1
`
`
`2 HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`3 These highlights do not include all the information needed to use
`
`4 dexmedetomidine hydrochloride safely and effectively. See full
`
`5 prescribing information for Precedex.
`
`6
`
`
`7 Precedex (dexmedetomidine hydrochloride) injection
`
`
`8 For intravenous infusion following dilution
`
`9
`Initial U.S. Approval: 1999
`
`10
`----------------------------RECENT MAJOR CHANGES--------------------------
`
`11 Dosage and Administration, Dosing Information (2.2)
`09/2010
`
`12 Dosage and Administration, Administration with Other Fluids (2.5) 09/2010
`
`13 Warnings and Precautions (5)
`09/2010
`
`
`14 Adverse Reactions, Clinical Studies Experience (6.1)
`09/2010
`
`15 Use in Special Populations, Pregnancy (8.1)
`09/2010
`
`16 Clinical Pharmacology, Pharmacokinetics (12.3)
`09/2010
`
`17 Animal Toxicology and/or Pharmacology (13.2)
`09/2010
`
`
`18 Clinical Studies, Intensive Care Unit Sedation (14.1)
`
`09/2010
`
`19
`----------------------------INDICATIONS AND USAGE---------------------------
`
`20 Precedex is a relatively selective alpha2-adrenergic agonist indicated for:
`
`
`21
`
`• Sedation of initially intubated and mechanically ventilated patients during
`
`22
`
`treatment in an intensive care setting. Administer Precedex by continuous
`
`23
`
`infusion not to exceed 24 hours. (1.1)
`
`24
`
`
`
`• Sedation of non-intubated patients prior to and/or during surgical and other
`
`25
`
`procedures. (1.2)
`
`26
`
`----------------------DOSAGE AND ADMINISTRATION-----------------------
`
`27
`Individualize and titrate Precedex dosing to desired clinical effect. (2.1)
`
`•
`28
`• Administer Precedex using a controlled infusion device. (2.1)
`
`29
`
`
`• Dilute vial contents in 0.9% sodium chloride solution to achieve required
`
`30
`
`concentration (4 mcg/mL) prior to administration. (2.4)
`
`31
`
`
`32 For Intensive Care Unit Sedation: Generally initiate at one mcg/kg over 10
`
`
`33 minutes, followed by a maintenance infusion of 0.2 to 0.7 mcg/kg/hr. (2.2)
`
`34 For Procedural Sedation: Generally initiate at one mcg/kg over 10 minutes,
`
`35
`followed by a maintenance infusion initiated at 0.6 mcg/kg/hr and titrated to
`
`36 achieve desired clinical effect with doses ranging from 0.2 to 1 mcg/kg/hr.
`
`
`
`37 Alternative doses recommended for patients over 65 years of age and awake
`
`38
`
` fiberoptic intubation patients. (2.2)
`
`39
`---------------------DOSAGE FORMS AND STRENGTHS----------------------
`40 200 mcg/2 mL (100 mcg/mL) in a glass vial (3)
`
`
`41
`-------------------------------CONTRAINDICATIONS------------------------------
`42 None (4)
`43
`-----------------------WARNINGS AND PRECAUTIONS-----------------------­
`
`44
`
`• Monitoring: Continuously monitor patients while receiving Precedex. (5.1)
`
`
`45
`
`• Bradycardia and sinus arrest: Have occurred in young healthy volunteers
`
`46
`with high vagal tone or with different routes of administration, e.g., rapid
`
`47
`
`
`intravenous or bolus administration. (5.2)
`
`48
`
`
`• Hypotension and bradycardia: May necessitate medical intervention. May
`
`49
`be more pronounced in patients with hypovolemia, diabetes mellitus, or
`
`50
`chronic hypertension, and in the elderly. Use with caution in patients with
`
`51
`
`advanced heart block or severe ventricular dysfunction. (5.2)
`
`52
`• Co-administration with other vasodilators or negative chronotropic agents:
`
`53
`Use with caution due to additive pharmacodynamic effects. (5.2)
`
`54
`• Transient hypertension: Observed primarily during the loading dose.
`
`
`55
`Consider reduction in loading infusion rate. (5.3)
`
`56
`
`
`• Arousability: Patients can become aroused/alert with stimulation; this
`
`57
`alone should not be considered as lack of efficacy (5.4)
`
`58
`
`• Prolonged exposure to dexmedetomidine beyond 24 hours may be
`
`59
`associated with tolerance and tachyphylaxis and a dose-related increase in
`
`60
`adverse events (5.6)
`
`61
`------------------------------ADVERSE REACTIONS-------------------------------
`
`62
`
`• The most common adverse reactions (incidence greater than 2%) are
`
`63
`
`
`hypotension, bradycardia, and dry mouth. (6.1)
`
`64
`
`
`
`• Adverse reactions associated with infusions greater than 24 hours in
`
`65
`
`duration include ARDS, respiratory failure, and agitation. (6.1)
`
`66
`
`
`67 To report SUSPECTED ADVERSE REACTIONS, contact Hospira, Inc
`
`
`68 at 1-888-441-4100 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
`
`
`69
`------------------------------DRUG INTERACTIONS-------------------------------
`
`70 Anesthetics, sedatives, hypnotics, opioids: Enhancement of pharmacodynamic
`
`71 effects. Reduction in dosage of Precedex or the concomitant medication may
`
`72 be required. (7.1)
`
`73
`------------------------USE IN SPECIFIC POPULATIONS-----------------------
`
`74
`• Geriatric patients: Dose reduction should be considered (2.2, 2.3, 5.1, 8.5)
`
`75
`• Hepatic impairment: Dose reduction should be considered (2.1, 2.2, 2.3,
`
`76
`
`5.6, 8.6)
`
`77
`
`
`
`• Pregnancy: Based on animal data, may cause fetal harm (8.1)
`
`78
`
`• Nursing Mothers: Caution should be exercised when administered to a
`
`79
`
`nursing woman (8.3)
`
`80
`
`81
`
`
`Revised: 09/2010
`
`
`
`
`
`82
`_______________________________________________________________________________________________________________________________________
`83
`
`116
`84 FULL PRESCRIBING INFORMATION: CONTENTS*
`8.5 Geriatric Use
`117
`85 1
`
`8.6 Hepatic Impairment
`INDICATIONS AND USAGE
`86
`118 9 DRUG ABUSE AND DEPENDENCE
`
`1.1
`Intensive Care Unit Sedation
`87
`119
`1.2 Procedural Sedation
`
`9.1 Controlled Substance
`120
`88 2 DOSAGE AND ADMINISTRATION
`
`
`
`9.2 Dependence
`89
`121 10 OVERDOSAGE
`
`
`
`2.1 Dosing Guidelines
`90
`122 11 DESCRIPTION
`2.2 Dosage Information
`91
`123 12 CLINICAL PHARMACOLOGY
`2.3 Dosage Adjustment
`92
`124
`
`2.4 Preparation of Solution
`12.1 Mechanism of Action
`93
`125
`2.5 Administration With Other Fluids
`
` 12.2 Pharmacodynamics
`94
`126
`
`2.6 Compatibility with Natural Rubber
`
`12.3 Pharmacokinetics
`95 3 DOSAGE FORMS AND STRENGTHS
`
`127 13 NONCLINICAL TOXICOLOGY
`128
`96 4 CONTRAINDICATIONS
`
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`129
`97 5 WARNINGS AND PRECAUTIONS
`
`
`
`
`13.2 Animal Toxicology and/or Pharmacology
`98
`130 14 CLINICAL STUDIES
`5.1 Drug Administration
`99
`131
`
`5.2 Hypotension, Bradycardia, and Sinus Arrest
`
`14.1 Intensive Care Unit Sedation
`100
`132
`
`5.3 Transient Hypertension
`
`
` 14.2 Procedural Sedation
`101
`133 16 HOW SUPPLIED/STORAGE AND HANDLING
`5.4 Arousability
`
`102
`134 17 PATIENT COUNSELING INFORMATION
`5.5 Withdrawal
`
`
`103
`135
`5.6 Tolerance and Tachyphylaxis
`
`
`136 *Sections or subsections omitted from the full prescribing information are not
`104
`
`5.7 Hepatic Impairment
`
`137
`105 6 ADVERSE REACTIONS
`
`
`listed.
`106
`6.1 Clinical Studies Experience
`
`107
`6.2 Postmarketing Experience
`
`108 7 DRUG INTERACTIONS
`
`
`109
`7.1 Anesthetics, Sedatives, Hypnotics, Opioids
`
`110
`
`7.2 Neuromuscular Blockers
`
`111 8 USE IN SPECIFIC POPULATIONS
`
`
`112
`
`
`8.1 Pregnancy
`
`113
`
`
`8.2 Labor and Delivery
`
`114
`8.3 Nursing Mothers
`
`115
`8.4 Pediatric Use
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Petition for Inter Partes Review of US 8,338,470
`Amneal Pharmaceuticals LLC – Exhibit 1007 – Page 1
`
`

`

`
`
`
`1 INDICATIONS AND USAGE
`
`1.1 Intensive Care Unit Sedation
`
`
`
`Precedex® is indicated 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.
`
`
`
`
`
`
`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.
`
`
`1.2 Procedural Sedation
`
`
`
`
`
`
`
`Precedex is indicated for sedation of non-intubated patients prior to and/or during surgical and other procedures.
`
`
`
`
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`
`2.1 Dosing Guidelines
`
`
`
`138
`
`
`139
`
`_______________________________________________________________________________________________________________________________________
`140
`
`
`FULL PRESCRIBING INFORMATION
`
`141
`
`142
`
`143
`144
`145
`146
`147
`
`148
`149
`150
`
`151
`152
`153
`
`154
`155
`
`156
`157
`
`
`
`
`158
`• Precedex dosing should be individualized and titrated to desired clinical response.
`
`
`
`
`159
`• Precedex is not indicated for infusions lasting longer than 24 hours
`
`
`
`160
`• Precedex should be administered using a controlled infusion device.
`
`
`161
`
`162 2.2 Dosage Information
`
`
`
`163
`
`
`INDICATION
`Initiation of Intensive Care Unit
`Sedation
`
`Table 1: Dosage Information
`DOSAGE AND ADMINISTRATION
`
`
`For adult patients: a loading infusion of up to one mcg/kg over 10 minutes.
`
`
`
`
`
`For patients being converted from alternate sedative therapy: a loading
`dose may not be required [see Dosage and Administration: Maintenance of
`
`
`Intensive Care Unit Sedation (2.2)].
`
`For patients over 65 years of age: a dose reduction should be considered [see
`
`
`
`
`Use in Specific Populations (8.5)].
`
`
`For patients with impaired hepatic function: a dose reduction should be
`
`considered [see Use in Specific Populations (8.6), Clinical Pharmacology
`
`(12.3)].
`
`Maintenance of Intensive Care
`
`Unit Sedation
`
`
`For adult patients: 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.
`For patients over 65 years of age: a dose reduction should be considered [see
`
`
`
`Use in Specific Populations (8.5)].
`
`
`For patients with impaired hepatic function: a dose reduction should be
`
`considered [see Use in Specific Populations (8.6), Clinical Pharmacology
`
`(12.3)].
`
`Petition for Inter Partes Review of US 8,338,470
`Amneal Pharmaceuticals LLC – Exhibit 1007 – Page 2
`
`

`

`For adult patients: a loading infusion of one mcg/kg over 10 minutes. For
`
`
`less invasive procedures such as ophthalmic surgery, a loading infusion of
`
`0.5 mcg/kg given over 10 minutes may be suitable.
`For awake fiberoptic intubation patients: a loading infusion of one mcg/kg
`
`
`
`over 10 minutes.
`
`For patients over 65 years of age: a loading infusion of 0.5 mcg/kg over 10
`
`
`
`minutes [see Use in Specific Populations (8.5)].
`
`For patients with impaired hepatic function:: a dose reduction should be
`
`considered [see Use in Specific Populations (8.6), Clinical Pharmacology
`(12.3)].
`
`
`
`
`For adult patients: the maintenance infusion is generally initiated at
`
`0.6 mcg/kg/hr and titrated to achieve desired clinical effect with doses ranging
`
`
`from 0.2 to 1 mcg/kg/hr. The rate of the maintenance infusion should be
`
`
`
`adjusted to achieve the targeted level of sedation.
`
`For awake fiberoptic intubation patients: a maintenance infusion of
`
`
`0.7 mcg/kg/hr is recommended until the endotracheal tube is secured.
`
`
`For patients over 65 years of age: a dose reduction should be considered [see
`
`
`
`
`Use in Specific Populations (8.5)].
`
`
`For patients with impaired hepatic function: a dose reduction should be
`
`considered [see Use in Specific Populations (8.6), Clinical Pharmacology
`(12.3)].
`
`
`
`
`164
`
`Initiation of Procedural
`
`Sedation
`
`Maintenance of Procedural
`
`
`Sedation
`
`
`2.3 Dosage Adjustment
`
`
`Due to possible pharmacodynamic interactions, a reduction in dosage of Precedex or other concomitant
`
`anesthetics, sedatives, hypnotics or opioids may be required when co-administered. [see Drug Interactions
`
`
`
`(7.1)].
`
`Dosage reductions may need to be considered for patients with hepatic impairment, and geriatric patients [see
`
`
`
`Warnings and Precautions (5.6), Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].
`
`
`
`2.4 Preparation of Solution
`
`Precedex must be diluted in 0.9% sodium chloride solution to achieve required concentration (4 mcg/mL) prior
`to administration. Preparation of solutions is the same, whether for the loading dose or maintenance infusion.
`
`Strict aseptic technique must always be maintained during handling of Precedex.
`
`
`
`
`
`
`
`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.
`
`
`Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
`administration, whenever solution and container permit.
`
`2.5 Administration with Other Fluids
`
`Precedex infusion should not be co-administered through the same intravenous catheter with blood or plasma
`
`because physical compatibility has not been established.
`
`
`Precedex has been shown to be incompatible when administered with the following drugs: amphotericin B,
`diazepam.
`
`
`
`Precedex has been shown to be compatible when administered with the following intravenous fluids:
`
`
`•
`
`•
`
`
`0.9% sodium chloride in water
`5% dextrose in water
`
`165
`166
`167
`168
`169
`170
`171
`172
`173
`174
`175
`176
`177
`178
`179
`180
`181
`182
`183
`184
`185
`186
`187
`188
`189
`190
`191
`192
`193
`194
`195
`196
`
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`Amneal Pharmaceuticals LLC – Exhibit 1007 – Page 3
`
`

`

`
`
`20% mannitol
`•
`• Lactated Ringer’s solution
`100 mg/mL magnesium sulfate solution
`•
`
`0.3% potassium chloride solution
`
`•
`
`
`
`
`2.6 Compatibility with Natural Rubber
`
`
`
`Compatibility studies have demonstrated the potential for absorption of Precedex 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.
`
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`200 mcg/2 mL (100 mcg/mL) in a glass vial
`
`
`
`4 CONTRAINDICATIONS
`None
`
`
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Drug Administration
`
`
`
`Precedex should be administered only by persons skilled in the management of patients in the intensive care or
`operating room setting. Due to the known pharmacological effects of Precedex, patients should be continuously
`monitored while receiving Precedex.
`
`
`5.2 Hypotension, Bradycardia, and Sinus Arrest
`Clinically significant episodes of bradycardia and sinus arrest have been reported with Precedex administration
`in young, healthy volunteers with high vagal tone or with different routes of administration including rapid
`
`
`intravenous or bolus administration.
`
`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
`intravenous 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 (e.g., glycopyrrolate, atropine) should be
`
`
`considered to modify vagal tone. In clinical trials, glycopyrrolate or atropine 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 and/or severe
`ventricular dysfunction. Because Precedex decreases sympathetic nervous system activity, hypotension and/or
`
`
`
`bradycardia may be expected to be more pronounced in patients with hypovolemia, diabetes mellitus, or chronic
`hypertension and in elderly patients.
`
`In clinical trials where other vasodilators or negative chronotropic agents were co-administered with Precedex
`
`
`
`an additive pharmacodynamic effect was not observed. Nonetheless, caution should be used when such agents
`are administered concomitantly with Precedex.
`
`5.3 Transient Hypertension
`
`
`
`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.
`
`
`5.4 Arousability
`
`
`
`
`Some patients receiving Precedex have been observed to be arousable and alert when stimulated. This alone
`
`should not be considered as evidence of lack of efficacy in the absence of other clinical signs and symptoms.
`
`
`
`5.5 Withdrawal
`
`Intensive Care Unit Sedation
`
`With administration up to 7 days, regardless of dose, 12 (5%) Precedex subjects experienced at least 1 event
`
`
`related to withdrawal within the first 24 hours after discontinuing study drug and 7 (3%) Precedex subjects
`
`197
`198
`199
`200
`201
`202
`203
`204
`205
`206
`207
`208
`209
`210
`211
`212
`213
`214
`215
`216
`217
`218
`219
`220
`221
`222
`223
`224
`225
`226
`227
`228
`229
`230
`231
`232
`233
`234
`235
`236
`237
`238
`239
`240
`241
`242
`243
`244
`245
`246
`247
`248
`249
`250
`251
`252
`253
`254
`255
`
`Petition for Inter Partes Review of US 8,338,470
`Amneal Pharmaceuticals LLC – Exhibit 1007 – Page 4
`
`

`

`
`
`experienced at least 1 event 24 to 48 hours after end of study drug. The most common events were nausea,
`
`
`vomiting, and agitation.
`
`
`Tachycardia and hypertension requiring intervention in the 48 hours following study drug discontinuation
`
`occurred at frequencies of <5%. If tachycardia and/or hypertension occurs after discontinuation of Precedex
`
`
`
`supportive therapy is indicated.
`
`
`Procedural Sedation
`
`Withdrawal symptoms were not seen after discontinuation of short term infusions of Precedex (<6 hours).
`
`
`5.6 Tolerance and Tachyphylaxis
`
`
`Use of dexmedetomidine beyond 24 hours has been associated with tolerance and tachyphylaxis and a dose­
`
`related increase in adverse reactions [see Adverse Reactions (6.1)].
`
`256
`257
`258
`259
`260
`261
`262
`263
`264
`265
`266
`267
`268
`269
`270
`271
`272
`273
`274
`275
`276
`277
`278
`279
`280
`281
`282
`
`283
`
`
`284 Most common treatment-emergent adverse reactions, occurring in greater than 2% of patients in both Intensive Care
`
`
`
`Unit and procedural sedation studies include hypotension, bradycardia and dry mouth.
`285
`
`286
`
`Intensive Care Unit Sedation
`287
`
`288
`
`Adverse reaction information is derived from the continuous infusion trials of Precedex for sedation in the Intensive
`289
`Care Unit setting in which 1007 patients received Precedex. The mean total dose was 7.4 mcg/kg (range: 0.8 to
`290
`
`
`84.1), mean dose per hour was 0.5 mcg/kg/hr (range: 0.1 to 6.0) and the mean duration of infusion of 15.9 hours
`291
`
`
`(range: 0.2 to 157.2). The population was between 17 to 88 years of age, 43% > 65 years of age, 77% male and 93%
`292
`
`
`Caucasian. Treatment-emergent adverse reactions occurring at an incidence of >2% are provided in Table 2. The
`293
`
`294 most frequent adverse reactions were hypotension, bradycardia and dry mouth. [see Warnings and Precautions
`
`
`
`
`
`(5.2)].
`295
`
`296
`
`
`
`6.1 Clinical Studies Experience
`Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the
`
`clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect
`the rates observed in practice.
`
`
`
`
`Use of Precedex has been associated with the following serious adverse reactions:
`
`• Hypotension, bradycardia and sinus arrest [see Warnings and Precautions (5.2)]
`
`
`• Transient hypertension [see Warnings and Precautions (5.3)]
`
`
`
`
`
`5.7 Hepatic Impairment
`
`
`
`Since Precedex clearance decreases with severity of hepatic impairment, dose reduction should be considered in
`patients with impaired hepatic function [see Dosage and Administration (2.2)].
`
`
`
`
`6 ADVERSE REACTIONS
`
`Petition for Inter Partes Review of US 8,338,470
`Amneal Pharmaceuticals LLC – Exhibit 1007 – Page 5
`
`

`

`
`
`297
`
`Table 2. Adverse Reactions With an Incidence > 2%— Intensive Care Unit Sedation Population < 24 hours*
`
`
`
`
`Randomized
`
`All Precedex
`Placebo
`Propofol
`Precedex
`(N=1007)
`(N=798)
`(N=400)
`(N=188)
`
`Adverse Event
`
`(%)
`(%)
`(%)
`(%)
` Hypotension
`25%
`24%
`12%
`13%
`
` Hypertension
`12%
`13%
`19%
`4%
` Nausea
`9%
`9%
`9%
`11%
`
`Bradycardia
`5%
`5%
`3%
`0
`
`
`
`
`
` Atrial fibrillation
`4%
`5%
`3%
`7%
`
`Pyrexia
`4%
`4%
`4%
`4%
`
` Dry mouth
`4%
`3%
`1%
`1%
` Vomiting
`3%
`3%
`5%
`3%
` Hypovolemia
`3%
`3%
`2%
`5%
`
` Atelectasis
`3%
`3%
`3%
`6%
`
`
`Pleural effusion
`
`2%
`2%
`1%
`6%
` Agitation
`2%
`2%
`3%
`1%
`
`Tachycardia
`2%
`2%
`4%
`1%
`
` Anemia
`2%
`2%
`2%
`2%
`
` Hyperthermia
`2%
`2%
`3%
`0
`
`
`
`
` Chills
`2%
`2%
`3%
`2%
` Hyperglycemia
`2%
`2%
`2%
`3%
` Hypoxia
`2%
`2%
`2%
`3%
`
`
` Post-procedural hemorrhage
`2%
`2%
`3%
`4%
`
`
`Pulmonary edema
`1%
`1%
`1%
`3%
`
` Hypocalcemia
`1%
`1%
`0
`2%
`
` Acidosis
`1%
`1%
`1%
`2%
`
`Urine output decreased
`1%
`1%
`0
`2%
`
`
`Sinus tachycardia
`1%
`1%
`1%
`2%
` Ventricular tachycardia
`<1%
`1%
`1%
`5%
` Wheezing
`<1%
`1%
`0
`2%
` Edema peripheral
`<1%
`0
`1%
`2%
`
`
`*
`26 subjects in the all Precedex group and 10 subjects in the randomized Precedex group had exposure for
`
`greater than 24 hours.
`
`
`Adverse reaction information was also derived from the placebo-controlled, continuous infusion trials of Precedex
`
`for sedation in the surgical intensive care unit setting in which 387 patients received Precedex for less than 24 hours.
`
`The most frequently observed treatment-emergent adverse events included hypotension, hypertension, nausea,
`
`bradycardia, fever, vomiting, hypoxia, tachycardia and anemia (see Table 3).
`
`
`
`Table 3: Treatment-Emergent Adverse Events Occurring in >1%
`
`Of All Dexmedetomidine-Treated Patients in the Randomized
`
`
`Placebo-controlled Continuous Infusion <24 Hours ICU Sedation Studies
`
`
`
`
`Randomized Dexmedetomidine
`Placebo
`Adverse Event
`
`
`(N=387)
`(N=379)
`
`
`
`
`
`298
`299
`300
`301
`302
`303
`304
`305
`
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`Amneal Pharmaceuticals LLC – Exhibit 1007 – Page 6
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`

`

`
`
`
`
`
`
`13%
`18%
`9%
`3%
`4%
`
` 6%
` 3%
` 4%
`5%
` 4%
`2%
` 1%
` 3%
` 3%
` 3%
`2%
` 2%
` 2%
` 1%
`<1%
`<1%
`
`
`
`
`
`
`28%
`16%
`11%
`7%
`5%
`4%
`
` 4%
`4%
`3%
`3%
`3%
`3%
`2%
`
` 2%
` 2%
`2%
`2%
`
` 2%
` 2%
` 2%
`2%
`
`
`
`
`
`
`
`
`Hypotension
`Hypertension
`Nausea
`Bradycardia
`Fever
`Vomiting
`Atrial Fibrillation
`Hypoxia
`Tachycardia
`Hemorrhage
`Anemia
`Dry Mouth
`Rigors
`Agitation
`Hyperpyrexia
`Pain
`Hyperglycemia
`Acidosis
`Pleural Effusion
`Oliguria
`Thirst
`
`
`
`306
`
`307
`In a controlled clinical trial, Precedex was compared to midazolam for ICU sedation exceeding 24 hours duration.
`
`
`308
`Key treatment emergent adverse events occurring in dexmedetomidine or midazolam treated patients in the
`
`
`
`309
`randomized active comparator continuous infusion long-term intensive care unit sedation study are provided in
`310
`Table 4. The number (%) of subjects who had a dose-related increase in treatment-emergent adverse events by
`
`
`311 maintenance adjusted dose rate range in the Precedex group is provided in Table 5.
`
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`Amneal Pharmaceuticals LLC – Exhibit 1007 – Page 7
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`

`
`
`312
`
`Adverse Event
`
`Table 4: Key Treatment-Emergent Adverse Events Occurring in Dexmedetomidine- or Midazolam-
`Treated Patients in the Randomized Active Comparator Continuous Infusion Long-Term Intensive
`Care Unit Sedation Study*
`
`
`Dexmedetomidine
`
`(N=244)
`56%
`28%
`42%
`5%
`28%
`25%
`10%
`12%
`11%
`19%
`9%
`7%
`7%
`7%
`6%
`5%
`
`5%
`2%
`2%
`2%
`1%
`
`
`Midazolam
`
`(N=122)
`56%
`27%
`19%
`1%
`42%
`44%
`10%
`15%
`15%
`30%
`13%
`2%
`6%
`2%
`6%
`6%
`
`3%
`1%
`1%
`6%
`7%
`
`
`Hypotension1
`
`Hypotension requiring intervention
`
`Bradycardia2
` Bradycardia requiring intervention
`
`Systolic Hypertension3
`
`Tachycardia4
`
`Tachycardia requiring intervention
`Diastolic Hypertension3
`Hypertension3
`
`
`
`Hypertension requiring intervention†
`Hypokalemia
`Pyrexia
`Agitation
`Hyperglycemia
`
`Constipation
`Hypoglycemia
`Respiratory Failure
`Renal Failure Acute
`
`
`Acute Respiratory Distress Syndrome
`Generalized edema
`Hypomagnesemia
` †Includes any type of hypertension.
`
`
`
`
`1. Hypotension was defined in absolute terms as Systolic blood pressure of <80 mmHg or Diastolic blood pressure of <50 mmHg or in
` relative terms as <30% lower than pre-study drug infusion value.
`
`
` 2. Bradycardia was defined in absolute terms as <40 bpm or in relative terms as <30% lower than pre-study drug infusion value.
`
`3. Hypertension was defined in absolute terms as Systolic blood pressure >180 mmHg or Diastolic blood pressure of >100 mmHg or in
`
`
`
`
` relative terms as >30% higher than pre-study drug infusion value.
`
`
`Tachycardia was defined in absolute terms as >120 bpm or in relative terms as >30% greater than pre-study drug infusion value.
`
`
`4.
`
`
`
`The following adverse events occurred between 2 and 5% for Precedex and Midazolam, respectively: renal failure
`
`
`acute (2.5%, 0.8%), acute respiratory distress syndrome (2.5%, 0.8%), and respiratory failure (4.5%, 3.3%).
`
`
`
`
`
`313
`314
`315
`316
`317
`318
`319
`320
`321
`322
`323
`
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`Amneal Pharmaceuticals LLC – Exhibit 1007 – Page 8
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`

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`
`
`
`
`> 0.7 to ≤ 1.1*
`
`
`N = 78
`
`5%
`8%
`5%
`5%
`
`4%
`6%
`3%
`
`> 1.1*
`
`N = 71
`
`14%
`14%
`9%
`7%
`
`9%
`10%
`9%
`
`Table 5. Number (%) of subjects who had a dose-related increase in Treatment Emergent Adverse
`Events by maintenance adjusted dose rate range in the Precedex group
`
` Precedex mcg/kg/hr
`
`≤ 0.7*
`
`Adverse Event
`N = 95
`
`6%
`Constipation
`5%
`Agitation
`5%
`Anxiety
`
`3%
`Oedema peripheral
`
`
`2%
`Atrial fibrillation
`2%
`Respiratory failure
`
`1%
`Acute respiratory distress syndrome
`
`*Average maintenance dose over the entire study drug administration
`
`
`Procedural Sedation
`Adverse reaction information is derived from the two trials for procedural sedation in which 318 patients received
`
`Precedex. The mean total dose was 1.6 mcg/kg (range: 0.5 to 6.7), mean dose per hour was 1.3 mcg/kg/hr (range:
`
`
`
`
`
`
`0.3 to 6.1) and the mean duration of infusion of 1.5 hours (range: 0.1 to 6.2). The population was between 18 to 93
`
`years of age, 30% > 65 years of age, 52% male and 61% Caucasian.
`
`Treatment-emergent adverse reactions occurring at an incidence of >2% are provided in Table 3. The most frequent
`adverse reactions were hypotension, bradycardia, and dry mouth [see Warnings and Precautions (5.2)]. Pre­
`
`
`specified criteria for the vital signs to be reported as adverse reactions are footnoted below the table. The decrease in
`
`
`
`
`respiratory rate and hypoxia was similar between Precedex and comparator groups in both studies.
`
`
`Table 6. Adverse Reactions With an Incidence > 2%— Procedural Sedation Population
`
`
`
`
`
`
`
`
`
`
`
`
`Precedex
`Placebo
`N = 318
`N = 113
`Adverse Event
`(%)
`(%)
`Hypotension1
`
`54%
`30%
`Respiratory depression2
`37%
`32%
`
` Bradycardia3
`14%
`4%
`
` Hypertension4
`13%
`24%
`
` Tachycardia5
`5%
`17%
`Nausea
`3%
`2%
`
`Dry mouth
`3%
`1%
`Hypoxia6
`
`2%
`3%
`Bradypnea
`2%
`4%
`
` 1 Hypotension was defined in absolute and relative terms as Systolic blood pressure of <80 mmHg or <30% lower
`
` than pre-study drug infusion value, or diastolic blood pressure of <50 mmHg
`
`
`
`
`2 Respiratory depression was defined in absolute and relative terms as respiratory rate (RR)<8 beats per minute or
`
`
`
`>25% decrease from baseline
`
`3 Bradycardia was defined in absolute and relative terms as <40 beats per minute or <30% lower than pre-study
`
`
`
`drug infusion value.
`
`4 Hypertension was defined in absolute and relative terms as Systolic blood pressure >180 mmHg or >30% higher
`
`
`
`
`
`
`
`
`
`
`
`than pre-study drug infusion value or diastolic blood pressure of >100 mmHg.
`
`5 Tachycardia was defined in absolute and relative terms as >120 beats per minute or >30% greater than pre-study
`
`
`drug infusion value.
`6 Hypoxia was defined in absolute and relative terms as SpO2 < 90% or 10% decrease from baseline
`
`6.2 Postmarketing Experience
`
`
`
`324
`
`325
`326
`327
`328
`329
`330
`331
`332
`333
`334
`335
`336
`
`337
`338
`339
`340
`341
`342
`343
`344
`345
`346
`347
`348
`349
`
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`

`

`
`
`350
`351
`352
`353
`354
`355
`
`
`The following adverse reactions have been identified during post approval use of Precedex. Because these
`reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably
`
`
`estimate their frequency or establish a causal relationship to drug exposure.
`
`
`Hypotension and bradycardia were the most common adverse reactions associated with the use of Precedex
`
`during post approval use of the drug.
`
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`
`
`Table 7: Adverse Reactions Experienced During Post-approval
` Use of Precedex
`
`
`
`
`
`356
`
`
`
`Preferred Term
`Fever, hyperpyrexia, hypovolemia,
`
`light anesthesia, pain, rigors
`
`Blood pressure fluctuation, heart disorder,
`
`
`hypertension, hypotension, myocardial infarction
`
`
`Dizziness, headache, neuralgia,
`
`
`neuritis, speech disorder, convulsion
`
`
`Abdominal pain, diarrhea, vomiting,
`nausea
`Arrhythmia, ventricular arrhythmia,
`bradycardia, hypoxia,
`atrioventricular block, cardiac arrest,
`extrasystoles, atrial fibrillation, heart
`
`block, t wave inversion, tachycardia,
`supraventricular tachycardia,
`ventricular tachycardia
`
`Increased gamma-glutamyl transpepsidase, hepatic function abnormal,
`hyperbilirubinemia, alanine transaminase,
`aspartate aminotransferase
`Acidosis, respiratory acidosis,
`hyperkalemia, increased alkaline
`phosphatase, thirst, hypoglycemia
`
`Agitation, confusion, delirium,
`
`hallucination, illusion
`Anemia
`
`
`Blood urea nitrogen increased, oliguria
`Apnea, bronchospasm, dyspnea,
`hypercapnia, hypoventilation, hypoxia,
`pulmonary congestion
`Increased sweating
`
`Hemorrhage
`Photopsia, abnormal vision
`
`
`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 Biliary
`System Disorders
`
`
`Metabolic and
`Nutritional
`Disorders
`Psychiatric
`Disorders
`Red Blood Cell
`Disorders
`Renal disorders
`
`Respiratory System
`Disorders
`
`Skin and
`
`Appendages
`Disorders
`Vascular disorders
`Vision Disorders
`
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`Amneal Pharmaceuticals LLC – Exhibit 1007 – Page 11
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`

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`
`
`7 DRUG INTERACTIONS
`
`
`
`7.1 Anesthetics, Sedatives, Hypnotics, Opioids
`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 Precedex and isoflurane,
`
`propofol, alfentanil and midazolam have been demonstrated. However, due to possible pharmacodynamic
`interactions, when co-administered with Precedex, a reduction in dosage of Precedex or the concomitant
`
`anesthetic, sedative, hypnotic or opioid may be required.
`
`
`
`7.2 Neuromuscular Blockers
`
`In one study of 10 healthy volunteers, administration of Precedex for 45 minutes at a plasma concentration
`
`
`
`
`of one ng/mL resulted in no clinically meaningful increases in the magnitude of neuromuscular blockade
`associated with rocuronium administration.
`
`8 USE IN SPECIFIC POPULATIONS
`
`
`
`
`8.1 Pregnancy
`Pregnancy Category C:
`
`There are no adequate and well-controlled studies of Precedex use in pregnant women. In an in-vitro human
`placenta study, placental transfer of dexmedetomidine occurred. In a study in the pregnant rat, placental transfer
`
`of dexmedetomidine was observed when radiolabeled dexmedetomidine was administered subcutaneously.
`
`
`
`
`
`Thus, fetal exposure should be expected in humans, and Precedex should be used during pregnancy only if the
`potential benefits justify the potential risk to the fetus.
`
`Teratogenic effects were not observed in rats following subcutaneous administration of dexmedetomidine
`
`
`
`
`