SUBLIMAZE - summary of medicine characteristics

Sublimaze

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 1ml of solution contains 78.5 micrograms fentanyl citrate equivalent to 50 micrograms per ml fentanyl base.

Excipient(s) with known effect:

Sodium 3.5 mg/ml.

For Sublimaze 2 and 5 ml ampoules: This medicine contains less than 1 mmol sodium (23 mg) per 2 and 5 ml ampoule, that is to say essentially ‘sodium-free’.

For Sublimaze 10 ml ampoule: This medicinal product 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.

For a full list of excipients, see section 6.1.

Solution for injection.

4.1 Therapeutic indications

Sublimaze is an opioid analgesic used:

a. In low doses to provide analgesia during short surgical procedures.

b. In high doses as an analgesic/res­piratory depressant in patients requiring assisted

ventilation.

c. In combination with a neuroleptic in the technique of neuroleptanalgesia.

d. In the treatment of severe pain, such as the pain of myocardial infarction.

4.2 Posology and method of administration

Prior to starting treatment with opioids, a discussion should be held with patients to put in place a strategy for ending treatment with fentanyl citrate in order to minimise the risk of addiction and drug withdrawal syndrome (see section 4.4).

Route of administration

Intravenous administration either as a bolus or by infusion.

Intramuscular administration.

Fentanyl should be given only in an environment where the airway can be controlled and by personnel who can control the airway (see section 4.4 Special warnings and precautions).

To avoid bradycardia, it is recommended to administer a small intravenous dose of an anti-cholinergic just before anaesthetic induction.

It is recommended to wear gloves while opening the ampoule (see section 6.6 Special precautions for disposal and other handling).

Posology

Sublimaze, by the intravenous route, can be administered to both adults and children. The dose of Sublimaze should be individualised according to age, body weight, physical status, underlying pathological condition, use of other drugs and type of surgery and anaesthesia. Adults

The usual dosage regimen in adults is as follows:

Doses in excess of 200 mcg are for use in anaesthesia only. As a premedicant, 1–2 ml Sublimaze may be given intramuscularly 45 minutes before induction of anaesthesia.

After intravenous administration in unpremedicated adult patients, 2 ml Sublimaze may be expected to provide sufficient analgesia for 10–20 minutes in surgical procedures involving low pain intensity. 10 ml Sublimaze injected as a bolus gives analgesia lasting about one hour. The analgesia produced is sufficient for surgery involving moderately painful procedures. Giving a dose of 50 mcg/kg Sublimaze will provide intense analgesia for some four to six hours, for intensely stimulating surgery.

Sublimaze may also be given as an infusion. In ventilated patients, a loading dose of Sublimaze may be given as a fast infusion of approximately 1 mcg/kg/min for the first 10 minutes followed by an infusion of approximately 0.1 mcg/kg/min.

Alternatively the loading dose of Sublimaze may be given as a bolus. Infusion rates should be titrated to individual patient response; lower infusion rates may be adequate. Unless it is planned to ventilate post-operatively, the infusion should be terminated at about 40 minutes before the end of surgery.

Lower infusion rates, e.g. 0.05–0.08 mcg/kg/minute are necessary if spontaneous ventilation is to be maintained. Higher infusion rates (up to 3 mcg/kg/minute) have been used in cardiac surgery.

Sublimaze is chemically incompatible with the induction agents thiopentone and methohexitone because of wide differences in pH.

Paediatric population

Children aged 12 to 17 years old:

Follow adult dosage.

Children aged 2 to 11 years old:

The usual dosage regimen in children is as follows:

4.3 Contraindications

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

Respiratory depression, obstructive airways disease.

Concurrent administration with monoamine oxidase inhibitors, or within 2 weeks of their discontinuation.

4.4 Special warnings and precautions for use

Warnings:

Drug dependence, tolerance and potential for abuse

For all patients, prolonged use of this product 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 medications, including over-the-counter medicines and medicines obtained on-line, 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 this medicine 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.

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 fentanyl.

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 take this drug during pregnancy, there is a risk that their newborn infants will experience neonatal withdrawal syndrome.

Hyperalgesia

Hyperalgesia may be diagnosed if the patient on long-term opioid therapy presents with increased pain. This might be qualitatively and anatomically distinct from pain related to disease progression or to breakthrough pain resulting from development of opioid tolerance. Pain associated with hyperalgesia tends to be more diffuse than the pre-existing pain and less defined in quality. Symptoms of hyperalgesia may resolve with a reduction of opioid dose.

Following intravenous administration of fentanyl, a transient fall in blood pressure may occur, especially in hypovolaemic patients. Appropriate measures to maintain a stable arterial pressure should be taken.

Respiratory Depression

As with all potent opioids, profound analgesia is accompanied by marked respiratory depression, which may persist into or recur in the early postoperative period. Care should be taken after large doses or infusions of fentanyl to ensure that adequate spontaneous breathing has been established and maintained before discharging the patient from the recovery area.

Significant respiratory depression will occur following the administration of fentanyl in doses in excess of 200 mcg. This, and the other pharmacological effects of fentanyl, can be reversed by specific opioid antagonists, but additional doses may be necessary because the respiratory depression may last longer than the duration of action of the opioid antagonist.

Resuscitation equipment and opioid antagonists should be readily available.

Hyperventilation during anaesthesia may alter the patient’s response to CO2, thus affecting respiration postoperatively.

Administration in labour may cause respiratory depression in the new born infant.

Cardiac disease

Bradycardia, and possibly cardiac arrest, can occur if the patient has received an insufficient amount of anticholinergic, or when fentanyl is combined with non-vagolytic muscle relaxants. Bradycardia can be antagonised by atropine.

Muscle rigidity

Muscular rigidity (morphine-like effect) may occur.

Rigidity, which may also involve the thoracic muscles, can be avoided by the following measures:

– slow IV injection (usually sufficient for lower doses);

– premedication with benzodiazepines;

– use of muscle relaxants.

Non-epileptic (myo)clonic movements can occur.

Precautions:

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

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 transient reduction of the cerebral perfusion pressure.

It is recommended to reduce dosage in the elderly and debilitated patients.

In uncontrolled hypothyroidism, pulmonary disease, decreased respiratory reserve, alcoholism and hepatic or renal impairment the dosage should be titrated with care and prolonged post-operative monitoring is required.

Patients on chronic opioid therapy or with a history of opioid abuse may require higher doses.

Myasthenia gravis

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

Interaction with neuroleptics

If fentanyl is administered with a neuroleptic, the user should be familiar with the special properties of each drug, particularly the difference in duration of action. When such a combination is used, there is a higher incidence of hypotension. Neuroleptics can induce extrapyramidal symptoms that can be controlled with anti-Parkinson agents.

Bile duct

As with other opioids, due to the anticholinergic effects, administration of fentanyl may lead to increases of bile duct pressure and, in isolated cases, spasms of the Sphincter of Oddi might be observed.

Serotonin Syndrome

alfentanil required will be less than usual. Concomitant use with Rapifen Intensive Care in spontaneously breathing patients may increase the risk of respiratory depression, profound sedation, coma, and death (see warnings and precautions).

Effect of Rapifen Intensive Care on other drugs

Following the administration of Rapifen Intensive Care, 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 or related drugs, during this period may disproportionally increase the risk for respiratory depression (see warnings and precautions).

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 Rapifen Intensive Care.

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 Rapifen Intensive Care.

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 Rapifen Intensive Care 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

Fentanyl can cross the placenta in early pregnancy. Studies in animals have shown some reproductive toxicity (see Section 5.3, Preclinical safety data). Administration during childbirth (including Caesarean section) is not recommended because fentanyl crosses the placenta and may suppress spontaneous respiration in the newborn period. If fentanyl is administered, assisted ventilation equipment must be immediately available for the mother and infant if required. An opioid antagonist for the child must always be available.

Regular use during pregnancy may cause drug dependence in the foetus, 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.

Breast-feeding

Administration to nursing women is not recommended as fentanyl may be secreted in breast milk and may cause respiratory depression in the infant.The risk/benefit of breast-feeding following fentanyl administration should be considered.

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 (see section 5.3 Preclinical safety data).

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 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:

– The medicine has been prescribed to treat a medical or dental problem and

– You have taken it according to the instructions given by the prescriber and in the information provided with the medicine and

– It was not affecting your ability to drive safely.

4.8 Undesirable effects

The safety of fentanyl IV was evaluated in 376 subjects who participated in 20 clinical trials evaluating fentanyl IV as an anaesthetic. These subjects took at least 1 dose of fentanyl IV and provided safety data. Based on pooled safety data from these clinical trials, the most commonly reported (>5% incidence) Adverse Reactions were (with % incidence): nausea (26.1); vomiting (18.6); muscle rigidity (10.4); hypotension (8.8); hypertension (8.8); bradycardia (6.1); and sedation (5.3).

Including the above-mentioned adverse reactions, Table 1 displays adverse reactions that have been reported with the use of fentanyl IV from either clinical trials or postmarketing experience.

The displayed frequency categories use the following convention: 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).

Table 1: Adverse Reactions

When a neuroleptic is used with fentanyl, the following adverse reactions may be observed: chills and/or shivering, restlessness, postoperative hallucinatory episodes and extrapyramidal symptoms (see Section 4.4).

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 at: www.mhra.gov.uk/yellowcard.

4.9 Overdose

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. Symptoms and signs:

The manifestations of fentanyl overdosage are generally an extension of its pharmacological action. Depending on the individual sensitivity, the clinical picture is determined primarily by the degree of respiratory depression, which varies from bradypnoea to apnoea.

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.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Anaesthetic general, opioid anaesthetic, ATC code: N01AH01

Fentanyl is a synthetic opiate with a clinical potency of 50 to 100 times that of morphine. Its onset of action is rapid and its duration of action is short. In man, a single IV dose of 0.5–1 mg/70 kg body weight immediately produces a pronounced state of surgical analgesia, respiratory depression, bradycardia and other typical morphine-like effects. The duration of action of the peak effects is about 30 minutes. All potent morphine-like drugs produce relief from pain, ventilatory depression, emesis, constipation, physical dependence, certain vagal effects and varying degrees of sedation. Fentanyl, however, differs from morphine not only by its short duration of action but also by its lack of emetic effect and minimal hypotensive activity in animals.

5.2 Pharmacokinetic properties

Some pharmacokinetic parameters for fentanyl are as follows:

Urinary excretion = 8%

Bound in plasma = 80%

Clearance (ml/min/kg) = 13±2

Volume of distribution (litres/kg) = 4.0±0.4

Estimates of terminal half-life range from 141 to 853 minutes.

Renal impairment

Data obtained from a study administering IV fentanyl in patients undergoing renal transplantation suggest that the clearance of fentanyl may be reduced in this patient population. If patients with renal impairment receive fentanyl, they should be observed carefully for signs of fentanyl toxicity and the dose reduced if necessary (see section 4.2 Posology and method of administration).

Obese Patients

An increase in clearance of fentanyl is observed with increased body weight. In patients with a BMI >30, clearance of fentanyl increases by approximately 10% per 10 kg increase of the fat free mass (lean body mass).

5.3 Preclinical safety data

In vitro fentanyl showed, like other opioid analgesics, mutagenic effects in a mammalian cell culture assay, only at cytotoxic concentrations and along with metabolic activation. Fentanyl showed no evidence of mutagenicity when tested in in vivo rodent studies and bacterial assays. In a two-year rat bioassay, fentanyl was not carcinogenic.

Some tests on female rats showed reduced fertility as well as embryo mortality. These findings were related to maternal toxicity and not a direct effect of the drug on the developing embryo. There was no evidence of teratogenic effects.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sodium chloride Water for injections

6.2 Incompatibilities

The product is chemically incompatible with the induction agents thiopentone and methohexitone because of the wide differences in pH.

6.3 Shelf life

36 months.

6.4 Special precautions for storage

Protect from light.

Do not store above 30°C.

Keep container in the outer carton.

6.5 Nature and contents of container

Colourless glass ampoules (Ph.Eur, USP Type I).

Pack size: packs of 10 and 50* of 2 ml and 5 ml* ampoules; packs of 5 and 10* of 10ml ampoules.

* not marketed

6.6 Special precautions for disposal

Wear gloves while opening ampoule.

Accidental dermal exposure should be treated by rinsing the affected area with water. Avoid usage of soap, alcohol, and other cleaning materials that may cause chemical or physical abrasions to the skin.

Store as a CD.

7 MARKETING AUTHORISATION HOLDER

Piramal Critical Care Limited

Suite 4, Ground Floor

Heathrow Boulevard – East Wing,

280 Bath Road,

West Drayton

UB7 0DQ

United Kingdom

Tel : 00441670562400

8 MARKETING AUTHORISATION NUMBER(S)

PL 37071/0004

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

26 February 1980