DIPRIVAN 10 MG / ML (1%) EMULSION FOR INJECTION OR INFUSION - patient leaflet, side effects, dosage

5. How to store Diprivan

Other possible side effects

The following side effects have been seen when Diprivan is used in intensive care at higher doses than recommended.

Very rare (may affect up to1 in 10,000 people)

• Heart failure.
• Inflamed pancreas (pancreatitis) which causes severe stomach pain.
• Too much acid in your blood. This may make you breathe more quickly.
• Increased amount of potassium in your blood.
• High blood level of a type of fat called lipids.
• Abnormal heart beat.
• Enlargement of the liver.
• Kidney failure.

The following side effects have been seen in children in intensive care when Diprivan has been stopped suddenly.

Common (may affect up to 1 in 10 people)

• ‘Withdrawal symptoms’. These include
• Keep this medicine out of the sight and reach of children.
• The doctor and hospital pharmacist are responsible for storing, using and disposing of Diprivan correctly.
• Store Diprivan between 2°C and 25°C. Do not freeze.
• Do not use Diprivan after the expiry date which is stated on the carton after EXP.

6. Contents of the pack and other information

What Diprivan looks like and contents of the pack

Diprivan 1% is a milky, white liquid. It comes in glass ampoules of 20 ml, glass vials of 50 ml or 100 ml, or pre-filled syringes of 20 ml or 50 ml.

Marketing Authorisation Holder and Manufacturer

The Marketing Authorisation for Diprivan 1% is held by

Aspen Pharma Trading Limited, 3016 Lake Drive, Citywest Business Campus, Dublin 24, Ireland Tel: +44 (0)1 748 828 391

Diprivan 1% is manufactured by Corden Pharma S.P.A, Viale dell’ Industria 3, 20867 Caponago, I­taly.

To listen to or request a copy of this leaflet in Braille, large print or audio please call, free of charge: 0800 198 5000 (UK only) Please be ready to give the following information: Product name

Diprivan 1%

Reference number 39699/0074

This is a service provided by the Royal National Institute of the Blind.

This leaflet was last revised in June 2020.

Trademarks are owned by or licensed to the Aspen Group of companies.

© 2020 Aspen Group of companies or its licensor. All rights reserved.

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Q

Target Controlled Infusion – Administration of Diprivan 1% by a Diprifusor TCI System in adults

Administration of Diprivan 1% by a Diprifusor TCI system is restricted to induction and maintenance of general anaesthesia in adults. It is not recommended for use in ICU sedation or sedation for surgical and diagnostic procedures, or in children.

Diprivan 1% may be administered by TCI only with a Diprifusor TCI system incorporating Diprifusor TCI software. Such systems will operate only on recognition of electronically tagged pre-filled syringes containing Diprivan 1% or 2% Injection. The Diprifusor TCI system will automatically adjust the infusion rate for the concentration of Diprivan recognised. Users must be familiar with the infusion pump users’ manual, and with the administration of Diprivan 1% by TCI and with the correct use of the syringe identification system.

The Diprifusor allows the anaesthetist to achieve and control a desired speed of induction and depth of anaesthesia by setting and adjusting target (predicted) blood concentrations of propofol. An alternative effect-site mode of administration may be accessible on some Diprifusors, but its safety and efficacy have not yet been established.

The Diprifusor TCI system assumes that the initial blood propofol concentration in the patient is zero. Therefore, in patients who have received prior propofol, there may be a need to select a lower initial target concentration when commencing Diprifusor TCI. Similarly, the immediate recommencement of Diprifusor TCI is not recommended if the pump has been switched off.

Guidance on propofol target concentrations is given below. In view of interpatient variability in propofol pharmacokinetics and pharmacodynamics, in both premedicated and unpremedicated patients the target propofol concentration should be titrated against the response of the patient in order to achieve the depth of anaesthesia required.

Induction and maintenance of general anaesthesia In adult patients under 55 years of age anaesthesia can usually be induced with target propofol concentrations in the region of 4–8 microgram/ml.

An initial target of 4 microgram/ml is recommended in premedicated patients and in unpremedicated patients an initial target of 6 microgram/ml is advised. Induction time with these targets is generally within the range of 60–120 seconds. Higher targets will allow more rapid induction of anaesthesia but may be associated with more pronounced haemodynamic and respiratory depression.

A lower initial target concentration should be used in patients over the age of about 55 years and in patients of ASA grades 3 and 4. The target concentration can then be increased in steps of 0.5–1 microgram/ml at intervals of 1 minute to achieve a gradual induction of anaesthesia. Supplementary analgesia will generally be required and the extent to which target concentrations for maintenance of anaesthesia can be reduced will be influenced by the amount of concomitant analgesia administered. Target propofol concentrations in the region of 3–6 microgram/ml usually maintain satisfactory anaesthesia.

The predicted propofol concentration on waking is generally in the region of 1–2 microgram/ml and will be influenced by the amount of analgesia given during maintenance.

Dilution and co-administration of Diprivan 1% with other drugs or infusion fluids (see also Additional precautions section)

Co-administration Technique	Additive or Diluent	Preparation	Precautions
Pre-mixing	Dextrose 5% intravenous infusion	Mix 1 part of Diprivan 1% with up to 4 parts of dextrose 5% intravenous infusion in either PVC infusion bags or glass infusion bottles. When diluted in PVC bags it is recommended that the bag should be full and that the dilution be prepared by withdrawing a volume of infusion fluid and replacing it with an equal volume of Diprivan 1%	Prepare aseptically immediately before administration. The mixture is stable for up to 6 hours
	Lidocaine hydrochloride injection (0.5% or 1% without preservatives)	Mix 20 parts of Diprivan 1% with up to 1 part of either 0.5% or 1% lidocaine hydrochloride injection	Prepare mixture aseptically immediately prior to administration. Use for induction only
	Alfentanil injection (500 microgram/ ml)	Mix Diprivan 1% with alfentanil injection in a ratio of 20:1 to 50:1 v/v	Prepare mixture aseptically; use within 6 hours of preparation
Co-administration via a Y-piece connector	Dextrose 5% intravenous infusion	Co-administer via a Y-piece connector	Place the Y-piece connector close to the injection site
	Sodium chloride 0.9% intravenous infusion	As above	As above
	Dextrose 4% with sodium chloride 0.18% intravenous infusion	As above	As above

• 4.3 Contraindi­cations

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

Diprivan 1% contains soya oil and should not be used in patients who are hypersensitive to peanut or soya.

Diprivan 1% must not be used in patients of 16 years of age or younger for sedation in intensive care (see section 4.4).

• 4.4 Special warnings and precautions for use

Diprivan 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 patient airway, artificial ventilation, oxygen enrichment and other resuscitative facilities should be readily available at all times. Diprivan 1% should not be administered by the person conducting the diagnostic or surgical procedure.

Abuse of, and dependence on Diprivan 1%, predominantly by health care professionals, have been reported. As with other general anaesthetics, the administration of Diprivan 1% without airway care may result in fatal respiratory complications.

When Diprivan 1% is administered for conscious sedation for surgical and diagnostic procedures, patients should be continually monitored for early signs of hypotension, airway obstruction and oxygen desaturation.

As with other sedative agents, when Diprivan 1% is used for sedation during operative procedures, involuntary patient movements may occur. During procedures requiring immobility these movements may be hazardous to the operative site.

An adequate period is needed prior to discharge of the patient to ensure full recovery after use of Diprivan 1%. Very rarely the use of Diprivan 1% may be associated with the development of a period of post-operative unconsciousness, which may be accompanied by an increase in muscle tone. This may or may not be preceded by a period of wakefulness. Although recovery is spontaneous, appropriate care of an unconscious patient should be administered.

Diprivan 1% induced impairment is not generally detectable beyond 12 hours. The effects of Diprivan 1%, the procedure, concomitant medications, the age and the condition of the patient should be considered when advising patients on:

• The advisability of being accompanied on leaving the place of administration
• The timing of recommencement of skilled or hazardous tasks such as driving
• The use of other agents that may sedate (Eg, benzodiazepines, opiates, alcohol.)

As with other intravenous anaesthetic agents, caution should be applied in patients with cardiac, respiratory, renal or hepatic impairment or in hypovolaemic or debilitated patients. Diprivan 1% clearance is blood flow dependent, therefore, concomitant medication that reduces cardiac output will also reduce Diprivan 1% clearance.

Diprivan 1% 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 Diprivan 1% is used in conjunction with other agents likely to cause a bradycardia.

As with other intravenous anaesthetic and sedative agents, patients should be instructed to avoid alcohol before and for at least 8 hours after administration of Diprivan 1%.

During bolus administration for operative procedures, extreme caution should be exercised in patients with acute pulmonary insufficiency or respiratory depression.

Concomitant use of central nervous system depressants eg., alcohol, general anaesthetics, narcotic analgesics, will result in accentuation of their sedative effects. When Diprivan 1% is combined with centrally depressant drugs administered parenterally, severe respiratory and cardiovascular depression may occur. It is recommended that Diprivan 1% is administered following the analgesic and the dose should be carefully titrated to the patient’s response (see Section 4.5).

During induction of anaesthesia, hypotension and transient apnoea may occur depending on the dose and use of premedicants and other agents.

Occasionally, hypotension may require use of intravenous fluids and reduction of the rate of administration of Diprivan 1% during the period of anaesthetic maintenance.

When Diprivan 1% is administered to an epileptic patient, there may be a risk of convulsion.

Appropriate care should be applied in patients with disorders of fat metabolism and in other conditions where lipid emulsions must be used cautiously (see section 4.2). Use is not recommended with electroconvulsive treatment.

As with other anaesthetics, sexual disinhibition may occur during recovery.

The benefits and risks of the proposed procedure should be considered prior to proceeding with repeated or prolonged use (>3 hours) of propofol in young children (< 3 years) and in pregnant women as there have been reports of neurotoxicity in preclinical studies, see Section 5.3.

Paediatric population

The use of Diprivan is not recommended in newborn infants as this patient population has not been fully investigated. Pharmacokinetic data (see section 5.2) indicate that clearance is considerably reduced in neonates and has a very high inter-individual variability. Relative overdose could occur on administering doses recommended for older children and result in severe cardiovascular depression.

Diprivan 2% is not recommended for use in children < 3 years of age due to difficulty in titrating small volumes.-Propofol must not be used in patients of 16 years of age or younger for sedation for intensive care as the safety and efficacy of propofol for sedation in this age group have not been demonstrated (see section 4.3).

Advisory statements concerning Intensive Care Unit management

Use of propofol emulsion infusions for ICU sedation has been associated with a constellation of metabolic derangements and organ system failures that may result in death. Reports have been received of combinations of the following: Metabolic acidosis, Rhabdomyolysis, Hyperkalaemia, Hepatomegaly, Renal failure, Hyperlipidaemia, Cardiac arrhythmia, Brugada-type ECG (elevated ST-segment and coved T-wave) and rapidly progressive Cardiac failure usually unresponsive to inotropic supportive treatment. Combinations of these events have been referred to as the Propofol Infusion Syndrome. These events were mostly seen in patients with serious head injuries and children with respiratory tract infections who received dosages in excess of those advised in adults for sedation in the intensive care unit.

The following appear to be the major risk factors for the development of these events: decreased oxygen delivery to tissues; serious neurological injury and/or sepsis; high dosages of one or more of the following pharmacological agents – vasoconstrictors, steroids, inotropes and/or Diprivan 1% (usually at dose rates greater than 4mg/kg/h for more than 48 hours).

Prescribers should be alert to these events in patients with the above risk factors and immediately discontinue propofol when the above signs develop. All sedative and therapeutic agents used in the intensive care unit (ICU), should be titrated to maintain optimal oxygen delivery and haemodynamic parameters. Patients with raised intra-cranial pressure (ICP) should be given appropriate treatment to support the cerebral perfusion pressure during these treatment modifications.

Treating physicians are reminded if possible not to exceed the dosage of 4 mg/kg/h.

Appropriate care should be applied in patients with disorders of fat metabolism and in other conditions where lipid emulsions must be used cautiously.

It is recommended that blood lipid levels should be monitored if propofol is administered to patients thought to be at particular risk of fat overload. Administration of propofol 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 propofol formulation; 1.0 mL of Diprivan contains approximately 0.1 g of fat.

Diprivan 1% contains 0.0018 mmol sodium per ml. To be taken into consideration by patients on a controlled sodium diet.

Additional precautions

Caution should be taken when treating patients with mitochondrial disease. These patients may be susceptible to exacerbations of their disorder when undergoing anaesthesia, surgery and ICU care. Maintenance of normothermia, provision of carbohydrates and good hydration are recommended for such patients. The early presentations of mitochondrial disease exacerbation and of the ‘propofol infusion syndrome’ may be similar.

Diprivan 1% contains no antimicrobial preservatives and supports growth of micro-organisms.

EDTA chelates metal ions, including zinc, and reduces microbial growth rates. The need for supplemental zinc should be considered during prolonged administration of Diprivan 1%, particularly in patients who are predisposed to zinc deficiency, such as those with burns, diarrhoea and/or major sepsis.

When Diprivan 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 Diprivan 1% and infusion equipment throughout the infusion period. Any infusion fluids added to the Diprivan 1% line must be administered close to the cannula site. Diprivan 1% must not be administered via a microbiological filter.

Diprivan 1% and any syringe containing Diprivan 1% are for single use in an individual patient. In accordance with established guidelines for other lipid emulsions, a single infusion of Diprivan 1% must not exceed 12 hours. At the end of the procedure or at 12 hours, whichever is the sooner, both the reservoir of Diprivan 1% and the infusion line must be discarded and replaced as appropriate.

• 4.5 Interaction with other medicinal products and other forms of interaction

Diprivan 1% has been used in association with spinal and epidural anaesthesia and with commonly used premedicants, neuromuscular blocking drugs, inhalational agents and analgesic agents; no pharmacological incompatibility has been encountered. Lower doses of Diprivan 1% may be required where general anaesthesia is used as an adjunct to regional anaesthetic techniques. Profound hypotension has been reported following anaesthetic induction with propofol in patients treated with rifampicin.

The concurrent administration of other CNS depressants such as pre-medication drugs, inhalation agents, analgesic agents may add to the sedative, anaesthetic and cardiorespiratory depressant effects of Diprivan 1% (see Section 4.4).

• 4.6 Fertility, pregnancy and lactation Pregnancy

The safety of Diprivan 1% during pregnancy has not been established.

Studies in animals have shown reproductive toxicity (see section 5.3). Diprivan 1% should not be given to pregnant women except when absolutely necessary. Diprivan 1% can, however, be used during an induced abortion.

Obstetrics

Diprivan 1% crosses the placenta and can cause neonatal depression. It should not be used for obstetric anaesthesia unless clearly necessary.

Breast-feeding

Studies of breastfeeding mothers showed that small quantities of Diprivan 1% are excreted in human milk. Women should therefore not breast-feed for 24 hours after administration of Diprivan 1%. Milk produced during this period should be discarded.

• 4.7 Effects on ability to drive and use machines Diprivan 1% has moderate influence on the ability to drive and use machines. Patients should be advised that performance at skilled tasks, such as driving and operating machinery, may be impaired for some time after general anaesthesia.

Diprivan 1% induced impairment is not generally detectable beyond 12 hours (Section 4.4).

• 4.8 Undesirable effects

General

Induction and maintenance of anaesthesia or sedation is generally smooth with minimal evidence of excitation. The most commonly reported ADRs are pharmacologically predictable side effects of an anaesthetic/se­dative agent, such as hypotension. The nature, severity and incidence of adverse events observed in patients receiving Diprivan 1% may be related to the condition of the recipients and the operative or therapeutic procedures being undertaken.

The following definitions of frequencies are used: 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 data).

Table of Adverse Drug Reactions

System Organ Class	Frequency	Undesirable Effects
Immune system disorders	Very rare	Anaphylaxis – may include angioe-dema, bronchospasm, erythema and hypotension
Metabolism and nutrition disorders	Not known (9)	Metabolic acidosis (5), hyperkalaemia (5), hyperlipidae-mia (5)
Psychiatric disorders	Not known (9)	Euphoric mood. Drug abuse and drug dependence (8)
Nervous system disorders	Common	Headache during recovery phase
	Rare	Epileptiform movements, including convulsions and opisthotonus during induction, maintenance and recovery
	Very rare	Postoperative unconsciousness
	Not known (9)	Involuntary movements
Cardiac disorders	Common	Bradycardia (1)
	Very rare	Pulmonary oedema
	Not known (9)	Cardiac arrhythmia (5), cardiac failure (5), (7)
Vascular disorders	Common	Hypotension (2)
	Uncommon	Thrombosis and phlebitis
Respiratory, thoracic and mediastinal disorders	Common	Transient apnoea during induction
	Not known (9)	Respiratory depression (dose dependent)
Gastrointestinal disorders	Common	Nausea and vomiting during recovery phase
	Very rare	Pancreatitis
Hepatobiliary disorders	Not known (9)	Hepatomegaly (5)
Musculoskeletal and connective tissue disorders	Not known (9)	Rhabdomyolysis (3), (5)
Renal and urinary disorders	Very rare	Discolouration of urine following prolonged administration
	Not known (9)	Renal failure(5)
Reproductive system and breast disorders	Very rare Not known	Sexual disinhibition Priapism
General disorders and administration site conditions	Very common	Local pain on induction (4)
	Very rare	Tissue necrosis (10) following accidental extravascu-lar administration
	Not known (9)	Local pain, swelling, following accidental extravascu-lar administration
Investigations	Not known (9)	Brugada type ECG (5), (6)
Injury, poisoning and procedural complications	Very rare	Postoperative fever

• (1) Serious bradycardias are rare. There have been isolated reports of progression to asystole.

• (2) Occasionally, hypotension may require use of intravenous fluids and reduction of the administration rate of Diprivan.

• (3) Very rare reports of rhabdomyolysis have been received where Diprivan has been given at doses greater than 4 mg/kg/hr for ICU sedation.

• (4) May be minimised by using the larger veins of the forearm and antecubital fossa. With Diprivan 1% local pain can also be minimised by the co-administration of lidocaine.

• (5) Combinations of these events, reported as “Propofol Infusion Syndrome”, may be seen in seriously ill patients who often have multiple risk factors for the development of the events, see section 4.4.

• (6) Brugada-type ECG – elevated ST-segment and coved T-wave in ECG.

• (7) Rapidly progressive cardiac failure (in some cases with fatal outcome) in adults. The cardiac failure in such cases was usually unresponsive to inotropic supportive treatment.

• (8) Abuse of and drug dependence on propofol, predominantly by health care professionals.

• (9) Not known as it cannot be estimated from the available clinical trial data.

• (10) Necrosis has been reported where tissue viability has been impaired.

Dystonia/dyskinesia have been reported.

Read all of this leaflet carefully before you start having this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any further questions, ask your doctor or nurse.
• If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not listed in this leaflet. See section 4.

What is in this leaflet

• 1. What Diprivan is and what it is used for

• 2. What you need to know before you use Diprivan

• 3. How to use Diprivan

• 4. Possible side effects

• 5. How to store Diprivan

• 6. Contents of the pack and other information

1. What Diprivan is and what it is used for

Diprivan contains a medicine called propofol. This belongs to a group of medicines called ‘general anaesthetics’. General anaesthetics are used to cause unconsciousness (sleep) so that surgical operations or other procedures can be performed. They can also be used to sedate you (so that you are sleepy but not completely asleep).

Diprivan will be given to you as an injection by a doctor.

In adults and children over 1 month of age it is used to:

• Help put you to sleep before an operation or other procedure.
• Keep you asleep during an operation or other procedure.
• Sedate you during diagnostic and surgical procedures, alone or in combination with local or regional anaesthesia.

In people over 16 years of age it is also used to:

• Sedate you when receiving artificial respiration in an Intensive Care Unit (ICU).

2. what you need to know before you use diprivan

Do not use Diprivan:

• If you are allergic to propofol or any of the other ingredients of this medicine (listed in section 6).
• If you are allergic to peanut or soya. This is because Diprivan contains soya oil.
• If you are 16 years of age or younger for sedation in intensive care.

If any of the above apply to you, do not have Diprivan and tell your doctor, anaesthetist or nurse. If you are not sure, talk to one of these people before having Diprivan.

Warnings and precautions

The use of Diprivan is not recommended in newborn infants.

Talk to your doctor, anaesthetist or nurse before using Diprivan.

Before you have this medicine, tell your doctor, anaesthetist or nurse

• If you have ever had a fit or convulsion.
• If you have ever been told that you have very high levels of fat in your blood.
• If you have ever been told that your body has problems using fat.
• If your body has lost lots of water (you are dehydrated).
• If you have any other health problems, such as problems with your heart, breathing, kidneys or liver.
• If you have been generally unwell for some time.
• If you have mitochondrial disease.

Studies in young animals and clinical data suggest that repeated or lengthy use of general anaesthetics or sedation drugs in children younger than 3 years or in pregnant women during their third trimester may have negative effects on the development of the child’s brain. Parents and caregivers should discuss the benefits, risks, timing and length of surgery or procedures requiring anaesthetics or sedation with your doctor. If you are not sure if any of the above apply to you, talk to your doctor or nurse before having

Diprivan.

Other medicines and Diprivan

Tell your doctor if you are taking or have recently taken or might take any other medicines. This includes medicines that you buy without a prescription and herbal medicines.

In particular, tell your doctor, anaesthetist or nurse if you are taking any of the following medicines:

• Rifampicin (for tuberculosis – TB)

Pregnancy and breast-feeding

Do not have Diprivan if you are pregnant unless absolutely necessary.

Studies have shown that small amounts of

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ref.: D300.043/G F.40

Diprivan can pass into breast milk. Therefore, you should not breastfeed your baby for 24 hours after taking Diprivan.

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine.

Driving and using machines

After having Diprivan, you may still feel sleepy for some time. Do not drive or use any tools or machines until you are sure the effects have worn off.

• If you are able to go home shortly after having Diprivan, do not drive a car or use any tools or machines.
• Ask your doctor when you can start doing these activities again and when you can go back to work.

Diprivan contains sodium, soya oil and disodium edetate

Diprivan contains sodium. If you are on a sodium controlled diet, you will need to take this into account.

Diprivan contains soya oil. If you are allergic to peanut or soya, do not use this medicinal product.

Diprivan contains disodium edetate. During prolonged use of Diprivan for intensive care, you may need to be given a zinc (a mineral) supplement.

3. how to use diprivan

You will be given Diprivan by a doctor. It will be given to you as an injection into a vein. This is usually in the back of your hand or in your forearm.

• The doctor will give you the injection using a needle or through a fine plastic tube called a ‘cannula’.
• The doctor can also use an electric pump to control how fast the injection is given. This may be done if you are having a long operation or if you are in an Intensive Care Unit.

4. possible side effects

Like all medicines, this medicine can cause side effects although not everybody gets them.

Side effects that can happen during anaesthesia

The following side effects can happen during