SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Ripol 10 mg/ml (1%) emulsion for injection/infusion

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

1 ml emulsion for injection/infusion contains 10 mg propofol.

Each 20 ml ampoule/vial contains 200 mg propofol.

Each 50 ml vial contains 500 mg propofol.

Each 100 ml vial contains 1000 mg propofol.

Excipients:

1 ml emulsion for injection/infusion contains 100 mg soya-bean oil, refined and 0.0018 mmol (0.04 mg) sodium.

Each 20 ml ampoule/vial contains 2 g soya-bean oil, refined and 0.036 mmol (0.8 mg) sodium.

Each 50 ml vial contains 5 g soya-bean oil, refined and 0.09 mmol (2 mg) sodium. Each 100 ml vial contains 10 g soya-bean oil, refined and 0.18 mmol (4 mg) sodium.

For a full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Emulsion for injection/infusion.

White aqueous isotonic oil-in-water emulsion.

Osmolarity: 285 to 320 mOsm/Kg. pH is in the range of 6.0 - 8.5.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Propofol 10 mg/ml emulsion for injection/infusion

Propofol 10 mg/ml is a short-acting intravenous general anaesthetic for:

-    Induction and maintenance of general anaesthesia in adults and paediatric patients > 1 month of age

-    Sedation for diagnostic and surgical procedures, alone or in combination with local or regional anaesthesia in adults and paediatric patients > 1 month of age

-    Sedation of ventilated patients > 16 years of age in the intensive care unit

4.2 Posology and method of administration

Ripol 10 mg/ml must only be administered in hospitals or adequately equipped day therapy units by physicians trained in anaesthesia or in the care of patients in intensive care.

Circulatory and respiratory functions should be constantly monitored (e.g. ECG, pulse oxymetry) and facilities for maintenance of a patient airways, artificial ventilation, and other resuscitation facilities should be immediately available at all times.

For sedation during surgical and diagnostic procedures Ripol 10 mg/ml should not be administered by the same person conducting the surgical or diagnostic procedure.

Ripol 10 mg/ml has no analgesic properties and therefore supplementary analgesic agents are generally required in addition to Ripol 10 mg/ml.

Posology

The dose of Ripol 10 mg/ml should be individualy adapted according to the patient’s response.

Rapid bolus administration (single or repeated) should not be used in the elderly as this may lead to cardiorespiratory depression.

General anaesthesia in adults

Induction of anaesthesia

For induction of anaesthesia Ripol 10 mg/ml must be titrated (20-40 mg propofol every 10 seconds) against the response of the patient until clinical signs show the onset of anaesthesia.

Usually an adult patient below 55 years will require 1.5 to 2.5 mg propofol/kg body weight.

In patients over 55 years and in patients of ASA (American Society of Anaesthesiologists) classification III and IV, especially in those with impaired cardiac function the requirements will generally be less and the total dose of Ripol 10 mg/ml may be reduced to a minimum of 1 mg propofol/kg body weight. These patients also need lower rates of administration (approximately 2 ml corresponding to 20 mg propofol every 10 seconds).

Maintenance of anaesthesia

Anaesthesia can be maintained by administering Ripol 10 mg/ml either by continuous infusion or repeat bolus injections (Ripol 10 mg/ml only).

Continuous Infusion:

When using a continuous infusion for maintenance of anaesthesia generally doses of 4 to 12 mg propofol/kg body weight/hr should be given. In elderly patients, patients in unstable general conditions, patients with impaired cardiac function or hypovolaemic patients and patients of ASA grades III and IV, the dosage of Ripol 10 mg/ml may be further reduced depending on the patient’s condition and on the applied anaesthetic method.

Repeat Bolus Injection:

For maintenance of anaesthesia using repeat bolus injections dosages of 25 mg up to 50 mg (=2.5 up to 5 ml Ripol 10 mg/ml) should be administered depending on the clinical requirements.

Sedation of mechanically ventilated patients during intensive care

Adults and adolescents    16 years of age)

When used to provide sedation for mechanically ventilated patients under intensive care conditions, the administration of Ripol 10 mg/ml as continuous infusion it is recommended. The rate of administration has to be adapted to the level of sedation required.

A satisfactory level of sedation can generally be achieved with a dosage of 0.3-4.0 mg propofol/kg body weight/hr (see section 4.4).

Administering Ripol 10 mg/ml through a TCI-system for sedation in intensive care is not recommended.

It is recommended that blood lipid levels be monitored should Ripol 10 mg/ml be administered to patients thought to be at particular risk of fat overload. Administration of Ripol 10 mg/ml 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 Ripol 10 mg/ml formulation; 1.0 ml of Ripol 10 mg/ml contains approximately 0.1g of fat.

If the duration of sedation is in excess of 3 days, lipids should be monitored in all patients.

Sedation for diagnostic and surgical interventions in adult patients

To provide sedation during surgical and diagnostic interventions, doses and administration rates need to be adapted to the clinical response.

Most patients will require 0.5 to 1.0 mg propofol/kg body weight over 1 to 5 minutes for induction of sedation.

For maintenance of sedation the Ripol 10 mg/ml infusion should be titrated until the desired level of sedation is achieved. Generally 1.5 to 4.5 mg propofol/kg body weight/hr will be required.

The infusion may be supplemented by bolus injections of 10 to 20 mg (1 to 2 ml Ripol 10 mg/ml) if a deeper level of sedation is rapidly required.

In patients older than 55 years and in patients of ASA classification III and IV the rate of administration and dosage may need to be reduced.

Paediatric population

General anaesthesia in paediatric patients (>1 month of age)

Ripol 10 mg/ml is not recommended for induction and maintenance of anaesthesia in paediatric patients less than one month of age (see section 4.4).

Induction of anaesthesia

For induction of anaesthesia Ripol 10 mg/ml should be titrated slowly until clinical signs show the onset of anaesthesia. The dose should be adjusted according to age and/or body weight. Most patients over 8 years of age require approximately 2.5 mg propofol/kg body weight for induction of anaesthesia.

In younger patients, especially between the age of 1 month and 3 years, dose requirements may be higher (2.5-4 mg propofol/kg body weight).

Maintenance of anaesthesia

A satisfactory level of anaesthesia can generally be attained with a continuous infusion or by repeated bolus injection, using a dosage of 9 - 15 mg propofol /kg body weight/hr. The dose needs to be individually adapted and special attention needs to be given to obtain adequate analgesia.

In younger children, especially between the age of 1 month and 3 years, dose requirements may be higher - within the recommended dosage limits.

For ASA III and IV patients lower doses are recommended (see section 4.4). Sedation of ventilated paediatric patients during intensive care

Ripol 10 mg/ml is contraindicated in paediatric patients of 16 years of age or younger in the indication for sedation in intensive care (see section 4.3).

Sedation for diagnostic and surgical interventions in paediatric patients (>1 month of age)

Doses and administration rates should be adjusted according to the required level of sedation and the clinical response. Most paediatric patients require 1 - 2 mg propofol/kg body weight for onset of sedation. Maintenance of sedation may be accomplished by titrating Ripol 10 mg/ml infusion to the desired level of sedation. Most patients require 1.5-9 mg propofol/kg body weight/hr. The infusion may be supplemented by bolus injections of up to 1 mg/kg b.w. if a deeper level of sedation is rapidly required.

In ASA III and IV patients lower doses may be required.

Method of administration

Containers should be shaken before use. If two layers can be seen after shaking, the emulsion should not be used.

Ripol 10 mg/ml is administered intravenously as an injection or as a continuous infusion, undiluted or diluted with glucose 50 mg/ml (5%) intravenous infusion solution or sodium chloride 9 mg/ml (0.9%) intravenous infusion solution or a combination solution of glucose 40 mg/ml (4%) and sodium chloride 1.8 mg/ml (0.18%) (see section 6.6).

Prior to use, the ampoule neck and rubber stopper should be disinfected using a medicinal alcohol (spray or dipped swab). After use, any remaining contents must be discarded (see section 6.6).

Ripol 10 mg/ml does not contain antimicrobial preservatives and is capable of supporting the growth of microorganisms. The emulsion must be drawn aseptically into a sterile syringe or infusion system immediately after opening the ampoule or spiking the vial.

Administration must commence without delay. During infusion sterility of Ripol 10 mg/ml as well as the infusion system must be maintained.

Medicinal products or liquids that are added to a running Ripol 10 mg/ml infusion should be added close to the cannula.

Ripol 10 mg/ml must not be administered via infusion systems that are provided with a microbiological filter.

The contents of one vial of Ripol 10 mg/ml and any infusion equipment are intended for single use in one patient.

Any remainder must be discarded immediately after use.

Infusion of undiluted Ripol 10 mg/ml

When Ripol 10 mg/ml is administered as a continuous infusion, it is recommended that equipment such as burettes, drop counter, syringe pumps or volumetric infusion pumps should always be used to control infusion rates.

As applies to parenteral administration of all kinds of fat emulsions, the duration of use for one infusion system for a continuous infusion of Ripol 10 mg/ml must not exceed 12 hours. The infusion system and the container must be discarded and replaced after a maximum of 12 hours.

The simultaneous administration of Ripol 10 mg/ml together with an infusion solution of glucose 50 mg/ml (5%), sodium chloride 9 mg/ml (0.9%) intravenous infusion solution or a combination solution of glucose 40 mg/ml (4%) and sodium chloride 1.8 mg/ml (0.18%) close to the Y-connector near the place of injection, is possible.

Any Ripol 10 mg/ml remaining at the end of the infusion period or after changing the system needs to be discarded and destroyed.

Infusion of diluted Ripol 10 mg/ml

When Ripol 10 mg/ml is administered diluted as a continuous infusion it is recommended that equipment such as burettes, drop counter, syringe pumps or volumetric infusion pumps should always be used to control infusion rates and to prevent the accidentaladministration of large volumes of diluted Ripol 10 mg/ml.

Ripol 10 mg/ml must not be mixed with other solutions for injection or infusion except those mentioned in section 6.6.

To reduce pain on the injection site lidocaine may be injected immediately before the use of Ripol 10 mg/ml or Ripol 10 mg/ml may be mixed, immediately prior to administration, with preservative-free lidocaine injection (see section 6.6). For the specific risks of lidocaine see sections 4.4 and 4.8.

The infusion system should be rinsed before administration of muscle relaxants like atracurium and mivacurium when using the same infusion system for Ripol 10 mg/ml.

Duration of administration

Ripol 10 mg/ml can be administered for a maximum of 7 days.

4.3 Contraindications

-    Hypersensitivity to the active substance or to any of the excipients

-    Hypersensitivity to soya or peanut

-    Sedation in the intensive care unit in paediatric patients of 16 years of age or younger (see section 4.4)

4.4 Special warnings and precautions for use

In patients with cardiac, respiratory, renal or hepatic impairment, or in elderly, debilitated, hypovolaemic or epileptic patients Ripol should be administered with caution and with a reduced administration rate (see section 4.2).

Propofol clearance is blood flow dependend, therefore, concomitant medication which reduces cardiac output will also reduce propofol clearance. If possible, cardiac, circulatory or pulmonary insufficiency and hypovolaemia should be compensated before administration of Ripol 10 mg/ml.

Before anaesthesia of an epileptic patient, it should be checked that the patient has received the antiepileptic treatment. Although several studies have demonstrated efficacy in treating status epilepticus, administration of propofol in epileptic patients may also increase the risk of seizure.

Ripol 10 mg/ml should be administered with caution when used to sedate patients undergoing some interventions where spontaneous movements are particularly undesirable, such as ophthalmic surgery.

Use of propofol is not recommended with electroconvulsive therapy.

In patients with severe cardiac impairment it is recommended that Ripol 10 mg/ml is given with great caution and under intensive monitoring

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

The risk of relative vagotonia may be increased because propofol lacks vagolytic activity. The intravenous administration of an anticholinergic agent before induction, or during maintenance of anesthesia should be considered, especially in situations where the vagal tone is likely to predominate or when Ripol 10 mg/ml is used in conjunction with other agents likely to cause bradycardia.

Paediatric patients

Administration of Ripol 10 mg/ml for anaesthesia in infants and children up to the age of 3 needs extra attention, although recent data shows that there are no clear safety differences in comparison to children older than 3 years.

The safety and efficacy of Ripol 10 mg/ml for (background) sedation in paediatric patients younger than 16 years of age have not been demonstrated (see section 4.3).

The use of Ripol 10 mg/ml is not recommended for newborn infants younger than 1 month as this patient population has not been fully investigated. Pharmacokinetic data (see section 5.2) indicate that clearance is considerably reduced in neonates with a very high inter-individual variability. Relative overdose could occur administering doses recommended for older children resulting in severe cardiovascular depression.

Although no causal relationship has been established, serious undesirable effects (including cases with fatal outcome) during (background) sedation in paediatric patients younger than 16 years of age have been reported during unlicensed use. These effects mostly concerned occurrence of metabolic acidosis, hyperlipidaemia, rhabdomyolysis and/or cardiac failure. These effects were most frequently seen in children with respiratory tract infections who received dosages in excess of those advised in adults for sedation in intensive care.

Similarly rare reports have been received of occurrence of metabolic acidosis, rhabdomyolysis, hyperkalaemia and/or rapidly progressive cardiac failure (in some cases with fatal outcome) in adults treated for more than 58 hours with dosages in excess of 5 mg propofol/kg body weight/hr. This exceeds the maximum dosage of 4 mg/kg body weight per hour, which is now recommended for sedation in intensive care. The affected patients mainly (but not exclusively) had serious head injuries associated with raised intracranial pressure (ICP). In such cases the cardiac failure was usually unresponsive to inotropic supportive treatment.

Prescribers are reminded not to exceed the dosage of 4 mg propofol/kg body weight/hr.

Prescribers should be alert to these possible undesirable effects and decrease the dosage or switch to an alternative sedative at the first sign of occurrence of symptoms. Patients with raised ICP should be given appropriate treatment to support the cerebral perfusion pressure during these treatment modifications.

Special care should be taken in patients with high intracranial pressure and low arterial pressure as there is a risk of significant decrease of the intracerebral perfusion pressure.

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

It is recommended that blood lipid levels should be monitored if Ripol 10 mg/ml is administered to patients thought to be at particular risk of fat overload and in all patients if duration of sedation is in excess of 3 days. Administration of Ripol 10 mg/ml 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 (e.g. parenteral nutrition) concurrently, a reduction in quantity should be made in

order to take account of the amount of lipid infused as part of the Ripol 10 mg/ml formulation; 1.0 ml of Ripol 10 mg/ml contains approximately 0.1g of fat.

Due to the higher doses to be usually applied in patients with severe overweight, the increased risk of adverse haemodynamic effects should be taken into consideration.

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 Ripol 10 mg/ml.

Dilutions of Ripol 10 mg/ml emulsion for injection/infusion with lidocaine solution must not be used in patients with hereditary predisposition to acute porphyria.

In rare cases there may be a phase of postoperative unconsciousness that may be accompanied by an increased muscle tone. The occurrence of such an event is not related to whether the patient was awake or not. Although consciousness retums spontaneously; unconscious patients should be kept under close observation.

Full recovery from general anaesthesia should be confirmed prior to discharge.

This medicinal product contains less than 1 mmol sodium (23 mg) per 100 ml, i.e. essentially ‘sodium- free’.

4.5 Interaction with other medicinal products and other forms of interaction

Ripol 10 mg/ml can be used in combination with other active substances for anaesthesia (premedications, volatile anaesthetics, analgesics, muscle relaxants, local anaesthetics). Until now no severe interactions with these active substances have been reported. Some of these centrally acting active substances may exhibit a circulatory and respiratory depressive effect, thus leading to increased effects when used together with Ripol 10 mg/ml.

Concomitant use of benzodiazepines, parasympatholytic agents or volatile anaesthetics has been reported to prolong the anaesthesia and to reduce the respiratory rate.

When used in addition to local anaesthesia the dosage of Ripol 10 mg/ml may need to be reduced.

After additional premedication with opioids there may be a higher incidence and longer duration of apnoea.

Bradycardia and cardiac arrest may occur after treatment with suxamethonium or neostigmine.

It should be taken into consideration that concomitant use of propofol and active substances for premedication, volatile agents or analgesic agents may potentiate anaesthesia and cardiovascular side effects. Concomitant use of central nervous depressants e. g. alcohol, general anaesthetics, narcotic analgesics will result in intensification of their sedative effects.

After administration of fentanyl, the blood level of propofol may be temporarily increased with an increase in the rate of apnoea.

Leucoencephalopathy has been reported with administration of lipid emulsions such as propofol in patients receiving ciclosporin.

4.6 Pregnancy and lactation

Pregnancy

There are no or limited amount of data from the use of propofol in pregnant women. Ripol 10 mg/ml should not be used during pregnancy unless the clinical condition of the woman requires treatment with propofol.

Propofol crosses the placenta and may be associated with neonatal depression (see section 5.3). High doses (more than 2.5 mg propofol/kg body weight for induction or 6 mg propofol/kg body weight/hr for maintenance of anaesthesia) should be avoided.

Breastfeeding

Propofol/metabolites are excreted in human milk of treated women. Breast-feeding should be discontinued during treatment with propofol and breast milk must be discarded for 24 hours after administration of propofol.

4.7 Effects on ability to drive and use machines

After administration of Ripol 10 mg/ml the patient should be kept under observation for an appropriate period of time. The patient should be instructed not to drive, operate machinery, or work in potentially hazardous situations. The patient should not be allowed to go home unaccompanied and should be instructed to avoid consumption of alcohol.

4.8 Undesirable effects

Commonly observed side effects of propofol are hypotension and respiratory depression. These effects depend on the propofol dose administered but also on the type of premedication and other concomitant medication. Specifically, the following side effects have been observed. The frequency categories are defined as follows:

(>1/10)

(>1/100 to <1/10)

(>1/1,000 to <1/100)

(>1/10,000 to <1/1,000)

(<1/10,000)

(cannot be estimated from the available data)

Frequencie s	Very common	Common	Uncommo n	Rare	Very rare	Not known
System Organ Class

Frequencie s	Very common	Common	Uncommo n	Rare	Very rare	Not known
System Organ Class
Immune system disorders					Severe hypersensiti vty reaction (anaphylaxis ) - including angiooedem a, bronchospas m, erythema and hypotension
Psychiatric disorders				Sexual disinhibition during recovery period		Euphoria , drug abuse (predomi nantly by health care professio nals)
Nervous system disorders		Minimal excitation, headache during recovery period		Epileptiform movements including convulsions and opisthotonus, vertigo, shivering and sensations of cold during recovery period	Postoperativ e unconscious ness (see section 4.4)	Spontane ous moveme nts and myocloni during induction of anaesthes ia
Cardiac disorders		Bradycardia1				Cardiac arrhythm ia4,
Vascular disorders		Mild to moderate hypotension	Marked hypotensio thrombosis , phlebitis
Respiratory , thoracic		Hyperventilat ion transient	Coughing during	Coughing during	Pulmonary oedema

Frequencie s	Very common	Common	Uncommo n	Rare	Very rare	Not known
System Organ Class
and mediastinal disorders		apnoea, coughing during induction of anaesthesia	maintenan ce of anaesthesia	recovery period
Gastrointes tinal disorders		Singultus during induction of anaesthesia, nausea and vomiting during recovery period			Pancreatitis after administrati on of propofol (a causal relationship could not be established)
Hepatobilia ry disorders						Hepatom egaly4
Renal and urinary disorders					Discolourati on of urine following prolonged administrati on	Renal failure4
General disorders and administrat ion site conditions	Local pain occurrin g during the initial injection	Hot flushes during induction of anaesthesia			Post operative fever	Rhabdo myolysis 5 metaboli c acidosis, hyperkal aemia, hyperlipi daemia, cardiac failure, sometim es with fatal outcome (most of these effects have been

Frequencie s	Very common	Common	Uncommo n	Rare	Very rare	Not known
System Organ Class
						observed in patients in intensive care with doses exceedin g 4 mg propofol/ kg body weight/hr ; see section 4.4), severe tissue response s after accidenta l paraveno us applicati on
Investigatio ns					Brugada type ECG4, 5

¹    during general anaesthesia bradycardia with progressive severity (asystole) may occur. The intravenous administration of an anticholinergic medicinal product prior to induction or during maintenance of anaesthesia should be considered (see section 4.4).

2

this may require a lowering of the administration rate and/or fluid replacement therapy; if necessary vasoconstrictive medicinal products. Account should be taken of the possibility of a severe drop in blood pressure in patients with impaired coronary or cerebral perfusion or those with hypovolaemia.

3

The local pain which may occur during the initial injection of propofol can be minimised by the co-administration of lidocaine (see section 4.2) and by injection or infusion into the larger veins of the forearm and antecubital fossa.

Upon co-administration of lidocaine the following undesirable effects may occur: giddiness, vomiting, drowsiness, convulsions, bradycardia, cardiac arrhythmia and shock.

⁴    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).

⁵    Brugada-type ECG - elevated ST-segment and coved T-wave in ECG.

4.9 Overdose

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.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Anaesthetics, general; other general anaesthetics, ATC code: N01AX10

After intravenous injection of propofol, onset of the hypnotic effect occurs rapidly. Depending on the rate of injection, the time to induction of anaesthesia is between 30 and 40 seconds. The duration of action after a single bolus administration is short due to the rapid metabolism and excretion (4 - 6 minutes).

With the recommended dosage schedule a clinically relevant accumulation of propofol after repeated bolus injection or after infusion has not been observed. Patients recover consciousness rapidly.

Bradycardia and hypotension occasionally occur during induction of anaesthesia probably due to a lack of vagolytic activity. The cardio-circulatory situation usually normalises during maintenance of anaesthesia.

Paediatric patients

Limited studies on the duration of propofol based anaesthesia in paediatric patients indicate safety and efficacy is unchanged up to a duration of 4 hours. Literature evidence of use in paediatric patients documents use for prolonged procedures without changes in safety or efficacy.

5.2 Pharmacokinetic properties

After intravenous administration about 98 % of propofol is bound to plasma protein.

Propofol is extensively distributed (central distribution volume from 0.2 to 0.79 l/kg body weight; steady-state volume is 1.8 - 5.3 l/kg body weight) and rapidly cleared from the body (total body clearance: 1.5-2 l/minute). Clearance occurs by metabolic processes, mainly in the liver where it is blood flow dependent to form inactive conjugates of propofol (glucoronides) and its corresponding metabolite quinol (glucoronides and sulphate compounds), which are excreted in urine (88% of the administered dose). All metabolites are inactive. Only 0.3% of the administered dose is excreted unchanged in the urine.

During elimination the decline of blood levels is slower. The elimination half-life during the B-phase is in the range of 30 to 60 minutes. Subsequently a third deep compartment becomes apparent, representing the re-distribution of propofol from weakly perfused tissue.

Clearance is higher in children compared with adults.

After a single dose of 3 mg/kg intravenously, propofol clearance/kg body weight increased with age as follows: Median clearance was considerably lower in neonates < 1 month old (n=25) (20 ml/kg/min) compared to older children (n= 36, age range 4 months - 7 years). Additionally inter-individual variability was considerable in neonates (range 3.7-78 ml/kg/min). Due to this limited trial data that indicates a large variability, no dose recommendations can be given for this age group.

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies on repeated dose toxicity or genotoxicity.

Carcinogenicity studies have not been conducted.

Reproductive toxicity studies have shown effects related to pharmacodynamic properties of propofol only at high doses. Teratogenic effects have not been observed.

In local tolerance studies, intramuscular injection resulted in tissue damage around the injection site.

6.1 List of excipients

Soya-bean oil, refined Purified egg phospholipids Glycerol

Sodium hydroxide (for pH-adjustment) Water for injections

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

The neuromuscular blocking agents, atracurium and mivacurium should not be given through the same infusion system as Ripol 10 mg/ml without prior flushing.

6.3 Shelf life

Shelf life before opening Ampoules/vials: 2 years

Shelf life after first opening/dilution

The mixture should be prepared aseptically immediately prior to administration and must be administered within 6 hours after preparation.

In accordance with established guidelines for other lipid emulsions, a single infusion of Propofol 10 mg/ml (1%) must not exceed 12 hours. At the end of the procedure or at 12 hours, whichever is the sooner, both the reservoir of Propofol 10 mg/ml (1%) and the infusion line must be discarded and replaced as appropriate.

Chemical and physical in-use stability of the medicinal product has been demonstrated for 24 hours at 25°C.

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user.

6.4 Special precautions for storage

Store below 30°C.

Do not freeze.

Keep the vial/ampoule in the outer carton in order to protect from light. For storage conditions of the diluted medicinal product, see section 6.3.

6.5 Nature and contents of container

20 ml emulsion for injection/infusion in colourless Type I glass ampoules/vials with bromobutyl rubber stopper in pack sizes of 5 ampoules/vials.

50 ml emulsion for injection/infusion in colourless Type I glass vials with bromobutyl rubber stopper in the pack size of 1 vial.

100 ml emulsion for injection/infusion in colourless Type I glass vials with bromobutyl rubber stopper in the pack size of 1 vial.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

Ripol 10 mg/ml should not be mixed prior to administration with injection or infusion fluids other than glucose 50 mg/ml (5%) intravenous infusion solution or sodium chloride 9 mg/ml (0.9%) intravenous infusion solution or a combination solution of glucose 40 mg/ml (4%) and sodium chloride 1.8 mg/ml (0.18%).

The maximum dilution must not exceed 1 part of Ripol 10 mg/ml and 4 parts of the above mentioned intravenous infusion solution (at least 2 mg propofol/ml). The mixture should be prepared aseptically immediately prior to administration and must be administered within 6 hours after preparation.

Further Ripol 10 mg/ml may be mixed, immediately prior to administration, with preservative-free lidocaine injection (20 parts Ripol 10 mg/ml with up to one part of 1% lidocaine injection solution).

The simultaneous administration of Ripol 10 mg/ml together with an intravenous infusion solution of glucose 50 mg/ml (5%) or sodium chloride 9 mg/ml (0.9%) intravenous infusion solution or a combination solution of glucose 40 mg/ml (4%) and sodium chloride 1.8 mg/ml (0.18%) close to the Y-connector near the place of injection, is possible.

For single use only.

Parenteral products should be inspected visually for particulate matter prior to administration. If particulate matter is evident emulsion should not be used.

Containers should be shaken before use. If two layers can be seen after shaking, the emulsion should not be used.

Prior to use, the ampoule neck and rubber stopper should be disinfected using a medicinal alcohol (spray or dipped swab).

Any remaining contents after use should be discarded.

Any unused product or waste material should be disposed of in accordance with local requirements.

7    MARKETING AUTHORISATION HOLDER

YES Pharmaceutical Development Services GmbH Bahnstr. 42 - 46

61381 Friedrichsdorf

Germany

8    MARKETING AUTHORISATION NUMBER(S)

PL 16866/0101

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

14/06/2012

10    DATE OF REVISION OF THE TEXT

15/02/2013