DEXMEDETOMIDINE HYDROCHLORIDE: Package Insert and Label Information (Page 3 of 4)

13 NONCLINICAL TOXICOLOGY

13.1 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 (E. 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, rat S9 metabolic activation. In contrast, dexmedetomidine was not clastogenic in the in vitro human lymphocyte chromosome aberration test with or without human S9 metabolic activation. Although dexmedetomidine was clastogenic in an in vivo mouse micronucleus test in NMRI mice, there was no evidence of clastogenicity in CD-1 mice. Fertility in male or female rats was not affected after daily subcutaneous injections of dexmedetomidine at doses up to 54 mcg/kg (less than the maximum recommended human intravenous dose on a mcg/m2 basis) administered from 10 weeks prior to mating in males, and 3 weeks prior to mating and during mating in females.

13.2 Animal Pharmacology & OR Toxicology

There were no differences in the adrenocorticotropic hormone (ACTH)-stimulated cortisol response in dogs following a single dose of dexmedetomidine compared to saline control. However, after continuous subcutaneous infusions of dexmedetomidine at 3 mcg/kg/hr and 10 mcg/kg/hr for one week in dogs (exposures estimated to be within the clinical range), the ACTH-stimulated cortisol response was diminished by approximately 27% and 40%, respectively, compared to saline-treated control animals indicating a dose-dependent adrenal suppression.

14 CLINICAL STUDIES

The safety and efficacy of dexmedetomidine hydrochloride in 0.9% sodium chloride injection has been evaluated in randomized, double-blind, placebo- controlled multicenter clinical trials in 1185 adult patients.

14.1 Intensive Care Unit Sedation

Two randomized, double-blind, parallel-group, placebo-controlled multicenter clinical trials included 754 adult patients being treated in a surgical intensive care unit. All patients were initially intubated and received mechanical ventilation. These trials evaluated the sedative properties of dexmedetomidine hydrochloride in 0.9% sodium chloride injection 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 dexmedetomidine hydrochloride in 0.9% sodium chloride injection 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 9.

Table 9: Ramsay Level of Sedation Scale

Clinical Score Level of Sedation Achieved
6 Asleep, no response
5 Asleep, sluggish response to light glabellar tap or loud auditory stimulus
4 Asleep, but with brisk response to light glabellar tap or loud auditory stimulus
3 Patient responds to commands
2 Patient cooperative, oriented, and tranquil
1 Patient anxious, agitated, or restless

In the first study, 175 adult patients were randomized to receive placebo and 178 to receive dexmedetomidine hydrochloride in 0.9% sodium chloride injection 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 one mcg/kg intravenous 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 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 hydrochloride in 0.9% sodium chloride injection (see Table 10).

A second prospective primary analysis assessed the sedative effects of dexmedetomidine hydrochloride in 0.9% sodium chloride injection 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 hydrochloride in 0.9% sodium chloride injection group maintained a Ramsay sedation score of ≥3 without receiving any midazolam rescue compared to the placebo group (see Table 10).

Table 10: Midazolam Use as Rescue Medication During Intubation (ITT)

Study One

Placebo (N = 175) Dexmedetomidine hydrochloride in 0.9% sodium chloride injection (N = 178) p-value
Mean Total Dose (mg) of Midazolam Standard deviation 19 mg53 mg 5 mg19 mg 0.0011*
Categorized Midazolam Use
0 mg 43 (25%) 108 (61%) <0.001**
0–4 mg 34 (19%) 36 (20%)
>4 mg 98 (56%) 34 (19%)

ITT (intent-to-treat) population includes all randomized patients.

* ANOVA model with treatment center.

** Chi-square.

A prospective secondary analysis assessed the dose of morphine sulfate administered to patients in the dexmedetomidine hydrochloride in 0.9% sodium chloride injection and placebo groups. On average, dexmedetomidine hydrochloride in 0.9% sodium chloride injection -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 hydrochloride in 0.9% sodium chloride injection patients received no morphine sulfate for pain versus 19% (33 of 175 patients) in the placebo group.

In a second study, 198 adult patients were randomized to receive placebo and 203 to receive dexmedetomidine hydrochloride in 0.9% sodium chloride injection 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 one mcg/kg intravenous 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 of rescue medication (propofol) needed to maintain sedation as specified while intubated.

Patients randomized to placebo received significantly more propofol than patients randomized to dexmedetomidine hydrochloride in 0.9% sodium chloride injection (see Table 11).

A significantly greater percentage of patients in the dexmedetomidine hydrochloride in 0.9% sodium chloride injection group compared to the placebo group maintained a Ramsay sedation score of ≥3 without receiving any propofol rescue (see Table 11).

Table 11: Propofol Use as Rescue Medication During Intubation (ITT)

Study Two

Placebo (N = 198) Dexmedetomidine hydrochloride in 0.9% sodium chloride injection (N = 203) p-value
Mean Total Dose (mg) of Propofol Standard deviation 513 mg782 mg 72 mg249 mg <0.0001*
Categorized Propofol Use
0 mg 47 (24%) 122 (60%) <0.001**
0–50 mg 30 (15%) 43 (21%)
>50 mg 121 (61%) 38 (19%)

* ANOVA model with treatment center.

** Chi-square

A prospective secondary analysis assessed the dose of morphine sulfate administered to patients in the dexmedetomidine hydrochloride in 0.9% sodium chloride injection and placebo groups. On average, dexmedetomidine hydrochloride in 0.9% sodium chloride injection -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 hydrochloride in 0.9% sodium chloride injection patients received no morphine sulfate for pain versus 15% (30 of 198 patients) in the placebo group.

In a controlled clinical trial, dexmedetomidine hydrochloride in 0.9% sodium chloride injection was compared to midazolam for ICU sedation exceeding 24 hours duration. Dexmedetomidine hydrochloride in 0.9% sodium chloride injection was not shown to be superior to midazolam for the primary efficacy endpoint, the percent of time patients were adequately sedated (81% versus 81%). In addition, administration of dexmedetomidine hydrochloride in 0.9% sodium chloride injection for longer than 24 hours was associated with tolerance, tachyphylaxis, and a dose-related increase in adverse events [see Adverse Reactions (6.1) ].

14.2 Procedural Sedation

The safety and efficacy of dexmedetomidine hydrochloride in 0.9% sodium chloride injection for sedation of non-intubated patients prior to and/or during surgical and other procedures was evaluated in two randomized, double-blind, placebo-controlled multicenter clinical trials. Study 1 evaluated the sedative properties of dexmedetomidine hydrochloride in 0.9% sodium chloride injection in patients having a variety of elective surgeries/procedures performed under monitored anesthesia care. Study 2 evaluated dexmedetomidine hydrochloride in 0.9% sodium chloride injection in patients undergoing awake fiberoptic intubation prior to a surgical or diagnostic procedure.

In Study 1, the sedative properties of dexmedetomidine hydrochloride in 0.9% sodium chloride injection were evaluated by comparing the percent of patients not requiring rescue midazolam to achieve a specified level of sedation using the standardized Observer’s Assessment of Alertness/Sedation Scale (see Table 12).

Table 12: Observer’s Assessment of Alertness/Sedation

Assessment Categories
Responsiveness Speech Facial Expression Eyes Composite Score
Responds readily to name spoken in normal tone Normal Normal Clear, no ptosis 5 (alert)
Lethargic response to name spoken in normal tone Mild slowing or thickening Mild relaxation Glazed or mild ptosis (less than half the eye) 4
Responds only after name is called loudly and/or repeatedly Slurring or prominent slowing Marked relaxation (slack jaw) Glazed and marked ptosis (half the eye or more) 3
Responds only after mild prodding or shaking Few recognizable words 2
Does not respond to mild prodding or shaking 1 (deep sleep)

Patients were randomized to receive a loading infusion of either dexmedetomidine hydrochloride in 0.9% sodium chloride injection 1 mcg/kg, dexmedetomidine hydrochloride in 0.9% sodium chloride injection 0.5 mcg/kg, or placebo (normal saline) given over 10 minutes and followed by a maintenance infusion started at 0.6 mcg/kg/hr. The maintenance infusion of study drug could be titrated from 0.2 mcg/kg/hr to 1 mcg/kg/hr to achieve the targeted sedation score (Observer’s Assessment of Alertness/Sedation Scale ≤4). Patients were allowed to receive rescue midazolam as needed to achieve and/or maintain an Observer’s Assessment of Alertness/Sedation Scale ≤4. After achieving the desired level of sedation, a local or regional anesthetic block was performed. Demographic characteristics were similar between the dexmedetomidine hydrochloride in 0.9% sodium chloride injection and comparator groups. Efficacy results showed that dexmedetomidine hydrochloride in 0.9% sodium chloride injection was more effective than the comparator group when used to sedate non-intubated patients requiring monitored anesthesia care during surgical and other procedures (see Table 13).

In Study 2, the sedative properties of dexmedetomidine hydrochloride in 0.9% sodium chloride injection were evaluated by comparing the percent of patients requiring rescue midazolam to achieve or maintain a specified level of sedation using the Ramsay Sedation Scale score ≥2 (see Table 9).

Patients were randomized to receive a loading infusion of dexmedetomidine hydrochloride in 0.9% sodium chloride injection 1 mcg/kg or placebo (normal saline) given over 10 minutes and followed by a fixed maintenance infusion of 0.7 mcg/kg/hr. After achieving the desired level of sedation, topicalization of the airway occurred. Patients were allowed to receive rescue midazolam as needed to achieve and/or maintain a Ramsay Sedation Scale ≥2. Demographic characteristics were similar between the dexmedetomidine hydrochloride in 0.9% sodium chloride injection and comparator groups. For efficacy results see Table 13.

Table 13: Key Efficacy Results of Procedural Sedation Studies

Study Loading Infusion Treatment Arm Number of Patients Enrolleda % Not Requiring Midazolam Rescue Confidenceb Interval on the Difference vs. Placebo Mean (SD) Total Dose (mg) of Rescue Midazolam Required Confidenceb Intervals of the Mean Rescue Dose
Study 1 Dexmedetomidine0.5 mcg/kg 134 40 37 (27, 48) 1.4 (1.7) -2.7 (-3.4, -2.0)
Dexmedetomidine 1 mcg/kg 129 54 51 (40, 62) 0.9 (1.5) -3.1 (-3.8, -2.5)
placebo 63 3 4.1 (3.0)
Study 2 Dexmedetomidine 1 mcg/kg 55 53 39 (20, 57) 1.1 (1.5) -1.8 (-2.7, -0.9)
placebo 50 14 2.9 (3.0)

a Based on ITT population defined as all randomized and treated patients.

b Normal approximation to the binomial with continuity correction.

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