This product should only be administered by professionals under conditions where medical monitoring equipment is available. Due to the known pharmacologic effects of this product, patients should be continuously monitored during infusion of this product.
Hypotension, Bradycardia, and Sinus Arrest
Clinically significant bradycardia and sinus arrest have been reported after administration of this product to healthy young volunteers with high vagal tone or a different mode of administration (e.g., rapid intravenous or push).
Hypotension and bradycardia have been reported in association with infusion of this product. If medical rescue is required, treatment may include reducing or discontinuing the infusion of this product, increasing the flow rate of intravenous fluids, elevation of the lower extremities, and the use of medications that elevate blood pressure. Because this product has the potential to exacerbate bradycardia caused by vagal stimulation, clinicians should be prepared to intervene. Intravenous administration of anticholinergic agents (e.g., glonium bromide, atropine) should be considered to reduce vagal tone. In clinical trials, atropine or gronethium bromide were effective in the treatment of most bradycardia events caused by this product. However, in some patients with significant cardiovascular dysfunction, further resuscitation is required.
Caution should be exercised when administering this product to patients with advanced heart block and/or severe ventricular insufficiency. Because this product reduces sympathetic nervous system activity, more hypotension and/or bradycardia may be expected in patients with hypovolemia, diabetes mellitus or chronic hypertension, and in elderly patients.
When other vasodilators or negative frequency-acting drugs are given, concomitant administration of this product may have additive pharmacodynamic effects and should be administered with caution.
Temporary Hypertension
The development of temporary hypertension has been observed primarily during loading doses and is related to the peripheral vasoconstrictive effects of this product. Transient hypertension usually does not require treatment, however a reduction in the loading infusion rate may be desirable.
Awareness
Some patients given this product are observed to be aroused and alert when stimulated. In the absence of other clinical signs and symptoms, this alone should not be considered evidence of lack of efficacy.
Discontinuation Symptoms
Sedation in the Intensive Care Unit: if this product is administered for more than 24 hours and is abruptly discontinued, it may result in discontinuation symptoms similar to those reported for another alpha 2-adrenergic agent, colistin. These symptoms include nervousness, agitation, and headache, accompanied or followed by a rapid rise in blood pressure and elevated plasma catecholamine concentrations.
Procedural sedation: no withdrawal symptoms were observed after discontinuation of a short-term infusion of the product (<6 hours).
Hepatic Impairment
Since the clearance of dexmedetomidine decreases with the severity of hepatic impairment, dose reduction should be considered in patients with hepatic impairment.
Dependence
The potential dependence of dexmedetomidine in humans has not been studied. However, since studies in rodents and primates have demonstrated that dexmedetomidine has similar pharmacologic effects to colistin, abrupt discontinuation of this product may produce colistin-like withdrawal symptoms.
Medication in Pregnant and Nursing Women
No sufficiently favorable clinical studies have been performed in pregnant women. Dexmedetomidine should be used in pregnant women only if the potential benefits outweigh the potential risks to the fetus.
The safety of this product has not been studied in pregnant women awaiting labor and delivery. Therefore, this product is not recommended during labor and delivery, including cesarean section.
It is not known whether this product is secreted into human milk. Radioisotope-traced dexmedetomidine is secreted in milk after subcutaneous administration to lactating female rats. Because many drugs are secreted in human milk, this product should be used with caution in nursing women.
Children's Use
The safety and efficacy of this product in pediatric patients younger than 18 years of age are not known. Therefore, this product is not recommended for use in these populations.
Geriatric Use
Dexmedetomidine is known to be excreted primarily through the kidneys, and the risk of adverse reactions to this drug is greater in patients with renal impairment. Elderly patients have reduced renal function, so dosage should be chosen carefully in elderly patients and monitoring of renal function may be useful.
In foreign clinical studies, 729 patients ≥65 years of age and 200 patients ≥75 years of age were used in intensive care unit sedation trials***.The incidence of bradycardia and hypotension after administration of this product was higher in patients over 65 years of age. Therefore, dose reduction should be considered when using this product in patients over 65 years of age. Clinical trials of procedural sedation*** included 131 patients ≥65 years of age and 47 patients ≥75 years of age. The incidence of hypotension was 72% in patients 65 years of age or older, 74% in patients 75 years of age or older, and 47% in patients 65 years of age or older. Therefore the loading dose should be reduced when using this product in patients 65 years of age or older, and an infusion of 0.5ug /kg over 10 minutes is recommended.
Drug Interactions
Anesthetics/Sedatives/Hypnotics/Opioids
Concomitant administration of this product and anesthetics, sedatives, hypnotics, and opioids may result in enhanced drug effects. Foreign research reports have identified the effects of dexmedetomidine hydrochloride with sevoflurane, isoflurane, propofol, alfentanil, and midazolam. There were no pharmacokinetic interactions between dexmedetomidine and isoflurane, propofol, alfentanil, and midazolam. However, due to possible pharmacodynamic interactions, lower doses of this product or concomitant anesthetics, sedatives, hypnotics, and opioids may be required when given concomitantly.
Neuromuscular Blockade
In a foreign study of 10 healthy volunteers, dexmedetomidine hydrochloride administered for 45 minutes at a plasma concentration of 1 ng/mL did not result in a clinically significant increase in the degree of neuromuscular blockade associated with rocuronium bromide administration.
Overdose
Foreign data show that in a tolerability clinical study in which doses of dexmedetomidine hydrochloride were administered to healthy volunteers at or above 0.2 to 0.7 ug /kg/hr, the maximum plasma concentration reached was approximately 13 times the upper limit of the therapeutic range. The most significant effects observed in the two subjects who reached the highest dose were first-degree atrioventricular block and second-degree heart block, followed by spontaneous resolution of atrioventricular block and heart block within one minute, with no hemodynamic effects noted.
Five patients overdosed on dexmedetomidine hydrochloride in a sedation study in the intensive care unit. No symptoms were reported in two of these patients; one patient received a 2 ug /kg loading dose over 10 minutes (twice the recommended loading dose) and one patient received a maintenance infusion dose of 0.8 ug /kg/hr. The other two patients who received a 2 ug /kg loading dose over 10 minutes developed bradycardia and/or hypotension. One patient who received a push of an undiluted loading dose of dexmedetomidine hydrochloride (19.4 ug /kg) experienced cardiac arrest and was successfully treated.
Pharmacology and Toxicology
Pharmacological Actions
Dexmedetomidine is a relatively selective a2-adrenergic receptor agonist with sedative effects. Selective effects on a2-adrenoceptors are seen in animals with slow intravenous infusion of dexmedetomidine 10-300ug/kg, but at higher doses (³1000mg/kg) slow intravenous infusion or rapid intravenous administration has effects on both a1- and a2- receptors. chromosome aberration test, and in vivo micronucleus test results in CD1 mice were negative.
Reproductive toxicity
No effects on fertility were observed in male or female rats given dexmedetomidine subcutaneously at doses of up to 54ug/kg per day (based on mg/m2, which is lower than the maximum recommended human intravenous dose) for 10 and 3 weeks prior to mating, respectively, up to the time of mating.
Dexmedetomidine was administered subcutaneously at doses up to 200ug/kg on days 5-16 of gestation in rats and 96ug/kg on days 6-18 of gestation in rabbits without teratogenic effects. Based on mg/m2, the rat dose was equivalent to twice the maximum recommended human intravenous dose administered; based on plasma drug AUC values, the rabbit exposure was similar to that at the maximum recommended human intravenous dose administered. Fetal toxicity was seen in rats at a dose of 200ug/kg, as evidenced by an increase in post-implantation loss and a decrease in the number of surviving pups. The no-effect dose was 20ug/kg (based on mg/m2, which is below the maximum recommended human intravenous administration dose).
Subcutaneous administration of dexmedetomidine to rats from day 16 of gestation to lactation resulted in reduced pup weight at doses of 8 and 32 ug/kg (based on mg/m2, which is below the maximum recommended human intravenous dose), and delayed development of motor function was seen in pups in the 32 ug/kg dose group. embryo and litter toxicity was also seen in the F2 generation in the 32 ug/kg dose group. No such toxicity was observed at the 2ug/kg dose.
Pregnant rats given radiolabeled dexmedetomidine by subcutaneous injection showed placental transport.
Pharmacokinetics
Data from foreign studies show that in studies in healthy volunteers (N=10), respiratory rate and oxygen saturation remained within normal ranges and no respiratory depression was seen when the dose range for intravenous infusion was 0.2 to 0.7ug /kg/hr.
Pharmacokinetic parameters of dexmedetomidine after intravenous infusion were as follows: distribution half-life (t1/2) of approximately 6 minutes for the rapid phase of distribution; terminal clearance half-life (t1/2) of approximately 2 hours; and steady-state volume of distribution (Vss) of approximately 118 liters. Clearance was approximately 39 L/h. The mean body weight at which clearance was evaluated was 72 kg.
Infusion of the product intravenously at 0.2 to 0.7ug/kg/hr until 24 hours of dexmedetomidine showed linear kinetics. Table 4 lists (after receiving the appropriate loading dose) the main drug effects after continuous 12- and 24-hour infusions of dexmedetomidine hydrochloride 0.17ug/kg/hr (target concentration of 0.3 ng/mL), 24-hour infusion of 0.33ug/kg/hr (target concentration of 0.6 ng/mL), and 24-hour infusion of 0.70ug/kg/hr (target concentration of 1.25 ng /mL) after the main pharmacokinetic parameters.
Table 4. Pharmacokinetic Parameters Mean±SD Parameters Load Infusion (min)/Total Infusion Time (hrs) 10min/12hrs 10min/24hrs 10min/24hrs 35min/24hrs Target Concentration (ng/mL) and Dose of Dexmedetomidine (mg/kg/hr) 0.3/0.17 0.3/0.17 0.6/0.33 1.25/0.70 t1/2 *, h 1.78±0.30 2.22±0.59 2.23±0.21 2.50±0.61 CL, L/h 46.3±8.3 43.1±6.5 35.3±6.8 36.5±7.5 Vss, L 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 * As reconciled mean and pseudo-fitted standard deviation.
# Avg Css=mean steady-state concentration of dexmedetomidine. (Sampled from 2.5 to 9 hours for a 12-hour infusion and from 2.5 to 18 hours for a 24-hour infusion).
Distribution:
The steady-state volume of distribution (Vss) of dexmedetomidine is approximately 118 liters. Protein binding of dexmedetomidine was evaluated in the plasma of normal healthy male and female volunteers. Its mean protein binding was 94% across the different concentration tests; protein binding was similar in males and females. Dexmedetomidine binding to plasma proteins was significantly reduced in subjects with hepatic injury compared with healthy subjects.
In vitro studies looking at the potential for fentanyl, ketorolac, theophylline, digoxin, and lidocaine to displace dexmedetomidine-binding proteins did not result in observed changes in dexmedetomidine plasma protein binding. The possibility of protein binding of phenytoin sodium, warfarin, ibuprofen, propranolol, theophylline, and digoxin being replaced by dexmedetomidine was also investigated in vitro, and the results showed that no drug appeared to have its protein binding significantly replaced by dexmedetomidine.
Metabolism:
Dexmedetomidine is almost completely biotransformed and is rarely excreted in its original form in the urine and feces. Biotransformation includes direct glucuronidation and cytochrome P450-mediated metabolism. The major metabolic pathways of dexmedetomidine are: direct N-glucosiduronidation to inactive metabolites; lipid hydroxylation (mainly mediated by CYP2A6) to produce 3-hydroxydexmedetomidine, 3-hydroxydexmedetomidine glucosinolate, and 3-carboxydexmedetomidine; and N-methylation of dexmedetomidine to produce 3-hydroxyN-methyldexmedetomidine, 3-carboxyN-methyldexmedetomidine, and N-methyl O-glucosinolate dexmedetomidine. methyl O-glucuronide dexmedetomidine.
Clearance:
The terminal clearance half-life (t1/2) of dexmedetomidine is approximately 2 hours, with a clearance rate of approximately 39 L/h. Mass-balance studies have demonstrated that an average of 95% of the radiolabeled dexmedetomidine is recovered in the urine and 4% in the feces after 9 days of intravenous infusion. Dexmedetomidine in its original form was detectable in the urine. Approximately 85% of the radioactive material was excreted in the urine within 24 hours after infusion of the product. Segmental isolation of the radioactive material excreted in the urine was confirmed to be N-glucosidated products in 34% of cases. In addition, the fatty hydroxylation products 3-hydroxydextromethorphan, 3-hydroxydextromethorphan glucosinolate, and 3-carboxylic acid dextromethorphan accounted for approximately 14%. Dexmedetomidine N-methylation yielded 3-hydroxyN-methyldexmedetomidine, 3-carboxyN-methyldexmedetomidine, and dexmedetomidine N-methyl O-glucosiduronate in approximately 18% of the cases.The N-methyl metabolite itself was a minor circulating constituent and was not detected in the urine. Approximately 28% of the urinary metabolites were not identified.
Sex:
No sex differences were observed in the pharmacokinetics of dexmedetomidine.
Elderly patients:
The pharmacokinetic properties of dexmedetomidine do not change with age. There were no differences in the pharmacokinetics of dexmedetomidine in young (18-40 years), middle-aged (41-65 years) and elderly (>65 years) subjects.
Pediatric Patients:
The pharmacokinetic properties of dexmedetomidine have not been studied in pediatric patients.
Hepatic Impairment:
In subjects with varying degrees of hepatic impairment (Child-Pugh classification A, B, or C), dexmedetomidine clearance values were lower than in healthy subjects. Mean clearance values in subjects with mild, moderate, and severe hepatic impairment were 74%, 64%, and 53% of those in normal healthy subjects, respectively, and mean clearance of free drug was 59%, 51%, and 32% of those in normal healthy subjects, respectively.
Although this product needs to be administered to be effective, patients with hepatic impairment may need to consider a reduction in the dose administered (see Dosage, Precautions).
Renal Impairment:
The pharmacokinetics (Cmax, Tmax, AUC, t1/2, CL, and Vss) of dexmedetomidine in subjects with severe renal impairment (creatinine clearance: <30 mL/min) were not significantly different from those in healthy subjects. However, the pharmacokinetics of dexmedetomidine metabolites in patients with renal impairment were not evaluated. Because most metabolites are excreted in the urine, prolonged infusion in patients with renal impairment is likely to result in metabolite accumulation (see DOSAGE AND ADMINISTRATION).
StorageShielded and airtight, stored at room temperature (10-30°C).
PackagingCylindrical vials: 5 vials/box; 10 vials/box.
Effective period 18 months.
Executive Standard YBH06092009
Dextromethorphan Hydrochloride Injection is an α2-adrenergic receptor agonist developed by Orion Pharma (Finland) and Abott (USA), first marketed in March 2000 in the United States and in January 2004 in Japan. It is the dextro-isomer of the α2-adrenoceptor agonist medetomidine. Compared with medetomidine, it is more selective for central α2-adrenoceptor agonism, has a shorter half-life, and has a very small dosage, and is clinically indicated for the sedation of patients who are intubated and placed on a ventilator at the beginning of intensive care treatment. The listed dosage form of this product is injection, in 2mL transparent vials or transparent ampoules, with a free base concentration of 0.1ug/mL.
Dexmedetomidine Hydrochloride Injection has been listed in foreign countries, and has been produced in China, and this drug is now being marketed by Jiangsu Xinchen Pharmaceutical Co.
Dexmedetomidine is the active dextro isomer of medetomidine, which has anti-sympathetic, sedative and analgesic effects. Compared with medetomidine, this product is more selective for central α2-adrenoceptor agonism, and it is 8 times more effective than colistin for α2-adrenoceptors.
In mediating the major pharmacologic and therapeutic effects of this product, the α2A receptor subtype plays an important role. α2A receptors are present at both the presynaptic and postsynaptic levels and are primarily involved in the inhibition of norepinephrine release and neuronal excitation. It inhibits the release of norepinephrine and terminates pain signaling by agonizing the presynaptic membrane α2 receptor. By agonizing the postsynaptic membrane receptor, dexmedetomidine inhibits sympathetic neural activity and thus induces a decrease in blood pressure and heart rate. When it binds to the α2 receptor in the spinal cord to produce an analgesic effect, it can lead to sedation and anxiety relief. It also reduces the dose of anesthetic agents, improves hemodynamic stability during surgery and reduces the incidence of local ischemia in the myocardium.
Clinical experience with this product in the United States over the past 5 years has shown that dexmedetomidine hydrochloride produces stable sedation and arousal, has a unique synergistic effect on the physiological and psychological needs of critically ill patients, and significantly reduces the dosage of anesthetics required to induce anesthesia; preoperative administration of this product reduces the dosage of opioid or non-opioid analgesics in the pre-operative and post-operative period, a characteristic that has important implications for anesthesia and intensive care; and can also reduce the dosage of anesthetics administered during surgery. This property is important for anesthesia and intensive care; it also promotes catecholamine hemodynamic stability, effectively reducing tracheal intubation, surgical stress, and hemodynamic responses during anesthesia and early recovery.