Dexmedetomidine
These highlights do not include all the information needed to use DEXMEDETOMIDINE INJECTION safely and effectively. See full prescribing information for DEXMEDETOMIDINE INJECTION. DEXMEDETOMIDINE Injection, for intravenous use. Initial U.S. Approval: 1999
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Mar 5, 2024
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Dexmedetomidine
Product Details
FDA regulatory identification and product classification information
FDA Identifiers
Product Classification
Product Specifications
INGREDIENTS (3)
Drug Labeling Information
PACKAGE LABEL.PRINCIPAL DISPLAY PANEL
PRINCIPAL DISPLAY PANEL
PRINCIPAL DISPLAY PANEL - VIAL LABEL
DEXMEDETOMIDINE INJECTION, USP
100MCG/ML 2ML
RX Only
PRINCIPAL DISPLAY PANEL - OUTER PACKAGE
NDC 71872-7323-1
DEXMEDETOMIDINE INJECTION, USP
100MCG/ML 2ML
1 - 2ML SINGLE-DOSE VIAL
RX Only
INDICATIONS & USAGE SECTION
1 INDICATIONS AND USAGE
1.1 Intensive Care Unit Sedation
Dexmedetomidine injection is indicated for sedation of initially intubated and
mechanically ventilated patients during treatment in an intensive care
setting. Dexmedetomidine injection should be administered by continuous
infusion not to exceed 24 hours.
Dexmedetomidine injection has been continuously infused in mechanically
ventilated patients prior to extubation, during extubation, and post-
extubation. It is not necessary to discontinue dexmedetomidine injection prior
to extubation.
1.2 Procedural Sedation
Dexmedetomidine injection is indicated for sedation of non-intubated patients
prior to and/or during surgical and other procedures.
Dexmedetomidine injection is a relatively selective alpha 2-adrenergic agonist indicated for:
- Sedation of initially intubated and mechanically ventilated patients during treatment in an intensive care setting. Administer dexmedetomidine injection by continuous infusion not to exceed 24 hours. ( 1.1)
- Sedation of non-intubated patients prior to and/or during surgical and other procedures. ( 1.2)
CONTRAINDICATIONS SECTION
4 CONTRAINDICATIONS
None.
None. ( 4)
ADVERSE REACTIONS SECTION
6 ADVERSE REACTIONS
The following clinically significant adverse reactions are described elsewhere
in the labeling:
• Hypotension, bradycardia and sinus arrest [ see Warnings and Precautions (5.2)]
• Transient hypertension [see Warnings and Precautions (5.3)]
6.1 Clinical Trials 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 the clinical trials of another drug and may not reflect
the rates observed in practice.
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.
Intensive Care Unit Sedation
Adverse reaction information is derived from the continuous infusion trials of
dexmedetomidine injection for sedation in the Intensive Care Unit setting in
which 1,007 adult patients received dexmedetomidine injection. The mean total
dose was 7.4 mcg/kg (range: 0.8 to 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 (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% Caucasian. Treatment-emergent adverse reactions
occurring at an incidence of >2% are provided in Table 2. The most frequent
adverse reactions were hypotension, bradycardia and dry mouth [see Warnings and Precautions (5.2)].
Table 2: Adverse Reactions with an Incidence >2%-Adult Intensive Care Unit Sedation Population <24 hours*
|
Adverse Event |
All Dexmedetomidine Injection |
Randomized Dexmedetomidine Injection |
Placebo |
Propofol |
|
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 dexmedetomidine injection group and 10 subjects in the randomized dexmedetomidine injection group had exposure for greater than 24 hours
Adverse reaction information was also derived from the placebo-controlled,
continuous infusion trials of dexmedetomidine injection for sedation in the
surgical intensive care unit setting in which 387 adult patients received
dexmedetomidine injection 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 Adult Patients in the Randomized Placebo-Controlled
Continuous Infusion <24 Hours ICU Sedation Studies
|
Adverse Event |
Randomized Dexmedetomidine |
Placebo |
|
Hypotension |
28% |
13% |
|
Hypertension |
16% |
18% |
|
Nausea |
11% |
9% |
|
Bradycardia |
7% |
3% |
|
Fever |
5% |
4% |
|
Vomiting |
4% |
6% |
|
Atrial Fibrillation |
4% |
3% |
|
Hypoxia |
4% |
4% |
|
Tachycardia |
3% |
5% |
|
Hemorrhage |
3% |
4% |
|
Anemia |
3% |
2% |
|
Dry Mouth |
3% |
1% |
|
Rigors |
2% |
3% |
|
Agitation |
2% |
3% |
|
Hyperpyrexia |
2% |
3% |
|
Pain |
2% |
2% |
|
Hyperglycemia |
2% |
2% |
|
Acidosis |
2% |
2% |
|
Pleural Effusion |
2% |
1% |
|
Oliguria |
2% |
<1% |
|
Thirst |
2% |
<1% |
In a controlled clinical trial, dexmedetomidine injection was compared to
midazolam for ICU sedation exceeding 24 hours duration in adult patients. 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 are provided in Table 4. The number
(%) of subjects who had a dose-related increase in treatment-emergent adverse
events by maintenance adjusted dose rate range in the dexmedetomidine
injection group is provided in Table 5.
Table 4: Key Treatment-Emergent Adverse Events Occurring in Dexmedetomidine-
or Midazolam-Treated Adult Patients in the Randomized Active Comparator
Continuous Infusion Long-Term Intensive Care Unit Sedation Study
|
Adverse Event |
Dexmedetomidine |
Midazolam |
|
Hypotension 1 |
56% |
56% |
|
Hypotension Requiring Intervention |
28% |
27% |
|
Bradycardia 2 |
42% |
19% |
|
Bradycardia Requiring Intervention |
5% |
1% |
|
Systolic Hypertension 3 |
28% |
42% |
|
Tachycardia 4 |
25% |
44% |
|
Tachycardia Requiring Intervention |
10% |
10% |
|
Diastolic Hypertension 3 |
12% |
15% |
|
Hypertension 3 |
11% |
15% |
|
Hypertension Requiring Intervention † |
19% |
30% |
|
Hypokalemia |
9% |
13% |
|
Pyrexia |
7% |
2% |
|
Agitation |
7% |
6% |
|
Hyperglycemia |
7% |
2% |
|
Constipation |
6% |
6% |
|
Hypoglycemia |
5% |
6% |
|
Respiratory Failure |
5% |
3% |
|
Renal Failure Acute |
2% |
1% |
|
Acute Respiratory Distress Syndrome |
2% |
1% |
|
Generalized Edema |
2% |
6% |
|
Hypomagnesemia |
1% |
7% |
†Includes any type of hypertension
1Hypotension 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
2Bradycardia was defined in absolute terms as <40 bpm or in relative terms as
≤30% lower than pre-study drug infusion value
3Hypertension 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
4Tachycardia was defined in absolute terms as >120 bpm or in relative terms as
≥30% greater than pre-study drug infusion value
The following adverse events occurred between 2 and 5% for Dexmedetomidine 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%).
Table 5: Number (%) of Adult Subjects Who Had a Dose-Related Increase in
Treatment Emergent Adverse Events by Maintenance Adjusted Dose Rate Range in
the Dexmedetomidine Injection Group
|
Dexmedetomidine Injection (mcg/kg/hr) | |||
|
Adverse Event |
≤0.7* |
>0.7 to ≤1.1* |
>1.1* |
|
Constipation |
6% |
5% |
14% |
|
Agitation |
5% |
8% |
14% |
|
Anxiety |
5% |
5% |
9% |
|
Edema Peripheral |
3% |
5% |
7% |
|
Atrial Fibrillation |
2% |
4% |
9% |
|
Respiratory Failure |
2% |
6% |
10% |
|
Acute Respiratory Distress Syndrome |
1% |
3% |
9% |
- Average maintenance dose over the entire study drug administration
Procedural Sedation
Adverse reaction information is derived from the two trials for procedural
sedation [see Clinical Studies (14.2)] in which 318 adult patients received
dexmedetomidine injection. 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, ASA I-IV, 30% ≥65 years of age, 52% male and
61% Caucasian.
Treatment-emergent adverse reactions occurring at an incidence of >2% are
provided in Table 6. 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
dexmedetomidine injection and comparator groups in both studies.
Table 6: Adverse Reactions With an Incidence >2%—Procedural Sedation Population
|
Adverse Event |
Dexmedetomidine Injection |
Placebo |
|
Hypotension 1 |
54% |
30% |
|
Respiratory Depression 2 |
37% |
32% |
|
Bradycardia 3 |
14% |
4% |
|
Hypertension 4 |
13% |
24% |
|
Tachycardia 5 |
5% |
17% |
|
Nausea |
3% |
2% |
|
Dry Mouth |
3% |
1% |
|
Hypoxia6 |
2% |
3% |
|
Bradypnea |
2% |
4% |
1Hypotension 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.
2Respiratory depression was defined in absolute and relative terms as
respiratory rate (RR) <8 beats per minute or > 25% decrease from baseline.
3Bradycardia was defined in absolute and relative terms as <40 beats per
minute or ≤30% lower than pre-study drug infusion value.
4Hypertension 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.
5Tachycardia was defined in absolute and relative terms as >120 beats per
minute or ≥30% greater than pre-study drug infusion value.
6Hypoxia was defined in absolute and relative terms as SpO2 <90% or 10%
decrease from baseline.
6.2 Postmarketing Experience
The following adverse reactions have been identified during post approval use
of dexmedetomidine injection. 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 dexmedetomidine injection during post approval use of the
drug.
Table 7: Adverse Reactions Experienced During Post-Approval Use of
Dexmedetomidine Injection
|
System Organ Class |
Preferred Term |
|
Blood and Lymphatic System Disorders |
Anemia |
|
Cardiac Disorders |
Arrhythmia, atrial fibrillation, atrioventricular block, bradycardia, cardiac arrest, cardiac disorder, extrasystoles, myocardial infarction, supraventricular tachycardia, tachycardia, ventricular arrhythmia, ventricular tachycardia |
|
Eye Disorders |
Photopsia, visual impairment |
|
Gastrointestinal Disorders |
Abdominal pain, diarrhea, nausea, vomiting |
|
General Disorders and Administration Site Conditions |
Chills, hyperpyrexia, pain, pyrexia, thirst |
|
Hepatobiliary Disorders |
Hepatic function abnormal, hyperbilirubinemia |
|
Investigations |
Alanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased, blood urea increased, electrocardiogram T wave inversion, gammaglutamyltransferase increased, electrocardiogram QT prolonged |
|
Metabolism and Nutrition Disorders |
Acidosis, hyperkalemia, hypoglycemia, hypovolemia, hypernatremia |
|
Nervous System Disorders |
Convulsion, dizziness, headache, neuralgia, neuritis, speech disorder |
|
Psychiatric Disorders |
Agitation, confusional state, delirium, hallucination, illusion |
|
Renal and Urinary Disorders |
Oliguria, polyuria |
|
Respiratory, Thoracic and Mediastinal Disorders |
Apnea, bronchospasm, dyspnea, hypercapnia, hypoventilation, hypoxia, pulmonary congestion, respiratory acidosis |
|
Skin and Subcutaneous Tissue Disorders |
Hyperhidrosis, pruritus, rash, urticaria |
|
Surgical and Medical Procedures |
Light anesthesia |
|
Vascular Disorders |
Blood pressure fluctuations, hemorrhage, hypertension, hypotension |
- The most common adverse reactions (incidence >2%) are hypotension, bradycardia, and dry mouth. ( 6.1)
- Adverse reactions associated with infusions >24 hours in duration include ARDS, respiratory failure, and agitation. ( 6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Piramal Critical Care at 1-800-414-1901, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
DRUG INTERACTIONS SECTION
7 DRUG INTERACTIONS
7.1 Anesthetics, Sedatives, Hypnotics, Opioids
Co-administration of dexmedetomidine injection 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 injection and isoflurane, propofol, alfentanil and midazolam
have been demonstrated. However, due to possible pharmacodynamic interactions,
when co-administered with dexmedetomidine injection, a reduction in dosage of
dexmedetomidine injection or the concomitant anesthetic, sedative, hypnotic or
opioid may be required.
7.2 Neuromuscular Blockers
In one study of 10 healthy adult volunteers, administration of dexmedetomidine
injection 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.
Anesthetics, Sedatives, Hypnotics, Opioids: Enhancement of pharmacodynamic effects. Reduction in dosage of dexmedetomidine hydrochloride or the concomitant medication may be required. ( 7.1)
DOSAGE FORMS & STRENGTHS SECTION
3 DOSAGE FORMS AND STRENGTHS
Dexmedetomidine Injection, USP is clear and colorless and is available as
follows.
Dexmedetomidine Injection, USP 200 mcg/2 mL (100 mcg/mL) in a glass vial with
pink cap. To be used after dilution.
Dexmedetomidine Injection, USP 200 mcg/2 mL (100 mcg/mL) in a glass vial with pink cap. To be used after dilution. ( 3)
USE IN SPECIFIC POPULATIONS SECTION
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category C
There are no adequate and well-controlled studies of dexmedetomidine injection
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 dexmedetomidine injection 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 during the period of fetal organogenesis
(from gestation day 5 to 16) with doses up to 200 mcg/kg (representing a dose
approximately equal to the maximum recommended human intravenous dose based on
body surface area) or in rabbits following intravenous administration of
dexmedetomidine during the period of fetal organogenesis (from gestation day 6
to 18) with doses up to 96 mcg/kg (representing approximately half the human
exposure at the maximum recommended dose based on plasma area under the time-
curve comparison). However, fetal toxicity, as evidenced by increased post-
implantation losses and reduced live pups, was observed in rats at a
subcutaneous dose of 200 mcg/kg. The no-effect dose in rats was 20 mcg/kg
(representing a dose less than the maximum recommended human intravenous dose
based on a body surface area comparison). In another reproductive toxicity
study when dexmedetomidine was administered subcutaneously to pregnant rats at
8 and 32 mcg/kg (representing a dose less than the maximum recommended human
intravenous dose based on a body surface area comparison) from gestation day
16 through weaning, lower offspring weights were observed. Additionally, when
offspring of the 32 mcg/kg group were allowed to mate, elevated fetal and
embryocidal toxicity and delayed motor development was observed in second
generation offspring.
8.2 Labor and Delivery
The safety of dexmedetomidine injection during labor and delivery has not been
studied.
8.3 Nursing Mothers
It is not known whether dexmedetomidine hydrochloride is excreted in human
milk. Radio-labeled dexmedetomidine administered subcutaneously to lactating
female rats was excreted in milk. Because many drugs are excreted in human
milk, caution should be exercised when dexmedetomidine injection is
administered to a nursing woman.
8.4 Pediatric Use
Safety and efficacy have not been established for Procedural or ICU Sedation
in pediatric patients. One assessor-blinded trial in pediatric patients and
two open label studies in neonates were conducted to assess efficacy for ICU
sedation. These studies did not meet their primary efficacy endpoints and the
safety data submitted were insufficient to fully characterize the safety
profile of dexmedetomidine injection for this patient population. The use of
dexmedetomidine for procedural sedation in pediatric patients has not been
evaluated.
8.5 Geriatric Use
Intensive Care Unit Sedation
A total of 729 patients in the clinical studies were 65 years of age and over.
A total of 200 patients 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 dexmedetomidine injection [see Warnings and Precautions (5.2)].Therefore, a dose reduction may be considered in
patients over 65 years of age [see Dosage and Administration (2.2, 2.3), Clinical Pharmacology (12.3)].
Procedural Sedation
A total of 131 patients in the clinical studies were 65 years of age and over.
A total of 47 patients were 75 years of age and over. Hypotension occurred in
a higher incidence in dexmedetomidine injection-treated patients 65 years or
older (72%) and 75 years or older (74%) as compared to patients <65 years
(47%). A reduced loading dose of 0.5 mcg/kg given over 10 minutes is
recommended and a reduction in the maintenance infusion should be considered
for patients greater than 65 years of age.
8.6 Hepatic Impairment
Since dexmedetomidine clearance decreases with increasing severity of hepatic
impairment, dose reduction should be considered in patients with impaired
hepatic function [see Dosage and Administration (2.2, 2.3) and Clinical Pharmacology (12.3)].
- Pregnancy: Based on animal data, may cause fetal harm. ( 8.1)
- Nursing Mothers: Caution should be exercised when administered to a nursing woman. ( 8.3)
- Geriatric Patients: Dose reduction should be considered. ( 2.2, 2.3, 5.2, 8.5)
- Hepatic Impairment: Dose reduction should be considered. ( 2.2, 2.3, 5.7, 8.6)
See 17 for PATIENT COUNSELING INFORMATION.
DRUG ABUSE AND DEPENDENCE SECTION
9 DRUG ABUSE AND DEPENDENCE
9.1 Controlled Substance
Dexmedetomidine injection (dexmedetomidine hydrochloride) is not a controlled
substance.
9.3 Dependence
The dependence potential of dexmedetomidine injection has not been studied in
humans. However, since studies in rodents and primates have demonstrated that
dexmedetomidine injection exhibits pharmacologic actions similar to those of
clonidine, it is possible that dexmedetomidine injection may produce a
clonidine-like withdrawal syndrome upon abrupt discontinuation [see Warnings and Precautions (5.5)].
OVERDOSAGE SECTION
10 OVERDOSAGE
The tolerability of dexmedetomidine injection was studied in one study in
which healthy adult 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 atrioventricular block and second
degree heart block. No hemodynamic compromise was noted with the
atrioventricular block and the heart block resolved spontaneously within one
minute.
Five adult patients received an overdose of dexmedetomidine injection in the
intensive care unit 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 dexmedetomidine injection (19.4
mcg/kg), had cardiac arrest from which he was successfully resuscitated.
DESCRIPTION SECTION
11 DESCRIPTION
Dexmedetomidine injection, USP (dexmedetomidine hydrochloride) is a sterile, nonpyrogenic solution suitable for intravenous infusion following dilution. Dexmedetomidine hydrochloride, USP is the S-enantiomer of medetomidine and is chemically described as (+)-4-(S)-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole monohydrochloride. Dexmedetomidine hydrochloride, USP has a molecular weight of 236.7 and the empirical formula is C 13H 16N 2• HCl and the structural formula is:
Dexmedetomidine hydrochloride, USP is a solid, white or almost white powder
that is freely soluble in water and alcohols, slightly soluble in methylene
chloride and acetone and has a pKa of 7.1. Its partition coefficient in-
octanol: water at pH 7.4 is 2.89.
Dexmedetomidine injection, USP is supplied as a clear, colorless, isotonic
solution with a pH of 4.5 to 7.0. Each mL contains 118 mcg of dexmedetomidine
hydrochloride, USP equivalent to 100 mcg (0.1 mg) of dexmedetomidine and 9 mg
of sodium chloride in water and is to be used after dilution. The solution is
preservative-free and contains no additives or chemical stabilizers.
NONCLINICAL TOXICOLOGY SECTION
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
Animal carcinogenicity studies have not been performed with dexmedetomidine.
Mutagenesis
Dexmedetomidine was not mutagenic in vitro, in either the bacterial reverse
mutation assay ( E. coliand 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.
Impairment of Fertility
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/m 2basis) administered from 10
weeks prior to mating in males, and 3 weeks prior to mating and during mating
in females.
13.2 Animal Toxicology and/or Pharmacology
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.
CLINICAL STUDIES SECTION
14 CLINICAL STUDIES
The safety and efficacy of dexmedetomidine injection has been evaluated in
four randomized, double-blind, placebo-controlled multicenter clinical trials
in 1,185 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 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 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 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
injection (see Table 10).
A second prospective primary analysis assessed the sedative effects of
dexmedetomidine 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 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 |
Dexmedetomidine Injection |
p-value | |
|
Mean Total Dose (mg) of Midazolam |
19 mg |
5 mg |
0.0011* |
|
Categorized Midazolam Use | |||
|
0 mg |
43 (25%) |
108 (61%) |
<0.001** |
|
0–4 mg |
34 (19%) |
36 (20%) | |
|
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 injection and placebo groups. On average, dexmedetomidine 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 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 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 injection (see Table 11).
A significantly greater percentage of patients in the dexmedetomidine
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 |
Dexmedetomidine Injection |
p-value | |
|
Mean Total Dose (mg) of Propofol |
513 mg |
72 mg |
<0.0001* |
|
Categorized Propofol Use | |||
|
0 mg |
47 (24%) |
122 (60%) |
<0.001** |
|
0–50 mg |
30 (15%) |
43 (21%) | |
|
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 injection and placebo groups. On average, dexmedetomidine 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 injection patients received no morphine sulfate for pain versus 15% (30 of 198 patients) in the placebo group.
In a controlled clinical trial, dexmedetomidine injection was compared to midazolam for ICU sedation exceeding 24 hours duration. Dexmedetomidine 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 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 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
injection in patients having a variety of elective surgeries/procedures
performed under monitored anesthesia care. Study 2 evaluated dexmedetomidine
injection in patients undergoing awake fiberoptic intubation prior to a
surgical or diagnostic procedure.
In Study 1, the sedative properties of dexmedetomidine 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 |
|
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 |
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 |
Patients were randomized to receive a loading infusion of either
dexmedetomidine injection 1 mcg/kg, dexmedetomidine 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 injection and comparator groups. Efficacy results showed that
dexmedetomidine 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 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 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 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 Enrolled****a |
% Not Requiring Midazolam Rescue |
ConfidencebInterval on the Difference vs. Placebo |
Mean (SD) Total Dose (mg) of Rescue Midazolam Required |
ConfidencebIntervals of the Mean Rescue Dose |
|
Study 1 |
Dexmedetomidine |
134 |
40 |
37 (27, 48) |
1.4 (1.7) |
-2.7 |
|
Dexmedetomidine |
129 |
54 |
51 (40, 62) |
0.9 (1.5) |
-3.1 | |
|
placebo |
63 |
3 |
|
4.1 (3.0) |
| |
|
Study 2 |
Dexmedetomidine |
55 |
53 |
39 (20, 57) |
1.1 (1.5) |
-1.8 |
|
placebo |
50 |
14 |
|
2.9 (3.0) |
|
aBased on ITT population defined as all randomized and treated patients.
bNormal approximation to the binomial with continuity correction.
HOW SUPPLIED SECTION
16 HOW SUPPLIED/STORAGE AND HANDLING
Dexmedetomidine Injection, USP
Dexmedetomidine injection, USP (dexmedetomidine hydrochloride) 200 mcg/2 mL
(100 mcg/mL) is clear and colorless, and available in 2 mL clear glass vials
with pink caps, supplied in packages of 25. The strength is based on the
dexmedetomidine base. Vials are intended for single-dose only. Discard unused
portion.
|
NDC No. |
Container |
Size |
|
66794-230-02 |
Vial |
2 mL |
Store at controlled room temperature, 25°C (77°F) with excursions allowed from 15°C to 30°C (59°F to 86°F). [See USP Controlled Room Temperature.]
PATIENT COUNSELING INFORMATION
17 PATIENT COUNSELING INFORMATION
Dexmedetomidine injection is indicated for short-term intravenous sedation. Dosage must be individualized and titrated to the desired clinical effect. Blood pressure, heart rate and oxygen levels will be monitored both continuously during the infusion of dexmedetomidine injection and as clinically appropriate after discontinuation.
- When dexmedetomidine injection is infused for more than 6 hours, patients should be informed to report nervousness, agitation, and headaches that may occur for up to 48 hours.
- Additionally, patients should be informed to report symptoms that may occur within 48 hours after the administration of dexmedetomidine injection such as: weakness, confusion, excessive sweating, weight loss, abdominal pain, salt cravings, diarrhea, constipation, dizziness or light-headedness.
Manufactured for:
Piramal Critical Care
Bethlehem, PA 18017, USA
Product of India
Issued: 12/2020
DOSAGE & ADMINISTRATION SECTION
2 DOSAGE AND ADMINISTRATION
2.1 Dosing Guidelines
• Dexmedetomidine injection dosing should be individualized and titrated to
desired clinical response.
• Dexmedetomidine injection is not indicated for infusions lasting longer than
24 hours.
• Dexmedetomidine injection should be administered using a controlled infusion
device.
2.2 Dosage Information
Table 1: Dosage Information
|
INDICATION |
DOSAGE AND ADMINISTRATION |
|
Initiation of Intensive Care Unit Sedation |
**For adult patients:**a loading infusion of one mcg/kg over 10 minutes. |
|
Maintenance of Intensive Care Unit Sedation |
**For adult patients:**a maintenance infusion of 0.2 to 0.7 mcg/kg/hour. The
rate of the maintenance infusion should be adjusted to achieve the desired
level of sedation. |
|
Initiation of Procedural Sedation |
**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. |
|
Maintenance of Procedural Sedation |
**For adult patients:**the maintenance infusion is generally initiated at 0.6
mcg/kg/hour and titrated to achieve desired clinical effect with doses ranging
from 0.2 to 1 mcg/kg/hour. The rate of the maintenance infusion should be
adjusted to achieve the targeted level of sedation. |
2.3 Dosage Adjustment
Due to possible pharmacodynamic interactions, a reduction in dosage of
dexmedetomidine injection 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 adult patients with hepatic
impairment, and geriatric patients [see Warnings and Precautions (5.7), Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].
2.4 Preparation of Solution
Strict aseptic technique must always be maintained during handling of
dexmedetomidine injection.
Parenteral drug products should be inspected visually for particulate matter
and discoloration prior to administration, whenever solution and container
permit.
Dexmedetomidine Injection, 200 mcg/2 mL (100 mcg/mL)
Dexmedetomidine injection must be diluted with 0.9% sodium chloride injection
to achieve required concentration (4 mcg/mL) prior to administration.
Preparation of solutions is the same, whether for the loading dose or
maintenance infusion.
To prepare the infusion, withdraw 2 mL of dexmedetomidine injection, and add
to 48 mL of 0.9% sodium chloride injection to a total of 50 mL. Shake gently
to mix well.
2.5 Administration with Other Fluids
Dexmedetomidine injection infusion should not be co-administered through the
same intravenous catheter with blood or plasma because physical compatibility
has not been established.
Dexmedetomidine injection has been shown to be incompatible when administered
with the following drugs: amphotericin B, diazepam.
Dexmedetomidine injection has been shown to be compatible when administered
with the following intravenous fluids:
• 0.9% sodium chloride in water
• 5% dextrose in water
• 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
dexmedetomidine hydrochloride to some types of natural rubber. Although
dexmedetomidine injection is dosed to effect, it is advisable to use
administration components made with synthetic or coated natural rubber
gaskets.
- Individualize and titrate dexmedetomidine injection dosing to desired clinical effect. ( 2.1)
- Administer dexmedetomidine injection using a controlled infusion device. ( 2.1)
- Dilute the 200 mcg/2 mL (100 mcg/mL) vial contents in 0.9% sodium chloride solution to achieve required concentration (4 mcg/mL) prior to administration. ( 2.4)
For Adult Intensive Care Unit Sedation:Generally initiate at one mcg/kg
over 10minutes, followed by a maintenance infusion of 0.2 to 0.7 mcg/kg/
hour. ( 2.2)
**For Adult Procedural Sedation:**Generally initiate at one mcg/kg over 10
minutes, followed by a maintenance infusion initiated at 0.6 mcg/kg/hour
and titrated to achieve desired clinical effect with doses ranging from 0.2 to
1 mcg/kg/hour. ( 2.2)
**Alternative Doses:**Recommended for patients over 65 years of age and awake
fiberoptic intubation patients. ( 2.2)
CLINICAL PHARMACOLOGY SECTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Dexmedetomidine injection is a relatively selective alpha2-adrenergic agonist
with sedative properties. Alpha2 selectivity is observed in animals following
slow intravenous infusion of low and medium doses (10-300 mcg/kg). Both alpha1
and alpha2 activity is observed following slow intravenous infusion of high
doses (≥1000 mcg/kg) or with rapid intravenous administration.
12.2 Pharmacodynamics
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 dexmedetomidine injection was administered by
intravenous infusion at doses within the recommended dose range (0.2–0.7
mcg/kg/hr).
12.3 Pharmacokinetics
Following intravenous administration, dexmedetomidine exhibits the following
pharmacokinetic parameters: a rapid distribution phase with a distribution
half-life (t 1/2) of approximately 6 minutes; a terminal elimination half-life
(t 1/2) of approximately 2 hours; and steady-state volume of distribution (V
ss) of approximately 118 liters. Clearance is estimated to be approximately 39
L/h. The mean body weight associated with this clearance estimate was 72 kg.
Dexmedetomidine exhibits linear pharmacokinetics in the dosage range of 0.2 to
0.7 mcg/kg/hr when administered by intravenous infusion for up to 24 hours.
Table 8 shows the main pharmacokinetic parameters when dexmedetomidine
injection was infused (after appropriate loading doses) at maintenance
infusion rates of 0.17 mcg/kg/hr (target plasma concentration of 0.3 ng/mL)
for 12 and 24 hours, 0.33 mcg/kg/hr (target plasma concentration of 0.6 ng/mL)
for 24 hours, and 0.70 mcg/kg/hr (target plasma concentration of 1.25 ng/mL)
for 24 hours.
Table 8: Mean ± SD Pharmacokinetic Parameters
|
Parameter |
Loading Infusion (min)/Total Infusion Duration (hrs) | |||
|
10 min/12 hrs |
10 min/24 hrs |
10 min/24 hrs |
35 min/24 hrs | |
|
Dexmedetomidine Target Plasma Concentration (ng/mL) and Dose (mcg/kg/hr) | ||||
|
0.3/0.17 |
0.3/0.17 |
0.6/0.33 |
1.25/0.70 | |
|
t1/2*, hour |
1.78 ± 0.30 |
2.22 ± 0.59 |
2.23 ± 0.21 |
2.50 ± 0.61 |
|
CL, liter/hour |
46.3 ± 8.3 |
43.1 ± 6.5 |
35.3 ± 6.8 |
36.5 ± 7.5 |
|
Vss, liter |
88.7 ± 22.9 |
102.4 ± 20.3 |
93.6 ± 17.0 |
99.6 ± 17.8 |
|
Avg Css #, ng/mL |
0.27 ± 0.05 |
0.27 ± 0.05 |
0.67 ± 0.10 |
1.37 ± 0.20 |
Abbreviations: t 1/2= half-life, CL = clearance, Vss = steady-state volume of distribution
- Presented as harmonic mean and pseudo standard deviation.
#Mean C ss= Average steady-state concentration of dexmedetomidine. The mean C sswas calculated based on post-dose sampling from 2.5 to 9 hours samples for 12 hours infusion and post-dose sampling from 2.5 to 18 hours for 24 hour infusions.
The loading doses for each of the above indicated groups were 0.5, 0.5, 1 and 2.2 mcg/kg, respectively.
Dexmedetomidine pharmacokinetic parameters after dexmedetomidine injection maintenance doses of 0.2 to 1.4 mcg/kg/hr for >24 hours were similar to the pharmacokinetic (PK) parameters after dexmedetomidine injection maintenance dosing for <24 hours in other studies. The values for clearance (CL), volume of distribution (V), and t 1/2were 39.4 L/hr, 152 L, and 2.67 hours, respectively.
Distribution
The steady-state volume of distribution (V ss) of dexmedetomidine was approximately 118 liters. Dexmedetomidine protein binding was assessed in the plasma of normal healthy male and female subjects. The average protein binding was 94% and was constant across the different plasma concentrations tested. Protein binding was similar in males and females. The fraction of dexmedetomidine that was bound to plasma proteins was significantly decreased in subjects with hepatic impairment compared to healthy subjects.
The potential for protein binding displacement of dexmedetomidine by fentanyl,
ketorolac, theophylline, 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 vitroand none of these compounds appeared to be significantly
displaced by dexmedetomidine.
Elimination
Metabolism
Dexmedetomidine undergoes almost complete biotransformation with very little
unchanged dexmedetomidine excreted in urine and feces. Biotransformation
involves 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 with a minor role of CYP1A2, CYP2E1, CYP2D6 and CYP2C19)
of dexmedetomidine to generate 3-hydroxy-dexmedetomidine, the glucuronide of
3-hydroxy-dexmedetomidine, and 3-carboxy-dexmedetomidine; and N-methylation of
dexmedetomidine to generate 3-hydroxy N-methyl-dexmedetomidine, 3-carboxy
N-methyl-dexmedetomidine, and dexmedetomidine-N-methyl O-glucuronide.
Excretion
The terminal elimination half-life (t 1/2) 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 intravenous 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-glucuronidation 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.
Specific Populations
Male and Female Patients
There was no observed difference in dexmedetomidine injection pharmacokinetics
due to gender.
Geriatric Patients
The pharmacokinetic profile of dexmedetomidine injection was not altered by
age. There were no differences in the pharmacokinetics of dexmedetomidine
injection in young (18–40 years), middle age (41–65 years), and elderly (>65
years) subjects.
Patients with 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 patients 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 dexmedetomidine injection is dosed to effect, it may be necessary to
consider dose reduction in subjects with hepatic impairment [see Dosage and Administration (2.2), Warnings and Precautions (5.7)].
Patients with Renal Impairment
Dexmedetomidine pharmacokinetics (C max, T max, AUC, t 1/2, CL, and Vss) were
not significantly different in patients with severe renal impairment
(creatinine clearance: <30 mL/min) compared to healthy subjects.
Drug Interaction Studies
In vitro studies: In vitro studies in human liver microsomes demonstrated no
evidence of cytochrome P450 mediated drug interactions that are likely to be
of clinical relevance.