Molecular formula: C 13H 16N2 HCl.
Molecular weight: 236.7
Shandong hongfuda pharmaceutical chemical co., ltd.
Drug name
Generic name: Dexmedetomidine Hydrochloride Injection
Commodity name:
English name: Dexmedetomidine injection
Hanyu pinyin: tomidine injection with beautiful phlogistic acid
composition
The main component of this product is dexmedetomidine hydrochloride, and its chemical name is (+)-4-(s)-[1-(2,3-dimethylphenyl) ethyl ]- 1H- imidazole hydrochloride.
Molecular formula: C 13H 16N2 HCl.
Molecular weight: 236.7
The auxiliary material of this product is sodium chloride.
Character; Role; letter
This product is a colorless or almost colorless clear liquid.
indicate
Used for sedation during tracheal intubation and mechanical ventilation in patients undergoing general anesthesia surgery.
standard
2ml∶200mg (calculated by dexmedetomidine)
dosage
Adult dose: 4mg /ml, 1mg/kg, and the infusion time exceeds 10 minutes.
Before taking this product, it must be diluted to a concentration of 4mg /ml with 0.9% sodium chloride solution, and 2mL of this product should be added into 48 ml of 0.9% sodium chloride injection to form a total solution of 50ml, which should be gently shaken. Strict aseptic techniques must always be maintained during the operation.
Dose adjustment:
Patients with hepatic and renal insufficiency and elderly patients may need to consider reducing the dose.
Drug compatibility:
counteraction
Because clinical trials are conducted in many different situations, the incidence of adverse reactions observed by one drug in clinical trials cannot be directly compared with that of another drug, and it may not necessarily reflect the adverse reactions observed in actual clinical applications.
Foreign research reports that the use of dexmedetomidine hydrochloride injection is related to the following serious adverse reactions:
Hypotension, bradycardia and sinus arrest (see precautions)
L Temporary hypertension (see precautions)
Foreign research reports that the most common adverse reactions related to treatment are hypotension, bradycardia and dry mouth.
The following (including post-marketing situation) are the adverse reactions that occurred in foreign clinical research:
Sedation in intensive care unit (ICU)
The information of adverse reactions came from 1007 patients who were sedated by continuous infusion of dexmedetomidine hydrochloride injection (Precedex) in intensive care unit. The average total dose was 7.4 mg /kg (range: 0.8~84. 1), the average hourly dose was 0.5 mg /kg/hr (range: 0. 1~6.0), and the average infusion time was 15.9 hours (range: 0.2 ~) 2% of adverse drug reactions. The most common adverse reactions are hypotension, bradycardia and dry mouth.
Table 1: Incidence >; 2% of adverse reactions-the body system of subjects taking sedatives in intensive care unit/
Adverse reaction index
Comprehensive treatment
N = 1007 percentile
Randomized treatment
N = 798 placebo
N = 400 propofol
In terms of blood vessels, n =188n (%) n (%) n (%) n (%) n (%).
hypertension
There were 248 patients with hypertension (25%)
123 ( 12%) 19 1 (24%)
10 1 ( 13%) 48 ( 12%)
76 ( 19%) 25 ( 13%)
Gastrointestinal reaction in 7 cases (4%)
Feel like vomiting
dry
90 cases (9%) vomited.
35 (4%)
34 (3%) 73 (9%)
22 (3%)
26 (3%) 36 (9%)
4 ( 1%)
2 1 (5%) 20 ( 1 1%)
1 ( 1%)
6 (3%) hearts.
bradycardia
atrial fibrillation
tachycardia
sinus tachy-cardia
There were 52 cases (5%) of ventricular tachycardia.
44 (4%)
20 (2%)
6 ( 1%)
4 (0%) 36 (5%)
37 (5%)
15 (2%)
6 ( 1%)
4 ( 1%) 10 (3%)
13 (3%)
17 (4%)
2 ( 1%)
3 ( 1%) 0
14 (7%)
2 ( 1%)
4 (2%)
9 cases (5%) had systemic and local symptoms.
themogenesis
high fever
Shiver with cold
Peripheral edema in 35 cases (4%)
19 (2%)
17 (2%)
4 (0%) 3 1 (4%)
16 (2%)
14 (2%)
2 (0%) 15 (4%)
12 (3%)
13 (3%)
2 ( 1%) 8 (4%)
4 (2%)
4 cases (2%) had metabolic and nutritional disorders.
Hypovolemia
Hyperglycemia
hypocalcemia
Acidosis 3 1 (3%)
17 (2%)
7 ( 1%)
6 ( 1%) 22 (3%)
15 (2%)
7 ( 1%)
5 ( 1%) 9 (2%)
7 (2%)
4 ( 1%) 9 (5%)
5 (3%)
4 (2%)
4 cases (2%) had diseases of respiratory system, chest and mediastinum.
Atelectasis
pleural effusion
Hypoxia/anoxia
pneumonedema
29 cases (3%) wheezing.
23 (2%)
16 (2%)
9 ( 1%)
4 (0%) 23 (3%)
16 (2%)
13 (2%)
9 ( 1%)
4 ( 1%) 13 (3%)
4 ( 1%)
8 (2%)
3 ( 1%)
1 (0%) 12 (6%)
12 (6%)
5 (3%)
5 (3%)
Four people (2%) had mental symptoms.
Agitation 20 (2%)16 (2%)1(3%)1(1%) blood and lymphatic system disorders.
Anemia19 (2%)18 (2%) 7 (2%) 4 (2%) injuries, poisoning and complications.
Hemorrhage15 (2%)13 (2%)10 (3%) 7 (4%) was observed after administration.
Urine volume decreased by 6 (1%) 6 (1%) 0 4 (2%) Program sedation:
Adverse reaction information came from two programmed sedation trials, in which * * * 3 18 patients received dexmedetomidine hydrochloride injection (Precedex). The average total dose was 1.6 mg /kg (range: 0.5~6.7), the average hourly dose was 1.3 mg /kg/hr (range: 0.3~6. 1), and the average infusion time was 1.5 hours.
Table 2 shows the incidence rate >; 2% of adverse drug reactions. The most common adverse reactions are hypotension, bradycardia and dry mouth. Footnotes in the form are the preset criteria for reporting vital signs as adverse reactions. In these two experiments, the respiratory rate decreased and the incidence of hypoxia was similar in the Precedex administration group and the control group.
Table 2: Incidence >; 2% of adverse reactions-programmed sedation of the subject's body system/
Adverse reaction index
N = 3 18 placebo
N = 1 13 n (%) n (%) vascular aspect.
Hypotension 1
Hypertension 173 (54%)
4 1 ( 13%) 34 (30%)
27 cases (24%) had diseases of respiratory system, chest and mediastinum.
Respiratory depression 5
Hypoxia/anoxia
Slow breathing 1 17 (37%)
7 (2%)
5 (2%) 36 (32%)
3 (3%)
5 hearts (4%).
Bradycardia 3
Tachycardia 4 45 (14%)
17 (5%) 4 (4%)
19 (17%) gastrointestinal reaction
Feel like vomiting
Dry mouth 10 (3%)
8 (3%) 2 (2%)
1 (1%) 1. The absolute and relative definition of hypotension is: systolic blood pressure.
2. The absolute and relative definitions of hypertension are: systolic blood pressure >; 180 mmHg or more than 30% higher than before infusion of test drug, or diastolic pressure >; 100 mm Hg.
3. The absolute and relative definition of bradycardia is < 40 beats per minute or less than 30% lower than the value before infusion.
4. The absolute and relative definition of tachycardia is the number of beats per minute >; 120 or more than 30% higher than before infusion.
5. The absolute and relative definition of respiratory depression is respiratory frequency.
6. The absolute and relative definition of hypoxia is spo 2.
After listing:
After Dexmedetomidine Hydrochloride Injection (Precedex) was approved for marketing, the following adverse reactions were observed. Because these adverse reactions are reported spontaneously by drug addicts with unknown sample size, it is impossible to accurately estimate their frequency or determine the causal relationship between adverse reactions and drugs.
After Precedex was approved for marketing, hypotension and bradycardia were the most common adverse reactions.
Table 3: Adverse reactions of Prebos after marketing: systemic preference: systemic fever, high fever, hypovolemia, mild anesthesia, pain, cardiovascular system stiffness (systemic condition), blood pressure fluctuation, heart disease, hypertension, hypotension, dizziness in central and peripheral nervous system of myocardial infarction, headache, neuralgia, neuritis, speech disorder, abdominal pain in gastrointestinal twitch, diarrhea, vomiting and nausea. Bradycardia, hypoxia, atrioventricular block, cardiac arrest, premature contraction, atrial fibrillation, cardiac block, T-wave inverted ventricular tachycardia, increased γ -glutamyl transpeptidase, abnormal liver function, hyperbilirubinemia, alanine aminotransferase, aspartate aminotransferase metabolism and malnutrition acidosis, respiratory acidosis, hyperkalemia, increased alkaline phosphatase, thirst, hypoglycemia agitation, and confusion. Erythrocyte anemia, kidney disease, increased blood urea nitrogen, oliguria, respiratory apnea, bronchospasm, dyspnea, hypercapnia, insufficient ventilation, hypoxia, pulmonary congestion, sweating of skin and accessories, increased blood vessel bleeding, visual impairment, flash hallucination and visual abnormality.
Those who are allergic to this product and its ingredients are prohibited.
Matters needing attention
Hypotension, bradycardia and sinus arrest
It is reported that healthy young volunteers with high vagus nerve tension or different administration methods (such as rapid intravenous injection or push injection) have clinically obvious bradycardia and sinus arrest after giving this product.
Medication for the elderly
As we all know, dexmedetomidine is mainly excreted through the kidney, and patients with renal dysfunction are at greater risk of adverse reactions. Elderly patients with renal function decline, elderly patients should carefully choose the dose, monitoring renal function may be useful.
In foreign clinical research, there are 729 patients over 65 years old and 200 patients over 75 years old in ICU sedation test. In patients over 65 years old, the incidence of bradycardia and hypotension after giving this product is high. Therefore, patients over 65 years old should consider reducing the dosage when using this product. In the clinical trial of programmed sedation, 13 1 patient was ≥65 years old, and 47 patients were ≥75 years old. The incidence of hypotension is 72% in people aged 65 and over, 74% in people aged 75 and over, and 47% in patients aged 65 and over. Therefore, patients over 65 years old should reduce the loading dose, and the recommended dose is 0.5mg /kg, and the infusion time is longer than 10 minute.
drug interaction
An anesthetic/sedative/hypnotic/opioid
Taking this product with anesthetics, sedatives, hypnotics and opioids at the same time may enhance the efficacy. Foreign research reports confirmed the effects of dexmedetomidine hydrochloride on sevoflurane, isoflurane, propofol, alfentanil and midazolam. There is no pharmacokinetic interaction between dexmedetomidine and isoflurane, propofol, alfentanil and midazolam. However, due to the possible pharmacodynamic interaction, it may be necessary to reduce the dosage of this product or the accompanying anesthetics, sedatives, sleeping pills and opioids when giving this product at the same time.
Neuromuscular block
In a foreign study of 10 healthy volunteers, dexmedetomidine hydrochloride was given for 45 minutes at a plasma concentration of 1ng/mL, which did not lead to a significant clinical increase in neuromuscular blockade related to rocuronium administration.
excessive
According to foreign data, in a tolerance clinical study, the dose of dexmedetomidine hydrochloride taken by healthy volunteers reached or exceeded 0.2~ 0.7 mg /kg/hr, and the maximum blood concentration reached was about 13 times of the upper limit of the treatment range. The most significant effects observed in the two subjects who reached the highest dose were first-degree atrioventricular block and second-degree cardiac block, and then the atrioventricular block and cardiac block were naturally eliminated within one minute, and no hemodynamic effect was found.
During the sedation study in ICU, five patients received an overdose of dexmedetomidine hydrochloride. Two of these patients reported no symptoms; One patient received a loading dose of 2 mg /kg for 10 minute (twice the recommended loading dose), and one patient received a maintenance infusion dose of 0.8 mg/kg/hr. The other two patients who received a loading dose of 2 mg /kg for 10 minutes developed bradycardia and/or hypotension. A patient who received undiluted dexmedetomidine hydrochloride loading dose (19.4mg /kg) suffered from cardiac arrest and was successfully treated.
Pharmacology and toxicology
pharmacological action
Dexmedetomidine is a relatively selective a2 adrenergic receptor agonist with sedative effect. The selective effect of dexmedetomidine10 ~ 300 mg/kg on a2- adrenergic receptors can be seen in animals, but at higher doses (&: Sup3 1000mg/kg) has effects on both a 1 and a2 receptors when administered by slow intravenous infusion or rapid intravenous injection.
Toxicological study
Intrinsic toxicity
The results of Ames test of dexmedetomidine and forward gene mutation test of mammalian cells were negative: the chromosome aberration test of human lymphocytes in vitro and the micronucleus test of NMRI mice in vivo under the condition of S9 metabolic activation of rats were positive, but the chromosome aberration test of human lymphocytes in vitro and the micronucleus test of CD 1 mice with or without S9 metabolic activation were negative.
Reproductive toxicity
Male or female rats were injected with dexmedetomidine subcutaneously every day from 10 week to 3 weeks before mating, which was as high as 54mg/kg (calculated by mg/m2, lower than the maximum recommended dose of human intravenous injection), and had no effect on fertility.
The dose of dexmedetomidine injected subcutaneously in rats on the 5th-16th day of pregnancy was as high as 200mg/kg, and that in rabbits on the 6th-18th day of pregnancy was as high as 96mg/kg. No teratogenic effect was found. Calculated by mg/m2, the rat dose is equivalent to twice the maximum recommended dose for human intravenous injection. According to the AUC value of plasma drugs, the exposure of rabbits is similar to that of human intravenous injection at the maximum recommended dose. Fetal toxicity of rats was observed at the dose of 200mg/kg, which indicated that the loss increased after implantation and the number of surviving offspring decreased. The no-impact dose is 20mg/kg (calculated by mg/m2, lower than the maximum recommended dose for human intravenous injection).
Dexmedetomidine was injected subcutaneously into rats from 65-438+06 days of pregnancy to lactation. At the dose of 8 and 32mg/kg (calculated by mg/m2, lower than the maximum recommended dose for human intravenous injection), the weight of the young was reduced. In the 32 mg/kg dose group, the young rats showed bradykinesia. Embryo and fetal toxicity were also observed in F2 generation of 32 mg/kg dose group. No toxicity was observed at a dose of 2 mg/kg.
Placental transport was observed in pregnant rats after subcutaneous injection of radiolabeled dexmedetomidine.
pharmacokinetics
Foreign research data show that in the study of healthy volunteers (N= 10), when the dosage of intravenous infusion is in the range of 0.2 ~ 0.7mg/kg/HR, the respiratory frequency and oxygen saturation remain in the normal range, and no respiratory depression is found.
After intravenous infusion, the pharmacokinetic parameters of dexmedetomidine are as follows: the distribution half-life (t 1/2) in the rapid distribution period is about 6 minutes; The terminal clearance half-life (t 1/2) is about 2 hours; The steady-state distribution volume (Vss) is about 1 18 liters. The clearance rate is about 39 liters/hour. The average weight of clearance rate is 72 kg.
Intravenous infusion of 0.2 ~ 0.7 mg/kg/hour of dexmedetomidine showed linear kinetics until 24 hours. Table 4 shows that (after receiving appropriate loading dose), dexmedetomidine hydrochloride was continuously infused17 mg/kg/hr (target concentration was 0.3ng/mL), 0.33mg/kg/hr (target concentration was 0.6ng/mL) and 0.70 mg/hr respectively.
Table 4. Average value of pharmacokinetic parameters SD parameter load infusion (minutes)/total infusion time (hours) 10 minutes/12 hours 10 minutes /24 hours 10 minutes /24 hours 35 minutes /24 hours dexmedetomidine target concentration (ng/mL HR)0.3/0. 17 0.3/0. 17 0.6/0.33 1.25/0.70 1/2 *，h 1.78 0.30 2.22 0.59 2.23 0.2 1.2.50 0 0.6 1 CL，L/h 46.3 8.3
# Avg Css= average steady-state concentration of dexmedetomidine. (12 hour infusion, 2.5~9 hours sampling, 24 hours infusion, 2.5~ 18 hours sampling).
Distribution:
The steady-state distribution volume (Vss) of dexmedetomidine is about 1 18 liters. To evaluate the protein binding of dexmedetomidine in the plasma of normal healthy male and female volunteers. In different concentration tests, the average protein binding rate was 94%. The protein binding rate of men and women is similar. Compared with healthy subjects, the binding function of dexmedetomidine to plasma protein in subjects with liver injury was significantly reduced.
The possibility of fentanyl, ketorolac, theophylline, digoxin and lidocaine replacing dexmedetomidine binding protein was observed in vitro. The results showed that the plasma protein binding rate of dexmedetomidine did not change. The possibility of protein binding of phenytoin sodium, warfarin, ibuprofen, propranolol, theophylline and digoxin being replaced by dexmedetomidine was also studied in vitro. The results showed that drug-free protein binding seemed to be obviously replaced by dexmedetomidine.
Metabolism:
Dexmedetomidine is almost completely biotransformed and rarely excreted from urine and feces in its original form. Biotransformation includes direct glucuronidation and cytochrome P450-mediated metabolism. The main metabolic pathways of dexmedetomidine are: direct N- glucuronic acid to inactive metabolites; Hydroxylation of fat (mainly mediated by CYP2A6) produces 3- hydroxydexmedetomidine, 3- hydroxydexmedetomidine glucoside and 3- carboxydexmedetomidine; N- methylation of dexmedetomidine produces 3- hydroxy N- methyl dexmedetomidine, 3- carboxy N- methyl dexmedetomidine and N- methyl O- glucoside dexmedetomidine.
Clear:
The terminal clearance half-life (t 1/2) of dexmedetomidine is about 2 hours, and the clearance rate is about 39 L/h. The mass balance study confirmed that after 9 days of intravenous infusion of radiolabeled dexmedetomidine, 95% of radioactive substances were recovered from urine and 4% were in feces. Dexmedetomidine can be detected in urine. About 85% of radioactive substances are excreted from urine within 24 hours after infusion of this product. Through fractionation, 34% of radioactive substances discharged from urine were identified as N- glucuronic acid products. In addition, 3- hydroxydexmedetomidine, 3- hydroxydexmedetomidine glucoside and 3- carboxylate dexmedetomidine account for about 14%. 3- hydroxy N- methyldexmedetomidine, 3- carboxy N- methyldexmedetomidine and N- methyl O- glucoside dexmedetomidine produced by N- methylation of dexmedetomidine account for about 18%. N- methyl metabolite itself is a secondary circulating component, which has not been detected in urine. About 28% of urinary metabolites have not been identified.
Gender:
There is no gender difference in pharmacokinetics of dexmedetomidine.
Elderly patients:
The pharmacokinetic characteristics of dexmedetomidine do not change with age. There is no difference in the pharmacokinetics of dexmedetomidine among young (18~40 years old), middle-aged (4 1~65 years old) and elderly (> 65 years old) subjects.
Pediatric patients:
The pharmacokinetic characteristics of dexmedetomidine in pediatric patients have not been studied.
Liver function damage:
The clearance rate of dexmedetomidine in patients with different degrees of liver function impairment (Child-Pugh classification A, B or C) is lower than that in healthy subjects. The average clearance rates of patients with mild, moderate and severe liver injury were 74%, 64% and 53% of those of normal healthy subjects, and the average clearance rates of free drugs were 59%, 565, 438+0% and 32% of those of normal healthy subjects, respectively.
Although the product needs to be effective, patients with liver function damage may need to consider reducing the dosage (see usage and dosage, precautions).
Renal function injury:
Subjects with severely impaired renal function (creatinine clearance rate:
Store in a closed place at room temperature (10-30℃) in the dark.
Packaging, penicillin bottle packaging. 5 bottles/box; 10 bottle/box.
The validity period is 18 months.
Implement the standard YBH06092009.
Approval number: National Medicine Zhunzi H20090248
Dexmedetomidine hydrochloride injection is an α2 adrenergic receptor agonist developed by Orion Pharma (Finland) and Abott (USA). It was first listed in the United States in March 2000 and in Japan from June 5 to 10, 2004. This product is the dextroisomer of α2- adrenoceptor agonist medetomidine, with short half-life and small dose, which is suitable for sedation of patients who start intubation and use ventilator in intensive care treatment. The marketed dosage form of this product is injection, 2mL transparent vial or ampoule, and the concentration of free alkali is 0. 1mg/mL.
Dexmedetomidine hydrochloride injection has been listed abroad and produced in China. Now Jiangsu Chen Xin Pharmaceutical Co., Ltd. is selling this drug.
Dexmedetomidine is the active dextroisomer of medetomidine, which has anti-sympathetic, sedative and analgesic effects. Compared with medetomidine, dexmedetomidine has stronger selectivity for central α2- adrenoceptor, and its selectivity for α2- adrenoceptor is 8 times that of clonidine.
α2A receptor subtype plays an important role in mediating the main pharmacological and therapeutic effects of this product. α2A receptor exists before and after synapse, which mainly involves inhibiting the release of norepinephrine and the excitement of neurons. This product can inhibit the release of norepinephrine and stop the transmission of pain signals by exciting α2 receptor in presynaptic membrane. By exciting postsynaptic membrane receptors, dexmedetomidine inhibits sympathetic nerve activity, which leads to the decrease of blood pressure and heart rate. When combined with α2 receptor in spinal cord to produce analgesic effect, it can lead to sedation and anxiety relief. This product can also reduce the dosage of anesthetic, improve the stability of hemodynamics during operation and reduce the incidence of myocardial ischemia.
The clinical experience of this product in the United States for more than 5 years shows that dexmedetomidine hydrochloride can produce stable sedative and resuscitation effects, and has a unique synergistic effect on the physiological and psychological needs of critically ill patients, which can obviously reduce the amount of anesthetic needed for induced anesthesia; Taking this product before operation can reduce the dosage of opioid or non-opioid analgesics before and after operation, which is of great significance to anesthesia and intensive care. It can also promote the stability of catecholamine hemodynamics, effectively reduce tracheal intubation, surgical stress and anesthesia, and restore early hemodynamic response.