Active ingredients: Dexetimide
Dexdor 100 micrograms / ml concentrate for solution for infusion
Why is Dexdor used? What is it for?
Dexdor contains an active substance called dexmedetomidine which belongs to a group of medicines called sedatives. It is used to induce sedation (a state of calm, drowsiness or sleep) for adult patients admitted to hospital intensive care units.
Contraindications When Dexdor should not be used
You must not be given Dexdor
- if you are allergic to dexmedetomidine or any of the other ingredients of this medicine (listed in section 6).
- if you have certain heart rhythm disturbances (grade 2 or 3 heart block). - if you have very low blood pressure that does not respond to treatment.
- if you have recently had a stroke or some other serious condition involving the blood supply to the brain.
Precautions for use What you need to know before taking Dexdor
Before being treated with this medicine, tell your doctor or nurse if any of the following conditions apply, as Dexdor should be used with caution:
- if you have a slower than normal heart rate (due to both illness and high levels of physical activity) - if you have low blood pressure
- if you have a low blood volume, for example after bleeding
- if you suffer from heart problems
- if you are elderly
- if you have a neurological disorder (for example head injury, spinal cord injury, or stroke) - if you have severe liver problems
- if you have ever developed a high fever after taking certain medicines, especially anesthetics
Interactions Which drugs or foods can change the effect of Dexdor
Tell your doctor or nurse if you are taking, have recently taken or might take any other medicines.
The following medicines may increase the effect of Dexdor:
- medicines that help you sleep or cause sedation (e.g. midazolam, propofol)
- potent pain relievers (e.g. opiates such as morphine, codeine)
- anesthetic medicines (e.g. sevoflurane, isoflurane)
If you are taking medicines that lower blood pressure and heart rate, co-administration of Dexdor may increase this effect. Dexdor must not be used with other medicines that cause temporary paralysis.
Warnings It is important to know that:
Pregnancy and breastfeeding
Dexdor should not be used during pregnancy or breastfeeding unless clearly necessary. Ask your doctor for advice before using this medicine.
Dosage and method of use How to use Dexdor: Dosage
Dexdor is given to you by a doctor or nurse in an intensive care hospital setting.
Your doctor will decide on the right dose for you. The amount of Dexdor depends on your age, weight, general health, level of sedation needed and how you respond to the medicine. Your doctor may adjust your dose if necessary, and will monitor your heart and blood pressure during treatment. Dexdor is diluted. and is given to you as an infusion (drip) into a vein.
Overdose What to do if you have taken too much Dexdor
If you are given too much Dexdor, your blood pressure may drop, your heart rate may slow down and you may feel more sleepy. Your doctor will know how to treat you based on your condition. If you have any further questions on the use of this medicine, ask your doctor.
Side Effects What are the side effects of Dexdor
Like all medicines, this medicine can cause side effects, although not everybody gets them.
Very common (affects more than 1 in 10 patients)
- Slowing of the heartbeat
- Low or high blood pressure.
Common (affects 1 to 10 users in 100)
- Chest pain or heart attack
- Accelerated heart rate
- Low or high blood sugar (amount of sugar in the blood)
- Changes in the pattern of breathing or respiratory arrest
- Nausea, vomiting or dry mouth
- Agitation
- High temperature
- Medication discontinuation symptoms
Uncommon (affects 1 to 10 users in 1,000)
- Reduced heart function
- Swelling of the stomach
- Thirst
- A condition where there is too much acid in the body
- Low level of albumin in the blood
- Shortness of breath
- Hallucinations
- The medicine is not effective enough
Reporting of side effects
If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the label and carton after EXP.
This medicinal product does not require any special storage temperatures. Keep the vials or ampoules in the outer carton to protect the medicine from light.
Other information
What Dexdor contains
- The active ingredient is dexmedetomidine. Each ml of concentrate contains dexmedetomidine hydrochloride equivalent to 100 micrograms of dexmedetomidine.
- The other ingredients are sodium chloride and water for injections.
Each 2 ml vial contains 200 micrograms of dexmedetomidine (as hydrochloride).
Each 2 ml vial contains 200 micrograms of dexmedetomidine (as hydrochloride).
Each 4 ml vial contains 400 micrograms of dexmedetomidine (as hydrochloride).
Each 10 ml vial contains 1000 micrograms of dexmedetomidine (as hydrochloride).
The concentration of the final solution after dilution should be 4 micrograms / ml or 8 micrograms / ml.
What Dexdor looks like and contents of the pack
Concentrate for solution for infusion (sterile concentrate).
The concentrate is a clear, colorless solution.
Containers
- 2ml glass vials
- Glass vials of 2, 5 or 10 ml
Packs
- 5 ampoules of 2 ml
- 25 vials of 2 ml
- 5 vials of 2 ml
- 4 vials of 4 ml
- 4 vials of 10 ml
Not all pack sizes may be marketed.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
DEXDOR 100 mcg / ML CONCENTRATE FOR SOLUTION FOR INFUSION
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each ml of concentrate contains dexmedetomidine hydrochloride equivalent to 100 mcg of dexmedetomidine.
Each 2ml vial contains 200mcg of dexmedetomidine.
Each 2 ml vial contains 200 mcg of dexmedetomidine.
Each 4 ml vial contains 400 mcg of dexmedetomidine.
Each 10 ml vial contains 1000 mcg of dexmedetomidine.
The concentration of the final solution after dilution should be 4 mcg / ml or 8 mcg / ml.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Concentrate for solution for infusion (sterile concentrate).
The concentrate is a clear, colorless solution with a pH between 4.5 - 7.0.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
For the sedation of adult patients in the Intensive Care Unit (ICU) who require a level of sedation no deeper than awakening in response to verbal stimulation (corresponding to the value 0 to - 3 on the Richmond Sedation-Agitation Scale (Richmond Agitation-Sedation Scale, RASS).
04.2 Posology and method of administration
For hospital use only. Dexdor must be administered by healthcare professionals who specialize in the management of patients in need of intensive care.
Dosage
Patients already intubated and sedated can be switched to dexmedetomidine with an initial infusion rate of 0.7 mcg / kg / h, which can subsequently be gradually changed within the dose range of 0.2 to 1.4 mcg / kg / h until the desired level of sedation is reached, which depends on the patient's response. For frail patients, a lower initial infusion rate should be considered. Dexmedetomidine is very potent and the infusion rate is expressed per hour. After dose adjustment, a new steady-state sedation level cannot be reached for one hour.
Maximum dose
The maximum dose of 1.4 mcg / kg / h should not be exceeded. Patients who do not achieve adequate sedation on the maximum dose of dexmedetomidine should be treated with an alternative sedative medicinal product.
Use of a loading dose of Dexdor is not recommended and is associated with increased adverse reactions. If necessary, propofol or midazolam may be administered until clinical effects of dexmedetomidine are achieved.
Duration
There is no experience of using Dexdor for more than 14 days. The use of Dexdor for longer than this should be regularly reassessed.
Special populations
Senior citizens
No dose adjustment is normally required for elderly patients.
Kidney failure
No dose adjustment is required for patients with renal insufficiency.
Hepatic insufficiency
Dexmedetomidine is metabolised in the liver and should be used with caution in patients with hepatic insufficiency. A reduced maintenance dose may be considered (see sections 4.4 and 5.2).
Pediatric population
The safety and efficacy of Dexdor in children aged 0 to 18 years have not been established. Currently available data are described in sections 4.8, 5.1 and 5.2, but no recommendation on a posology can be made.
Method of administration
Dexdor should only be administered by diluted intravenous infusion, using a controlled infusion device. For instructions on dilution of the medicinal product before administration, see section 6.6.
04.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Advanced heart block (grade 2 or 3) if not paced (by pacemaker).
Uncontrolled hypotension.
Acute cerebrovascular conditions.
04.4 Special warnings and appropriate precautions for use
Monitoring
Dexdor is intended for use in intensive care settings and is not recommended for use in other settings. During the infusion with Dexdor, all patients should undergo constant cardiac monitoring. Respiration should be monitored in non-intubated patients due to the risk of respiratory depression and in some cases apnea (see section 4.8).
General Precautions
Since Dexdor should not be administered by loading dose or bolus, those using this medicinal product should be prepared to use an alternative sedative for acute agitation control or during procedures, especially during the first hours of treatment. Some patients who have received Dexdor, are arousal and alert when stimulated.In the absence of other clinical signs and symptoms this should not be regarded as evidence of lack of efficacy.
Dexdor should not be used as an induction agent for intubation or to provide sedation while using muscle relaxant medicines.
Dexmedetomidine lacks the anticonvulsant action of some other sedatives and therefore does not suppress the activity of the underlying seizures.
Care should be taken when administering dexmedetomidine with other substances with sedative action or with cardiovascular activity, as additive effects may occur.
Cardio-vascular effects and precautions
Dexmedetomidine reduces heart rate and blood pressure through central sympatholytic action, but at higher concentrations causes peripheral vasoconstriction leading to hypertension (see section 5.1). Dexmedetomidine does not normally cause profound sedation and patients can be easily awakened. Dexmedetomidine does not it is therefore suitable for patients who do not tolerate this profile of effects, for example those requiring continuous deep sedation or with severe cardiovascular instability.
Caution should be exercised when administering dexmedetomidine to patients with pre-existing bradycardia. Data on the effects of Dexdor in patients with cholinergic heart rate or dose reduction if necessary. Patients with high athleticism and low resting heart rate may be particularly sensitive to the bradycardic effects of alpha-2 receptor agonists, and cases of transient sinus arrest have been reported.
The hypotensive effects of dexmedetomidine may be of greater importance in those patients with pre-existing hypotension (especially if unresponsive to vasopressor medicinal products), hypovolaemia, chronic hypotension or reduced functional reserve, such as in patients with severe ventricular dysfunction and elderly patients; these cases deserve special assistance (see section 4.3). Hypotension does not normally require specific treatment, but, where necessary, those using this medicinal product should be prepared to intervene with dose reduction, fluids and / or vasoconstrictors.
Patients with reduced peripheral autonomic nervous system activity (eg due to spinal cord injury) may have more pronounced haemodynamic changes after starting the dexmedetomidine infusion and should therefore be treated with caution.
Transient arterial hypertension concomitant with peripheral vasoconstriction effects was mainly observed during the loading dose which is therefore not recommended. Treatment of hypertension is generally not necessary, but it may be advisable to decrease the rate of continuous infusion.
At higher concentrations local vasoconstriction may be of greater importance in patients with ischemic heart disease or severe cerebrovascular disease and therefore should be carefully monitored. In patients who develop signs of myocardial or cerebral ischaemia, dose reduction or treatment discontinuation should be considered.
Patients with hepatic insufficiency
Care should be taken in case of severe hepatic insufficiency as excessive dosage may increase the risk of adverse reactions, excessive sedation or a prolonged effect as a consequence of the reduced clearance of dexmedetomidine.
Patients with neurological diseases
Experience with the use of dexmedetomidine in severe neurological conditions, such as head injury and after neurosurgery, is limited and should be used with caution in these cases, especially if deep sedation is required. Dexmedetomidine can reduce cerebral blood flow and intracranial pressure and this must be taken into consideration when choosing therapy.
Other
Rarely, alpha-2 agonists have been associated with withdrawal reactions when abruptly stopped after prolonged use. This possibility should be considered if the patient develops agitation and hypertension shortly after discontinuation of dexmedetomidine.
It is not known whether the use of dexmedetomidine is safe in individuals susceptible to malignant hyperthermia and therefore its use is not recommended. Dexdor treatment should be discontinued in case of prolonged fever of unknown origin.
04.5 Interactions with other medicinal products and other forms of interaction
Interaction studies have only been conducted in adults.
Concomitant administration of dexmedetomidine with anesthetics, sedatives, hypnotics and opioids may result in increased effects, including sedative, anesthetic and cardiorespiratory effects. Specific studies have confirmed increased effects with isoflurane, propofol, alfentanil and midazolam. No pharmacokinetic interactions have been demonstrated between dexmedetomidine and isoflurane, propofol, alfentanil and midazolam.However, due to the possible pharmacodynamic interaction, when co-administered with dexmedetomidine, a reduction in the dose of dexmedetomidine or the concomitantly administered anesthetic, sedative, hypnotic or opioid may be necessary.
Inhibition of CYP enzymes, including CYP2B6 by dexmedetomidine was studied by incubation with human liver microsomes. One study conducted in vitro suggests the existence of a potential interaction in vivo between dexmedetomidine and substrates with dominant metabolism by CYP2B6.
It was observed in vitro an "induction by dexmedetomidine on CYP1A2, CYP2B6, CYP2C8, CYP2C9 and CYP3A4, and an" induction in vivo. The clinical significance of this induction is unknown.
The possibility of increased hypotensive and bradycardic effects in patients treated with other medicinal products that cause such effects, e.g. beta blockers, should be considered, although the additional effects were modest in an interaction study with esmolol.
04.6 Pregnancy and breastfeeding
Pregnancy
There are no or limited data from the use of dexmedetomidine in pregnant women.
Animal studies have shown reproductive toxicity (see section 5.3). Dexdor is not recommended during pregnancy and in women of childbearing potential who are not using contraceptive measures.
Feeding time
Available data in rats showed excretion of dexmedetomidine or metabolites in milk. Risks to newborns cannot be ruled out. A decision must be made whether to discontinue breast-feeding or to discontinue dexmedetomidine therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
Fertility
In fertility studies in rats, dexmedetomidine had no effect on male or female fertility.
04.7 Effects on ability to drive and use machines
Not relevant.
04.8 Undesirable effects
Summary of the safety profile
The most frequently reported adverse reactions with dexmedetomidine are hypotension, hypertension and bradycardia, occurring in approximately 25%, 15% and 13% of patients, respectively. Hypotension and bradycardia were also the most frequent serious adverse reactions related to dexmedetomidine occurring in 1.7% and 0.9% of patients randomized to the Intensive Care Unit (ICU), respectively.
Table of adverse reactions
The adverse reactions listed in Table 1 were collected from pooled data from clinical trials conducted in the ICU.
Adverse reactions are ranked in order of frequency, the most frequent first, according to the following convention: very common (≥ 1/10), common (≥ 1/100,
Table 1. Adverse reactions
Metabolism and nutrition disorders
Common: Hyperglycaemia, hypoglycemia
Uncommon: Metabolic acidosis, hypoalbuminaemia
Psychiatric disorders
Common: Agitation
Uncommon: Hallucinations
Cardiac pathologies
Very common: Bradycardia *
Common: Myocardial ischaemia or infarction, tachycardia
Uncommon: First degree atrioventricular block, cardiac output decreased
Vascular pathologies :
Very common: Hypotension *, hypertension *
Respiratory, thoracic and mediastinal disorders
Common: Respiratory depression
Uncommon: Dyspnea, apnea
Gastrointestinal disorders
Common: Nausea, vomiting, dry mouth
Uncommon: Abdominal distension
General disorders and administration site conditions
Common: Withdrawal syndrome, hyperthermia
Uncommon: Ineffectiveness of the drug, thirst
* See section on description of selected adverse reactions
Description of selected adverse reactions
Clinically significant hypotension or bradycardia should be treated as described in section 4.4.
In relatively healthy subjects out of the ICU and treated with dexmedetomidine, bradycardia occasionally led to sinus arrest or pause. Symptoms responded to leg elevation and use of anticholinergics such as atropine or glycopyrrolate. In isolated cases, bradycardia has progressed to periods of asystole in patients with pre-existing bradycardia. Hypertension has been associated with use of a loading dose. and this reaction can be reduced by avoiding such a loading dose or by reducing the rate of infusion or the amount of the loading dose.
Pediatric population
Infants older than 1 month, predominantly in the post-operative phase, have been evaluated for treatment for up to 24 hours in the ICU and a similar safety profile to that of adults has been demonstrated. Data in neonates (28-44 weeks of gestation) are very limited and restricted to maintenance doses ≤ 0.2 mcg / kg / h. A single case of hypothermic bradycardia in a newborn has been reported in the literature.
Reporting of suspected adverse reactions
Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system.
04.9 Overdose
Symptoms
Several cases of dexmedetomidine overdose have been reported in both clinical trials and post-marketing experience. In these cases, higher dexmedetomidine infusion rates have been reported, reaching 60 mcg / kg / h for 36 minutes and 30 mcg / kg / h for 15 minutes in a 20 month old baby and an adult respectively The most common adverse reactions reported and related to overdose in these cases included bradycardia, hypotension, excessive sedation, somnolence and cardiac arrest.
Management
In the event of an overdose with clinical symptoms, the infusion of dexmedetomidine should be reduced or stopped. The expected effects are primarily cardiovascular and should be treated according to clinical indications (see section 4.4). At high concentrations, hypertension may be more important than "hypotension. In clinical trials, cases of sinus arrest either resolved spontaneously or responded to treatment with atropine and glycopyrrolate.
Resuscitation was required in isolated cases of severe overdose resulting in cardiac arrest.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: Psycholeptics, other hypnotics and sedatives, ATC code: N05CM18
Dexmedetomidine is a selective alpha-2 adrenergic receptor agonist with a wide range of pharmacological properties. It has a sympatholytic effect by inhibiting the release of noradrenaline in sympathetic nerve endings. The sedative effects are mediated by the decreased firing activity of the locus coeruleus, the predominant noradrenergic nucleus which is located in the brain stem. Administration of dexmedetomidine allows a reduction in the dose of analgesics and anesthetics / analgesics. Cardiovascular effects depend on the dose; at lower infusion rates, central effects predominate, leading to decreased heart rate and blood pressure. At higher doses, peripheral vasoconstrictor effects prevail, leading to an increase in systemic vascular resistance and blood pressure, while the "bradycarding effect is further emphasized. Dexmedetomidine is relatively free of respiratory depressant effects when administered alone to healthy subjects. In placebo-controlled clinical trials conducted in post-operative ICU patients previously intubated and sedated with midazolam or propofol, Dexdor significantly reduced urgent use of sedatives (midazolam or propofol) and opioids during sedation to a maximum 24 hours. Most patients treated with dexmedetomidine did not require any additional sedative treatment. Patients could be successfully extubated without interrupting the Dexdor infusion. Studies conducted outside the ICU have confirmed that Dexdor can be safely administered to patients without endotracheal intubation if adequate monitoring is provided.
In a medicalized and ICU population that required predominantly mild to moderate prolonged sedation (RASS 0 to -3) for up to 14 days, dexmedetomidine was similar to midazolam (ratio 1.07; 95% CI 0.971-1.176) and propofol (ratio 1.00; 95% CI 0.922-1.075) considering time in the target sedation interval; dexmedetomidine reduced the duration of mechanical ventilation compared to midazolam and reduced intubation time compared to midazolam and propofol Compared to propofol and midazolam, patients were awakened more easily, were more cooperative and better able to communicate the presence or absence of pain.
Patients treated with dexmedetomidine had more frequent hypotension and bradycardia, but less tachycardia than those treated with midazolam; had more frequent tachycardia, but hypotension similar to patients treated with propofol. In a midazolam comparison study, delirium as measured by CAM-ICU scale was reduced and delirium-related adverse events were lower for dexmedetomidine than for propofol. Patients who were withdrawn due to insufficient sedation were switched to propofol or midazolam. The risk of insufficient sedation was increased in patients difficult to sedate with standard care immediately prior to switching to therapy.
Evidence of pediatric efficacy was observed in a dose-controlled ICU study in a "large postoperative population aged 1 month to ≤ 17 years. Approximately 50% of dexmedetomidine-treated patients did not require therapy. supportive with midazolam during a treatment period [median] of 20.3 hours, not exceeding 24 hours. No data are available for treatment> 24 hours. Data in neonates (28-44 weeks of gestation) are very limited and restricted to lower doses (≤ 0.2 μg / kg / h) (see sections 5.2 and 4.4) Neonates may be particularly sensitive to the bradycardic effects of Dexdor in the presence of hypothermia and in conditions of heart rate-dependent cardiac output.
In double-blind comparator-controlled studies conducted in the Intensive Care Unit (ICU), the incidence of cortisol suppression in dexmedetomidine-treated patients (n = 778) was 0.5% versus 0% in patients. treated with midazolam (n = 338) or propofol (n = 275).
The event was reported as mild in 1 case and moderate in 3 cases.
05.2 Pharmacokinetic properties
The pharmacokinetics of dexmedetomidine were evaluated during short-term intravenous (i.v.) administration in healthy volunteers and during long-term infusion in ICU patients.
Distribution
Dexmedetomidine exhibits a two-compartment distribution pattern.
In healthy volunteers, it exhibits a rapid distribution phase with a central estimate of the distribution half-life (t½?) Of approximately 6 minutes.
The mean estimate of the terminal elimination half-life (t½) is approximately 1.9-2.5 h (min 1.35, max 3.68 h) and the mean estimate of the steady-state volume of distribution (Vss) is approximately 1.16-2.16 l / kg (90 - 151 liters.). Plasma clearance (Cl) has an estimated mean value of 0.46-0.73 l / h / kg (35.7- 51 , 1 l / h) The mean body weight associated with these estimates of Vss and Cl was 69 kg.
The plasma pharmacokinetics of dexmedetomidine are similar in patients admitted to the ICU after infusion> 24 h. The estimated pharmacokinetic parameters are: t1 / 2 about 1.5 hours, Vss about 93 liters and Cl about 43 l / h. The pharmacokinetics of dexmedetomidine are linear over the dose range 0.2-1.4 μg / kg / h and there is no accumulation in treatments lasting up to 14 days. Dexmedetomidine is 94% bound to plasma proteins. plasma protein is constant in the concentration range between 0.85 and 85 ng / ml. Dexmedetomidine binds to both human serum albumin and alpha-1-acid glycoprotein. Albumin is the major binding protein of dexmedetomidine in plasma.
Biotransformation and elimination
Dexmedetomidine is mainly eliminated through hepatic metabolism. There are three types of initial metabolic reactions; Direct N-glucuronidation, direct N-methylation and cytochrome P450 catalyzed oxidation. The most abundant circulating metabolites of dexmedetomidine are the two N-glucuronide isomers. The metabolite H-1, N-methyl 3-hydroxymethyl dexmedetomidine O-glucuronide, is also one of the major circulating metabolites after the biotransformation of dexmedetomidine. Cytochrome P-450 catalyzes the formation of two minor circulating metabolites: 3-hydroxymethyl dexmedetomidine produced by the hydroxylation of the 3-methyl group of dexmedetomidine and H-3 produced by the oxidation of the imidazole ring. Available data suggest that the formation of oxidized metabolites is mediated by several forms of CYP (CYP2A6, CYP1A2, CYP2E1, CYP2D6 and CYP2C19). These metabolites have negligible pharmacological activity.
Following the IV administration of radioactively labeled dexmedetomidine, an average of 95% of the radioactivity was detected in the urine and 4% in the faeces after nine days. The major metabolites excreted in the urine are the two N-glucuronide isomers, which together account for approximately 34% of the dose, and N-methyl 3-hydroxymethyl dexmedetomidine O-glucuronide, which accounts for 14.51% of the dose. Minor metabolites such as dexmedetomidine carboxylic acid, 3-hydroxymethyl dexmedetomidine and its O-glucuronide individually comprise 1.11-7.66% of the dose. Less than 1% of the unchanged drug was recovered. in the urine. Approximately 28% of the metabolites found in urine are unidentified minor metabolites.
Special populations
No major pharmacokinetic differences were observed based on gender or age. Binding of dexmedetomidine to plasma proteins is reduced in subjects with hepatic impairment compared to healthy subjects. The mean percentage of free dexmedetomidine in plasma ranged from 8.5% in healthy subjects to 17.9% in subjects with severe hepatic insufficiency. In subjects with varying degrees of hepatic insufficiency (Child-Pugh Class A, B or C) the hepatic clearance of dexmedetomidine was decreased and the plasma clearance time t1 / 2 was prolonged. The mean plasma clearance values of unbound dexmedetomidine for subjects with mild, moderate and severe hepatic impairment were 59%, 51% and 32%, respectively, of those observed in normal healthy subjects. The mean t1 / 2 for subjects with mild, moderate, or severe hepatic impairment was prolonged to 3.9; 5.4, and 7.4 hours, respectively. Even if dexmedetomidine is administered until effect, a reduction of the starting / maintenance dose may need to be considered in patients with hepatic impairment depending on the degree of impairment and response.
The pharmacokinetics of dexmedetomidine in subjects with severe renal impairment (creatinine clearance
Data in infants (28 - 44 weeks of gestation) up to children of 17 years of age are limited. The half-life of dexmedetomidine in children (1 month to 17 years) appears similar to that seen in adults, but in neonates (less than 1 month) appears longer. In the age groups 1 month to 6 years, the adjusted plasma clearance weight-based appeared higher but decreased in older children. Weight-adjusted plasma clearance in neonates (less than 1 month) appeared lower (0.9 l / h / kg) than in older age groups due to immaturity The available data are summarized in the following table:
05.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, single and repeated dose toxicity and genotoxicity.
In reproductive toxicity studies, dexmedetomidine had no effect on male and female fertility in the rat and no teratogenic effects were observed in the rat or rabbit. In the rabbit study, intravenous administration of a maximum dose of 96 mcg / kg / day gave an exposure similar to that observed clinically. In the rat, subcutaneous administration at a maximum dose of 200 mcg / kg / day caused a increased embryofoetal mortality and decreased fetal body weight. These effects were associated with evident signs of maternal toxicity. A decrease in fetal body weight was also observed in the rat fertility study at the dose of 18 mcg / kg / day and was accompanied by delayed ossification at doses of 54 mcg / kg / day. The observed exposure levels in the rat are below the clinical exposure range.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Sodium chloride
Water for injections
06.2 Incompatibility
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
Compatibility studies have shown potential adsorption of dexmedetomidine by some types of natural rubber.
06.3 Period of validity
3 years
After dilution
Chemical and physical in-use stability has been demonstrated for 24 hours at 25 ° C.
From a microbiological point of view, the product should be used immediately.
If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2-8 ° C, unless dilution has taken place in controlled aseptic conditions and validate.
06.4 Special precautions for storage
This medicinal product does not require any special storage temperatures. Keep the vials or ampoules in the outer carton to protect the medicine from light.
For storage conditions after dilution of the medicinal product, see section 6.3.
06.5 Nature of the immediate packaging and contents of the package
2 ml type I glass vials
2, 5 or 10 ml Type I glass vials (with fill volumes of 2, 4 and 10 ml), gray bromobutyl rubber closure with fluoropolymer coating.
Packs
5 x 2ml vials
25 x 2ml vials
5 x 2 ml vials
4 x 4 ml vials
4 x 10 ml vials
Not all pack sizes may be marketed.
06.6 Instructions for use and handling
Ampoules and vials are intended for single patient use.
Preparation of the solution
Dexdor can be diluted in glucose 50 mg / ml (5%), Ringer, mannitol and sodium chloride 9 mg / ml (0.9%) solution for injection in order to achieve the required concentration of 4 mcg / ml or 8 mcg / ml before administration. See the table below for the volumes needed to prepare the infusion.
In case the required concentration is 4 mcg / ml
In case the required concentration is 8 mcg / ml
The solution must be gently shaken to mix it well.
Dexdor should be visually checked for the presence of particles and color changes prior to administration.
Dexdor is compatible when administered with the following intravenous solutions and the following medicines:
Ringer's lactate, 5% glucose solution, sodium chloride 9 mg / ml (0.9%) solution for injection, 200 mg / ml (20%) mannitol, thiopental sodium, etomidate, vecuronium bromide, pancuronium bromide, succinylcholine , atracurium besylate, mivacurium chloride, rocuronium bromide, glycopyrrolate bromide, phenylephrine hydrochloride, atropine sulfate, dopamine, noradrenaline, dobutamine, midazolam, morphine sulfate, fentanyl citrate, plasma-substitutes.
Unused medicine and waste derived from this medicine must be disposed of in accordance with local regulations.
07.0 MARKETING AUTHORIZATION HOLDER
Orion Corporation
Orionintie 1
FI-02200 Espoo
Finland
08.0 MARKETING AUTHORIZATION NUMBER
EU / 1/11/718 / 001-002, EU / 1/11/718/004, EU / 1/11/718 / 006-007
041468012
041468024
041468048
041468063
041468075
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: 16 September 2011
Latest renewal date:
