INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION
SUBLIMAZE® 2 mL injection
SUBLIMAZE® 10 mL injection

© J-C 2000                ZAF.- 236880/V1 V

SCHEDULING STATUS:
Schedule 7

PROPRIETARY NAME
(and dosage form):

SUBLIMAZE^® 2 mL injection
SUBLIMAZE^® 10 mL injection

COMPOSITION:
Each mL contains 0,0785 mg (78,5 micrograms) fentanyl citrate equivalent to 0,05 mg (50 micrograms) fentanyl base. It is a sterile, preservative-free isotonic aqueous solution also containing sodium chloride and water for injection.

PHARMACOLOGICAL CLASSIFICATION:
A.2.7 Narcotic analgesics.

PHARMACOLOGICAL ACTION:
Pharmacodynamics
SUBLIMAZE is a narcotic analgesic. Fentanyl obtunds stress-related hormonal changes at higher doses. A dose of 100 micrograms (2,0 mL) is approximately equivalent in analgesic activity to 10 mg of morphine. The onset of action is rapid. However, the maximum analgesic and respiratory depressant effect may not be noted for several minutes. The usual duration of action of the analgesic effect is approximately 30 minutes after a single intravenous dose of up to 100 micrograms. Depth of analgesia is dose elated and can be adjusted to the pain level of the surgical procedure.
Fentanyl, depending upon the dose and speed of administration, can cause muscle rigidity as well as euphoria, miosis and bradycardia. Histamine release may occur.
All actions of fentanyl are reversible by a specific narcotic antagonist, such as naloxone.
Pharmacokinetics
After intravenous injection in normal volunteers, fentanyl plasma concentrations fall rapidly, with sequential distribution half-lives of about 1 minute and 18 minutes and a terminal elimination half-life of approximately 8 hours.
Fentanyl has a V_c (volume of distribution of the central compartment) of 13 L and a total V_dss (distribution volume at steady-state) of 339 L. The plasma-protein binding of fentanyl is about 84%.
Fentanyl is metabolised mainly in the liver. Fentanyl clearance is 574 mL/min. Approximately 75% of the administered dose is excreted within 24 hours and only 10 % of the dose is eliminated as unchanged drug.

INDICATIONS
SUBLIMAZE is indicated :

-	for use as a narcotic analgesic supplement in general or regional anaesthesia.
-	for administration with a neuroleptic such as droperidol as an anaesthetic premedication; for induction of anaesthesia; and as an adjunct in the maintenance of general and regional anaesthesia.
-	for use as an anaesthetic agent with oxygen in selected high-risk patients undergoing major surgery.

CONTRA-INDICATIONS
SUBLIMAZE is contra-indicated in patients with a known intolerance to fentanyl. It should not be administered to children 2 years of age or younger because safety in this age group has not yet been established.
SUBLIMAZE should not be administered to patients suffering from bronchial asthma or in heart failure secondary to chronic lung disease.
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 operation on the biliary tract.
Risks and potential benefits should be considered before this drug is administered to pregnant patients, as the safety of SUBLIMAZE in pregnancy has not been established.
Administration (I.M. or I.V.) during childbirth (including caesarean section) is not recommended because fentanyl crosses the placenta and because the foetal respiratory centre is particularly sensitive to opiates. If fentanyl is nevertheless administered, an antidote for the child should always be at hand.
Fentanyl may enter the maternal milk. Therefore, nursing is not recommended for 24 hours following the administration of this drug. The administration of narcotic analgesics is contra-indicated in patients taking mono-amine oxidase inhibitors or within 10 days of stopping such treatment, and in alcoholism.

WARNINGS

Secondary respiratory depression after the operation has been observed.

SUBLIMAZE should be administered only by persons specifically trained in the use of intravenous anaesthetics and management of the respiratory effects of potent opioids.
An opioid antagonist, resuscitative equipment and oxygen should be readily available.
Adequate facilities should be available for postoperative monitoring and ventilation of patients administered anaesthetic doses of SUBLIMAZE in particular where doses above 10 micrograms/kg are used. These facilities should be fully equipped to handle all degrees of respiratory depression.
SUBLIMAZE can produce drug 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.
If SUBLIMAZE is administered with droperidol, 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 and fluids and other countermeasures should be available to manage hypotension. Droperidol can induce extrapyramidal symptoms that can be controlled with anti-Parkinson agents.

DOSAGE AND DIRECTIONS FOR USE
The dosage of SUBLIMAZE should be individualised according to age, bodyweight, physical status, underlying pathological condition, use of other drugs and anaesthesia.
The initial dose should be reduced in the elderly and in debilitated patients. The effect of the initial dose should be taken into account in determining supplemental doses. To avoid bradycardia, it is recommended to administer a small intravenous dose of an anticholinergic just before induction. Droperidol may be given to prevent nausea and vomiting.

USE AS AN ANALGESIC SUPPLEMENT TO GENERAL ANAESTHESIA
Low dose: 2 micrograms/kg
Fentanyl in small doses is useful for minor, but painful surgery.
Moderate dose: 2 - 20 micrograms/kg
Where surgery becomes more complicated, a larger dose will be required. The duration of activity is dependent on dosage.
High dose: 20 - 50 micrograms/kg.
During major surgical procedures, in which surgery is longer and during which the stress response would be detrimental to the well-being of the patient, dosages of 20 - 50 micrograms/kg of fentanyl with nitrous oxide/oxygen have been shown to have an attenuating effect. When dosages in this range have been used during surgery, post-operative ventilation and observation are essential in view of the possibility of extended post-operative respiratory depression. Supplemental doses of 25 - 250 micrograms (0,5 - 5 mL) should be tailored to the needs of the patient and to the anticipated time till completion of the operation.
USE AS AN ANAESTHETIC AGENT
When attenuation of the response to surgical stress is especially important, doses of 50 -100 micrograms/kg may be administered with oxygen and a muscle relaxant. This technique provides anaesthesia without necessitating the use of additional anaesthetic agents. In certain cases, doses of up to 150 micrograms/kg may be required to produce this anaesthetic effect. Fentanyl has been used in this fashion for open heart surgery and certain other major surgical procedures for whom protection of the myocardium from excess oxygen demand is particularly indicated.
USE AS AN ADJUNCT TO LOCAL ANAESTHESIA
Intravenous: 0,07 -1,4 micrograms/kg.
USE AS A PRE-SURGICAL MEDICATION
Intramuscular: 0,07 -1,4 micrograms/kg, 30 to 60 minutes prior to surgery.
POST OPERATIVE USE
For use in the recovery room period. 0,07 - 1,4 micrograms/kg intramuscularly. May be repeated in one to two hours as needed.
Use in the elderly
The dose should be reduced in the elderly or debilitated patients.
Use in children
For the induction and maintenance in children aged 2 -12 years, a reduced dose as low as 2-3 micrograms/kg is recommended.
Compatibility
If desired, fentanyl may be mixed with sodium chloride or glucose intravenous infusions. Such dilutions are compatible with plastic infusion sets. These should be used within 24 hours of preparation.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS
The adverse reactions associated with SUBLIMAZE are respiratory depression, apnoea, muscular rigidity (which may involve the thoracic muscles), myoclonic movements, bradycardia, hypotension, nausea, vomiting and dizziness. Anorexia, constipation, confusion and sweating have also been reported. Micturition may be difficult and there may be ureteric or biliary spasm. Dry mouth, facial flushing, vertigo, palpitations, faintness, sedation, restlessness, changes of mood and miosis may also occur. These effects are more common in ambulant patients than those at rest in bed. Raised intracranial pressure occurs in some patients.
Other, less frequently reported adverse reactions are:
Laryngospasm
Allergic reactions (such as anaphylaxis, bronchospasm, pruritus, urticaria) and asystole have been reported.
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 anti-parkinson agents.
Vital signs should be monitored routinely.
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 postoperative period. Respiratory depression secondary to chest wall rigidity has been reported in the postoperative period. Intraoperative hyperventilation may further alter postoperative response to CO₂. Patients who have received SUBLIMAZE should remain under appropriate surveillance. Resuscitation equipment 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.
If respiratory depression does occur during anaesthesia, assisted or controlled respiration will provide adequate ventilation without reversing analgesia. Respiratory depression can be reversed by administration of the narcotic antagonist, naloxone, which, it should be noted, may also reverse analgesia.
Respiratory depression may result with intravenous administration of SUBLIMAZE if it is administered too rapidly.
SUBLIMAZE has weak cholinergic activity and should be used with caution in patients with cardiac arrhythmias. Bradycardia and possibly asystole 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 treated with atropine. Nitrous oxide has been reported to produce cardiovascular depression when given with higher doses of SUBLIMAZE.
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.
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 agents (other than adrenaline) should be considered. Because of the alpha-adrenergic blocking action of droperidol, adrenaline may paradoxically decrease the blood pressure in patient treated with droperidol.
In the supine position, therapeutic doses of opioids have no major 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.
Elevated blood pressure, with or without pre-existing hypertension, has been reported following administration of SUBLIMAZE combined with droperidol. This might be due to unexplained alterations in sympathetic activity following large doses; however, it is also frequently attributed to anaesthetic and surgical stimulation during light anaesthesia.
Induction of muscle rigidity which may also involve the thoracic muscles, can occur, but can be avoided 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.
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, or shock. Such patients also require prolonged post operative monitoring.
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 gastro-intestinal 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.
Care should be taken when SUBLIMAZE is given to patients with myasthenia gravis.
It is usually recommended to discontinue MAO-inhibitors 2 weeks prior to any surgical or anaesthetic procedure. However, several reports describe the uneventful use of fentanyl during surgical or anaesthetic procedures in patients on MAO-inhibitors.
Interactions
Agents such as barbiturates, benzodiazepines, tricyclic antidepressants, phenothiazines, hypnotics, opioid pre-medication, neuroleptic, halogenic gases and other non-selective central nervous system depressants (e.g. alcohol) may potentiate the respiratory depression of narcotics. When patients have received such agents, the dose of fentanyl required will be less than usual. Likewise, following the administration of fentanyl, the dose of other central nervous system depressant medicines should be reduced.
Fentanyl, a high clearance drug, is rapidly and extensively metabolised mainly by CYP3A4. Itraconazole (a potent CYP3A4 inhibitor) at 200 mg/day given orally for 4 days had no significant effect on the pharmacokinetics of IV fentanyl. Oral ritonavir (one of the most potent CYP3A4 inhibitors) reduced the clearance of IV fentanyl by two thirds; however peak plasma concentrations after a single dose of IV fentanyl were not affected. When fentanyl is used in a single dose, the concomitant use of potent CYP3A4 inhibitors such as ritonavir requires special patient care and observation. With continuous treatment, dose reduction of fentanyl may be required to avoid accumulation of fentanyl, which may increase the risk of prolonged or delayed respiratory depression.
Although clinical data are lacking, in-vitro data suggest that other potent cytochrome P450 3A4 enzyme inhibitors (e.g. fluconazole, ketoconazole, erythromycin, diltiazem and cimetidine) may inhibit the metabolism of fentanyl.
Effects on driving ability and use of machinery.
Patients should only drive or operate a machine if sufficient time has elapsed after the administration of fentanyl.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
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 bradyapnoea to apnoea.
Treatment
In the presence of hypoventilation or apnoea, oxygen should be administered and respiration should be assisted or controlled as indicated. A specific narcotic 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 depressed respiration 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.

IDENTIFICATION
A clear, colourless solution.

PRESENTATION
2 mL ampoules packed in cartons of 5 and 30 ampoules. 10 mL ampoules packed in cartons of 5 ampoules.

STORAGE DIRECTIONS
Store below 25°C. Protect from light.
KEEP OUT OF REACH OF CHILDREN.

REGISTRATION NUMBERS
2 mL: B/2.7/1014
10 mL: Q/2.7/34

NAME AND BUSINESS ADDRESS OF THE APPLICANT
JANSSEN PHARMACEUTICA (PTY) LTD.
(Reg. No. 80/11122/07)
15th Road
HALFWAY HOUSE
1685

DATE OF PUBLICATION OF THIS PACKAGE INSERT
2 mL: 19 April 1984.
10 mL: 21 January 1983.

JANSSEN-CILAG

Updated on this site: January 2001
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