1. Name Of The Medicinal Product
Alfentanil 5 mg/ml solution for injection
2. Qualitative And Quantitative Composition
Each 1 ml of Alfentanil 5 mg/ml solution for injection contains:
Alfentanil hydrochloride, monohydrate 5.44 mg,
equivalent to 5.0 mg alfentanil base
For excipients, see 6.1.
3. Pharmaceutical Form
Solution for Injection
The product is a clear and colourless solution.
4. Clinical Particulars
4.1 Therapeutic Indications
Alfentanil 5 mg/ml solution for injection is a potent opioid analgesic with a very rapid onset of action. It is indicated for analgesia and suppression of respiratory activity in mechanically ventilated patients on intensive care and to provide analgesic cover for painful manoeuvres. It will aid compliance with mechanical ventilation, and tolerance of the endotracheal tube. Intravenous relief during brief painful procedures such as physiotherapy, endotracheal suction, etc. Despite being mechanically ventilated, patients may be awake in the presence of adequate analgesia.
4.2 Posology And Method Of Administration
At the proposed doses, Alfentanil 5 mg/ml solution for injection has no sedative activity. Therefore supplementation with an appropriate hypnotic or sedative agent is recommended. Admixture is not advisable due to the need to individually titrate both agents.
Alfentanil given by infusion should only be given in areas where facilities are available to deal with respiratory depression and where continuous monitoring is performed. Alfentanil should only be prescribed by physicians familiar with the use of potent opioids when given by continuous iv infusion.
Method of administration
For intravenous infusions.
Dosage
Alfentanil 5 mg/ml solution for injection should be diluted with sodium chloride intravenous infusion BP, glucose intravenous infusion BP, or compound sodium lactate intravenous infusion BP (Hartmann's solution). Such dilutions are compatible with plastic bags and giving sets. These dilutions should be used within 24 hours of preparation.
Once the patient has been intubated, mechanical ventilation can be initiated using the following dosage regimen:
The recommended initial infusion rate for mechanically ventilated adult patients is 2 mg per hour (equivalent to 0.4 ml per hour) of undiluted Alfentanil 5 mg/ml solution for injection. For a 70 kg patient, this corresponds to approximately 30 micrograms per kilogram per hour.
More rapid control may initially be gained by using a loading dose. For example, a dose of 5 mg may be given in divided doses over a period of 10 minutes, during which time careful monitoring of blood pressure and heart rate should be performed. If hypotension or bradycardia occurs, the rate of administration should be reduced accordingly and other appropriate measures instituted.
The dose to produce the desired effects should then be individually determined and reassessed regularly to ensure that the optimum dose is being used.
In clinical trials, patient requirements have generally been met with doses of 0.5 to 10 mg alfentanil per hour.
Additional bolus doses of 0.5 – 1.0 mg alfentanil may be given to provide analgesia during short painful procedures.
The elderly and those patients with liver impairment and hypothyroidism will require lower doses. Obese patients may require a dose based on their lean body mass.
Adolescents and young adults will require higher than average doses. There is little experience of use of alfentanil to treat children in intensive care.
The maximum recommended duration of treatment with alfentanil infusions is 4 days.
Present data suggest that clearance of alfentanil is unaltered in renal failure. However there is an increased free fraction and hence dosage requirements may be less than in the patient with normal renal function.
4.3 Contraindications
Alfentanil hydrochloride is contraindicated in patients with known hypersensitivity to the drug and other opioids.
Obstructive airway disease or respiratory depression if not ventilating.
Concurrent administration with monoamine oxidase inhibitors or within 2 weeks of their discontinuation.
Administration in labour or before clamping of the cord during Caesarian section due to the possibility of respiratory depression in the new-born infant.
4.4 Special Warnings And Precautions For Use
Warnings
Alfentanil should be administered only by persons specifically trained in the use of intravenous and general anaesthetic agents and the management of respiratory effects of potent opioids.
An opioid antagonist, resuscitative and intubation equipment and oxygen should be readily available.
Because of the possibility of delayed respiratory depression, monitoring of the patient must continue well after surgery.
Alfentanil hydrochloride administered in initial dosages up to 20 µg/kg may cause skeletal muscle rigidity, particularly of the truncal muscles. The incidence and severity of muscle rigidity is usually dose-related. Administration of alfentanil at anaesthetic induction dosages (above 130 µg/kg) will consistently produce muscular rigidity with an immediate onset. The onset of muscular rigidity occurs earlier than with other opioids. Alfentanil may produce muscular rigidity that involves all skeletal muscles, including those of the neck and extremities. The incidence may be reduced by: 1) routine methods of administration of neuromuscular blocking agents for balanced opioid anaesthesia; 2) administration of up to 1/4 of the full paralyzing dose of a neuromuscular blocking agent just prior to administration of alfentanil at dosages up to 130 µg/kg; following loss of consciousness, a full paralyzing dose of a neuromuscular blocking agent should be administered; or 3) simultaneous administration of alfentanil and a full paralyzing dose of a neuromuscular blocking agent when alfentanil is used in rapidly administered anaesthetic dosages (above 130 µg/kg).
The neuromuscular blocking agent used should be appropriate for the patient's cardiovascular status. Adequate facilities should be available for postoperative monitoring and ventilation of patients administered alfentanil. It is essential that these facilities be fully equipped to handle all degrees of respiratory depression.
Patients receiving monitored anaesthesia care should be continuously monitored by persons not involved in the conduct of the surgical or diagnostic procedure; oxygen supplementation should be immediately available and provided where clinically indicated; oxygen saturation should be continuously monitored; the patient should be observed for early signs of hypertension, apnea, upper airway obstruction and/or oxygen desaturation.
Severe and unpredictable potentiation of monoamine oxidase (MAO) inhibitors has been reported for other opioid analgesics, and rarely with alfentanil. Therefore when alfentanil is administered to patients who have received MAO inhibitors within 14 days, appropriate monitoring and ready availability of vasodilators and beta-blockers for the treatment of hypertension is recommended.
Precautions
Delayed respiration depression, respiratory arrest, bradycardia, asystole, arrhythmias and hypotension have also been reported. Therefore, vital signs must be monitored continuously.
General
The initial dose of alfentanil should be appropriately reduced in elderly and debilitated patients. The effect of the initial dose should be considered in determining supplemental doses. In obese patients (more then 20% above ideal total body weight), the dosage of alfentanil should be determined on the basis of lean body weight. In one clinical trial, the dose of alfentanil required to produce anaesthesia, as determined by appearance of delta waves in EEG, was 40% lower in geriatric patients than that needed in healthy young patients.
In patients with compromised liver function and in geriatric patients, the plasma clearance of alfentanil may be reduced and postoperative recovery may be prolonged.
Induction doses of alfentanil should be administered slowly (over three minutes). Administration may produce loss of vascular tone and hypotension. Consideration should be given to fluid replacement prior to induction.
Diazepam administered immediately prior to or in conjunction with high doses of alfentanil may produce vasodilation, hypotension and result in delayed recovery.
Bradycardia produced by alfentanil may be treated with atropine. Severe bradycardia and asystole have been successfully treated with atropine and conventional resuscitative methods.
The hemodynamic effects of a particular muscle relaxant and the degree of skeletal muscle relaxation required should be considered in the selection of a neuromuscular blocking agent.
Following an anaesthetic induction dose of alfentanil, requirements for volatile inhalation anaesthetics of alfentanil infusion are reduced by 30 to 50% for the first hour of maintenance.
Alfentanil infusions should be discontinued at least 10-15 minutes prior to the end of surgery during general anaesthesia. During administration of alfentanil for monitored anaesthesia care, infusions may be continued to the end of the procedure.
Respiratory depression caused by opioid analgesics can be reversed by opioid antagonists such as naloxone. Because the duration of respiratory depression produced by alfentanil may last longer than the duration of the opioid antagonist action, appropriate surveillance should be maintained. As with all potent opioids, profound analgesia is accompanied by respiratory depression and diminished sensitivity to CO2 stimulation which may persist into or recur in the postoperative period.
Intraoperative hyperventilation may further add to respiratory depression. Appropriate postoperative monitoring should be employed, particularly after infusions and large doses of alfentanil, to ensure that adequate spontaneous breathing is established and maintained in the absence of stimulation prior to discharging the patient from the recovery area.
Head injuries
Alfentanil may obscure the clinical course of patients with head injuries.
Impaired respiration
Alfentanil should be used with caution in patients with pulmonary disease, decreased respiratory reserve or potentially compromised respiration. In such patients, opioids may additionally decrease respiratory drive and increase airway resistance. During anaesthesia, this can be managed by assisted or controlled respiration.
Impaired hepatic or renal function
In patients with liver or kidney dysfunction, alfentanil should be administered with caution due to the importance of these organs in the metabolism and excretion of alfentanil.
Pediatric use
Adequate data to support the use of alfentanil in children under 12 years of age are not presently available.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Monoamine oxidase (MAO) inhibitors may potentiate the effects of narcotics. It is not recommended to take alfentanil who have received MAO inhibitors within 14 days.
Alfentanil is metabolised mainly via the human cytochrome P450 3A4 enzyme. Available human pharmacokinetic data indicate that the metabolism of alfentanil may be inhibited by fluconazole, erythromycin, diltiazem and cimetedine (known cytochrome P450 3A4 enzyme inhibitors). In vitro data suggest that other potent P450 3A4 enzyme inhibitors (e.g. ketoconazole, ritonavir) may also inhibit the metabolism of alfentanil. This could increase the risk of prolonged or delayed respiratory depression. The concomitant use of such active substances requires special patient care and observation, in particular, it may be necessary to lower the dose of alfentanil.
Both the magnitude and duration of central nervous system and cardiovascular effects may be enhanced when alfentanil is administered in combination with other CNS depressants such as barbiturates, tranquilizers, opioids, or inhalation general anaesthetics. Postoperative respiratory depression may be enhanced or prolonged by these agents. In such cases of combined treatment, the dose of one or both agents should be reduced. Limited clinical experience indicates that requirements for volatile inhalation anaesthetics are reduced by 30 to 50% for the first sixty (60) minutes following alfentanil induction.
Treatment with drugs which may depress the heart or increase vagal tone, such as beta-blockers and anaesthetic agents, may predispose to bradycardia or hypertension.
Bradycardia and possibly asystole can occur when alfentanil is combined with non-vagolytic muscle relaxants.
Perioperative administration of drugs affecting hepatic blood flow or enzyme function may reduce plasma clearance and prolong recovery.
4.6 Pregnancy And Lactation
Pregnancy
Alfentanil has been shown to have an embryocidal effect in rats and rabbits when given in doses 2.5 times the upper human dose for a period of 10 days to over 30 days. These effects could have been due to maternal toxicity (decreased food consumption with increased mortality) following prolonged administration of the drug.
No evidence of teratogenic effects has been observed after administration for alfentanil in rats or rabbits.
There are no adequate and well-controlled studies in pregnant women. Alfentanil should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Labor and Delivery
There are insufficient data to support the use of alfentanil in labor and delivery. Placental transfer of the drug has been reported: therefore, use in labor and delivery is not recommended.
Nursing Mothers
In one study of nine women undergoing postpartum tubal ligation, significant levels of alfentanil were detected in colostrum four hours after administration of 60 µg/kg of alfentanil, with no detectable levels present after 28 hours. Caution should be exercised when alfentanil is administered to a nursing woman.
4.7 Effects On Ability To Drive And Use Machines
No studies on the effects of alfentanil on the ability to drive and use machines have been performed.
However, where early discharge is envisaged patients should be advised not to drive or operate machinery for 24 hours following administration.
4.8 Undesirable Effects
Undesirable effects in patients receiving alfentanil are generally mild and transient.
The most common adverse reactions of opioids are respiratory depression and skeletal muscle rigidity, particularly of the truncal muscles. Alfentanil may produce muscular rigidity that involves the skeletal muscles of the neck and extremities.
The adverse experience profile from patients receiving alfentanil for monitored anaesthesia care is similar to the profile established with alfentanil during general anaesthesia. Respiratory events reported during monitored anaesthesia care included hypoxia, apnea, and bradypnea. Other adverse events reported by patients receiving alfentanil for monitored anaesthesia care, in order of decreasing frequency, were nausea, hypotension, vomiting, pruritus, confusion, somnolence and agitation.
Summarising the adverse effects reported in the currently available literature (clinical trials and case reports, representing 2029 patients), the incidence of adverse reactions probably or possibly related to alfentanil sorted according to the affected organ system is shown in Table 1.
Table 1. Adverse reactions probably or possibly related to alfentanil sorted by frequency and organ system
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A more detailed summary of probably or possibly to alfentanil use related adverse events is compiled in Table 2. Nausea and vomiting are the most frequent observed adverse events, then cardiovascular reactions and respiratory effects. All other adverse events reported are uncommon and rare.
Table 2. Frequency of adverse reactions possibly or probably related to alfentanil, reported in clinical trials
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4.9 Overdose
Overdosage would be manifested by extension of the pharmacological actions of alfentanil hydrochloride. No experience of overdosage with alfentanil was reported during clinical trials. The duration of respiratory depression following overdosage with alfentanil may be longer than the duration of action of the opioid antagonist. Administration of an opioid antagonist should not preclude immediate establishment of a patent airway, administration of oxygen, and assisted or controlled ventilation as indicated for hypoventilation or apnea. If respiratory depression is associated with muscular rigidity, a neuromuscular blocking agent may be required to facilitate assisted or controlled ventilation. Intravenous fluids and vasoactive agents may be required to manage hemodynamic instability.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: opioid anesthetics, ATC code: N01AH02 (Alfentanil)
Alfentanil hydrochloride is an opioid analgesic with a rapid onset of action.
At doses of 8-40 µg/kg for surgical procedures lasting up to 30 minutes, alfentanil provides analgesic protection against hemodynamic responses to surgical stress with recovery times generally comparable to those seen with equipotent fentanyl dosages.
For longer procedures, doses of up to 75 µg/kg attenuate hemodynamic responses to laryngoscopy, intubation and incision, with recovery time comparable to fentanyl. At doses of 50-75 µg/kg followed by a continuous infusion of 0.5-3.0 µg/kg/min, alfentanil attenuates the catecholamine response with more rapid recovery and reduced need for postoperative analgesics as compared to patients administered enflurane. At doses of 5 µg/kg, alfentanil provides analgesia for the conscious but sedated patient. Based on patient response, doses higher than 5 µg/kg may be needed. Elderly or debilitated patients may require lower doses.
Alfentanil has an immediate onset of action. At dosages of approximately 105 µg/kg, alfentanil produces hypnosis as determined by EEG patterns; an aesthetic ED90 of 182 µg/kg for alfentanil in unpremedicated patients has been determined, based upon the ability to block response to placement of a nasopharyngeal airway. Based on clinical trials, induction dosage requirements range from 130-245 µg/kg. For procedures lasting 30-60 minutes, loading dosages of up to 50 µg/kg produce the hemodynamic responses to endotracheal intubation and skin incision comparable to those from fentanyl. A pre-intubation loading dose of 50-75 µg/kg prior to a continuous infusion attenuates the response to laryngoscopy, intubation and incision. Subsequent administration of alfentanil infusion administered at a rate of 0.5-3 µg/kg/min with nitrous oxide/oxygen attenuates sympathetic responses to surgical stress with more rapid recovery than enflurane.
Requirements for volatile inhalation anaesthetics were reduce by 30 to 50% during the first 60 minutes of maintenance in patients administered anaesthetic doses (above 130 µg/kg) of alfentanil as compared to patients given doses of 4-5 mg/kg thiopental for anaesthetic induction. At anaesthetic induction dosages, alfentanil provides a deep level of anaesthesia during the first hour of anaesthetic maintenance and provides attenuation of the hemodynamic response during intubation and incision.
Following an anaesthetic dose of alfentanil, requirements for alfentanil infusion are reduced by 30 to 50% for the first hour of maintenance.
Patients with compromised liver function and those over 65 years of age have been found to have reduced plasma clearance and extended terminal elimination of alfentanil, which may prolong postoperative recovery.
Bradycardia may be seen in patients administered alfentanil. The incidence and degree of bradycardia may be more pronounced when alfentanil is administered in conjunction with non-vagolytic neuromuscular blocking agents or in the absence of anticholinergic agents such as atropine.
Administration of intravenous diazepam immediately prior to or following high doses of alfentanil has been shown to produce decreases in blood pressure that may be secondary to vasodilation; recovery may also be prolonged.
Patients administered doses up to 200 µg/kg of alfentanil have shown no significant increase in histamine levels and no clinical evidence of histamine release.
Skeletal muscle rigidity is related to the dose and speed of administration of alfentanil. Muscular rigidity will occur with an immediate onset following anaesthetic induction dosages. Preventative measures may reduce the rate and severity.
The duration and degree of respiratory depression and increased airway resistance usually increase with dose, but have also been observed at lower doses. Although higher doses may produce apnea and a longer duration of respiratory depression, apnea may also occur at low doses.
During monitored anaesthesia care, attention must be given to the respiratory effects of alfentanil injection. Decreased oxygen saturation, apnea, decreased respiratory rate, and upper airway obstruction can occur.
5.2 Pharmacokinetic Properties
High intrasubject and intersubject variability in the pharmacokinetic disposition of alfentanil has been reported.
The pharmacokinetics of alfentanil can be described as a three-compartment model with sequential distribution half-lives of 1 and 14 minutes; and a terminal elimination half-life of 90-111 minutes (as compared to a terminal elimination half-life of approximately 475 minutes for fentanyl and approximately 265 minutes for sufentanil at doses of 250 µg). The liver is the major site of biotransformation.
Alfentanil has an apparent volume of distribution of 0.4-1 L/kg, which is approximately one-fourth to one-tenth that of fentanyl, with an average plasma clearance of 5 ml/kg/min as compared to approximately 8 ml/kg/min for fentanyl.
Only 1.0% of the dose is excreted as unchanged drug; urinary excretion is the major route of elimination of metabolites. Plasma protein binding of alfentanil is approximately 92%.
In one study involving 15 patients administered alfentanil with nitrous oxide/oxygen, a narrow range of plasma alfentanil concentrations, approximately 310-340 ng/ml, was shown to provide adequate anaesthesia for intra-abdominal surgery, while lower concentrations, approximately 190 ng/ml, blocked responses to skin closure. Plasma concentrations between 100-200 ng/ml provided adequate anaesthesia for superficial surgery.
Repeated or continuous administration of alfentanil produces increasing plasma concentrations and an accumulation of the drug, particularly in patients with reduced plasma clearance.
5.3 Preclinical Safety Data
Single and repeated dose toxicity: Alfentanil may be assessed as a drug having low toxic potential at therapeutic doses. Toxic reactions occur principally as extension of the specific pharmacodynamic effects. Consequently, symptoms secondary due to suppression of the function of the central nervous system dominate in the event of acute overdose, e.g., respiratory suppression. Lesions of the cortical regions and the limbic system may be produced in rats after supratherapeutic doses.
The intravenous LD50 of alfentanil is 43-51 mg/kg in rats, 72-74 mg/kg in mice, 72-82 mg/kg in guinea pigs and 60-88 mg/kg in dogs. On the basis of experimental data in rats, a therapeutic index of 1080 was calculated after intravenous administration of alfentanil.
Alfentanil is indicated for short-term use only. Subchronic and chronic toxicity data should not be required. Theoretically, alfentanil hydrochloride can produce drug dependence of the morphine type and therefore has the potential for being abused.
Carcinogenesis, mutagenesis, and impairment of fertility:
No long-term animal studies of alfentanil have been performed to evaluate carcinogenic potential. No structural chromosome mutations were produced in the in vivo micronucleus test in female rats at single intravenous doses of alfentanil as high as 20 mg/kg body weight (approximately 40 times the upper human dose), equivalent to a dose of 103 mg/m² body surface area. No dominant lethal mutations were produced in the in vivo dominant lethal test in male and female mice at the maximum intravenous dose of 20 mg/kg (60 mg/m²). No mutagenic activity was revealed in the in vitro Ames Salmonella typhimurium test, with and without metabolic activation.
Reproductive effects of alfentanil cannot be fully excluded, if administered at supratherapeutic doses in particular. Alfentanil should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus. Caution should be exercised when alfentanil is administered to a nursing woman.
Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction.
Preclinical effects were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.
Adverse reactions not observed in clinical studies, but seen in animals at exposure levels similar to clinical exposure levels and with possible relevance to clinical use were not observed.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Sodium chloride, sodium hydroxide and water for injections
6.2 Incompatibilities
This medicinal product must not be mixed with other medicinal products except those mentioned in 6.6.
6.3 Shelf Life
Shelf-life before first opening
3 years
Shelf-life after dilution
Chemical and physical in-use stability of the dilutions (see section 6.6) has been demonstrated for 48 hours.
From the microbiological point of view, the dilutions 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 to 8 °C, unless dilution has taken place in controlled and validated aseptic conditions.
6.4 Special Precautions For Storage
No special precautions for storage
6.5 Nature And Contents Of Container
Clear glass ampoules (Ph Eur Type I, one point cut) containing 5 mg/1 ml.
Original pack containing 5 or 10 ampoules of 1 ml each.
6.6 Special Precautions For Disposal And Other Handling
Alfentanil 5 mg/ml solution for injection should be diluted with sodium chloride intravenous infusion BP, glucose intravenous infusion BP, or compound sodium lactate intravenous infusion BP (Hartmann's solution) to a convenient concentration. Such dilutions are compatible with plastic bags and giving sets.
Any unused solution from opened ampoules should be discarded.
Any unused product or waste material should be disposed of in accordance with local requirements.
7. Marketing Authorisation Holder
hameln pharma plus gmbh
Langes Feld 13
D-31789 Hameln
Germany
8. Marketing Authorisation Number(S)
PL 25215/0006
9. Date Of First Authorisation/Renewal Of The Authorisation
24/11/2010
10. Date Of Revision Of The Text
24/11/2010
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