INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION

Logo PROVIVE 1% (Emulsion for Injection)

SCHEDULING STATUS:
S5

PROPRIETARY NAME
(and dosage form)

PROVIVE 1% (Emulsion for Injection)

COMPOSITION
1 mL of emulsion for injection contains 10 mg
propofol.

PHARMACOLOGICAL CLASSIFICATION
A.2.1 Anaesthetics.

PHARMACOLOGICAL ACTION
Pharmacodynamics:
Propofol (2,6-di-isopropylphenol) is a short-acting sedative hypnotic with a rapid onset of action of approximately 30 seconds. The mechanism of action is poorly understood. Falls in mean arterial blood pressure and slight changes in heart rate are observed when propofol is administered for induction and maintenance of anaesthesia. Bradycardia and hypotension reported during induction of anaesthesia may be caused by a cerebral vagotonic effect or inhibition of sympathetic activity. Ventilatory depression can occur following administration of propofol. Propofol reduces cerebral blood flow, intracranial pressure and cerebral metabolism. Recovery from anaesthesia is usually rapid and clear-headed. Propofol has an anti-emetic effect. Propofol, at the concentrations likely to occur clinically, does not inhibit the synthesis of adrenocortical hormones.
Pharmacokinetics: Propofol is 98% bound to plasma proteins. The decline in propofol concentrations following a bolus dose, or following the termination of an infusion, can be described by a three compartment open model. The first phase is characterized by a rapid distribution (half-life 2 to 4 minutes) followed by rapid elimination (half-life 30 to 60 minutes) and a slower final phase, representative of redistribution of propofol from poorly perfused tissue. Propofol is extensively distributed and rapidly cleared form the body (total body clearance 1,5 to 2 litres/minute). Clearance occurs by metabolic processes, mainly in the liver, to form inactive conjugates of propofol and its corresponding quinol, which are excreted in the urine. The pharmacokinetics is linear over the recommended range of infusion rates of propofol. Under the usual maintenance regimens, significant accumulation of propofol does not occur. Less than 0,3% of the administered dose is excreted unchanged in urine.

INDICATIONS
The induction and maintenance of general anaesthesia, as part of a balanced anaesthetic technique in patients over the age of three years.
Sedation of ventilated adult patients receiving intensive care, for a period of up to 72 hours.

CONTRA-INDICATIONS
Known hypersensitivity to propofol. Appropriate care should be applied in patients with disorders of fat metabolism, patients predisposed to fat embolism and in other conditions where lipid emulsions must be used cautiously. Fat metabolism may be disturbed in conditions such as renal insufficiency, uncompensated diabetes mellitus, certain forms of liver insufficiency, metabolic disorders, severe trauma including long-bone and multiple fractures, and sepsis. PROVIVE 1% is not recommended in neonates and premature infants. PROVIVE 1% must not be used for sedation of patients less than 16 years of age in the Intensive Care Unit. Sedation of children of all ages with croup or epiglottitis receiving intensive care.

WARNINGS
Use with caution in patients with an allergy to egg or soya protein.
Respiration will be depressed and must be monitored to ensure adequate gas exchange. Special care should be exercised when used with other respiratory depressants.
A generalised systemic reaction, which may be anaphylactic in nature (including angioedema, bronchospasm, erythema and hypotension), may occur following PROVIVE 1% administration.
When PROVIVE 1% is administered to an epileptic patient, there may be a risk of convulsion.
In debilitated patients, elderly patients, patients with cardiac, respiratory, renal or hepatic impairment or in hypovolaemic or epileptic patients PROVIVE 1% should be administered with caution and a reduced administration rate. Cardiac, circulatory or pulmonary insufficiency and hypovolaemia should be compensated before administration of PROVIVE 1%. In the elderly, debilitated or ASA III or IV patients, rapid single or repeated bolus administration should not be used in order to minimise undesirable cardiorespiratory side effects.

INTERACTIONS
Lower doses may be required when general anaesthesia is carried out in conjunction with regional anaesthesia.
Concomitant use of benzodiazepines, parasympatholytic agents or inhalational anaesthetics has been reported to prolong the anaesthesia and to reduce the respiratory rate.
After supplementary pre-medication of opiates, apnoea may occur with increasing frequency and over a prolonged period. Bradycardia and cardiac arrest may occur after treatment with suxamethonium or neostigmine.
When PROVIVE 1% is combined with centrally depressant drugs administered parenterally, severe respiratory and cardiovascular depression may occur. After administration of fentanyl, the blood level of propofol may be temporarily increased. Leucoencephalopathy has been reported with administration of lipid emulsions such as propofol in patients receiving cyclosporine.

PREGNANCY AND LACTATION
Pregnancy:
PROVIVE 1% should not be used in pregnancy. PROVIVE 1% crosses the placenta and may be associated with neonatal depression.
It should not be used for obstetric anaesthesia.
PROVIVE 1% has been used, however, during termination of pregnancy in the first trimester.
Lactation: In mothers who are breast-feeding, safety to the neonate has not been established.

DOSAGE AND DIRECTIONS FOR USE
Supplementary analgesic agents are required in addition to PROVIVE 1%, where analgesia is required. PROVIVE 1% has been used in association with spinal and epidural anaesthesia and with commonly used premedicants, neuromuscular blocking agents, inhalation and analgesic agents; no pharmacological incompatibility has been encountered. Dosage adjustment may be necessary when used together with the above agents, particularly the narcotics (e.g. morphine, pethidine and fentanyl), combination of opioids and sedatives (e.g. benzodiazepines, barbiturates, droperidol, etc.), supplementary analgesic agents (e.g. nitrous oxide or opioids) and the potent inhalational agents (e.g. isoflurane, enflurane and halothane).
Where general anaesthesia with PROVIVE 1% is used simultaneously with a regional anaesthetic technique, lower doses of PROVIVE 1% may be required.
When PROVIVE 1% is used undiluted to maintain anaesthesia, it is recommended that equipment such as drop counters, syringe pumps or volumetric infusion pumps should always be used to control infusion rates.
PROVIVE 1% can be used for infusion undiluted in glass infusion bottles or from plastic syringes.
PROVIVE 1% can be diluted with 5% dextrose intravenous infusion only, in PVC infusion bags or glass infusion bottles. Dilutions, which must not exceed 1 in 5 (2 mg propofol per mL), should be prepared aseptically immediately before administration and must be used within 6 hours of preparation. The dilution may be used with a variety of infusion control techniques, but a giving set alone will not avoid the risk of accidental uncontrolled infusion of large volume or diluted PROVIVE 1%. A burette, drop counter or volumetric pump must be included in the infusion line. The risk of uncontrolled infusion must be taken into account when deciding the maximum amount of PROVIVE 1% in the burette.
It is recommended that, when using diluted PROVIVE 1%, the volume of 5% dextrose removed from the infusion bag during the dilution process is totally replaced in volume by PROVIVE 1% emulsion.
PROVIVE 1% may be administered via a Y-piece close to the injection site, into intravenous infusion of dextrose 5% or sodium chloride 0,9%.
PROVIVE 1% may be premixed with alfentanil injection. In order to reduce pain on initial injection, that part of the PROVIVE 1% used for induction may be mixed with lignocaine injection in the ratio of 20 parts PROVIVE 1% with up to 1 part of 1% lignocaine injection immediately prior to administration.
It is recommended that blood lipid levels be monitored routinely should PROVIVE 1% be administered to patients thought to be at particular risk of fat overload. Administration of PROVIVE 1% should be adjusted appropriately if the monitoring indicates that fat is being inadequately cleared from the body. If the patient is receiving other intravenous lipid concurrently, a reduction in quantity should be made in order to take account of the amount of lipid infused as part of the PROVIVE 1% formulation; 1,0 mL of PROVIVE 1% contains 0,1 g of fat.
Patients with hypovolaemia should have fluid-volume deficits corrected prior to administration of PROVIVE 1%.
Incompatibilities: PROVIVE 1% should not be mixed prior to administration with injections or infusion fluids other than 5% dextrose or lignocaine injection or alfentanil injection (see above). The neuromuscular blocking agents atracurium and mivacurium should not be given through the same intravenous line as PROVIVE 1% without prior flushing.
In-use Precautions
General:
Containers should be shaken before use. PROVIVE 1% should be inspected for particulate matter and discolouration before administration. Do not use if there is evidence of separation of the phases of the emulsion. PROVIVE 1% contains no anti-microbial preservatives and the vehicle supports growth of micro-organisms.
When PROVIVE 1% is to be aspirated it must be drawn aseptically into a sterile syringe or giving set immediately after opening the ampoule or breaking the vial seal. Administration must commence without delay. Asepsis must be maintained for both PROVIVE 1% and infusion equipment throughout the infusion period.
Any infusion fluids added to the PROVIVE 1% line must be administered close to the cannula site.
PROVIVE 1% must not be administered via a microbiological filter.
Any container or syringe containing PROVIVE 1% is for single use in a single patient only.
General Anaesthesia: In accordance with established guidelines for other lipid emulsions a single infusion of PROVIVE 1% must not exceed 6 hours. The syringe or giving set and any unused portion of PROVIVE 1% or solution containing PROVIVE 1% must be discarded at the end of the surgical procedure, or at 6 hours, whichever is the sooner, and replaced as appropriate.
Intensive Care Sedation: Administration should commence promptly and must be completed within 12 hours after the vial has been spiked. The tubing and any unused portion of PROVIVE 1% must be discarded after 12 hours. If PROVIVE 1% is transferred to a syringe or other container prior to administration, the handling procedures for General Anaesthesia (above) should be followed and the product should be discarded and administration lines changed after 6 hours.
DOSAGE IN ADULTS (including elderly)
Induction of General Anaesthesia:
In unpremedicated and premedicated patients: Most adult patients aged less than 55 years are likely to require 1,5 to 2,5 mg/kg (0,15 to 0,25 mL/kg) of PROVIVE 1%, (approximately 4 mL every 10 seconds in an average healthy adult) by slow bolus injection or infusion titrated against the response of the patient until clinical signs show onset of anaesthesia. The total dose required can be reduced by lower rates of administration (20 to 50 mg/min [2 to 5 mL/min]). Over the age of 55 years the requirements will generally be less. In patients of ASA Grades III and IV, lower rates of administration should be used (approximately 20 mg (2 mL) every 10 seconds).
Maintenance of General Anaesthesia: Anaesthesia can be maintained by administering PROVIVE 1% either by continuous infusion or by repeat bolus injections to prevent the clinical signs of light anaesthesia.
Infusion: The average rate of administration varies between patients, but rates in the region of 4 to 12 mg/kg/hr (0,4 to 1,2 mL/kg/hr) usually maintain satisfactory anaesthesia. Slightly higher rates of administration may be required for 10 to 20 minutes after induction of anaesthesia.
Repeat Bolus Injections: As a guide, increments of 25 mg (2,5 mL) to 50 mg (5,0 mL) may be used.
Sedation during Intensive Care: To provide sedation for ventilated adult patients undergoing intensive care, it is recommended that PROVIVE 1% be given by continuous infusion, for up to 72 hours. Adjust infusion rate according to the depth of sedation required. Rates of 0,3 to 4,0 mg/kg/hr should achieve satisfactory sedation. Rates above 4,0 mg/kg/hr are not recommended.

DOSAGE IN CHILDREN
PROVIVE 1% is not recommended for use in children less than 3 years of age.
Induction of Anaesthesia: When used to induce anaesthesia, it is recommended that PROVIVE 1% should be titrated slowly until the clinical signs show the onset of anaesthesia.
The dose should be adjusted for age and/or body weight.
Most children over 8 years of age are likely to require approximately 2,5 mg propofol/kg body weight for induction of anaesthesia. Under this age the dose requirement may be higher. The initial dose should be 3 mg propofol/kg body weight. If necessary, additional doses in steps of 1 mg propofol/kg body weight can be administered. Due to lack of clinical experience, lower dosages are recommended for young patients at increased risk (ASA Grades III and IV).
Maintenance of General Anaesthesia: Administer PROVIVE 1% by infusion or repeat bolus injection to maintain the depth of anaesthesia required. The required rate of administration varies considerably between patients. 9 to 15 mg/kg/hr (0,9 to 1,5 mL/kg/hr) usually achieves satisfactory anaesthesia.
Sedation during Intensive Care: PROVIVE 1% must not be used for sedation in children under 16 years of age as safety and efficacy have not been demonstrated. Serious adverse events (including fatalities) have been observed from spontaneous reports of unlicensed use and these events were seen most often in children with respiratory tract infections, given doses in excess of those recommended for adults.

SIDE EFFECTS AND SPECIAL PRECAUTIONS
Side-effects
Very common: (>1/10)
Common: (>1/100 <1/10)
Uncommon: (>1/1000 <1/100)
Rare: (>1/10 000 <1/1000)
Very Rare: (<1/10 000)
General disorders and administration site conditions
Very common: Injection site: local pain that can be minimized by co-administration of lignocaine and by the use of the larger veins of forearm and antecubital fossa.
After co-administration of lignocaine the following undesirable effects may occur
Rare: Giddiness, vomiting, drowsiness, convulsions, bradycardia, cardiac arrhythmia and shock, post-operative fever.
Very Rare: Rhabdomyolysis, metabolic acidosis, hyperkaleamia and cardiac failure sometimes with fatal outcome have been observed with doses exceeding 4 mg/kg/hr.
Cardiac disorders
Common: Tachycardia.
Rare: Premature ventricular contractions, premature atrial contractions, abnormal ECG, ST segment depression, thrombosis.
Vascular disorders
Common: Hypotension, flushing, hypertension.
Uncommon: Marked hypotension may require use of intravenous fluids and a reduction in the rate of administration of PROVIVE 1%. Account should be taken of the possibility of severe drop in blood pressure in patients with impairment coronary or cerebral perfusion or those with hypovolaemia.
Rare: Syncope, phlebitis.
Nervous system disorders
Common: Involuntary movements, excitation.
Rare: Headache, shivering or sensations of cold during recovery period. Epileptiform movements including convulsions and opisthotonos.
Gastro-intestinal disorders
Rare: Nausea and vomiting during recovery period.
Endocrine disorders
Very Rare: Pancreatitis.
Respiratory, thoracic and mediastinal disorders
Common: Apnoea, hiccup, coughing.
Very Rare: Pulmonary oedema.
Psychiatric disorders
Rare: Euphoria during recovery.
Reproductive system disorder
Rare: Sexual disinhibition during recovery.
Renal and urinary disorders
Rare: Discolouration of urine following prolonged administration.
Skin and subcutaneous tissue disorders
Very Rare: Tissue reactions experienced on accidental extravasation.
Immune system disorders
Rare: Clinical features of anaphylaxis, which may include Quincke’s oedema, bronchospasm, erythema and hypotension.
Special precautions
Appropriate care should be applied in patients with disorders of fat metabolism, patients predisposed to fat embolism and in other conditions where lipid emulsions must be used cautiously. Fat metabolism may be disturbed in conditions such as renal insufficiency, uncompensated diabetes, certain forms of liver insufficiency, metabolic disorders, severe trauma including long-bone and multiple fractures and sepsis.
PROVIVE 1% should not be administered in patients with advanced cardiac failure or other severe myocardial diseases except with extreme caution and intensive monitoring.
Due to a higher dosage in obese patients, the risk of haemodynamic effects on the cardiovascular system should be taken into consideration. Special care should be recognized in patients with a high intracranial pressure and a low mean arterial pressure, as there is a risk of a significant decrease of the intracerebral perfusion pressure.
Use of PROVIVE 1% is not recommended with electroconvulsive therapy.
PROVIVE 1% should be given by those trained in anaesthesia (or, where appropriate, doctors trained in the care of patients in intensive care). Patients should be constantly monitored and facilities for maintenance of a patent airway, artificial ventilation and oxygen enrichment and other resuscitative facilities should be readily available at all times.
PROVIVE 1% should not be administered by the person conducting the diagnostic or surgical procedure. An adequate period is needed prior to discharge of the patient to ensure full recovery after general anaesthesia.
The pharmacokinetics of propofol may be prolonged in people with chronic hepatic cirrhosis or chronic renal impairment. Recovery times may double as a result. The effects of acute hepatic or renal failure on the pharmacokinetics of propofol have not been studied.
Propofol lacks vagolytic activity and has been associated with reports of bradycardia, occasionally profound and also asystole. The intravenous administration of an anticholinergic agent before induction, or during maintenance of anaesthesia should be considered, especially in situations where vagal tone is likely to predominate or when PROVIVE 1% is used in conjunction with other agents likely to cause a bradycardia.
Patients should be advised that performance at skilled tasks, such as driving and operating machinery, might be impaired for some time after general anaesthesia. The patient should not be allowed to go home unaccompanied, and should be instructed to avoid consumption of alcohol.
Lipids should be monitored in ICU treatment after 3 days.
PROVIVE 1% contains soybean oil, which may cause severe allergic reaction in rare cases.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
See “SIDE-EFFECTS AND SPECIAL PRECAUTIONS”. Accidental overdosage is likely to cause cardiorespiratory depression. Respiratory depression should be treated by artificial ventilation with oxygen. Cardiovascular depression would require lowering of the patient’s head, and, if severe, use of plasma expanders and pressor agents.

IDENTIFICATION
Milky white homogenous emulsion.

PRESENTATION
10 mL, 20 mL, 50 mL clear colourless glass vials and 100 mL clear colourless glass bottle with a grey rubber closure, aluminium seal and flip-off cap.

STORAGE INSTRUCTIONS
Store below 25ºC. Protect from light.
Do not refrigerate or freeze.
Discard any unused portions. Not multiple dose vials.
KEEP OUT OF REACH OF CHILDREN.

REGISTRATION NUMBER
39/2.1/0447

Version 4 October 2005

NAME AND BUSINESS ADDRESS OF THE HOLDER OF THE CERTIFICATE OF REGISTRATION
Pharmaplan (Pty) Ltd.
106 16th Road
Midrand

DATE OF PUBLICATION OF THE PACKAGE INSERT
4 October 2005

New addition to this site: May 2014
Source
: Pharmaceutical Industry

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