Dexmedetomidine hydrochloride

5 WARNINGS AND PRECAUTIONS Monitoring: Continuously monitor patients while receiving dexmedetomidine hydrochloride injection. ( 5.1 ) Bradycardia and sinus arrest: Have occurred in young healthy volunteers with high vagal tone or with different routes of administration, e.g., rapid intravenous or bolus administration. ( 5.2 ) Hypotension and Bradycardia: May necessitate medical intervention. May be more pronounced in patients with hypovolemia, diabetes mellitus, or chronic hypertension, and in the elderly. Use with caution in patients with advanced heart block or severe ventricular dysfunction. ( 5.2 ) Co-administration with Other Vasodilators or Negative Chronotropic Agents: Use with caution due to additive pharmacodynamic effects. ( 5.2 ) Transient Hypertension: Observed primarily during the loading dose. Consider reduction in loading infusion rate. ( 5.3 ) Arousability: Patients can become aroused/alert with stimulation; this alone should not be considered as lack of efficacy. ( 5.4 ) Prolonged exposure to dexmedetomidine beyond 24 hours may be associated with tolerance and tachyphylaxis and a dose-related increase in adverse events. ( 5.6 ) 5.1 Drug Administration Dexmedetomidine hydrochloride injection should be administered only by persons skilled in the management of patients in the operating room setting. Due to the known pharmacological effects of dexmedetomidine hydrochloride injection, patients should be continuously monitored while receiving dexmedetomidine hydrochloride injection. 5.2 Hypotension, Bradycardia, and Sinus Arrest Clinically significant episodes of bradycardia and sinus arrest have been reported with dexmedetomidine hydrochloride injection administration in young, healthy adult 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 dexmedetomidine hydrochloride infusion. Some of these cases have resulted in fatalities. If medical intervention is required, treatment may include decreasing or stopping the infusion of dexmedetomidine hydrochloride injection, increasing the rate of intravenous fluid administration, elevation of the lower extremities, and use of pressor agents. Because dexmedetomidine hydrochloride injection 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 dexmedetomidine hydrochloride injection-induced bradycardia. However, in some patients with significant cardiovascular dysfunction, more advanced resuscitative measures were required. Caution should be exercised when administering dexmedetomidine hydrochloride injection to patients with advanced heart block and/or severe ventricular dysfunction. Because dexmedetomidine hydrochloride injection 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 dexmedetomidine hydrochloride injection an additive pharmacodynamic effect was not observed. Nonetheless, caution should be used when such agents are administered concomitantly with dexmedetomidine hydrochloride injection. 5.3 Transient Hypertension Transient hypertension has been observed primarily during the loading dose in association with the initial peripheral vasoconstrictive effects of dexmedetomidine hydrochloride injection. 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 dexmedetomidine hydrochloride injection 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 Procedural Sedation In adult subjects, withdrawal symptoms were not seen after discontinuation of short term infusions of dexmedetomidine hydrochloride injection (<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) ]. 5.7 Hepatic Impairment Since dexmedetomidine hydrochloride injection 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 The most common adverse reactions (incidence greater than 2%) are hypotension, bradycardia, and dry mouth. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Accord Healthcare Inc. at 1-866-941-7875 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 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 dexmedetomidine hydrochloride injection 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) ] Most common treatment-emergent adverse reactions, occurring in greater than 2% of patients in procedural sedation studies include hypotension, bradycardia and dry mouth. *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. 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 and comparator groups in both studies. Table 6: Adverse Reactions With an Incidence > 2%—Procedural Sedation Population Adverse Event Dexmedetomidine (N = 318) (%) Placebo (N = 113) (%) Hypotension 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. 54% 30% Respiratory Depression Respiratory depression was defined in absolute and relative terms as respiratory rate (RR) < 8 beats per minute or > 25% decrease from baseline. 37% 32% Bradycardia Bradycardia was defined in absolute and relative terms as < 40 beats per minute or ≤ 30% lower than pre-study drug infusion value. 14% 4% Hypertension 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. 13% 24% Tachycardia Tachycardia was defined in absolute and relative terms as > 120 beats per minute or ≥ 30% greater than pre-study drug infusion value. 5% 17% Nausea 3% 2% Dry Mouth 3% 1% Hypoxia Hypoxia was defined in absolute and relative terms as SpO 2 < 90% or 10% decrease from baseline. 2% 3% Bradypnea 2% 4% 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of dexmedetomidine. 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 during post approval use of the drug. Table 7: Adverse Reactions Experienced During Post-approval Use of Dexmedetomidine 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, gammaglutamyl transferase 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 Surgical and Medical Procedures Light anesthesia Vascular Disorders Blood pressure fluctuation, hemorrhage, hypertension, hypotension

<table ID="_RefID0EOGAE" width="100%"><caption>Table 6: Adverse Reactions With an Incidence &gt; 2%&#x2014;Procedural Sedation Population</caption><col width="24%"/><col width="45%"/><col width="10%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule "><paragraph><content styleCode="bold">Adverse Event</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule "><paragraph><content styleCode="bold">Dexmedetomidine </content> <content styleCode="bold">(N = 318)</content> <content styleCode="bold">(%)</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule "><paragraph><content styleCode="bold">Placebo</content> <content styleCode="bold">(N = 113)</content> <content styleCode="bold">(%)</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule "><paragraph> Hypotension <footnote ID="_Ref361904969">Hypotension was defined in absolute and relative terms as Systolic blood pressure of &lt; 80 mmHg or &#x2264; 30% lower than pre-study drug infusion value, or Diastolic blood pressure of &lt; 50 mmHg.</footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule "><paragraph>54%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule "><paragraph>30%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule "><paragraph> Respiratory Depression <footnote ID="_Ref361904904">Respiratory depression was defined in absolute and relative terms as respiratory rate (RR) &lt; 8 beats per minute or &gt; 25% decrease from baseline.</footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule "><paragraph>37%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule "><paragraph>32%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule "><paragraph> Bradycardia <footnote ID="_Ref361904982">Bradycardia was defined in absolute and relative terms as &lt; 40 beats per minute or &#x2264; 30% lower than pre-study drug infusion value.</footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule "><paragraph>14%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule "><paragraph>4%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule "><paragraph> Hypertension <footnote ID="_Ref361905002">Hypertension was defined in absolute and relative terms as Systolic blood pressure &gt; 180 mmHg or &#x2265; 30% higher than pre-study drug infusion value or Diastolic blood pressure of &gt; 100 mmHg.</footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule "><paragraph>13%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule "><paragraph>24%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule "><paragraph> Tachycardia <footnote ID="_Ref361905010">Tachycardia was defined in absolute and relative terms as &gt; 120 beats per minute or &#x2265; 30% greater than pre-study drug infusion value.</footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule "><paragraph>5%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule "><paragraph>17%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule "><paragraph> Nausea </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule "><paragraph>3%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule "><paragraph>2%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule "><paragraph> Dry Mouth </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule "><paragraph>3%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule "><paragraph>1%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule "><paragraph> Hypoxia <footnote ID="_Ref361905018">Hypoxia was defined in absolute and relative terms as SpO 2 &lt; 90% or 10% decrease from baseline. </footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule "><paragraph>2%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule "><paragraph>3%</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule "><paragraph> Bradypnea </paragraph></td><td align="center" styleCode="Rrule Botrule Lrule "><paragraph>2%</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule "><paragraph>4%</paragraph></td></tr></tbody></table>

<table><caption>Table 7: Adverse Reactions Experienced During Post-approval Use of Dexmedetomidine </caption><thead styleCode="Lrule Rrule Toprule Botrule"><tr><th align="left" styleCode="Lrule Rrule Toprule Botrule"><content styleCode="bold">System Organ Class</content></th><th align="left" styleCode="Lrule Rrule Toprule Botrule"><content styleCode="bold">Preferred Term</content></th></tr></thead><tbody><tr><td styleCode="Lrule Rrule Toprule Botrule" valign="top"><paragraph>Blood and Lymphatic System Disorders </paragraph></td><td styleCode="Lrule Rrule Toprule Botrule" valign="top"><paragraph>Anemia</paragraph></td></tr><tr><td styleCode="Lrule Rrule Toprule Botrule" valign="top"><paragraph>Cardiac Disorders </paragraph></td><td styleCode="Lrule Rrule Toprule Botrule" valign="top"><paragraph>Arrhythmia, atrial fibrillation, atrioventricular block, bradycardia, cardiac arrest, cardiac disorder, extrasystoles, myocardial infarction, supraventricular tachycardia, tachycardia, ventricular arrhythmia, ventricular tachycardia </paragraph></td></tr><tr><td styleCode="Lrule Rrule Toprule Botrule" valign="top"><paragraph>Eye Disorders</paragraph></td><td styleCode="Lrule Rrule Toprule Botrule" valign="top"><paragraph>Photopsia, visual impairment</paragraph></td></tr><tr><td styleCode="Lrule Rrule Toprule Botrule" valign="top"><paragraph>Gastrointestinal Disorders</paragraph></td><td styleCode="Lrule Rrule Toprule Botrule" valign="top"><paragraph>Abdominal pain, diarrhea, nausea, vomiting</paragraph></td></tr><tr><td styleCode="Lrule Rrule Toprule Botrule" valign="top"><paragraph>General Disorders and Administration Site Conditions</paragraph></td><td styleCode="Lrule Rrule Toprule Botrule" valign="top"><paragraph>Chills, hyperpyrexia, pain, pyrexia, thirst</paragraph></td></tr><tr><td styleCode="Lrule Rrule Toprule Botrule" valign="top"><paragraph>Hepatobiliary Disorders</paragraph></td><td styleCode="Lrule Rrule Toprule Botrule" valign="top"><paragraph>Hepatic function abnormal, hyperbilirubinemia</paragraph></td></tr><tr><td styleCode="Lrule Rrule Toprule Botrule" valign="top"><paragraph>Investigations</paragraph></td><td styleCode="Lrule Rrule Toprule Botrule" valign="top"><paragraph>Alanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased, blood urea increased, electrocardiogram T wave inversion, gammaglutamyl transferase increased, electrocardiogram QT prolonged</paragraph></td></tr><tr><td styleCode="Lrule Rrule Toprule Botrule" valign="top"><paragraph>Metabolism and Nutrition Disorders</paragraph></td><td styleCode="Lrule Rrule Toprule Botrule" valign="top"><paragraph>Acidosis, hyperkalemia, hypoglycemia, hypovolemia, hypernatremia</paragraph></td></tr><tr><td styleCode="Lrule Rrule Toprule Botrule" valign="top"><paragraph>Nervous System Disorders </paragraph></td><td styleCode="Lrule Rrule Toprule Botrule" valign="top"><paragraph>Convulsion, dizziness, headache, neuralgia, neuritis, speech disorder</paragraph></td></tr><tr><td styleCode="Lrule Rrule Toprule Botrule" valign="top"><paragraph>Psychiatric Disorders</paragraph></td><td styleCode="Lrule Rrule Toprule Botrule" valign="top"><paragraph>Agitation, confusional state, delirium, hallucination, illusion</paragraph></td></tr><tr><td styleCode="Lrule Rrule Toprule Botrule" valign="top"><paragraph>Renal and Urinary Disorders</paragraph></td><td styleCode="Lrule Rrule Toprule Botrule" valign="top"><paragraph>Oliguria, polyuria</paragraph></td></tr><tr><td styleCode="Lrule Rrule Toprule Botrule" valign="top"><paragraph>Respiratory, Thoracic and Mediastinal Disorders </paragraph></td><td styleCode="Lrule Rrule Toprule Botrule" valign="top"><paragraph>Apnea, bronchospasm, dyspnea, hypercapnia, hypoventilation, hypoxia, pulmonary congestion, respiratory acidosis</paragraph></td></tr><tr><td styleCode="Lrule Rrule Toprule Botrule" valign="top"><paragraph>Skin and Subcutaneous Tissue Disorders</paragraph></td><td styleCode="Lrule Rrule Toprule Botrule" valign="top"><paragraph>Hyperhidrosis</paragraph></td></tr><tr><td styleCode="Lrule Rrule Toprule Botrule" valign="top"><paragraph>Surgical and Medical Procedures</paragraph></td><td styleCode="Lrule Rrule Toprule Botrule" valign="top"><paragraph>Light anesthesia</paragraph></td></tr><tr><td styleCode="Lrule Rrule Toprule Botrule" valign="top"><paragraph>Vascular Disorders</paragraph></td><td styleCode="Lrule Rrule Toprule Botrule" valign="top"><paragraph>Blood pressure fluctuation, hemorrhage, hypertension, hypotension</paragraph></td></tr></tbody></table>