Active ingredients: Cisatracurium
Nimbex 2 mg / ml solution for injection / infusion
Nimbex 5 mg / ml solution for injection / infusion
Why is Nimbex used? What is it for?
Nimbex contains a substance called cisatracurium. This substance belongs to a group of medicines called muscle relaxants.
Nimbex is used for:
- Relax muscles during surgery in adults and children aged at least 1 month, including heart surgery
- To facilitate tracheal intubation if a patient needs breathing aid
- To relax muscles in ICU patients. Ask your doctor if you want to find out more about this medicine.
Contraindications When Nimbex should not be used
Do not use Nimbex:
- if you are allergic to cisatracurium, or to other muscle relaxants or to any of the other ingredients of Nimbex (listed in section 6)
- if you have previously had an adverse reaction with the use of an anesthetic
If you think any of these apply to you, do not take Nimbex. If you are not sure, talk to your doctor, nurse or pharmacist first.
Precautions for use What you need to know before taking Nimbex
Before taking this medicine, talk to your doctor, nurse or pharmacist:
- If you have muscle weakness, pain or difficulty coordinating movements (myasthenia gravis) check also if: (for 10 ml only) You have neuromuscular diseases, such as muscle wasting disease, paralysis, motor neuron disease or cerebral palsy
- If you have a "burn that needs medical treatment.
If you are not sure if any of the above apply to you, ask your doctor, nurse or pharmacist before you are given Nimbex.
Interactions Which drugs or foods may change the effect of Nimbex
Tell your doctor if you are taking, have recently taken or might take any other medicines, including medicines obtained without a prescription.
In particular, consult your doctor if you are taking any of these medicines:
- anesthetics (used to reduce pain and aching sensation during surgery)
- antibiotics (used to treat infections)
- medicines for irregular heartbeats (antiarrhythmics)
- medicines for high blood pressure
- diuretics, such as furosemide
- joint inflammation medicines, such as chloroquine or penicillamines
- steroids
- medicines for seizures (epilepsy), such as phenytoin or carbamazepine
- medicines for mental disorders, such as lithium, or chlorpromazine (which can also be used for nausea)
- medicines containing magnesium
- anticholinesterases for the treatment of Alzheimer's such as donepezil.
Warnings It is important to know that:
Pregnancy and breastfeeding
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine.
Driving and using machines
If you have only been in the hospital for one day, your doctor will tell you how long to wait before you leave the hospital or drive a car. It may be dangerous to drive too soon after having an "surgery."
Dose, Method and Time of Administration How to use Nimbex: Posology
You will never be expected to administer this medicine yourself. It will always be given to you by a person qualified to do so.
Nimbex can be given:
- as a single injection into a vein (venous bolus injection)
- as a continuous infusion into a vein. The drug is released slowly over a long period of time.
- Your doctor will decide on the method of administration and the required dose. Which will depend on the following factors:
- your body weight - the required amount and duration of muscle relaxant activity - your response to the medicine.
Children under 1 month should not be given this medicine.
Overdose What to do if you have taken too much Nimbex
Nimbex must always be administered under strict supervision. However, if you think you have been given more than you should talk to your doctor or nurse immediately.
If you have any further questions on the use of this medicine, ask your doctor.
Side Effects What are the side effects of Nimbex
Like all medicines, Nimbex can cause side effects, although not everybody gets them.
If you experience a side effect, please contact your doctor. This includes any possible side effects not listed in this leaflet.
Allergic reactions (may affect less than 1 in 10,000 people)
If you have an allergic reaction, call your doctor or nurse right away. Signs of allergy may include: - sudden wheezing, chest pain or tightness in the chest - swelling of the eyelids, face, lips, mouth or tongue - sudden rash or hives anywhere on the body - collapse.
Talk to your doctor, nurse or pharmacist if you notice any of the following:
Common (may affect less than 1 in 10 people)
- reduced heart rate
- lowering of blood pressure.
Uncommon (may affect less than 1 in 100 people)
- rash or redness of the skin
- wheezing or coughing.
Very rare (may affect less than 1 in 10,000 people)
- muscle weakness or pain.
Reporting of side effects
If you get any side effects, talk to your doctor, nurse or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system at www.agenziafarmaco.gov. .it / en / responsible ".. By reporting side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
Keep Nimbex out of the sight and reach of children.
Do not use Nimbex after the expiry date which is stated on the label and carton. The expiry date refers to the last day of the month.
Store in a refrigerator (2 ° C - 8 ° C). Do not freeze.
Store in the original container to protect the product from light.
If diluted, store the infusion solution between 2 ° C and 8 ° C and use within 24 hours. The solution for infusion should be discarded if not used within 24 hours.
Do not throw any medicines down the drain. Ask your pharmacist or nurse how to throw away medicines you no longer use. This will help protect the environment.
Other information
What does Nimbex contain
- The active substance is 2 mg / ml or 5 mg / ml cisatracurium (as besylate).
- The other ingredients are benzenesulfonic acid (32% w / v) and water for injections.
What Nimbex looks like and contents of the pack
Nimbex 2 mg / ml solution for injection / infusion is available in:
- 2.5 ml in ampoules (glass) pack of 5 ampoules (each 2.5 ml ampoule contains 5 mg of cisatracurium)
- 5 ml in ampoules (glass) pack of 5 ampoules (each 5 ml ampoule contains 10 mg of cisatracurium)
- 10 ml in ampoules (glass) pack of 5 ampoules (each 10 ml ampoule contains 20 mg of cisatracurium)
- 25 ml in ampoules (glass) pack of 2 ampoules (each 25 ml ampoule contains 50 mg of cisatracurium)
Nimbex 5 mg / ml solution for injection / infusion comes in a 30 ml glass bottle. Each 30 ml bottle contains 150 mg of cisatracurium.
Not all pack sizes may be marketed.
The following information is intended for medical or healthcare professionals only
This medicine is a single dose.
Use only clear, colorless or light yellow or greenish-yellow solutions.
The product must be visually inspected before use, and if the visual appearance is changed or the container is damaged, the product must be discarded.
When diluted to concentrations between 0.1 and 2 mg / mL, Nimbex has been shown to be chemically and physically stable for 24 hours at 5 ° C and 25 ° C in the following infusion solutions (both in polyvinyl chloride containers both polypropylene):
- Sodium chloride 0.9% w / v
- Glucose 5% w / v
- Glucose with sodium chloride (4% w / v and 0.18% w / v respectively)
- Glucose with sodium chloride (2.5% w / v and 0.45% w / v respectively)
This product does not contain preservatives the dilution should be done immediately before use, otherwise see section 5.
Nimbex has been shown to be compatible with the following medications, commonly used perioperatively, mixed under conditions that simulate administration by intravenous infusion via a "Y" injection set: alfentanil hydrochloride, droperidol, fentanyl citrate, midazolam hydrochloride and sufentanil citrate . When other drugs besides Nimbex are administered through the same needle or cannula, it is important that each drug is eliminated by draining an adequate amount of a suitable infusion solution (e.g. sodium chloride 0.9% w / v).
As with other intravenous drugs, if a small caliber vein is chosen as the injection site Nimbex should be injected into the vein with a liquid suitable for intravenous administration, such as sodium chloride for intravenous injection (0.9% w / v).
Unused medicine and wastes derived from this medicine must be disposed of in accordance with local regulations.
Nimbex 2 mg / ml solution for injection / infusion
Instructions for opening the vial (applicable only to the 2 mg / ml vial)
The vials are equipped with a safety pre-opening system and must be opened as follows:
- hold the lower part of the vial with one hand;
- place the other hand on top by placing your thumb over the colored dot and exert pressure.
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
NIMBEX
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Sterile solution containing 2 mg of cisatracurium (bis-cation) per ml as cisatracurium besylate (BAN, pINN).
The product does not contain antimicrobial preservatives and is supplied in a vial.
Sterile solution containing 5 mg of cisatracurium (bis-cation) per ml as cisatracurium besylate (BAN, pINN). The product does not contain antimicrobial preservatives and is supplied in a vial.
Chemical description
Nimbex (cisatracurium besylate), (1R, 1 "R, 2R, 2" R) -2.2 "- (3,11-diketo-4,10-dioxythridecamethylene) bis (1,2,3,4-tetrahydro- 6,7-dimethoxy-2-methyl-1-eratrilisoquinolinium) dibenzenesulfonate.
Cisatracurium besylate is one of the ten isomers of atracurium besylate, which make up about 15% of the compound.
For excipients see 6.1
03.0 PHARMACEUTICAL FORM
Injectable solution.
The solution is colorless to pale yellow / greenish-yellow. Virtually free of visible particles.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Nimbex is a non-depolarising, intermediate-acting neuromuscular blocker for intravenous use.
Nimbex is indicated in a wide range of surgical procedures and in the ICU. It is combined with general anesthesia or sedation in the ICU to release skeletal muscle and facilitate tracheal intubation and artificial respiration.
04.2 Posology and method of administration
Nimbex must not be mixed in the same syringe or administered simultaneously through the same needle with an injectable propofol emulsion or with alkaline solutions such as thiopentone sodium (see section 6.2).
Nimbex does not contain antimicrobial preservatives and is intended for single patient use.
Monitoring
In common with other neuromuscular blockers, monitoring of neuromuscular function is recommended during use of Nimbex in order to assess the dose required for adequate neuromuscular block in each patient.
Administration by injection (IV bolus)
Dosage in adults
Tracheal intubation
The recommended dose of Nimbex for tracheal intubation in adults is 0.15 mg / kg body weight.
This dose results in good / excellent conditions for tracheal intubation 120 seconds after administration of Nimbex following induction of anesthesia with propofol.
Higher doses shorten the induction time of neuromuscular block. The table below summarizes the mean pharmacodynamic data following administration of Nimbex at doses of 0.1-0.4 mg / kg body weight in healthy adult patients during opioid anesthesia (thiopentone / fentanyl / midazolam) or with propofol .
* Response as a single twitch or train of four of the adductor thumb muscle after supramaximal electrical stimulation of the ulnar nerve.
Anesthesia with enflurane or isoflurane can prolong the clinical efficacy time of an initial dose of Nimbex by up to 15%.
Maintenance
Neuromuscular block can be prolonged with maintenance doses of Nimbex. A dose of 0.03 mg / kg body weight, administered during opioid or propofol anesthesia, generally extends clinically effective neuromuscular block by approximately 20 minutes. Consecutive additional doses of Nimbex do not lead to a progressive prolongation of the effect.
Spontaneous recovery
Once initiated, spontaneous recovery and its rate are independent of the dose of Nimbex administered.
During opioid or propofol anesthesia the median times to recovery from 25 to 75% and 5 to 95% are approximately 13 and 30 minutes, respectively.
Pharmacological antagonism
The neuromuscular block produced by Nimbex can be easily reversed with standard doses of anticholinesterase agents. The mean times to recovery from 25 to 75% and full clinical recovery (T4 / T1 ratio ≥ 0.7) are approximately 4 and 9 minutes after administration of antagonist agents, respectively, around 10% of T1 recovery.
Dosage in pediatric patients between 1 month and 12 years
Tracheal Intubation: As for adults, the recommended intubation dose of Nimbex is 0.15 mg / kg body weight, administered rapidly over 5-10 seconds. This dose produces good to excellent conditions for tracheal intubation in patients. 120 seconds after the injection of Nimbex.
The table below contains the pharmacodynamic data for this dose.
Nimbex has not been evaluated for intubation in ASA Class III-IV of pediatric patients. There are limited data on the use of Nimbex in pediatric patients under 2 years of age undergoing major or long-term surgery. duration.
In pediatric patients 1 month to 12 years of age, Nimbex has a shorter effective clinical duration and a faster spontaneous recovery profile than that seen in adults under the same anesthetic conditions. Small differences in the pharmacodynamic profile were observed between the age groups 1 to 11 months and 1 and 12 years which are summarized in the following table:
Pediatric patients aged 1 to 11 months
Pediatric patients aged 1 to 12 years
When Nimbex is not required for intubation: a dose below 0.15 mg / kg can be used. The table below shows the pharmacodynamic data for doses of 0.08 and 0.1 mg / kg for pediatric patients aged 2 to 12 years:
Administration of Nimbex after suxamethonium has not been evaluated in pediatric patients (see section 4.5).
Halothane may prolong the clinically effective duration of a dose of Nimbex by up to 20%. No information is available on the use of Nimbex in children during anesthesia with other halogenated fluorocarbon anesthetics, but these agents can be expected to prolong the duration of clinical efficacy of a dose of Nimbex.
Maintenance (pediatric patients 2 to 12 years)
Neuromuscular block can be prolonged with maintenance doses of Nimbex. In pediatric patients 2 to 12 years of age, a dose of 0.02 mg / kg body weight, administered during halothane anesthesia, generally extends clinically effective neuromuscular block by approximately 9 minutes. Consecutive additional doses of Nimbex do not lead to a progressive prolongation of the effect.
There are insufficient data to recommend a maintenance dose in pediatric patients below 2 years of age. However, very limited data from clinical studies in pediatric patients less than 2 years of age suggest that a maintenance dose of 0.03 mg / kg can prolong the clinical efficacy of neuromuscular block for up to 25 minutes during opioid anesthesia.
Spontaneous recovery
Once recovery from neuromuscular block has begun, the rate of recovery is independent of the dose of Nimbex administered. During opioid or halothane anesthesia, the median times to recovery of 25 to 75% and 5 to 95% are approximately 11 and 28 minutes, respectively.
Pharmacological antagonism
The neuromuscular block produced by Nimbex can be rapidly reversed with standard doses of anticholinesterase agents. Mean recovery times from 25 to 75% and full clinical recovery (T4 / T1 ratio ≥ 0.7) are approximately 2 and 5 minutes after administration of antagonist agents, respectively, around 13% of T1 recovery.
Administration by infusion
Dosage in adults and children between 2 and 12 years
Maintenance of neuromuscular block can be achieved with the "Nimbex infusion. An infusion rate of 3 mcg / kg body weight / min (0.18 mg / kg / hour) is recommended to report the T1 reduction between" 89 and 99% after spontaneous recovery signs. After an initial period of stabilization of neuromuscular block, an infusion of 1-2 mcg / kg body weight / min (0.06-0.12 mg / kg / hour) should be suitable to maintain block in this range in the most patients.
A reduction of the infusion rate of up to 40% may be necessary when Nimbex is administered during anesthesia with isoflurane or enflurane (see section 4.5).
The infusion rate should be adjusted according to the concentration of Nimbex in the infusion solution, the desired degree of neuromuscular block and the patient's weight. The table below provides guidelines for the administration of Nimbex (undiluted).
Infusion rate of Nimbex 2 - Solution for injection 2 mg / ml
Continuous infusion of Nimbex at a constant rate was not associated with progressive increase or decrease in neuromuscular blocking effect.
Spontaneous recovery from neuromuscular block following discontinuation of the Nimbex infusion proceeds comparably to recovery after single dose administration.
Dosage in infants under one month of age
The use of Nimbex in neonates is not recommended as it has not been studied in this patient population.
Dosage in the elderly
No dose changes are required in elderly patients. In these patients, Nimbex has a similar pharmacodynamic profile to that seen in young adult patients but, as with other neuromuscular blockers, it may exhibit a slightly slower induction.
Dosage in patients with impaired renal function
No dose changes are required in patients with renal insufficiency. In these patients, Nimbex has a similar pharmacodynamic profile to that seen in patients with normal renal function but may exhibit a slightly slower onset.
Dosage in patients with impaired liver function
No dose changes are required in patients with severe hepatic impairment. In these patients, Nimbex has a similar pharmacodynamic profile to that seen in patients with normal hepatic function but may have a slightly faster onset.
Dosage in patients with cardiovascular diseases
When given as a rapid bolus injection (5 to 10 seconds) in adult patients with severe cardiovascular disease (New York Heart Association Class I-III) undergoing coronary artery bypass grafting, Nimbex, in the dosages studied [up to 0.4 mg / kg (8xED95 included)], was not associated with clinically significant cardiovascular effects. However, there are limited data for doses above 0.3 mg / kg in this patient population.
Nimbex has not been evaluated in children undergoing cardiac surgery.
Dosage in patients admitted to intensive care units
Nimbex was administered as a bolus and / or infusion to adult patients admitted to intensive care units.
An initial infusion rate of Nimbex of 3 mcg / kg body weight / min (0.18 mg / kg / hour) is recommended for adult patients admitted to intensive care units. There may be a wide inter-patient variability in the required dosages and these may increase or decrease over time. In clinical trials, the mean rate of infusion was 3 mcg / kg / min (range 0.5 to 10.2 mcg / kg body weight / min or 0.03 to 0.6 mg / kg / hour).
The median time to spontaneous full recovery after prolonged infusion (up to 6 days) of Nimbex in ICU patients was 50 minutes.
Infusion rate of Nimbex 5 - Solution for injection 5 mg / ml
The recovery profile after Nimbex infusion in patients admitted to intensive care units is independent of the duration of the infusion.
04.3 Contraindications
Nimbex is contraindicated in patients with known hypersensitivity to cisatracurium, atracurium or benzenesulfonic acid.
04.4 Special warnings and appropriate precautions for use
Product specific information
Cisatracurium paralyzes the respiratory muscles as well as other skeletal muscles, but has no effect on consciousness or the pain threshold. Nimbex, therefore, should only be administered by, or under the supervision of, anesthetists or other physicians familiar with the use and action of neuromuscular blockers. Adequate instrumentation must be available for endotracheal intubation, pulmonary ventilation and suitable arterial oxygenation.
Caution should be exercised when administering Nimbex to patients who have exhibited hypersensitivity to other neuromuscular blockers as a high rate of cross-sensitivity (greater than 50%) has been reported between neuromuscular blockers (see section 4.4).
Cisatracurium has no significant ganglionic and vagal blocking properties. Therefore, Nimbex has no significant effect on heart rate and does not counteract the bradycardia produced by many anesthetic agents or by vagal stimulation during surgery.
Patients with myasthenia gravis and other neuromuscular diseases have increased sensitivity to non-depolarizing neuromuscular blockers. An initial dose not exceeding 0.02 mg / kg of Nimbex is recommended in these patients.
Severe alterations in the acid-base and / or hydro-electrolyte balance can increase or decrease the sensitivity of patients to neuromuscular blockers.
There is no information on the use of Nimbex in infants less than one month of age as it has not been studied in this patient population.
Nimbex has not been studied in patients with a history of malignant hyperthermia. Studies in pigs predisposed to malignant hyperthermia indicate that Nimbex does not cause this syndrome.
No studies have been performed with NIMBEX in patients undergoing surgery with induced hypothermia (25 ° to 28 ° C). As with other neuromuscular blockers the rate of infusion required to maintain adequate muscle relaxation in these conditions could be significantly reduced.
Nimbex has not been studied in patients with burns; however, as with other nondepolarizing neuromuscular blockers, the possibility of an increase in required doses and a reduction in duration of action should be considered when Nimbex is administered to these patients.
Nimbex is a hypotonic solution and should not be used in the same infusion set as a blood transfusion.
Patients admitted to intensive care units (ICU)
When administered in high doses to laboratory animals, laudanosine, a metabolite of Nimbex and atracurium, has been associated with transient hypotension, and in some species, with cerebral excitatory effects. In more sensitive animal species, such effects occurred at plasma concentrations of laudanosine similar to those observed in some patients admitted to the ICU following prolonged atracurium infusion.
In accordance with the expected reduced infusion doses of Nimbex, the plasma concentrations of laudanosine are approximately one third of those present after atracurium infusion.
Rare cases of seizures have occurred in patients admitted to intensive care units following administration of atracurium and other agents.
Such patients usually presented with one or more pathological conditions predisposing to seizures (eg head trauma, hypoxic encephalopathy, cerebral edema, viral encephalitis, uremia).
A causal relationship with laudanosine has not been established.
04.5 Interactions with other medicinal products and other forms of interaction
Many drugs, including the following, have been shown to influence the extent and / or duration of the effect of non-depolarizing neuromuscular blockers:
Increased effect: anesthetics such as halothane, enflurane and isoflurane (see section 4.2), ketamine, other nondepolarizing neuromuscular blockers or other drugs such as antibiotics (including aminoglycosides, polymyxin, spectinomycin, spectinomycline, tetracyclines, lincomycin and clindamycin), antiarrhythmic drugs (including propranolol, calcium channel blockers, lidocaine, procainamide, quinidine), diuretics (including furosemide and possibly thiazides, mannitol and acetazolamide), magnesium and lithium salts, ganglion blockers (trimetaphane, hexamethonium).
Reduced effect was observed in patients on chronic phenytoin or carbamazepine therapy.
Previous administration of suxamethonium has no effect on the duration of neuromuscular block following bolus doses of Nimbex or on the required infusion rate.
Administration of suxamethonium to prolong the effects of nondepolarizing neuromuscular blockers may result in a complex and prolonged block which may be difficult to reverse with anticholinesterases.
Rarely, certain drugs can aggravate or make manifest a latent myasthenia gravis or induce a myasthenic syndrome; an increase in sensitivity to nondepolarizing neuromuscular blockers would be consequent to this development. Such drugs include various antibiotics, beta-blockers (propranolol, oxprenolol), antiarrhythmic drugs (procainamide, quinidine), antirheumatic drugs (chloroquine, Dpenicillamine), trimetaphane, chlorpromazine, steroids, phenytoin and lithium.
Treatment with anticholinesterase drugs, commonly used in the treatment of Alzheimer's disease, such as donepezil, can shorten the duration and reduce the extent of neuromuscular block with cisatracurium.
04.6 Pregnancy and breastfeeding
There are no adequate data from the use of Nimbex in pregnancy.Animal studies are insufficient to detect effects on pregnancy and / or embryonal / fetal development, and / or parturition and / or postnatal development (see section 5.3). The potential risk for humans is unknown.
Nimbex should not be given to pregnant women.
There is no information regarding the excretion of Nimbex or its metabolites in human breast milk.
04.7 Effects on ability to drive and use machines
This precaution is not relevant to the use of Nimbex. Nimbex is always used in combination with a general anesthetic and therefore the usual precautions regarding the performance of activities after general anesthesia should be observed.
04.8 Undesirable effects
In order to determine the very common to uncommon frequency of adverse events, data from summary clinical trial results were used.
The following convention has been used for the classification of adverse events in terms of frequency: very common ≥1 / 10, common ≥1 / 100 -
Data from clinical studies
Cardiac pathologies
Common: bradycardia.
Vascular pathologies
Common: hypotension.
Uncommon: skin redness.
Respiratory, thoracic and mediastinal disorders
Uncommon: bronchospasm.
Skin and subcutaneous tissue disorders
Uncommon: rash.
Post-marketing data
Disorders of the immune system
Very rare: anaphylactic reaction.
Anaphylactic reactions of varying degrees of severity have been observed after administration of neuromuscular blocking agents. Very rarely, severe anaphylactic reactions have been reported in patients administered Nimbex concomitantly with one or more anesthetic agents.
Musculoskeletal and connective tissue disorders
Very rare: myopathy, muscle weakness.
Some cases of muscle weakness and / or myopathy have been reported following prolonged use of muscle relaxants in severe patients admitted to the ICU. Most patients were concomitantly treated with corticosteroids. These events have rarely been reported in association with Nimbex and no causal link has been established.
04.9 Overdose
Symptoms and signs
The main effect of Nimbex overdose is prolonged muscle paralysis and its consequences.
Treatment
In these cases it is essential to maintain pulmonary ventilation and arterial oxygenation until adequate spontaneous respiration is re-established. Complete sedation may be necessary, as Nimbex does not alter the state of consciousness. Recovery can be accelerated by the administration of anticholinesterase agents administered as soon as signs of spontaneous recovery are evident.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Nimbex is a neuromuscular blocker, ATC code: M03A C11
Nimbex is a musculoskeletal relaxant, non-depolarising benzylisoquinoline with an intermediate duration of action.
Clinical studies in humans indicated that Nimbex is not associated with dose dependent histamine release even up to doses of 8 x ED95.
Mechanism of action
Nimbex binds to the cholinergic receptors of the neuromuscular junction, competitively antagonizing the action of acetylcholine and causing neuromuscular block. This action is easily antagonized by anticholinesterase agents such as neostigmine or edrophonium.
The ED95 (the dose required to produce a 95% reduction in the contraction response of the adductor of the thumb to ulnar nerve stimulation) of Nimbex is estimated to be 0.05 mg per kg of body weight during opioid anesthesia (thiopentone / fentanyl / midazolam ).
The ED95 of Nimbex in children during halothane anesthesia is 0.04 mg / kg.
05.2 Pharmacokinetic properties
Nimbex is degraded into laudanosine and the monoquaternary acrylate metabolite through a spontaneous non-enzymatic decomposition mechanism called "Hofmann elimination" which occurs at physiological pH and temperature. The monoquaternary metabolite is in turn hydrolyzed by non-specific plasma esterases and forms monoquaternary alcohol. The elimination of Nimbex is predominantly an independent organ, but the liver and kidneys are the main sites for the clearance of its metabolites. These metabolites do not possess neuromuscular blocking activity.
Pharmacokinetics in adult patients
The non-compartmental pharmacokinetics of Nimbex are dose independent within the studied "range" (0.1 to 0.2 mg / kg or 2 to 4 times the ED95). Pharmacokinetic models confirm and extend this limit to 0. , 4 mg / kg (8 times l "ED95). Pharmacokinetic parameters after doses of 0.1 and 0.2 mg / kg of Nimbex administered to healthy adult surgical patients are summarized in the table below:
Pharmacokinetics in elderly patients
There are no clinically relevant differences in the pharmacokinetics of Nimbex between elderly patients and young adults. The recovery profile is also unchanged.
Pharmacokinetics in patients with hepatic / renal insufficiency
There are no clinically relevant differences in the pharmacokinetics of Nimbex between patients with severe hepatic or renal insufficiency and healthy young adults. The recovery profile is also unchanged.
Pharmacokinetics during infusion
The pharmacokinetics of Nimbex after infusion are similar to that below after single bolus administration. The recovery profile after Nimbex infusion is independent of the duration of the infusion and is similar to that following single bolus administration.
Pharmacokinetics in patients admitted to intensive care units
The pharmacokinetics of Nimbex in ICU patients following prolonged infusion are similar to those following single bolus or infusion administration in healthy adult surgical patients. The recovery profile after Nimbex infusion in patients admitted to the intensive care unit is independent of the duration of the infusion.
Concentrations of metabolites are higher in ICU patients with impaired renal and / or hepatic function (see section 4.4). These metabolites do not contribute to the onset of neuromuscular block.
05.3 Preclinical safety data
Acute toxicity
Significant acute toxicity studies could not be conducted with Nimbex. For toxicity symptoms see section 4.9.
Subacute toxicity
Repeated dosing studies for three weeks in dogs and monkeys showed no signs of compound specific toxicity.
Mutagenicity
Nimbex was not mutagenic in one test in vitro of microbial mutagenesis at concentrations up to 5000 mcg / per plate.
In a cytogenesis test in vivo in the rat, no significant chromosomal abnormalities were found at SC doses. up to 4 mg / kg.
Nimbex was found to be mutagenic in one test in vitro on mouse lymphoma cells, at concentrations of 40 mcg / ml and above.
A single positive mutagenic response to a drug used infrequently and / or for short periods is of questionable clinical relevance.
Carcinogenicity
Carcinogenicity studies have not been conducted.
Reproductive toxicity
No fertility studies have been conducted. Reproduction studies in rats revealed no adverse effects of Nimbex on fetal development.
Local tolerability
The result of an intra-arterial study in rabbits showed that Nimbex is well tolerated and no drug related changes were found.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
32% w / v benzenesulfonic acid solution; water for injections.
06.2 Incompatibility
Cisatracurium besylate degradation has been shown to occur more rapidly in solution
Lactated Ringer's and Lactated Ringer's 5% dextrose solution than other infusion solutions mentioned in section 6.6. Therefore it is recommended not to use Lactated Ringer's Solution and 5% Lactated Ringer's Dextrose Solution to dilute Nimbex prior to infusion.
Since Nimbex is stable only in acidic solutions, it should not be mixed in the same syringe or administered simultaneously through the same needle with alkaline solutions such as thiopentone sodium.
It is not compatible with ketorolac tromethamine or propofol injectable emulsion.
06.3 Period of validity
Validity before reconstitution: 2 years.
The chemical-physical stability of the product in use has been demonstrated for at least 24 hours at 5 ° C and 25 ° C (see section 6.6).
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 ° C to 8 ° C, unless reconstitution did not take place under validated and controlled aseptic conditions.
06.4 Special precautions for storage
Store in a refrigerator (2 ° C - 8 ° C). Do not freeze. Keep the bottle in the outer carton.
Protect the medicine from light.
06.5 Nature of the immediate packaging and contents of the package
Nimbex 2 - Solution for injection 2 mg / ml comes in packs of 5 ampoules of 2.5 ml, 5 ml, 10 ml and 2 ampoules of 25 ml.
Nimbex 5 - Solution for injection 5 mg / ml is presented in a pack of 1 vial of 30 ml.
Clear neutral glass vials (type I).
Clear clear glass vial (type I) with synthetic / bromobutyl rubber stopper and aluminum seal with plastic cap.
IT IS POSSIBLE THAT NOT ALL PACKAGES ARE MARKETED
06.6 Instructions for use and handling
This product is for single use only.
Use only clear, colorless or light yellow or greenish-yellow solutions.
The product must be visually inspected before use, and if the visual appearance is changed or the container is damaged, the product must be discarded.
When diluted to concentrations between 0.1 and 2 mg / ml, Nimbex has been shown to be chemically and physically stable for 24 hours at 5 - 25 ° C in the following infusion solutions (in both polyvinyl chloride containers and polypropylene):
- Sodium chloride 0.9% w / v
- Glucose 5% w / v
- Glucose with sodium chloride (4% w / v and 0.18% w / v respectively)
- Glucose with sodium chloride (2.5% w / v and 0.45% w / v respectively)
However, since the Nimbex packs do not contain substances with antibacterial action, it is recommended to carry out the dilution immediately before use, otherwise the diluted solution must be stored as indicated in paragraph 6.3.
Nimbex has been shown to be compatible with the following medications, commonly used in the perioperative setting, mixed under conditions that simulate administration by intravenous infusion via a "Y" injection set: alfentanil hydrochloride, droperidol, fentanyl citrate, midazolam hydrochloride and sufentanil citrate. When other drugs besides Nimbex are administered through the same needle or cannula, it is important that each drug is eliminated by draining an adequate amount of a suitable infusion solution (eg sodium chloride 0.9% w / v).
As for other drugs, if a small caliber vein is chosen as the injection site, the residues of Nimbex must be eliminated by the latter by making a suitable infusion solution flow into the vein itself (eg sodium chloride 0.9% w / v ).
Instructions for opening the vial (applicable to 2 mg / ml vials)
The vials are equipped with a safety pre-opening and must be opened as follows:
- hold the lower part of the vial with one hand;
- place the other hand on the upper part, placing the thumb over the COLORED DOT and exert pressure.
07.0 MARKETING AUTHORIZATION HOLDER
The Wellcome Foundation Ltd. - Greenford - Great Britain.
Legal and sales representative: GlaxoSmithKline S.p.A. - Verona.
08.0 MARKETING AUTHORIZATION NUMBER
Nimbex 2
AIC n. 031975016 - 5 ampoules of 2.5 ml
AIC n. 031975028 - 5 vials of 5 ml
AIC n. 031975030 - 5 vials of 10 ml
AIC n. 031975042 - 2 ampoules of 25 ml
Nimbex 5
AIC n. 031975055 - 1 vial of 30 ml
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
26 August 1996 / August 2005
10.0 DATE OF REVISION OF THE TEXT
October 2009
