Precedex

RECENT MAJOR CHANGES Dosage and Administration, Preparation of Solution (2.4) 10/2024

1 INDICATIONS AND USAGE 1.1 Intensive Care Unit Sedation PRECEDEX is indicated for sedation of initially intubated and mechanically ventilated adult 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 adult 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 adult patients prior to and/or during surgical and other procedures. PRECEDEX is indicated for sedation of non-intubated pediatric patients aged 1 month to less than 18 years prior to and during non-invasive procedures. PRECEDEX is a alpha 2 -adrenergic receptor agonist indicated for: Sedation of initially intubated and mechanically ventilated patients during treatment in an intensive care setting. Administer Precedex 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) Sedation of non-intubated pediatric patients aged 1 month to less than 18 years prior to and during non-invasive procedures. (1.2)

2 DOSAGE AND ADMINISTRATION 2.1 Administration Instructions PRECEDEX dosing should be individualized and titrated to desired clinical response. PRECEDEX is not indicated for infusions lasting longer than 24 hours. PRECEDEX should be administered using a controlled infusion device. 2.2 Recommended Dosage Table 1: Recommended Dosage in Adult Patients INDICATION DOSAGE AND ADMINISTRATION Initiation of Intensive Care Unit Sedation For adult patients : a loading infusion of one mcg/kg over 10 minutes . For adult patients being converted from alternate sedative therapy :a loading dose may not be required For patients over 65 years of age : Consider a dose reduction [see USE IN SPECIFIC POPULATIONS (8.5)]. For adult patients with impaired hepatic function : Consider a dose reduction [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 mcg/kg/ hour to 0.7 mcg/kg/ hour. The rate of the maintenance infusion should be adjusted to achieve the desired level of sedation. For patients over 65 years of age : Consider a dose reduction [see USE IN SPECIFIC POPULATIONS (8.5)]. For adult patients with impaired hepatic function : Consider a dose reduction [see USE IN SPECIFIC POPULATIONS (8.6), CLINICAL PHARMACOLOGY (12.3)] 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. For awake fiberoptic intubation in adult 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 adult patients with impaired hepatic function:Consider a dose reduction [see USE IN SPECIFIC POPULATIONS (8.6), CLINICAL PHARMACOLOGY (12.3)]. 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 mcg/kg/ hour to 1 mcg/kg/ hour . Adjust the rate of the maintenance infusion to achieve the targeted level of sedation. For awake fiberoptic intubation in adult patients : a maintenance infusion of 0.7 mcg/kg/ hour is recommended until the endotracheal tube is secured. For patients over 65 years of age : Consider a dose reduction [see USE IN SPECIFIC POPULATIONS (8.5)]. For adult patients with impaired hepatic function : Consider a dose reduction [see USE IN SPECIFIC POPULATIONS (8.6), CLINICAL PHARMACOLOGY (12.3)]. Table 2: Recommended Dosage in Pediatric Patients Initiation of Sedation During Non‐invasive Procedures For pediatric patients: •1 month to less than 2 years: a loading infusion of 1.5 mcg/kg over 10 minutes. •2 to less than 18 years: a loading infusion of 2 mcg/kg over 10 minutes. Consider a reduction in dosage if clinically indicated. Maintenance of Sedation During Non-invasive Procedures For pediatric patients: •1 month to less than 18 years: the maintenance infusion is generally initiated at 1.5 mcg/kg/ hour and titrated to achieve desired clinical effect with dosage ranging from 0.5 mcg/kg/ hour to 1.5 mcg/kg/ hour . As clinically warranted, titrate the maintenance dose to individual patient clinical response. 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 adult patients with hepatic impairment, and geriatric patients [see Warnings and Precautions (5.9), 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 PRECEDEX. Parenteral drug products should be inspected visu …

3 DOSAGE FORMS AND STRENGTHS PRECEDEX Presentations Requiring Dilution: PRECEDEX (dexmedetomidine hydrochloride) injection is a clear and colorless solution, to be used after dilution. It is available as: •200 mcg/2 mL (100 mcg/mL) single-dose vial. PRECEDEX Presentations that are Ready To Use: PRECEDEX (dexmedetomidine hydrochloride) in 0.9% sodium chloride injection is a clear and colorless solution, ready to use. It is available as: •PRECEDEX 80 mcg/20 mL (4 mcg/mL) single-dose vial. •PRECEDEX 200 mcg/50 mL (4 mcg/mL) single-dose glass bottle. •PRECEDEX 400 mcg/100 mL (4 mcg/mL) single-dose glass bottle. •PRECEDEX 1,000 mcg/250 mL (4 mcg/mL) single-dose glass bottle. •PRECEDEX 200 mcg/50 mL (4 mcg/mL) single-dose flexible container. •PRECEDEX 400 mcg/100 mL (4 mcg/mL) single-dose flexible container. •PRECEDEX 1,000 mcg/250 mL (4 mcg/mL) single-dose flexible container. Precedex Injection, 200 mcg/2 mL (100 mcg/mL) in a glass vial. To be used after dilution. (3) Precedex in 0.9% Sodium Chloride Injection 80 mcg/20 mL (4 mcg/mL) in a 20 mL glass vial. Ready to use. (3) Precedex in 0.9% Sodium Chloride Injection 200 mcg/50 mL (4 mcg/mL) in a 50 mL glass bottle. Ready to use. (3) Precedex in 0.9% Sodium Chloride Injection 400 mcg/100 mL (4 mcg/mL) in a 100 mL glass bottle. Ready to use. (3)

4 CONTRAINDICATIONS None None. (4)

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 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. 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 PRECEDEX for sedation in the Intensive Care Unit setting in which 1,007 adult patients received PRECEDEX. 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 3. The most frequent adverse reactions were hypotension, bradycardia and dry mouth [see Warnings and Precautions (5.2)]. Table 3: Adverse Reactions with an Incidence >2%-Adult Intensive Care Unit Sedation Population 1% Of All Dexmedetomidine-Treated Adult Patients in the Randomized Placebo-Controlled Continuous Infusion 180 mmHg or Diastolic blood pressure of >100 mmHg or in relative terms as 30% higher than pre-study drug infusion value. 4 Tachycardia was defined in absolute terms as >120 bpm or in relative terms as 30% greater than pre-study drug infusion value. Adverse Event Dexmedetomidine (N = 244) Midazolam (N = 122) 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% 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%). Table 6. Number (%) of Adult Subjects Who Had a Dose-Related Increase in Treatment Emergent Adverse Events by Maintenance Adjusted Dose Rate Range in the Precedex Group *Average maintenance dose over the entire study drug administration Precedex mcg/kg/hr Adverse Event 0.7* (N = 95) >0.7 to 1.1* (N = 78) >1.1* (N = 71) 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% Adult Procedural Sedation Adverse reaction information is derived from the two trials for adult procedural sedation [see Clinical Studies (14.2)] in which 318 adult 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, ASA IIV, 30% 65 years of age, 52% male and 61% Caucasian. Treatment-emergent adverse reactions occurring in adults at an incidence of >2% are provided in Table 7. The most frequent adverse reactions were hypotension, bradycardia, and dry mouth [see Warnings and Precautions (5.2)]. Pre-specified criteria fo …

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 adult 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. Anesthetics, Sedatives, Hypnotics, Opioids: Enhancement of pharmacodynamic effects. Reduction in dosage of Precedex or the concomitant medication may be required. (7.1)

8 USE IN SPECIFIC POPULATIONS SECTION Risk Summary Available data from published randomized controlled trials and case reports over several decades of use with intravenously administered dexmedetomidine during pregnancy have not identified a drug-associated risk of major birth defects and miscarriage; however, the reported exposures occurred after the first trimester. Most of the available data are based on studies with exposures that occurred at the time of caesarean section delivery, and these studies have not identified an adverse effect on maternal outcomes or infant Apgar scores. Available data indicate that dexmedetomidine crosses the placenta. In animal reproduction studies, fetal toxicity that lower fetal viability and reduced live fetuses occurred with subcutaneous administration of dexmedetomidine to pregnant rats during organogenesis at doses 1.8 times the maximum recommended human dose (MRHD) of 17.8 mcg/kg/day. Developmental toxicity (low pup weights and adult offspring weights, decreased F1 grip strength, increased early implantation loss and decreased viability of second-generation offspring) occurred when pregnant rats were subcutaneously administered dexmedetomidine at doses less than the clinical dose from late pregnancy through lactation and weaning (see Data). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively. Data Animal Data Increased post-implantation losses and reduced live fetuses in the presence of maternal toxicity (i.e. decreased body weight) were noted in a rat embryo-fetal development study in which pregnant dams were administered subcutaneous doses of dexmedetomidine 200 mcg/kg/day (equivalent to 1.8 times the intravenous MRHD of 17.8 mcg/kg/day based on body surface area [BSA]) during the period of organogenesis (Gestation Day [GD] 6 to 15). No malformations were reported. No malformations or embryo-fetal toxicity were noted in a rabbit embryo-fetal development study in which pregnant does were administered dexmedetomidine intravenously at doses of up to 96 mcg/kg/day (approximately half the human exposure at the MRHD based on AUC) during the period of organogenesis (GD 6 to 18). Reduced pup and adult offspring birth weights, and grip strength were reported in a rat developmental toxicology study in which pregnant females were administered dexmedetomidine subcutaneously at doses of 8 mcg/kg/day (0.07 times the MRHD based on BSA) during late pregnancy through lactation and weaning (GD 16 to postnatal day [PND] 25). Decreased viability of second generation offspring and an increase in early implantation loss along with delayed motor development occurred in the 32 mcg/kg/day group (equivalent to less than the clinical dose based on BSA) when first generation offspring were allowed to mate. This study limited dosing to hard palate closure (GD 15 to 18) through weaning instead of dosing from implantation (GD 6 to 7) to weaning (PND 21). In a study in the pregnant rat, placental transfer of dexmedetomidine was observed when radiolabeled dexmedetomidine was administered subcutaneously. 8.2 Lactation Risk Summary Available published literature reports the presence of dexmedetomidine in human milk following intravenous administration (see Data) . There is no information regarding the effects of dexmedetomidine on the breastfed infant or the effects on milk production. Advise women to monitor the breastfed infant for irritability. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for PRECEDEX and any potential adverse effects on the breastfed infant from PRECEDEX or from the underlying condition. Data In two published clinical s …

11 Description PRECEDEX (dexmedetomidine hydrochloride) injection (100 mcg/mL) is a sterile, nonpyrogenic solution suitable for intravenous infusion following dilution. PRECEDEX (dexmedetomidine hydrochloride) in 0.9% Sodium Chloride Injection (4 mcg/mL) is a sterile, nonpyrogenic ready to use solution suitable for intravenous infusion. PRECEDEX contains dexmedetomidine hydrochloride as the active pharmaceutical ingredient. Dexmedetomidine hydrochloride is a central alpha2-adrenergic agonist. Dexmedetomidine hydrochloride is the S-enantiomer of medetomidine. Dexmedetomidine hydrochloride chemical name is 1H-Imidazole, 4-[1-(2,3-dimethylphenyl)ethyl]-, monohydrochloride, (S). Dexmedetomidine hydrochloride has a molecular weight of 236.7 and the empirical formula is C 13 H 16 N •HCl and the structural formula is: Dexmedetomidine hydrochloride is a white or almost white powder that is freely soluble in water and has a pKa of 7.1. Its partition coefficient in-octanol: water at pH 7.4 is 2.89. PRECEDEX Injection is intended to be used after dilution. It is supplied as a clear, colorless, isotonic solution with a pH between 4.5 to 7.0. Each mL contains 118 mcg of dexmedetomidine hydrochloride (equivalent to 100 mcg or 0.1 mg of dexmedetomidine) and 9 mg of sodium chloride in water for injection. The solution is preservative-free and contains no additives or chemical stabilizers. PRECEDEX in 0.9% Sodium Chloride Injection is ready to be used. It is supplied as a clear, colorless, isotonic solution with a pH between 4.5 to 8.0. Each mL contains 4.72 mcg of dexmedetomidine hydrochloride (equivalent to 4 mcg or 0.004 mg of dexmedetomidine) and 9 mg sodium chloride in water for injection. The solution is preservative-free and contains no additives or chemical stabilizers. Formula1.jpg

10 OVERDOSAGE The tolerability of PRECEDEX was studied in one study in which healthy adult subjects were administered doses at and above the recommended dose of 0.2 mcg/kg/hr 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 PRECEDEX 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 PRECEDEX (19.4 mcg/kg), had cardiac arrest from which he was successfully resuscitated.

HOW SUPPLIED/STORAGE AND HANDLING Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F). [See USP Controlled Room Temperature.] Do not use if product is discolored or if precipitate matter is present. PRECEDEX (dexmedetomidine hydrochloride) injection 200 mcg/2 mL (100 mcg/mL) is clear and colorless. The strength is based on the dexmedetomidine base. Discard unused portion. PRECEDEX (dexmedetomidine hydrochloride in 0.9% Sodium Chloride) injection (4 mcg/mL) is clear and colorless. The strength is based on the dexmedetomidine base. Discard unused portion. Product repackaged by: Henry Schein, Inc., Bastian, VA 24314 From Original Manufacturer/Distributor's NDC and Unit of Sale To Henry Schein Repackaged Product NDC and Unit of Sale Total Strength/Total Volume (Concentration) per unit NDC 0409-1638-02 Tray of 25 single-dose clear glass vials NDC 0404-9938-02 1 2 mL single-dose clear glass vial in a bag (Vial bears NDC 0409-1638-32) 200 mcg/2 mL (100 mcg/mL) Image8.jpg Image9.jpg