ALFENTANIL 5 MG/ML SOLUTION FOR INJECTION
Active substance: ALFENTANIL HYDROCHLORIDE
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SUMMARY OF PRODUCT CHARACTERISTICS
1
NAME OF THE MEDICINAL PRODUCT
Alfentanil 5 mg/ml, Solution for Injection
2
QUALITATIVE AND QUANTITATIVE COMPOSITION
Each ml of Alfentanil solution for injection contains 5 mg alfentanil (as hydrochloride) per ml. For a full list of excipients, see section 6.1.
3
PHARMACEUTICAL FORM
Solution for injection. A clear colourless solution.
4
4.1
CLINICAL PARTICULARS
Therapeutic indications
Alfentanil 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 bolus doses of Alfentanil 5 mg/ml (0.5 mg/ml) may be used to provide additional pain 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. At the proposed doses, Alfentanil 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.
4.2
Posology and method of administration
For intravenous infusions.
Dosage Alfentanil 5 mg/ml should be diluted with sodium chloride intravenous infusion BP, dextrose 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). 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
Known intolerance of alfentanil or other morphinomimetics. Pregnancy, and concurrent administration with monoamine oxidase inhibitors.
4.4
Special warnings and precautions for use
Warnings: Following administration of Alfentanil, a fall in blood pressure may occur. The magnitude of this effect may be exaggerated in the hypovolaemic patient or in the presence of concomitant sedative medication. Appropriate measures to maintain a stable arterial pressure should be taken. Like other opioids, alfentanil may cause bradycardia, an effect which may be marked and rapid in onset but which can be antagonised by atropine. Particular care must be taken following treatment with drugs which may depress the heart or increase vagal tone, such as anaesthetic agents or beta-blockers since they may predispose to bradycardia or hypotension. Heart rate and blood pressure should therefore be monitored carefully. If hypotension or bradycardia occurs, the rate of administration of alfentanil should be reduced and other appropriate measures instituted. Asystole following bradycardia has been reported on very rare occasions in non-atropinised patients. Therefore it is advisable to be prepared to administer an anticholinergic drug. Care must be taken if the patient has received monoamine oxidase inhibitors within the previous 2 weeks. Significant respiratory depression and loss of consciousness will occur following administration of alfentanil in doses in excess of 1 mg and is dose-related. If
necessary for assessment purposes, naloxone or other specific antagonists may be administered to reverse the opioid respiratory depression and other pharmacological effects of alfentanil. More than one dose of naloxone may be required in view of its short half life. Muscle rigidity (morphine-like effect) may occur, in which case neuromuscular blocking drugs may be helpful. Precautions: It is wise to reduce the dosage in the elderly and debilitated patient. In hypothyroidism, pulmonary disease, decreased respiratory reserve, alcoholism and liver or renal impairment the dosage should be titrated with care and prolonged monitoring may be required. Patients on chronic opioid therapy or with a history of opioid abuse may require higher doses. Non-epileptic (myo)clonic movements can occur. As with all potent opioids, profound analgesia is accompanied by marked respiratory depression, which may persist into or recur in the early post infusion period. Care should therefore be taken throughout the weaning period and adequate spontaneous respiration should be established and maintained in the absence of stimulation or ventilatory support. Following cessation of the infusion, the patient should be closely observed for at least 6 hours. Prior use of opioid medication may enhance or prolong the respiratory depressant effects of alfentanil. The use of rapid bolus injections of opioids should be avoided in patients with compromised intracerebral compliance; in such patients a transient decrease in the mean arterial pressure has occasionally been accompanied by a transient reduction of the cerebral perfusion pressure. This medicinal product contains less than 1 mmol sodium (23 mg) per 5 mg dose, i.e. essentially 'sodium-free'.
4.5
Interaction with other medicinal products and other forms of interaction
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 cimetidine (known cytochrome P450 3A4 enzyme inhibitors). In vitro data suggest that other potent cytochrome P450 3A4 enzyme inhibitors (e.g. ketoconazole, itraconazole, ritonavir) may also inhibit the metabolism of alfentanil. This could increase the risk of prolonged or delayed respiratory depression. The concomitant use of such drugs
requires special patient care and observation; in particular, it may be necessary to lower the dose of Alfentanil. Treatment with drugs which may depress the heart or increase vagal tone, such as beta-blockers and anaesthetic agents, may predispose to bradycardia or hypotension. Bradycardia and possibly asystole can occur when Alfentanil 5 mg/ml is combined with non-vagolytic muscle relaxants. Prior use of opioid premedication, barbiturates, benzodiazepines, neuroleptics, halogenic gases and other non-selective CNS depressants may enhance or prolong the respiratory depressant effects of alfentanil. If other narcotic or CNS depressant drugs are used concurrently with alfentanil, the effects of the drugs can be expected to be additive. When patients have received such drugs, the dose of alfentanil required will be less than usual. Likewise, following the administration of alfentanil, the dose of other CNS-depressant drugs should be reduced.
4.6
Pregnancy and lactation
Animal studies are insufficient with respect to effects on pregnancy. Although no teratogenic or acute embryotoxic effects have been observed in animal experiments, the potential risk for humans is unknown. Alfentanil should not be used in pregnancy unless clearly necessary. I.V. administration during childbirth (including Caesarean section) is not recommended, because alfentanil crosses the placenta and because the foetal respiratory centre is particularly sensitive to opiates. If, however, alfentanil is administered, an antidote should always be at hand for the child. Alfentanil may appear in breast milk. It is therefore recommended that breast feeding is not initiated within 24 hours of treatment.
4.7
Effects on ability to drive and use machines
Where early discharge is envisaged, patients should be advised not to drive or operate machinery for the 24 hours following administration.
4.8
Undesirable effects
The most frequently reported ADRs (incidence 10%) are: nausea and vomiting. Undesirable effects listed below in Table 1 have been reported in a clinical trial and/or from spontaneous reports from post-marketing experience. The following terms and frequencies are applied: very common ( 1/10), common ( 1/100 to < 1/10), uncommon ( 1/1000 to < 1/100), rare ( 1/10,000 to < 1/1000), very rare (< 1/10,000), and not known (frequency cannot be estimated from the available data). Adverse drug reactions from spontaneous reports during worldwide postmarketing experience with Alfentanil that met threshold criteria are included. Unlike for clinical trials, precise frequencies cannot be provided for spontaneous reports. The frequency for these reports is therefore classified as 'not known'.
Table 1 Adverse drug reactions reported in clinical trials and/or postmarketing Body System/Organ Class Frequency Category Immune system disorders Uncommon Allergic reactions (such as anaphylaxis, bronchospasm, urticaria) Clinical trials Spontaneous Reportsa
Psychiatric Disorders Common Somnolence
Uncommon
Disorientation, Agitation, Euphoria
Nervous system disorders Common Muscle rigidity (may also involve thoracic muscles) Myoclonic movements, Dizziness
Uncommon
Headache
Not known
Loss of consciousness (Postoperative period), Convulsion
Eye disorders
Uncommon
Blurred/double vision Miosis
Not known
Cardiac disorders
Common
Bradycardia, Tachycardia Arrhythmia
Uncommon
Not known
Cardiac arrest
Vascular Disorders Common Hypotension, Hypertension
Respiratory, thoracic, and mediastinal disorders Common Apnoea, Respiratory depression Cough, Recurrence of respiratory depression, Laryngospasm,
Uncommon
Hiccup Not known Respiratory arrest (including fatal outcome)
Gastrointestinal disorders Very common Nausea, Vomiting
Skin and subcutaneous tissue disorders Uncommon Pruritis, Sweating
General disorders and administration site conditions Uncommon Injection site pain, Shivering Pyrexia
Not known
a: Listed are only those adverse drug reactions that were not identified in clinical trials
4.9
Overdose
The manifestations of alfentanil overdose are generally an extension of its pharmacological action, which include the following:Action: Bradycardia: Hypoventilation or apnoea: Anticholinergics such as atropine or glycopyrrolate; O2 administration, assisted or controlled respiration and an opioid antagonist may be required;
Muscle rigidity:
Intravenous neuromuscular blocking agent may be given.
If hypotension is severe or persists, the possibility of hypovolaemia should be considered and controlled with appropriate parenteral fluid administration. The suggested treatments given above do not preclude the use of other clinically indicated counter measures. Body temperature and adequate fluid intake should be maintained and the patient observed for 24 hours. A specific narcotic antagonist (eg naloxone) should be available to treat respiratory depression.
5
5.1
PHARMACOLOGICAL PROPERTIES
Pharmacodynamic properties
In man, alfentanil at therapeutic doses has no detrimental effects on myocardial performance. The cardiovascular stability is remarkable both in healthy and poor-risk patients. The only changes seen in blood pressure and heart rate were transient, slight decreases occurring immediately after induction. The incidence and degree of respiratory depression is less and of shorter duration after alfentanil than with fentanyl. Like other narcotic analgesics, alfentanil increases the amplitude of the EEG and reduces its frequency. Alfentanil reduces intraocular pressure by about 45%. It blocks increases in plasma cortisol and in plasma antidiuretic and growth hormones throughout surgery, and prevents increases in plasma catecholamines up to, but not during or after, cardiopulmonary bypass in patients undergoing open heart surgery.
5.2
Pharmacokinetic properties
After bolus injections ranging from 2.4 to 125 g/kg, plasma levels in man decay triexponentially with a terminal half life of approx. 90 minutes. Total distribution volume varies from 0.4 to 1.0 l/kg, indicating a limited distribution of alfentanil to the tissues. Plasma clearance, varying from 3.3 to 8.3 ml/kg/min represents approximately one third of liver plasma flow indicating that elimination of alfentanil is not flow dependent. Since only 0.4% of the dose is excreted with the urine as unchanged drug, elimination of alfentanil occurs mainly by metabolism.
These main parameters in patients undergoing surgery are similar to those in healthy volunteers. Only when the drug was given as the sole anaesthetic in a continuous high infusion over about 5 hours was the clearance of alfentanil reduced resulting in a plasma half-life of about 200 minutes, the distribution volume not being markedly changed. Plasma protein binding of alfentanil is 92%, mainly due to a strong binding to the 'acute phase' 1-acid-glycoprotein. It is not bound to the blood cells. Pharmacokinetics were comparable in rats, dogs and man. In children, alfentanil has been shown to have a much shorter half-life than adults, whereas the elderly show a longer half-life for alfentanil, after IV bolus doses.
5.3
Preclinical safety data
Preclinical effects observed were only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.
6
6.1
PHARMACEUTICAL PARTICULARS
List of excipients
Sodium chloride Water for injections Hydrochloric acid* Sodium hydroxide* * for occasional pH adjustment only
6.2
Incompatibilities
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
6.3
Shelf life
24 months (unopened).
24 hours (dilutions).
6.4
Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5
Nature and contents of container
Type I Ph Eur clear glass ampoules containing 1 ml. 10 ampoules per carton.
6.6
Special precautions for disposal
If desired, Alfentanil Solution for Injection can be mixed with sodium chloride injection BP, dextrose injection BP or compound sodium lactate injection BP (Hartmann's solution). Such dilutions are compatible with plastic bags and giving sets. These dilutions should be used within 24 hours of preparation.
7
MARKETING AUTHORISATION HOLDER
Auden McKenzie (Pharma Division) Ltd Mckenzie House Bury Street Ruislip Middlesex HA4 7TL
8
MARKETING AUTHORISATION NUMBER(S)
PL 17507/0037
9
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
23/03/2010
10
DATE OF REVISION OF THE TEXT
23/03/2010
1
NAME OF THE MEDICINAL PRODUCT
Alfentanil 5 mg/ml, Solution for Injection
2
QUALITATIVE AND QUANTITATIVE COMPOSITION
Each ml of Alfentanil solution for injection contains 5 mg alfentanil (as hydrochloride) per ml. For a full list of excipients, see section 6.1.
3
PHARMACEUTICAL FORM
Solution for injection. A clear colourless solution.
4
4.1
CLINICAL PARTICULARS
Therapeutic indications
Alfentanil 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 bolus doses of Alfentanil 5 mg/ml (0.5 mg/ml) may be used to provide additional pain 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. At the proposed doses, Alfentanil 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.
4.2
Posology and method of administration
For intravenous infusions.
Dosage Alfentanil 5 mg/ml should be diluted with sodium chloride intravenous infusion BP, dextrose 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). 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
Known intolerance of alfentanil or other morphinomimetics. Pregnancy, and concurrent administration with monoamine oxidase inhibitors.
4.4
Special warnings and precautions for use
Warnings: Following administration of Alfentanil, a fall in blood pressure may occur. The magnitude of this effect may be exaggerated in the hypovolaemic patient or in the presence of concomitant sedative medication. Appropriate measures to maintain a stable arterial pressure should be taken. Like other opioids, alfentanil may cause bradycardia, an effect which may be marked and rapid in onset but which can be antagonised by atropine. Particular care must be taken following treatment with drugs which may depress the heart or increase vagal tone, such as anaesthetic agents or beta-blockers since they may predispose to bradycardia or hypotension. Heart rate and blood pressure should therefore be monitored carefully. If hypotension or bradycardia occurs, the rate of administration of alfentanil should be reduced and other appropriate measures instituted. Asystole following bradycardia has been reported on very rare occasions in non-atropinised patients. Therefore it is advisable to be prepared to administer an anticholinergic drug. Care must be taken if the patient has received monoamine oxidase inhibitors within the previous 2 weeks. Significant respiratory depression and loss of consciousness will occur following administration of alfentanil in doses in excess of 1 mg and is dose-related. If
necessary for assessment purposes, naloxone or other specific antagonists may be administered to reverse the opioid respiratory depression and other pharmacological effects of alfentanil. More than one dose of naloxone may be required in view of its short half life. Muscle rigidity (morphine-like effect) may occur, in which case neuromuscular blocking drugs may be helpful. Precautions: It is wise to reduce the dosage in the elderly and debilitated patient. In hypothyroidism, pulmonary disease, decreased respiratory reserve, alcoholism and liver or renal impairment the dosage should be titrated with care and prolonged monitoring may be required. Patients on chronic opioid therapy or with a history of opioid abuse may require higher doses. Non-epileptic (myo)clonic movements can occur. As with all potent opioids, profound analgesia is accompanied by marked respiratory depression, which may persist into or recur in the early post infusion period. Care should therefore be taken throughout the weaning period and adequate spontaneous respiration should be established and maintained in the absence of stimulation or ventilatory support. Following cessation of the infusion, the patient should be closely observed for at least 6 hours. Prior use of opioid medication may enhance or prolong the respiratory depressant effects of alfentanil. The use of rapid bolus injections of opioids should be avoided in patients with compromised intracerebral compliance; in such patients a transient decrease in the mean arterial pressure has occasionally been accompanied by a transient reduction of the cerebral perfusion pressure. This medicinal product contains less than 1 mmol sodium (23 mg) per 5 mg dose, i.e. essentially 'sodium-free'.
4.5
Interaction with other medicinal products and other forms of interaction
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 cimetidine (known cytochrome P450 3A4 enzyme inhibitors). In vitro data suggest that other potent cytochrome P450 3A4 enzyme inhibitors (e.g. ketoconazole, itraconazole, ritonavir) may also inhibit the metabolism of alfentanil. This could increase the risk of prolonged or delayed respiratory depression. The concomitant use of such drugs
requires special patient care and observation; in particular, it may be necessary to lower the dose of Alfentanil. Treatment with drugs which may depress the heart or increase vagal tone, such as beta-blockers and anaesthetic agents, may predispose to bradycardia or hypotension. Bradycardia and possibly asystole can occur when Alfentanil 5 mg/ml is combined with non-vagolytic muscle relaxants. Prior use of opioid premedication, barbiturates, benzodiazepines, neuroleptics, halogenic gases and other non-selective CNS depressants may enhance or prolong the respiratory depressant effects of alfentanil. If other narcotic or CNS depressant drugs are used concurrently with alfentanil, the effects of the drugs can be expected to be additive. When patients have received such drugs, the dose of alfentanil required will be less than usual. Likewise, following the administration of alfentanil, the dose of other CNS-depressant drugs should be reduced.
4.6
Pregnancy and lactation
Animal studies are insufficient with respect to effects on pregnancy. Although no teratogenic or acute embryotoxic effects have been observed in animal experiments, the potential risk for humans is unknown. Alfentanil should not be used in pregnancy unless clearly necessary. I.V. administration during childbirth (including Caesarean section) is not recommended, because alfentanil crosses the placenta and because the foetal respiratory centre is particularly sensitive to opiates. If, however, alfentanil is administered, an antidote should always be at hand for the child. Alfentanil may appear in breast milk. It is therefore recommended that breast feeding is not initiated within 24 hours of treatment.
4.7
Effects on ability to drive and use machines
Where early discharge is envisaged, patients should be advised not to drive or operate machinery for the 24 hours following administration.
4.8
Undesirable effects
The most frequently reported ADRs (incidence 10%) are: nausea and vomiting. Undesirable effects listed below in Table 1 have been reported in a clinical trial and/or from spontaneous reports from post-marketing experience. The following terms and frequencies are applied: very common ( 1/10), common ( 1/100 to < 1/10), uncommon ( 1/1000 to < 1/100), rare ( 1/10,000 to < 1/1000), very rare (< 1/10,000), and not known (frequency cannot be estimated from the available data). Adverse drug reactions from spontaneous reports during worldwide postmarketing experience with Alfentanil that met threshold criteria are included. Unlike for clinical trials, precise frequencies cannot be provided for spontaneous reports. The frequency for these reports is therefore classified as 'not known'.
Table 1 Adverse drug reactions reported in clinical trials and/or postmarketing Body System/Organ Class Frequency Category Immune system disorders Uncommon Allergic reactions (such as anaphylaxis, bronchospasm, urticaria) Clinical trials Spontaneous Reportsa
Psychiatric Disorders Common Somnolence
Uncommon
Disorientation, Agitation, Euphoria
Nervous system disorders Common Muscle rigidity (may also involve thoracic muscles) Myoclonic movements, Dizziness
Uncommon
Headache
Not known
Loss of consciousness (Postoperative period), Convulsion
Eye disorders
Uncommon
Blurred/double vision Miosis
Not known
Cardiac disorders
Common
Bradycardia, Tachycardia Arrhythmia
Uncommon
Not known
Cardiac arrest
Vascular Disorders Common Hypotension, Hypertension
Respiratory, thoracic, and mediastinal disorders Common Apnoea, Respiratory depression Cough, Recurrence of respiratory depression, Laryngospasm,
Uncommon
Hiccup Not known Respiratory arrest (including fatal outcome)
Gastrointestinal disorders Very common Nausea, Vomiting
Skin and subcutaneous tissue disorders Uncommon Pruritis, Sweating
General disorders and administration site conditions Uncommon Injection site pain, Shivering Pyrexia
Not known
a: Listed are only those adverse drug reactions that were not identified in clinical trials
4.9
Overdose
The manifestations of alfentanil overdose are generally an extension of its pharmacological action, which include the following:Action: Bradycardia: Hypoventilation or apnoea: Anticholinergics such as atropine or glycopyrrolate; O2 administration, assisted or controlled respiration and an opioid antagonist may be required;
Muscle rigidity:
Intravenous neuromuscular blocking agent may be given.
If hypotension is severe or persists, the possibility of hypovolaemia should be considered and controlled with appropriate parenteral fluid administration. The suggested treatments given above do not preclude the use of other clinically indicated counter measures. Body temperature and adequate fluid intake should be maintained and the patient observed for 24 hours. A specific narcotic antagonist (eg naloxone) should be available to treat respiratory depression.
5
5.1
PHARMACOLOGICAL PROPERTIES
Pharmacodynamic properties
In man, alfentanil at therapeutic doses has no detrimental effects on myocardial performance. The cardiovascular stability is remarkable both in healthy and poor-risk patients. The only changes seen in blood pressure and heart rate were transient, slight decreases occurring immediately after induction. The incidence and degree of respiratory depression is less and of shorter duration after alfentanil than with fentanyl. Like other narcotic analgesics, alfentanil increases the amplitude of the EEG and reduces its frequency. Alfentanil reduces intraocular pressure by about 45%. It blocks increases in plasma cortisol and in plasma antidiuretic and growth hormones throughout surgery, and prevents increases in plasma catecholamines up to, but not during or after, cardiopulmonary bypass in patients undergoing open heart surgery.
5.2
Pharmacokinetic properties
After bolus injections ranging from 2.4 to 125 g/kg, plasma levels in man decay triexponentially with a terminal half life of approx. 90 minutes. Total distribution volume varies from 0.4 to 1.0 l/kg, indicating a limited distribution of alfentanil to the tissues. Plasma clearance, varying from 3.3 to 8.3 ml/kg/min represents approximately one third of liver plasma flow indicating that elimination of alfentanil is not flow dependent. Since only 0.4% of the dose is excreted with the urine as unchanged drug, elimination of alfentanil occurs mainly by metabolism.
These main parameters in patients undergoing surgery are similar to those in healthy volunteers. Only when the drug was given as the sole anaesthetic in a continuous high infusion over about 5 hours was the clearance of alfentanil reduced resulting in a plasma half-life of about 200 minutes, the distribution volume not being markedly changed. Plasma protein binding of alfentanil is 92%, mainly due to a strong binding to the 'acute phase' 1-acid-glycoprotein. It is not bound to the blood cells. Pharmacokinetics were comparable in rats, dogs and man. In children, alfentanil has been shown to have a much shorter half-life than adults, whereas the elderly show a longer half-life for alfentanil, after IV bolus doses.
5.3
Preclinical safety data
Preclinical effects observed were only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.
6
6.1
PHARMACEUTICAL PARTICULARS
List of excipients
Sodium chloride Water for injections Hydrochloric acid* Sodium hydroxide* * for occasional pH adjustment only
6.2
Incompatibilities
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
6.3
Shelf life
24 months (unopened).
24 hours (dilutions).
6.4
Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5
Nature and contents of container
Type I Ph Eur clear glass ampoules containing 1 ml. 10 ampoules per carton.
6.6
Special precautions for disposal
If desired, Alfentanil Solution for Injection can be mixed with sodium chloride injection BP, dextrose injection BP or compound sodium lactate injection BP (Hartmann's solution). Such dilutions are compatible with plastic bags and giving sets. These dilutions should be used within 24 hours of preparation.
7
MARKETING AUTHORISATION HOLDER
Auden McKenzie (Pharma Division) Ltd Mckenzie House Bury Street Ruislip Middlesex HA4 7TL
8
MARKETING AUTHORISATION NUMBER(S)
PL 17507/0037
9
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
23/03/2010
10
DATE OF REVISION OF THE TEXT
23/03/2010
Source: Medicines and Healthcare Products Regulatory Agency
Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date, and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or drug combination in no way should be construed to indicate that the drug or drug combination is safe, effective or appropriate for any given patient. If you have questions about the drugs you are taking, check with your doctor, nurse or pharmacist.
