- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
DilutionUltiva may be further diluted after reconstitution (see section 6.4 and 6.6 for storage conditions of the reconstituted/diluted product and the recommended diluents).For manually-controlled infusion Ultiva can be diluted to concentrations of 20 to 250 micrograms/ml (50 micrograms/ml is the recommended dilution for adults and 20 to 25 micrograms/ml for paediatric patients aged 1 year and over).For TCI the recommended dilution of Ultiva is 20 to 50 micrograms/ml.(See Section 6.6 Instructions for use/handling for additional information, including tables to help titrate Ultiva to the patient's anaesthetic needs).
4.2.1 General AnaesthesiaThe administration of Ultiva must be individualised based on the patient's response. Specific dosing guidelines for patients undergoing cardiac surgery are provided in section 4.2.2 below.
Administration by Manually-Controlled InfusionThe following table summarises the starting infusion rates and dose range:DOSING GUIDELINES FOR ADULTS
|INDICATION||BOLUS INJECTION (micrograms/kg)||CONTINUOUS INFUSION (micrograms/kg/min)|
|Induction of anaesthesia||1(give over not less than 30 seconds)||0.5 to 1||_|
|Maintenance of anaesthesia in ventilated patients|
| Nitrous oxide (66%)||0.5 to 1||0.4||0.1 to 2|
| Isoflurane (starting dose 0.5MAC)||0.5 to 1||0.25||0.05 to 2|
| Propofol (Starting dose 100 micrograms/kg/min)||0.5 to 1||0.25||0.05 to 2|
Administration by Target-Controlled InfusionInduction and maintenance of anaesthesia in ventilated patients: Ultiva TCI should be used in association with an intravenous or inhalational hypnotic agent during the induction and maintenance of anaesthesia in ventilated adult patients (see the table in Dosing Guidelines For Adults under 18.104.22.168). In association with these agents, adequate analgesia for induction of anaesthesia and surgery can generally be achieved with target blood remifentanil concentrations ranging from 3 to 8 nanograms/ml. Ultiva should be titrated to individual patient response. For particularly stimulating surgical procedures target blood concentrations up to 15 nanograms/ml may be required. At the doses recommended above, remifentanil significantly reduces the amount of hypnotic agent required to maintain anaesthesia. Therefore, isoflurane and propofol should be administered as recommended above to avoid an increase of haemodynamic effects such as hypotension and bradycardia (see Table and Concomitant medication subsection in 22.214.171.124).For information on blood remifentanil concentrations achieved with manually-controlled infusion see Table 6.There are insufficient data to make recommendations on the use of TCI for spontaneous ventilation anaesthesia.Guidelines for discontinuation/continuation into the immediate post-operative period: At the end of surgery when the TCI infusion is stopped or the target concentration reduced, spontaneous respiration is likely to return at calculated remifentanil concentrations in the region of 1 to 2 nanograms/ml. As with manually-controlled infusion, post-operative analgesia should be established before the end of surgery with longer acting analgesics (see Guidelines for discontinuation under Administration by manually-controlled infusion in section 126.96.36.199)As there are insufficient data, the administration of Ultiva by TCI for the management of post-operative analgesia is not recommended.
188.8.131.52 Paediatric patients (1 to12 years of age)Co-administration of Ultiva and an intravenous anaesthetic agent for induction of anaesthesia has not been studied in detail and is therefore not recommended. Ultiva TCI has not been studied in paediatric patients and therefore administration of Ultiva by TCI is not recommended in these patients.When given by bolus injection Ultiva should be administered over not less than 30 seconds. Surgery should not commence until at least 5 minutes after the start of the Ultiva infusion, if a simultaneous bolus dose has not been given. For sole administration of nitrous oxide (70%) with Ultiva, typical maintenance infusion rates should be between 0.4 and 3 micrograms/kg/min, and although not specifically studied, adult data suggest that 0.4 micrograms/kg/min is an appropriate starting rate. Paediatric patients should be monitored and the dose titrated to the depth of analgesia appropriate for the surgical procedure.Induction of anaesthesia: The use of remifentanil for induction of anaesthesia in patients aged 1 to12 years is not recommended as there are no data available in this patient population.Maintenance of anaesthesia: The following doses of Ultiva are recommended for maintenance of anaesthesia:DOSING GUIDELINES FOR PAEDIATRIC PATIENTS (1 to12 years of age)
|*CONCOMITANT ANAESTHETIC AGENT||BOLUS INJECTION (micrograms/kg)||CONTINUOUS INFUSION (micrograms/kg/min)|
|Halothane (starting dose 0.3MAC)||1||0.25||0.05 to 1.3|
|Sevoflurane (starting dose 0.3MAC)||1||0.25||0.05 to 0.9|
|Isoflurane (starting dose 0.5MAC)||1||0.25||0.06 to 0.9|
184.108.40.206 Neonates/infants (aged less than 1 year):There is limited clinical trial experience of remifentanil in neonates and infants (aged under 1 year old; see section 5.1). The pharmacokinetic profile of remifentanil in neonates/infants (aged less than 1 year) is comparable to that seen in adults after correction for body weight differences (see section 5.2). However, because there are insufficient clinical data, the administration of Ultiva is not recommended for this age group. Use for Total Intravenous anaesthesia (TIVA): There is limited clinical trial experience of remifentanil of TIVA in infants (see section 5.1). However, there are insufficient clinical data to make dosage recommendations.
4.2.2 Cardiac anaesthesia
Administration by Manually-Controlled InfusionDOSING GUIDELINES FOR CARDIAC ANAESTHESIA
|INDICATION||BOLUS INJECTION (micrograms/kg)||CONTINUOUS INFUSION (micrograms/kg/min)|
|Induction of anaesthesia||Not recommended||1||_|
|Maintenance of anaesthesia in ventilated patients:|
| Isoflurane (starting dose 0.4MAC)||0.5 to 1||1||0.003 to 4|
| Propofol (Starting dose 50 micrograms/kg/min)||0.5 to 1||1||0.01 to 4.3|
|Continuation of post-operative analgesia, prior to extubation||Not recommended||1||0 to 1|
Guidelines for post-operative patient managementContinuation of Ultiva post-operatively to provide analgesia prior to weaning for extubation: It is recommended that the infusion of Ultiva should be maintained at the final intra-operative rate during transfer of patients to the post-operative care area. Upon arrival into this area, the patient's level of analgesia and sedation should be closely monitored and the Ultiva infusion rate adjusted to meet the individual patient's requirements (see section 4.2.3 for further information on management of intensive care patients).Establishment of alternative analgesia prior to discontinuation of Ultiva: Due to the very rapid offset of action of Ultiva, no residual opioid activity will be present within 5 to 10 minutes after discontinuation. Prior to discontinuation of Ultiva, patients must be given alternative analgesic and sedative agents at a sufficient time in advance to allow the therapeutic effects of these agents to become established. It is therefore recommended that the choice of agent(s), the dose and the time of administration are planned, before weaning the patient from the ventilator. Guidelines for discontinuation of Ultiva: Due to the very rapid offset of action of Ultiva, hypertension, shivering and aches have been reported in cardiac patients immediately following discontinuation of Ultiva (see section 4.8 Undesirable effects). To minimise the risk of these occurring, adequate alternative analgesia must be established (as described above), before the Ultiva infusion is discontinued. The infusion rate should be reduced by 25% decrements in at least 10-minute intervals until the infusion is discontinued. During weaning from the ventilator the Ultiva infusion should not be increased and only down titration should occur, supplemented as required with alternative analgesics. Haemodynamic changes such as hypertension and tachycardia should be treated with alternative agents as appropriate.When other opioid agents are administered as part of the regimen for transition to alternative analgesia, the patient must be carefully monitored. The benefit of providing adequate post-operative analgesia must always be balanced against the potential risk of respiratory depression with these agents.
Administration by Target-Controlled InfusionInduction and maintenance of anaesthesia: Ultiva TCI should be used in association with an intravenous or inhalational hypnotic agent during the induction and maintenance of anaesthesia in ventilated adult patients (see table in Dosing Guidelines for Cardiac Anaesthesia under 4.2.2). In association with these agents, adequate analgesia for cardiac surgery is generally achieved at the higher end of the range of target blood remifentanil concentrations used for general surgical procedures. Following titration of remifentanil to individual patient response, blood concentrations as high as 20 nanograms/ml have been used in clinical studies. At the doses recommended above, remifentanil significantly reduces the amount of hypnotic agent required to maintain anaesthesia. Therefore, isoflurane and propofol should be administered as recommended above to avoid an increase of haemodynamic effects such as hypotension and bradycardia (see Table and Concomitant medication subsection in 4.2.2).For information on blood remifentanil concentrations achieved with manually-controlled infusion see Table 6.Guidelines for discontinuation/continuation into the immediate post-operative period: At the end of surgery when the TCI infusion is stopped or the target concentration reduced, spontaneous respiration is likely to return at calculated remifentanil concentrations in the region of 1 to 2 nanograms/ml. As with manually-controlled infusion, post-operative analgesia should be established before the end of surgery with longer acting analgesics (see Guidelines for discontinuation under Administration by manually-controlled infusion in section 4.2.2.)As there are insufficient data, the administration of Ultiva by TCI for the management of post-operative analgesia is not recommended.
4.2.3 Use in Intensive CareUltiva can be used for the provision of analgesia in mechanically ventilated intensive care patients. Sedative agents should be added as appropriate. Ultiva has been studied in mechanically ventilated intensive care patients in well controlled clinical trials for up to three days. As patients were not studied beyond three days, no evidence of safety and efficacy for longer treatment has been established. Therefore, the use of Ultiva is not recommended for a duration of treatment greater than 3 days.Ultiva TCI has not been studied in intensive care patients and therefore administration of Ultiva by TCI is not recommended in these patients.In adults, it is recommended that Ultiva is initiated at an infusion rate of 0.1 micrograms/kg/min (6 micrograms/kg/h) to 0.15 micrograms/kg/min (9 micrograms/kg/h). The infusion rate should be titrated in increments of 0.025 micrograms/kg/min (1.5 micrograms/kg/h) to achieve the desired level of sedation and analgesia. A period of at least 5 minutes should be allowed between dose adjustments. The level of sedation and analgesia should be carefully monitored, regularly reassessed and the Ultiva infusion rate adjusted accordingly. If an infusion rate of 0.2 micrograms/kg/min (12 micrograms/kg/h) is reached and the desired level of sedation is not achieved, it is recommended that dosing with an appropriate sedative agent is initiated (see below). The dose of sedative agent should be titrated to obtain the desired level of sedation. Further increases to the Ultiva infusion rate in increments of 0.025 micrograms/kg/min (1.5 micrograms/kg/h) may be made if additional analgesia is required. The following table summarises the starting infusion rates and typical dose range for provision of analgesia and sedation in individual patients:DOSING GUIDELINES FOR USE OF ULTIVA WITHIN THE INTENSIVE CARE SETTING
|CONTINUOUS INFUSION micrograms/kg/min (micrograms/kg/h)|
|0.1 (6) to 0.15 (9)||0.006 (0.36) to 0.74 (44.4)|
|Sedative Agent||Bolus (mg/kg)||Infusion (mg/kg/h)|
|Propofol||Up to 0.5||0.5|
|Midazolam||Up to 0.03||0.03|
220.127.116.11 Paediatric intensive care patientsThe use of remifentanil in intensive care patients under the age of 18 years is not recommended as there are no data available in this patient population.
18.104.22.168 Renally-impaired intensive care patientsNo adjustments to the doses recommended above are necessary in renally-impaired patients, including those undergoing renal replacement therapy; however the clearance of the carboxylic acid metabolite is reduced in patients with renal impairment (see Section 5.2 Pharmacokinetic properties).
4.2.4 Special patient populations22.214.171.124. Elderly (over 65 years of age)General anaesthesia: The initial starting dose of remifentanil administered to patients over 65 should be half the recommended adult dose and then shall be titrated to individual patient need as an increased sensitivity to the pharmacological effects of remifentanil has been seen in this patient population. This dose adjustment applies to use in all phases of anaesthesia including induction, maintenance, and immediate post-operative analgesia. Because of the increased sensitivity of elderly patients to Ultiva, when administering Ultiva by TCI in this population the initial target concentration should be 1.5 to 4 ng/ml with subsequent titration to response.Cardiac anaesthesia: No initial dose reduction is required (see section 4.2.2.).Intensive Care: No initial dose reduction is required (see section 4.2.3.).
126.96.36.199 Obese patientsFor manually-controlled infusion it is recommended that for obese patients the dosage of Ultiva should be reduced and based upon ideal body weight as the clearance and volume of distribution of remifentanil are better correlated with ideal body weight than actual body weight.With the calculation of lean body mass (LBM) used in the Minto model, LBM is likely to be underestimated in female patients with a body mass index (BMI) greater than 35 kg/m2 and in male patients with BMI greater than 40 kg/m2. To avoid underdosing in these patients, remifentanil TCI should be titrated carefully to individual response.
188.8.131.52 Renal impairmentOn the basis of investigations carried out to date, a dose adjustment in patients with impaired renal function, including intensive care patients, is not necessary.184.108.40.206. Hepatic impairmentStudies carried out with a limited number of patients with impaired liver function, do not justify any special dosage recommendations. However, patients with severe hepatic impairment may be slightly more sensitive to the respiratory depressant effects of remifentanil (see section 4.4). These patients shall be closely monitored and the dose of remifentanil shall be titrated to individual patient need.
220.127.116.11 NeurosurgeryLimited clinical experience in patients undergoing neurosurgery has shown that no special dosage recommendations are required.
18.104.22.168 ASA III/IV patientsGeneral anaesthesia: As the haemodynamic effects of potent opioids can be expected to be more pronounced in ASA III/IV patients, caution should be exercised in the administration of Ultiva in this population. Initial dosage reduction and subsequent titration to effect is therefore recommended. In paediatric patients, there are insufficient data to make a dosage recommendation.For TCI, a lower initial target of 1.5 to 4 nanograms/ml should be used in ASA III or IV patients and subsequently titrated to response.Cardiac anaesthesia: No initial dose reduction is required (see section 4.2.2).
Rapid offset of action /Transition to alternative analgesiaDue to the very rapid offset of action of Ultiva, no residual opioid activity will be present within 5 to 10 minutes after the discontinuation of Ultiva. For those patients undergoing surgical procedures where post-operative pain is anticipated, analgesics should be administered prior to discontinuation of Ultiva. The possibility of tolerance, hyperalgesia and associated haemodynamic changes should be considered when used in Intensive Care Unit. Prior to discontinuation of Ultiva, patients must be given alternative analgesic and sedative agents. Sufficient time must be allowed to reach the therapeutic effect of the longer acting analgesic. The choice of agent(s), the dose and the time of administration should be planned in advance and individually tailored to be appropriate for the patient's surgical procedure and the level of post-operative care anticipated. When other opioid agents are administered as part of the regimen for transition to alternative analgesia, the benefit of providing adequate post-operative analgesia must always be balanced against the potential risk of respiratory depression with these agents.
Discontinuation of TreatmentSymptoms following withdrawal of Ultiva including tachycardia, hypertension and agitation have been reported infrequently upon abrupt cessation, particularly after prolonged administration of more than 3 days. Where reported, re-introduction and tapering of the infusion has been beneficial. The use of Ultiva in mechanically ventilated intensive care patients is not recommended for duration of treatment greater than 3 days.
Inadvertent administrationA sufficient amount of Ultiva may be present in the dead space of the IV line and/or cannula to cause respiratory depression, apnoea and/or muscle rigidity if the line is flushed with IV fluids or other drugs. This may be avoided by administering Ultiva into a fast flowing IV line or via a dedicated IV line which is removed when Ultiva is discontinued.
Muscle rigidity - prevention and managementAt the doses recommended muscle rigidity may occur. As with other opioids, the incidence of muscle rigidity is related to the dose and rate of administration. Therefore, bolus injections should be administered over not less than 30 seconds.Muscle rigidity induced by remifentanil must be treated in the context of the patient's clinical condition with appropriate supporting measures including ventilatory support. Excessive muscle rigidity occurring during the induction of anaesthesia should be treated by the administration of a neuromuscular blocking agent and/or additional hypnotic agents. Muscle rigidity seen during the use of remifentanil as an analgesic may be treated by stopping or decreasing the rate of administration of remifentanil. Resolution of muscle rigidity after discontinuing the infusion of remifentanil occurs within minutes. Alternatively an opioid antagonist may be administered, however this may reverse or attenuate the analgesic effect of remifentanil.
Respiratory depression prevention and managementAs with all potent opioids, profound analgesia is accompanied by marked respiratory depression. Therefore, remifentanil should only be used in areas where facilities for monitoring and dealing with respiratory depression are available. The appearance of respiratory depression should be managed appropriately, including decreasing the rate of infusion by 50%, or by a temporary discontinuation of the infusion. Unlike other fentanyl analogues, remifentanil has not been shown to cause recurrent respiratory depression even after prolonged administration. However, as many factors may affect post-operative recovery it is important to ensure that full consciousness and adequate spontaneous ventilation are achieved before the patient is discharged from the recovery area.
Cardiovascular effectsThe risk of cardiovascular effects such as hypotension and bradycardia (see section 4.8 Undesirable Effects), which may rarely lead to asystole/cardiac arrest may be reduced by lowering the rate of infusion of Ultiva or the dose of concurrent anaesthetics or by using IV fluids, vasopressor or anticholinergic agents as appropriate.Debilitated, hypovolaemic, and elderly patients may be more sensitive to the cardiovascular effects of remifentanil.
Neonates/infantsThere is limited data available on use in neonates/infants under 1 year of age (see sections 22.214.171.124 and 5.1).
Drug abuseAs with other opioids remifentanil may produce dependency.
Labour and deliveryThe safety profile of remifentanil during labour or delivery has not been demonstrated. There are insufficient data to recommend remifentanil for use during labour and Caesarean section. Remifentanil crosses the placental barrier and fentanyl analogues can cause respiratory depression in the child.
|o The medicine has been prescribed to treat a medical or dental problem and o You have taken it according to the instructions given by the prescriber and in the information provided with the medicine and o It was not affecting your ability to drive safely.|
Immune System Disorders
|Rare:||Allergic reactions including anaphylaxis have been reported in patients receiving remifentanil in conjunction with one or more anaesthetic agents.|
|Not known:||Drug dependence|
Nervous System Disorders
|Very common:||Skeletal muscle rigidity|
|Rare:||Sedation (during recovery from general anaesthesia)|
|Rare:||Asystole/cardiac arrest, usually preceded by bradycardia, has been reported in patients receiving remifentanil in conjunction with other anaesthetic agents.|
|Not known:||Atrioventricular block|
Respiratory, Thoracic and Mediastinal Disorders
|Common:||Acute respiratory depression, apnoea|
|Very common:||Nausea, vomiting|
Skin and Subcutaneous Tissue Disorders
General Disorders and Administration Site Conditions
|Not known:||Drug tolerance|
Discontinuation of treatmentSymptoms following withdrawal of remifentanil including tachycardia, hypertension and agitation have been reported infrequently upon abrupt cessation, particularly after prolonged administration of more than 3 days (see section 4.4). Reporting of suspected adverse reactionsReporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
|Surgical intervention||Age (y), (N)||Study condition (maintenance)||Extubation (min) (mean (SD))|
|Lower abdominal/urological surgery||0.5-16 (120)||TIVA: propofol (5 - 10 mg/kg/h) + remifentanil (0.125 - 1.0 μg/kg/min)||11.8 (4.2)|
|Inhalation anaesthesia: sevoflurane (1.0 - 1.5 MAC) and remifentanil (0.125 - 1.0 μg/kg/min)||15.0 (5.6) (p<0.05)|
|ENT-surgery||4-11 (50)||TIVA: propofol (3 mg/kg/h) + remifentanil (0.5 μg/kg/min)||11 (3.7)|
|Inhalation anaesthesia: desflurane (1.3 MAC) and N2O mixture||9.4 (2.9) Not significant|
|General or ENT surgery||2-12 (153)||TIVA: remifentanil (0.2 - 0.5 μg/kg/min) + propofol (100 - 200 μg/kg/min)||Comparable extubation times (based on limited data)|
|Inhalation anaesthesia: sevoflurane (1 - 1.5 MAC) + N2O mixture|
MetabolismRemifentanil is an esterase metabolised opioid that is susceptible to metabolism by non-specific blood and tissue esterases. The metabolism of remifentanil results in the formation of an essentially inactive carboxylic acid metabolite (1/4600th as potent as remifentanil). The half life of the metabolite in healthy adults is 2 hours. Approximately 95% of remifentanil is recovered in the urine as the carboxylic acid metabolite. Remifentanil is not a substrate for plasma cholinesterase.
Cardiac anaesthesiaThe clearance of remifentanil is reduced by approximately 20% during hypothermic (28°C) cardiopulmonary bypass. A decrease in body temperature lowers elimination clearance by 3% per degree centigrade.
Renal impairmentThe rapid recovery from remifentanil-based sedation and analgesia is unaffected by renal status.The pharmacokinetics of remifentanil are not significantly changed in patients with varying degrees of renal impairment even after administration for up to 3 days in the intensive care setting. The clearance of the carboxylic acid metabolite is reduced in patients with renal impairment. Especially in intensive care patients with moderate/severe renal impairment, the concentration of the carboxylic acid metabolite may exceed 250-fold the level of remifentanil at steady-state in some patients. Clinical data demonstrate that the accumulation of the metabolite does not result in clinically relevant μ-opioid effects even after administration of remifentanil infusions for up to 3 days in these patients.There is no evidence that remifentanil is extracted during renal replacement therapy.The carboxylic acid metabolite is extracted during haemodialysis by 25 - 35 %.
Hepatic impairmentThe pharmacokinetics of remifentanil are not changed in patients with severe hepatic impairment awaiting liver transplant, or during the anhepatic phase of liver transplant surgery. Patients with severe hepatic impairment may be slightly more sensitive to the respiratory depressant effects of remifentanil. These patients should be closely monitored and the dose of remifentanil should be titrated to the individual patient need.
Paediatric patientsThe average clearance and steady state volume of distribution of remifentanil are increased in younger children and decline to young healthy adult values by age 17. The elimination half-life of remifentanil in neonates is not significantly different from that of young healthy adults. Changes in analgesic effect after changes in infusion rate of remifentanil should be rapid and similar to those seen in young healthy adults. The pharmacokinetics of the carboxylic acid metabolite in paediatric patients 2-17 years of age are similar to those seen in adults after correcting for differences in body weight.
ElderlyThe clearance of remifentanil is slightly reduced (approximately 25%) in elderly patients >65 years) compared to young patients. The pharmacodynamic activity of remifentanil increases with increasing age. Elderly patients have a remifentanil EC50 for formation of delta waves on the electroencephalogram (EEG) that is 50% lower than young patients; therefore, the initial dose of remifentanil should be reduced by 50% in elderly patients and then carefully titrated to meet the individual patient need. Placental and milk transferIn a human clinical trial, the mean ratio of maternal arterial to umbilical venous concentration indicated that the neonate was exposed to concentration of remifentanil in foetal blood was approximately 50% concentration of remifentanil to that in the mother. The mean umbilical arterio-venous ratio of remifentanil concentrations was approximately 30% suggesting metabolism of remifentanil in the neonate.
Reproductive toxicity studiesRemifentanil has been shown to reduce fertility in male rats when administered daily by intravenous injection for at least 70 days at a dose of 0.5mg/kg, or approximately 250 times the maximum recommended human bolus dose of 2 micrograms/kg. The fertility of female rats was not affected at doses up to 1mg/kg when administered for at least 15 days prior to mating. No teratogenic effects have been observed with remifentanil at doses up to 5mg/kg in rats and 0.8mg/kg in rabbits. Administration of remifentanil to rats throughout late gestation and lactation at doses up to 5mg/kg IV had no significant effect on the survival, development, or reproductive performance of the F1 generation.
GenotoxicityRemifentanil was devoid of genotoxic activity in bacteria and in rat liver or mouse bone marrow cells in vivo. However, a positive response was seen in vitro in different mammalian cell systems in the presence of a metabolic activation system. This activity was seen only at concentrations more than three orders of magnitude higher than therapeutic blood levels.
|Drug Delivery Rate(micrograms/kg/min)||Infusion Delivery Rate (ml/kg/h) for Solution Concentrations of|
|20 micrograms/ml1 mg/50 ml||25 micrograms/ml1 mg/40 ml||50 micrograms/ml1 mg/20 ml||250 micrograms/ml10 mg/40 ml|
|Table 2. Ultiva for Injection Infusion Rates (ml/h) for a 20 micrograms/ml Solution|
|Infusion Rate(micrograms/kg/min)||Patient Weight (kg)|
|Table 3. Ultiva for Injection Infusion Rates (ml/h) for a 25 micrograms/ml Solution|
|Infusion Rate(micrograms/kg/min)||Patient Weight (kg)|
|Table 4. Ultiva for Injection Infusion Rates (ml/h) for a 50 micrograms/ml Solution|
|Infusion Rate(micrograms/kg/min)||Patient Weight (kg)|
|Table 5. Ultiva for Injection Infusion Rates (ml/h) for a 250 micrograms/ml Solution|
|Infusion Rate(micrograms/kg/min)||Patient Weight (kg)|
|The following table provides the equivalent blood remifentanil concentration using a TCI approach for various manually-controlled infusion rates at steady state:|
|Ultiva Infusion Rate (micrograms/kg/min)||Remifentanil Blood Concentration (nanograms/ml)|
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