Events Occurring in >1% of All
`Dexmedetomidine-Treated Patients in the Randomized Placebo-controlled
`Continuous Infusion ICU Sedation Studies
`Dexmedetomidine
`Placebo
`(N=387)
`(N=379)
`30%
`15%
`11%
`10%
`8%
`4%
`6%
`7%
`6%
`4%
`2%
`3%
`2%
`3%
`1%
`3%
`2%
`1%
`<1%
`2%
`1%
`2%
`2%
`<1%
`2%
`<1%
`
`Hypotension
`Nausea-,,-.
`Bradycardia
`Atrial Fibrillation
`Hypoxia""
`Anemia
`Pain
`Pleural Effusion
`Infection
`Leukocytosis
`Oliguria
`Pulmonary Edema
`Thirst
`
`Petition for Inter Partes Review of US 8,338,470
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`
`

`

`Dexmedetomidine HCI
`Draft Labeling
`
`December 17, 1999
`1 1
`
`The treatment-emergent adverse events in Table 6 were reported in <]% of all
`dexmedetomidine-treated patients and are potentially clinically relevant.
`
`Potentially Clinically Relevant Treaiment-Emergent Adverse Events to
`Table 6:
`Dexmedetomidine Reported in <1% Patients in the Continuous Infusion ICU Sedation
`Trials
`
`Body System
`Body as a Whole
`Cardiovascular Disorders, General
`
`Central and Peripheral Nervous System
`Disorders
`Gastrointestinal System Disorders
`Heart Rate and Rhythm Disorders
`
`Liver and Bilian System Disorders
`Metabolic and Nutritional Disorders
`
`Psychiatric Disorders
`
`Red Blood Cell Disorders
`Respiratory System Disorders
`
`Skin and Appendages Disorders
`Vision Disorders
`
`Preferred Term
`Fever. Hyperpyrexia. Hypovolemia. Light Anesthesia. Pain. Rigors
`Blood pressure fluctuation. Heart disorder, Aggravated
`hypenension
`Dizziness, Headache, Neuralgia, Neuritis, Speech disorder
`
`Abdominal pain, Diarrhea, Vomiting.
`Arrhythmia, Ventricular arrhythmia, AV block. Cardiac arrest,
`Exirasystoles, Atrial fibrillation. Heart block. T wave inversion.
`Tachycardia. Supraventricular tachycardia. Ventricular tachycardia
`Increased GGT, Increased SGOT, Increased SGPT,
`Acidosis, Respiratory acidosis. Hyperkalemia, Increased alkaline
`phosphatase. Thirst
`Agitation, Confusion, Delirium, Hallucination, Illusion,
`Somnolence
`Anemia
`Apnea, Bronchospasm, Dyspnea, Hypercapnia, Hypoventilation.
`Hypoxia. Pulmonary congestion
`Increased sweating
`Photopsia. Abnormal vision
`
`DRUG ABUSE AND DEPENDENCE
`PRECEDEX (dexmedetomidine hydrochloride) is not a controlled substance.
`
`The dependence potential of dexmedetomidine has not been studied in humans.
`However, since studies in rodents and primates have demonstrated that dexmedetomidine
`exhibits pharmacologic actions similar to those of clonidine, it is possible that
`PRECEDEX may produce a clonidine-like withdrawal syndrome upon abrupt
`discontinuatfohf See PRECAUTIONS, Withdrawal).
`
`OVERDOSAGE
`The tolerability of PRECEDEX was noted in one study in which healthy subjects were
`administered doses at and above the recommended dose of 0.2 to 0.7 mcg/kg/hr. The
`maximum blood concentration achieved in this study was approximately 13 times the
`upper boundary of the therapeutic range. The most notable effects observed in two
`subjects who achieved the highest doses were first degree AV block and second degree
`heart block. No hemodynamic compromise was noted with the AV block and the heart
`block resolved spontaneously within one minute.
`
`Petition for Inter Partes Review of US 8,338,470
`Amneal Pharmaceuticals LLC – Exhibit 1009 – Page 11
`
`

`

`Dexmedetomidine HC1
`December 17, 1999
`Draft Labeling
`12
`Five patients received an overdose of PRECEDEX in the 1CU sedation studies. Two of
`these patients had no symptoms reported; one patient received a 2 mcg/kg loading dose
`over 10 minutes (twice the recommended loading dose) and one patient received a
`maintenance infusion of 0.8 mcg/kg/hr. Two other patients who received a 2 mcg/kg
`loading dose over -10 minutes, experienced bradycardia and/or hypotension. One patient
`who received a loading bolus dose of undiluted PRECEDEX (19.4 mcg/kg), had cardiac
`arrest from which he was successfully resuscitated.
`
`DOSAGE AND ADMINISTRATION
`PRECEDEX should be administered using a controlled infusion device.
`
`PRECEDEX dosing should be individualized and titrated t5 the desired clinical effect.
`For adult patients, PRECEDEX is generally initiated with a loading infusion of 1 (one)
`mcg/kg over 10 minutes, followed by a maintenance infusion of 0.2 to 0.7 mcg/kg/hr.
`The rate of the maintenance infusion should be adjusted to achieve the desired level of
`sedation. Dexmedetomidine is not indicated for infusions lasting longer than 24
`hours.
`
`PRECEDEX has been continuously infused in mechanically ventilated patients prior to
`extubation, during extubation, and post-extubation. It is not necessary to discontinue
`PRECEDEX prior to extubation provided the infusion does not exceed 24 hours.
`
`Dosage Adjustment
`Dosage reductions may need to be considered for patients with renal or hepatic
`impairment (see CLINICAL PHARMACOLOGY,"Pharmacokinetics &
`'
`PRECAUTIONS, Hepatic Impairment).
`
`Dilution Prior to Administration
`PRECEDEX must be diluted in 0.9% sodium chloride solution prior to
`administration.
`
`Preparation'Sf solutions is the same, whether for the loading dose or maintenance
`infusion.
`.
`
`To prepare the infusion, withdraw 2 mL of PRECEDEX and add to 48 mL of 0.9%
`Sodium Chloride injection to a total of 50 mL. Shake gently to mix well.
`
`Administration With Other Fluids
`Compatibility of PRECEDEX with coadministration of blood, serum, or plasma has not
`been established. PRECEDEX has been shown to be compatible when administered with
`the following intravenous fluids and drugs:
`
`Petition for Inter Partes Review of US 8,338,470
`Amneal Pharmaceuticals LLC – Exhibit 1009 – Page 12
`
`

`

`Dexmedetomidine HC1
`Draft Labeling
`
`December 17, 1999
`13
`
`Lactated Ringers
`5% dextrose in water, 0.9% sodium chloride in water, 20% mannitol, thiopental sodium,
`etomidate, vecuronium bromide, pancuronium bromide, succinylcholine, atracurium
`besylate, mivacurium chloride, glycopyrrolate bromide, phenylephrine HC1, atropine
`sulfate, midazolam, morphine sulfate, fentanyl citrate, and a plasma-substitute.
`
`Handling Procedures
`Parenteral products should be inspected visually for particulate matter and discoloration
`prior to administration. Strict aseptic technique must always be maintained during
`handling of PRECEDEX. Ampules and vials are intended'for single use only.
`
`Compatibility studies have demonstrated the potential for adsorption of dexmedetomidine
`to some types of natural rubber. Although PRECEDEX is dosed to effect, it is advisable
`to use administration components made with synthetic or coated natural rubber gaskets.
`
`PRECEDEX must be diluted in 0.9% sodium chloride solution to achieve the
`required concentrations prior to administration. Preparation of solutions is the same,
`whether for the loading or maintenance infusion (see DOSAGE AND
`ADMINISTRATION).
`
`HOW SUPPLIED
`PRECEDEX (dexmedetomidine hydrochloride injection), 100 mcg/mL as the base is
`available in 2 mL clear glass vials and 2 mL clear glass ampules.
`
`2 mL vial (NDC XXXX-XXXX-XX)
`2 mL ampule (NDC XXXX-XXXX-XX)
`
`Store at controlled room temperature, 250C (77° F) with excursions allowed from 15° to
`30oC (590to 860F).
`Manufactured and Distributed by:
`Abbott Laboratories
`North Chicago, IL 60064
`
`Licensed from:
`Orion Corporation
`Espoo. Finland
`
`RA05979-Rl-Rev. Dec., 1998
`
`Petition for Inter Partes Review of US 8,338,470
`Amneal Pharmaceuticals LLC – Exhibit 1009 – Page 13
`
`