Sublimaze 10 Ml/2 ml Injection

SUBLIMAZE is indicated:

• for use as an opioid analgesic supplement during intravenous, inhalation or regional anaesthesia.
• as a co-induction anaesthetic for intravenous or inhalation anaesthesia.

The dosage of SUBLIMAZE should be individualised according to age, body mass, physical status, underlying pathological condition, use of other medicines, and type of surgery and anaesthesia. The effect of the initial dose should be taken into account in determining supplemental doses. To avoid bradycardia, a small intravenous dose of an anticholinergic just before induction may be administered.

Use as an analgesic supplement to intravenous or inhalation anaesthesia

Analgesia during anaesthetic induction 1 u2013 10 u03bcg/kg.

Analgesia during maintenance of anaesthesia For both balanced anaesthesia and total intravenous anaesthesia (TIVA), dose amounts and the intervals between doses should be adjusted to account for the duration and severity of the surgical procedure.

Bolus administration 0,5 u2013 10 u03bcg/kg.

Continuous infusion 0,5 u2013 5 u03bcg/kg/h.

Use as an anaesthetic medicine When attenuation of the response to surgical stress is especially important, doses of 50 u2013 100 u03bcg/kg may be administered with oxygen and a muscle relaxant. This technique provides anaesthesia without necessitating the use of additional anaesthetic medicines. In certain cases, doses up to 150 u03bcg/kg may be required to produce this anaesthetic effect. SUBLIMAZE has been used in this fashion for open heart surgery and certain other major surgical procedures in patients for whom protection of the myocardium from excess oxygen demand is particularly indicated.

Special populations

Use in the elderly and debilitated patients The dose should be reduced in the elderly (> 65 years of age) and in debilitated patients. The effect of the initial dose should be taken into account in determining supplemental doses.

Obese patients In obese patients there is a risk of overdosing if the dose is calculated based on the body mass. Obese patients should be dosed based on estimated lean body mass rather than on body mass only.

Renal impairment In patients with renal impairment reduced dosing of SUBLIMAZE should be considered and these patients should be observed carefully for signs of fentanyl toxicity (see section 5.2).

Use in children For the induction and maintenance in children aged 2 u2013 12 years, a reduced dose as low as 1 u2013 3 u03bcg/kg in divided doses is recommended.

Method of administration SUBLIMAZE is administered by the intravenous route.

SUBLIMAZE is contraindicated in patients with a known intolerance to fentanyl, or any other ingredient of SUBLIMAZE, or to other opioids. SUBLIMAZE should not be administered to patients with uncontrolled bronchial asthma or heart failure secondary to chronic lung disease, due to the potential for histamine release. It should not be used in patients who may be susceptible to respiratory depression, especially in the presence of cyanosis and excessive bronchial secretion, or comatose patients who may have a head injury or brain tumour and conditions in which increased intracranial pressure occurs, and after an operation on the biliary tract. The administration of SUBLIMAZE is contraindicated in patients taking monoamine oxidase inhibitors or within 14 days of stopping such treatment, and in alcoholism (see section 4.5).

Tolerance and opioid use disorder (abuse and dependence) Tolerance, physical dependence and psychological dependence may develop upon repeated administration of opioids. Repeated use of opioids may lead to opioid use disorder (OUD). Abuse or intentional misuse of opioids may result in overdose and/or death. The risk of developing OUD is increased in patients with a personal or a family history (parents or siblings) of substance use disorders (including alcohol use disorder), in current tobacco users or in patients with a personal history of other mental health disorders (e.g. major depression, anxiety and personality disorders).

For all patients, prolonged use of SUBLIMAZE may lead to drug dependence (addiction), even at therapeutic doses. The risks are increased in individuals with current or past history of substance misuse disorder (including alcohol misuse) or mental health disorder (e.g. major depression). Additional support and monitoring may be necessary when prescribing for patients at risk of opioid misuse. A comprehensive patient history should be taken to document concomitant medicines, including over-the-counter medicines and medicines obtained online, and past and present medical and psychiatric conditions. Patients may find that treatment is less effective with chronic use and express a need to increase the dose to obtain the same level of pain control as initially experienced. Patients may also supplement their treatment with additional pain relievers. These could be signs that the patient is developing tolerance. The risks of developing tolerance should be explained to the patient. Overuse or misuse may result in overdose and/or death. It is important that patients only use medicines that are prescribed for them at the dose they have been prescribed and do not give SUBLIMAZE to anyone else. Patients should be closely monitored for signs of misuse, abuse or addiction. The clinical need for analgesic treatment should be reviewed regularly. Because of the risks, including fatal outcome, associated with accidental ingestion, misuse and abuse, patients and their health care providers must be advised to keep SUBLIMAZE in a safe and secure place, not accessible by others.

Drug withdrawal syndrome Prior to starting treatment with any opioids, a discussion should be held with patients to put in place a withdrawal strategy for ending treatment with SUBLIMAZE. Drug withdrawal syndrome may occur upon abrupt cessation of therapy or dose reduction. When a patient no longer requires therapy, it is advisable to taper the dose gradually to minimise symptoms of withdrawal. Tapering from a high dose may take weeks to months. The opioid drug withdrawal syndrome is characterised by some or all of the following: restlessness, lacrimation, rhinorrhoea, yawning, perspiration, chills, myalgia, mydriasis and palpitations. Other symptoms may also develop including irritability, agitation, anxiety, hyperkinesia, tremor, weakness, insomnia, anorexia, abdominal cramps, nausea, vomiting, diarrhoea, increased blood pressure, increased respiratory rate or heart rate.

If women receive SUBLIMAZE during pregnancy, there is a risk that their newborn infants will experience neonatal withdrawal syndrome.

Opioid-induced hyperalgesia and allodynia Opioid-induced hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. This condition differs from tolerance, which is the need for increasing doses of opioids to maintain a defined effect. Symptoms of OIH include (but may not be limited to) increased levels of pain upon opioid dosage increase, decreased levels of pain upon opioid dosage decrease, or pain from ordinarily non-painful stimuli (allodynia). These symptoms may suggest OIH only if there is no evidence of underlying disease progression, opioid tolerance, opioid withdrawal, or addictive behaviour. Cases of OIH have been reported, both with short-term and longer-term use of opioid analgesics. Though the mechanism of OIH is not fully understood, multiple biochemical pathways have been implicated. Medical literature suggests a strong biological plausibility between opioid analgesics and OIH and allodynia. If a patient is suspected to be experiencing OIH, carefully consider appropriately decreasing the dose of the current opioid analgesic or opioid rotation (safely switching the patient to a different opioid moiety).

Secondary respiratory depression after the operation has been observed. SUBLIMAZE should be administered only by health care providers specifically trained in the use of intravenous anaesthetics and management of the respiratory effects of potent opioids. Safety has not been demonstrated in children younger than 2 years of age.

Respiratory depression Respiratory depression may result with intravenous administration of SUBLIMAZE. The risk of respiratory depression is increased if SUBLIMAZE is administered in high dose or too rapidly. Respiratory depression is related to the dose and rate of administration and can be reversed by specific antagonists (naloxone), but additional doses of the latter may be necessary because the respiratory depression may last longer than the duration of the action of the opioid antagonist. Profound analgesia is accompanied by marked respiratory depression and diminished sensitivity to CO2 stimulation, which can persist or recur in the post-operative period. Respiratory depression secondary to chest wall rigidity has been reported in the post-operative period. Intraoperative hyperventilation may further alter post-operative response to CO2. Patients who have received SUBLIMAZE should remain under appropriate surveillance. Resuscitation equipment, oxygen and a narcotic antagonist should be readily available to manage apnoea. Care should be taken after infusion of large doses of SUBLIMAZE to ensure adequate spontaneous breathing has been established and maintained before the patient is released from the recovery area. Adequate facilities should be available for post-operative monitoring and ventilation of patients administered anaesthetic doses of SUBLIMAZE, in particular where doses above 10 u03bcg/kg are used. These facilities should be fully equipped to handle all degrees of respiratory depression. If respiratory depression does occur during anaesthesia, assisted or controlled ventilation will provide adequate respiratory support without reversing analgesia. Respiratory depression can be reversed by administration of the narcotic antagonist, naloxone, which may also reverse analgesia.

Risk from concomitant use of central nervous system (CNS) depressants, especially benzodiazepines or related medicines Concomitant use of SUBLIMAZE and CNS depressants, especially benzodiazepines or related medicines, in spontaneously breathing patients, may increase the risk of profound sedation, respiratory depression, coma and death. If a decision is made to administer SUBLIMAZE concomitantly with a CNS depressant, especially a benzodiazepine or a related medicine, the lowest effective dose of both medicines should be administered, for the shortest period of concomitant use. Patients should be carefully monitored for signs and symptoms of respiratory depression and profound 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 Induction of muscle rigidity (morphine-like effect) which may also involve the thoracic muscles, can occur, but can be ameliorated by the following measures: slow intravenous injection (ordinarily sufficient for lower doses), premedication with benzodiazepines and the use of muscle relaxants. Non-epileptic (myo)clonic movements can occur.

Precautions SUBLIMAZE should be given only in an environment where the airway can be controlled and by personnel who can control the airway.

Cardiac disease SUBLIMAZE has weak cholinergic activity and should be used with caution in patients with cardiac dysrhythmias. Bradycardia and possibly cardiac arrest with asystole can occur if the patient has received an insufficient amount of anticholinergic medicine, or when SUBLIMAZE is combined with non-vagolytic muscle relaxants. Bradycardia can be treated with atropine. Nitrous oxide has been reported to produce cardiovascular depression when given with SUBLIMAZE. In the supine position, therapeutic doses of opioids such as SUBLIMAZE have minimal effect on blood pressure or cardiac rate and rhythm. SUBLIMAZE may induce hypotension, especially in hypovolaemic patients. Appropriate measures to maintain a stable arterial pressure should be taken.

Special dosing conditions The use of rapid bolus injections of opioids should be avoided in patients with compromised intracerebral compliance; in such patients the transient decrease in the mean arterial pressure has occasionally been accompanied by a short-lasting reduction of the cerebral perfusion pressure. SUBLIMAZE can produce dependence of the morphine type and therefore has the potential for being abused. Patients on chronic opioid therapy or with a history of opioid abuse, may require higher doses. It is recommended to reduce the dosage in the elderly and in debilitated patients. SUBLIMAZE should be titrated with caution in patients with the following conditions:

• uncontrolled hypothyroidism
• pulmonary disease
• decreased respiratory reserve
• alcoholism
• adrenocortical insufficiency
• impaired renal or hepatic function
• prostatic hypertrophy
• shock.

Such patients also require prolonged post-operative monitoring.

Interaction with neuroleptics If SUBLIMAZE is administered with a neuroleptic medicine, such as droperidol, the user should be familiar with the special properties of each medicine, particularly the difference in duration of action. When such a combination is used, there is a higher incidence of hypotension, and fluids and other countermeasures should be available to manage hypotension. Neuroleptic medicines, such as droperidol, can induce extrapyramidal symptoms that can be controlled with antiparkinson medicines. Vital signs should be monitored routinely. When SUBLIMAZE is used with a tranquilliser such as droperidol, hypotension may occur. If it occurs, the possibility of hypovolaemia should also be considered and managed with appropriate parenteral fluid therapy. Repositioning the patient to improve venous return to the heart should be considered when operative conditions permit. Care should be exercised in moving and positioning of patients because of the possibility of orthostatic hypotension. If volume expansion with fluids plus other countermeasures do not correct hypotension, the administration of pressor medicines other than epinephrine (adrenaline) should be considered. Because of the alpha-adrenergic blocking action of droperidol, epinephrine (adrenaline) may paradoxically decrease the blood pressure in patients treated with droperidol. Elevated blood pressure, with or without pre-existing hypertension, has been reported following administration of SUBLIMAZE combined with droperidol. This might be due to alterations in sympathetic activity following large doses of droperidol; however, it is also frequently attributed to anaesthetic and surgical stimulation during light anaesthesia.

It is imperative to discontinue MAO inhibitors 2 weeks prior to any surgical or anaesthetic procedure.

Bile duct Due to the anticholinergic effects, administration of SUBLIMAZE may lead to increases of bile duct pressure, and spasms of the sphincter of Oddi might be observed.

Serotonin syndrome Caution is advised when SUBLIMAZE is coadministered with medicines that affect the serotonergic neurotransmitter systems. The development of a potentially life-threatening serotonin syndrome may occur with the concomitant use of serotonergic medicines, such as selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs), and with medicines which impair metabolism of serotonin (including monoamine oxidase inhibitors [MAOIs]). This may occur within the recommended dose (see sections 4.3 and 4.5). Serotonin syndrome may include mental status changes (e.g. agitation, hallucinations, coma), autonomic instability (e.g. tachycardia, labile blood pressure, hyperthermia), neuromuscular abnormalities (e.g. hyperreflexia, incoordination, rigidity), and/or gastrointestinal symptoms (e.g. nausea, vomiting, diarrhoea). If serotonin syndrome is suspected, rapid discontinuation of SUBLIMAZE should be considered (see sections 4.3 and 4.5).

When a tranquilliser is used with SUBLIMAZE, pulmonary arterial pressure may be decreased. This fact should be considered by those who conduct diagnostic and surgical procedures where interpretation of pulmonary arterial pressure measurements might determine final management of the patient. When high dose or anaesthetic doses of SUBLIMAZE are used, even relatively small dosages of diazepam may cause cardiovascular depression. The use of SUBLIMAZE should be avoided in patients with raised intracranial pressure. An antidiuretic effect and hypothermia may occur. SUBLIMAZE increases tone in smooth muscle, especially the sphincters of the gastrointestinal tract. Contact dermatitis has been reported, and pain and irritation may occur on injection. It should be used with caution in patients with inflammatory or obstructive bowel disease.

Myasthenia gravis In patients with myasthenia gravis, careful consideration should be applied in the use of certain anticholinergics and neuromuscular-blocking pharmaceutical medicines prior to, and during, the administration of a general anaesthetic regimen, which includes administering intravenous fentanyl, such as SUBLIMAZE.

Paediatric patients Techniques that involve analgesia in a spontaneously breathing child should only be used as part of an anaesthetic technique, or given as part of a sedation/analgesia technique, with experienced personnel in an environment that can manage sudden chest wall rigidity requiring intubation, or apnoea requiring airway support.

Sodium content SUBLIMAZE 2 mL: This medicine contains less than 1 mmol sodium (23 mg) per 2 mL ampoule, that is to say it is essentially sodium free. SUBLIMAZE 10 mL: This medicine contains 35,4 mg sodium per 10 mL ampoule, equivalent to 1,8 % of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Effect of other medicines on SUBLIMAZE Central nervous system (CNS) depressants Medicines such as barbiturates, benzodiazepines, tricyclic antidepressants, phenothiazines, hypnotics, opioid premedication, neuroleptics, general anaesthetics, gabapentinoids (gabapentin and pregabalin), halogenic gases and other non-selective central nervous system depressants (e.g. alcohol) may potentiate the respiratory depression of opioids. When patients have received such medicines, the dose of SUBLIMAZE required will be less than usual. Concomitant use with SUBLIMAZE in spontaneously breathing patients may increase the risk of respiratory depression, profound sedation, coma and death (see section 4.4).

Cytochrome P450 3A4 (CYP3A4) inhibitors SUBLIMAZE, a high clearance medicine, is rapidly and extensively metabolised mainly by CYP3A4. When SUBLIMAZE is used, the concomitant use of a CYP3A4 inhibitor may result in a decrease in fentanyl clearance. With single-dose SUBLIMAZE administration, the period of risk for respiratory depression may be prolonged, which may require special patient care and longer observation. Oral ritonavir (one of the most potent CYP3A4 inhibitors) reduced the clearance of a single IV SUBLIMAZE by two thirds; however, peak plasma concentrations after a single dose of IV SUBLIMAZE were not affected. With multiple-dose SUBLIMAZE administration, the risk for acute and/or delayed respiratory depression may be increased, and a dose reduction of SUBLIMAZE may be required to avoid accumulation of fentanyl.

When SUBLIMAZE is used in a single dose, the concomitant use of potent CYP3A4 inhibitors such as ritonavir requires special patient care and observation. Itraconazole (a potent CYP3A4 inhibitor) at 200 mg/day given orally for 4 days had no significant effect on the pharmacokinetics of a single IV SUBLIMAZE dose. Coadministration of fluconazole or voriconazole and SUBLIMAZE may result in an increased exposure to fentanyl. With continuous treatment, dose reduction of SUBLIMAZE may be required to avoid accumulation of SUBLIMAZE, which may increase the risk of prolonged or delayed respiratory depression. Although clinical data are lacking, in vitro data suggest that other potent CYP3A4 enzyme inhibitors (e.g. fluconazole, ketoconazole, erythromycin, diltiazem and cimetidine) may inhibit the metabolism of fentanyl.

Serotonergic medicines Coadministration of fentanyl with a serotonergic agent, such as a selective serotonin reuptake inhibitor (SSRI) or a serotonin norepinephrine reuptake inhibitor (SNRI), or a monoamine oxidase inhibitor (MAOI), may increase the risk of serotonin syndrome, a potentially life-threatening condition (see section 4.3).

Effect of SUBLIMAZE on other medicines Following the administration of SUBLIMAZE, the dose of other CNS-depressant medicines 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 post-operative period. Administration of a CNS depressant, such as a benzodiazepine or related medicines, during this period may disproportionally increase the risk for respiratory depression (see section 4.4).

The total plasma clearance and volume of distribution of etomidate is decreased by a factor 2 to 3 without a change in half-life when administered with SUBLIMAZE. Simultaneous administration of SUBLIMAZE and intravenous midazolam results in an increase in the terminal plasma half-life and a reduction in the plasma clearance of midazolam. When these medicines are coadministered with SUBLIMAZE their dose may need to be reduced. When SUBLIMAZE is used with a neuroleptic such as droperidol, chills and/or shivering, restlessness, post-operative hallucinatory episodes and extrapyramidal symptoms may be observed. Extrapyramidal symptoms may be controlled with antiparkinson medicines.

Pregnancy There are no adequate data from the use of SUBLIMAZE in pregnant women. SUBLIMAZE crosses the placenta. Studies in animals have shown some reproductive toxicity. The potential risk for humans is unknown. Administration during childbirth (including caesarean section) is not recommended prior to delivery because SUBLIMAZE crosses the placenta and because the neonatal respiratory centre is particularly sensitive to opiates. If SUBLIMAZE is nevertheless administered, assisted ventilation equipment must be immediately available for the mother and infant, if required. An antidote (opioid antagonist) for the newborn should always be at hand. Regular use during pregnancy may cause drug dependence in the fetus, leading to withdrawal symptoms in the neonate. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.

Administration during labour may depress respiration in the neonate and an antidote for the child should be readily available.

Breastfeeding SUBLIMAZE is excreted into human milk. Therefore, breastfeeding is not recommended for 24 hours following the administration of SUBLIMAZE.

Fertility There are no clinical data on the effects of fentanyl on male or female fertility. In animal studies, some tests on rats showed reduced female fertility at maternal toxic doses.

Patients should only drive or operate a machine if 24 hours have elapsed after administration of SUBLIMAZE.

Clinical trial data The safety of SUBLIMAZE was evaluated in 376 subjects who participated in 20 clinical trials evaluating SUBLIMAZE used as an anaesthetic. These subjects took at least one dose of SUBLIMAZE and provided safety data. Adverse drug reactions (ADRs), as identified by the investigator, reported for > 1 % of SUBLIMAZE-treated subjects in these studies are shown in Table 1.

Table 1: Adverse reactions reported by > 1 % of SUBLIMAZE-treated subjects

System organ class Adverse reaction Fentanyl IV (n = 376) % Nervous system disorders Sedation 5,3 Dizziness 3,7 Dyskinesia 3,2 Eye disorders Visual disturbances 1,9 Cardiac disorders Bradycardia 6,1 Tachycardia 4,0 Dysrhythmia 2,9 Vascular disorders Hypotension 8,8 Hypertension 8,8 Vein pain 2,9 Respiratory, thoracic and mediastinal disorders Apnoea 3,5 Bronchospasm 1,3 Laryngospasm 1,3 Gastrointestinal disorders Nausea 26,1 Vomiting 18,6 Skin and subcutaneous tissue disorders Allergic dermatitis 1,3 Musculoskeletal and connective tissue disorders Muscle rigidity (which may also involve the thoracic muscles) 10,4 Injury, poisoning and procedural complications Post-operative confusion 1,9 Neurological anaesthetic complications 1,1

Additional adverse reactions (ADR) that occurred in < 1 % of SUBLIMAZE-treated subjects in the 20 clinical trials are listed below in Table 2.

Table 2: Adverse reactions reported by < 1 % of SUBLIMAZE-treated subjects

System organ class Adverse reaction Psychiatric disorders Euphoric mood Nervous system disorders Headache Vascular disorders Blood pressure fluctuation Phlebitis Respiratory, thoracic and mediastinal disorders Hiccups Hyperventilation General disorders and administration site conditions Chills Hypothermia Injury, poisoning and procedural complications Post-operative agitation Procedural complication Airway complication of anaesthesia

Post-marketing data Adverse reactions first identified during post-marketing experience with SUBLIMAZE are included in Table 3. In each table, the frequencies are provided according to the following convention: Very common u2265 1/10 Common u2265 1/100 and < 1/10 Uncommon u2265 1/1 000 and < 1/100 Rare u2265 1/10 000 and < 1/1 000 Very rare < 1/10 000, including isolated reports. In Table 3, adverse reactions are presented by frequency category based on spontaneous reporting rates, while in Table 4, the same adverse reactions are presented by frequency category based on incidence in clinical trials or epidemiology studies, when known.

Table 3: Adverse reactions identified during post-marketing experience with SUBLIMAZE from spontaneous reporting

Immune system disorders Very rare: Hypersensitivity (such as anaphylactic shock, anaphylactic reaction, urticaria) Nervous system disorders Very rare: Convulsions, loss of consciousness, myoclonus Cardiac disorders Very rare: Cardiac arrest (see section 4.3.) Respiratory, thoracic and mediastinal disorders Very rare: Respiratory depression (see section 4.3.) Skin and subcutaneous tissue disorders Very rare: Pruritus

Table 4: Adverse reactions identified during post-marketing experience with SUBLIMAZE by frequency category estimated from clinical trials or epidemiologic studies

Immune system disorders Not known: Hypersensitivity (such as anaphylactic shock, anaphylactic reaction, urticaria) Psychiatric disorders Common: Agitation Uncommon: Euphoric mood Not known: Delirium, drug dependence (see section 4.4) Nervous system disorders Very common: Muscle rigidity (which may also involve the thoracic muscles) Common: Dyskinesia, sedation, dizziness Uncommon: Headache Not known: Convulsions, loss of consciousness, myoclonus Eye disorders Common: Visual disturbance Cardiac disorders Common: Bradycardia, tachycardia, arrhythmia Not known: Cardiac arrest (see section 4.3.) Vascular disorders Common: Hypotension, hypertension, venous pain Uncommon: Phlebitis, blood pressure fluctuation Respiratory, thoracic and mediastinal disorders Common: Laryngospasm, bronchospasm, apnoea Uncommon: Hyperventilation, hiccups Not known: Respiratory depression (see section 4.3.) Gastrointestinal disorders Very common Nausea, vomiting Uncommon Dysphagia Skin and subcutaneous tissue disorders Common: Allergic dermatitis Not known: Pruritus General disorders and administration site conditions Uncommon: Chills, hypothermia, drug withdrawal syndrome Not known: Drug withdrawal syndrome (see section 4.4) Injury, poisoning and procedural complications Common: Post-operative confusion Uncommon: Airway complication of anaesthesia When SUBLIMAZE is used with a neuroleptic such as droperidol, chills and/or shivering, restlessness, post-operative hallucinatory episodes, and extrapyramidal symptoms may be observed. Extrapyramidal symptoms may be controlled with antiparkinson medicines (see section 4.3).

Patients should be informed of the signs and symptoms of overdose and to ensure that family and friends are also aware of these signs and to seek immediate medical help if they occur.

Signs and symptoms An overdosage of fentanyl manifests itself as an extension of its pharmacological actions. Depending on the individual sensitivity, the clinical picture is determined primarily by the degree of respiratory depression, which varies from bradypnoea to apnoea. Toxic leukoencephalopathy has been observed with fentanyl overdose.

Treatment In the presence of hypoventilation or apnoea, oxygen should be administered, and lung ventilation should be assisted or controlled as indicated. A specific opioid antagonist, such as naloxone, should be used as indicated to control respiratory depression. This does not preclude the use of more immediate countermeasures. The respiratory depression may last longer than the effect of the antagonist; additional doses of the latter may therefore be required. If impaired breathing is associated with muscular rigidity, an intravenous neuromuscular agent might be required to facilitate assisted or controlled respiration. The patient should be carefully observed; body warmth and adequate fluid intake should be maintained. If hypotension is severe or if it persists, the possibility of hypovolaemia should be considered, and if present, it should be controlled with appropriate parenteral fluid administration.