This information is intended for use by health professionals

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 5.44 mg, equivalent to 5.0 mg alfentanil base

Excipient with known effect

This medicine contains less than 1 mmol sodium (23 mg) per each 5mg dose, that is to say essentially 'sodium-free'.

For the full list of excipients, see section 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 bolus doses of Alfentanil (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.

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.

Dosage

Adults

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 maximum recommended duration of treatment with alfentanil infusions is 4 days.

Paediatric patients

Alfentanil 5 mg/ml solution for injection is not recommended for use in children in intensive care. Currently available data are described in section 5.2 but no recommendation on a posology can be made.

Elderly and debilitated patients

The elderly (>65 years of age) and those patients with liver impairment and hypothyroidism will require lower doses. Obese patients may require a dose based on their lean body mass.

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.

Method of administration

For intravenous infusion.

4.3 Contraindications

Hypersensitivity to the active substance, to other opioids, or to any of the excipients listed in section 6.1.

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:

Following administration of Alfentanil 5 mg/ml solution for injection, 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.

Cardiac arrest 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 5 mg/ml solution for injection 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.

Risk from concomitant use of sedative medicines such as benzodiazepines or related drugs

Concomitant use of Alfentanil and sedative medicines such as benzodiazepines or related drugs may result in sedation, respiratory depression, coma and death. Because of these risks, concomitant prescribing with these sedative medicines should be reserved for patients for whom alternative treatment options are not possible. If a decision is made to prescribe Alfentanil concomitantly with sedative medicines, the lowest effective dose should be used, and the duration of treatment should be as short as possible.

The patients should be followed closely for signs and symptoms of respiratory depression and sedation. In this respect, it is strongly recommended to inform patients and their caregivers to be aware of these symptoms (see section 4.5).

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. Resuscitation equipment and opioid antagonists should be readily available. 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.

Sodium content

This medicine contains less than 1 mmol sodium (23 mg) per each 5mg dose, that is to say essentially 'sodium-free'.

4.5 Interaction with other medicinal products and other forms of interaction

Drugs modifying the effect of alfentanil

Sedative medicines such as benzodiazepines or related drugs

The concomitant use of opioids with sedative medicines such as benzodiazepines or related drugs increases the risk of sedation, respiratory depression, coma and death because of additive CNS depressant effect. The dose and duration of concomitant use should be limited (see section 4.4).

Other Central Nervous System (CNS) depressants

Drugs such as barbiturates, neuroleptics, general anaesthetics and other non-selective CNS depressants (e.g. alcohol) may enhance or prolong the respiratory depressant effects of opioids. 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. Concomitant use with Alfentanil 5 mg/ml solution for injection in spontaneously breathing patients may increase the risk of respiratory depression, profound sedation, coma, and death.

Effect of Alfentanil on other drugs

Following the administration of alfentanil, the dose of other CNS-depressant drugs should be reduced. This is particularly important after surgery, because profound analgesia is accompanied by marked respiratory depression, which can persist or recur in the postoperative period. Administration of a CNS depressant, such as a benzodiazepine, during this period may disproportionally increase the risk for respiratory depression (see above).

In combination with alfentanil, the blood concentrations of propofol are 17% higher than in the absence of alfentanil. The concomitant use of alfentanil and propofol may require a lower dose of Alfentanil 5 mg/ml solution for injection.

Cytochrome P450 3A4 (CYP3A4) inhibitors

Alfentanil is metabolised mainly via the human cytochrome P450 3A4 enzyme. In vitro data suggest that potent cytochrome P450 3A4 enzyme inhibitors (e.g., ketoconazole, itraconazole, ritonavir) may inhibit the metabolism of alfentanil. Available human pharmacokinetic data indicate that the metabolism of alfentanil is inhibited by fluconazole, voriconazole, erythromycin, diltiazem and cimetidine (known cytochrome P450 3A4 enzyme inhibitors). 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 5 mg/ml solution for injection.

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 cardiac arrest can occur when Alfentanil 5 mg/ml solution for injection is combined with non-vagolytic muscle relaxants.

Monoamine Oxidase Inhibitors (MAOI)

It is usually recommended to discontinue MAO-inhibitors 2 weeks prior to any surgical or anaesthetic procedure.

Serotonergic drugs

Coadministration of alfentanil with a serotonergic agent, such as Selective Serotonin Reuptake Inhibitors (SSRIs), Serotonin Norepinephrine Reuptake Inhibitors (SNRIs), or Monoamine Oxidase Inhibitors (MAOIs), may increase the risk of serotonin syndrome, a potentially life-threatening condition.

4.6 Fertility, pregnancy and lactation

Pregnancy

Although no teratogenic or acute embryotoxic effects have been observed in animal experiments, insufficient data are available to evaluate any harmful effects in humans.

Consequently, it is necessary to consider possible risks and potential advantages before administering this drug to pregnant patients.

Labour and Delivery

Intravenous administration during childbirth (including caesarian section) is not recommended because Alfentanil crosses the placenta and because the foetal respiratory centre is particularly sensitive to opioids. If Alfentanil is administered nevertheless, assisted ventilation equipment must be immediately available for use if required.

An opioid antagonist for the child must always be available. The half-life of the opioid antagonist may be shorter than the half-life of alfentanil, therefore, repeated administration of the opioid antagonist must be considered.

Breastfeeding

Alfentanil may appear in breast milk. Therefore, breast-feeding or use of expressed breast milk is not recommended within 24 hours following the administration of Alfentanil.

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 at least 24 hours following administration.

This medicine can impair cognitive function and can affect a patient's ability to drive safely. This class of medicine is in the list of drugs included in regulations under 5a of the Road Traffic Act 1988. When prescribing this medicine, patients should be told:

The medicine is likely to affect your ability to drive

Do not drive until you know how the medicine affects you

It is an offence to drive while under the influence of this medicine

However, you would not be committing an offence (called 'statutory defence') if:

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 or in the information provided with the medicine and

o It was not affecting your ability to drive safely

4.8 Undesirable effects

Adverse Reactions

The most frequently reported Adverse reactions (incidence ≥10%) are: nausea and vomiting. Undesirable effects listed below in Table 1 have been reported in clinical trials (1157 subjects) 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 (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); and not known (cannot be estimated from the available clinical trial data).

Adverse 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 Reactions reported in clinical trials and/or postmarketing

Frequency Category

System Organ Class

Very Common (≥1/10)

Common (≥1/100 to <1/10)

Uncommon (≥1/1,000 to <1/100)

Rare ≥1/10,000 to <1/1,000

Not Known

Immune System Disorders

Hypersensitivity (including anaphylactic reaction, anaphylactoid reaction and urticaria

Psychiatric Disorders

Euphoric Mood

Agitation; Crying

Disorientation

Nervous System Disorders

Movement Disorder; Dizziness; Sedation; Dyskinesia

Headache; Somnolence; Unresponsive to Stimuli

Loss of Consciousness (postoperative period); Convulsion; Myoclonus

Eye Disorders

Visual Disturbance

Miosis

Cardiac Disorders

Bradycardia; Tachycardia

Arrhythmia; Heart Rate Decreased

Cardiac Arrest

Vascular Disorders

Hypotension; Hypertension; Blood Pressure Decreased; Blood Pressure Increased

Vein Pain

Respiratory, Thoracic and Mediastinal Disorders

Apnoea

Hiccups; Hypercapnia; Laryngospasm; Respiratory Depression (including fatal outcome)

Bronchospasm; Epistaxis

Respiratory Arrest; Cough

Gastrointestinal Disorders

Nausea; Vomiting

Skin and Subcutaneous Tissue Disorders

Dermatitis Allergic; Hyperhidrosis

Pruritus

Erythema; Rash

Musculoskeletal and Connective Tissue Disorders

Muscle Rigidity

Renal and urinary disorders

Urinary retention

General Disorders and Administration Site Conditions

Chills; Injection Site Pain; Fatigue

Pain

Pyrexia

Injury, Poisoning and Procedural Complications

Procedural Pain

Agitation Postoperative; Airway Complication of Anaesthesia; Confusion Postoperative

Anaesthetic Complication Neurological; Procedural Complication; Endotracheal Intubation Complication

Paediatric population

Frequency, type and severity of adverse reactions in children are expected to be the same as in adults, with the exception of the following:

Mild to moderate muscle rigidity has been seen frequently in neonates, although the number of neonates included in clinical studies was small. Severe rigidity and jerking can occur less commonly and may be accompanied by transient impaired ventilation, especially with high doses of Alfentanil or with a rapid rate of intravenous injection.

Reporting of suspected adverse reactions

Reporting 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 - Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

The manifestations of alfentanil overdose are generally an extension of its pharmacological action, which include the following:

Action

Bradycardia

Anticholinergics such as atropine or glycopyrrolate.

Hypoventilation or apnoea

O2 administration, assisted or controlled respiration and an opioid antagonist may be required.

Muscle rigidity

Intravenous neuromuscular blocking agent may be given.

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 opioid antagonist (e.g. naloxone) should be available to treat respiratory depression.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: opioid anaesthetics, ATC code: N01AH02 (Alfentanil)

In humans, 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 opioid 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

Alfentanil is a synthetic opioid with µ-agonist pharmacological effects.

After bolus injections ranging from 2.4 to 125 micrograms/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' α1-acid-glycoprotein. It is not bound to the blood cells. Pharmacokinetics were comparable in rats, dogs and man. The elderly show a longer half-life for alfentanil, after IV bolus doses.

Special Populations

Paediatric population

The data in children are limited. The values for the pharmacokinetic parameters are shown in the table below.

Pharmacokinetic Parameters of Alfentanil in Paediatric Subjects

t1/2β

(hr)

CL

(mL/kg/min)

Vdss

(L/kg)

Preterm Neonates (0-27 days)

Gestational age 25-40 weeks; n= 68

0.7-8.8

0.9-8.4

0.3-1.2

Term Neonates (0-27 days)

Gestational age: 35-41 weeks; n= 18

4.1-5.5

1.7-3.2

0.5-0.8

Infants & Toddlers

28 days - 23 months; n= 34

0.9-1.2

7.7-13.1

0.4-1.1

Children

2-11 years; n= 32

0.7-1.3

4.7-10.2

0.2-1.0

Adolescents

12-14 years; n= 3

1.1-1.9

5.5-7.4

0.3-0.6

Note: Data for neonates, infants, and children are given as range of mean values.

CL = clearance, Vdss = volume of distribution at steady state, t1/2β = half-life in the elimination phase.

Protein binding in newborns is 75% and increases in children to 85%.

Pharmacokinetic information on the use of alfentanil in children is limited. Alfentanil is metabolized by CYP3A4. CYP3A4 activity is low in neonates and increases after birth to reach 30 to 40% of adult levels at 1 month of age. Activity of CYPA4 increases further to 45% at 6 months, 80% at 12 months.

Hepatic Impairment

After administration of a single intravenous dose of 50 microgram/kg, the terminal half-life in cirrhotic patients is significantly longer than in controls. The volume of distribution remains unchanged. The free fraction of alfentanil increases in cirrhotic patients to 18.5% compared with 11.5% in controls. This increase in free fraction together with a reduction in clearance from 3.06 mL/min/kg in controls to 1.60 mL/min/kg in cirrhotic patients will result in a more prolonged and pronounced effect (see Section 4.4.).

Renal Impairment

The volume of distribution and clearance of the free fraction is similar in renal failure patients and healthy controls. The free fraction of alfentanil in patients with renal failure is increased to 12.4 to 19 % compared with 10.3 to 11% in controls. This may result in an increase in clinical effects of alfentanil (see Section 4.4.).

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. 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 pharmaceuticals ltd

Nexus, Gloucester Business Park

Gloucester, GL3 4AG

United Kingdom

8. Marketing authorisation number(s)

PL 01502/0107

9. Date of first authorisation/renewal of the authorisation

05/05/2006

10. Date of revision of the text

06/03/2019