The legally binding text is the original French version TRANSPARENCY COMMITTEE OPINION. 24 June 2009

Transcription

1 The legally binding text is the original French version TRANSPARENCY COMMITTEE OPINION 24 June 2009 PROPOFOL LIPURO 1% (10 mg/ml) emulsion for injection or for infusion B/5 glass ampoules of 20 ml (CIP code: ) B/10 glass vials of 50 ml (CIP code: ) B/10 glass vials of 100 ml (CIP code: ) Applicant: B BRAUN MEDICAL SAS propofol ATC code: N01AX10 Date of Marketing Authorisation: 19 April 2002 Reason for request: Reassessment of IAB level following the submission of new tolerance data. Medical, Economic and Public Health Assessment Division 1/8

2 1 CHARACTERISTICS OF THE MEDICINAL PRODUCT 1.1. Active ingredient propofol Excipients: glycerol, medium chain triglycerides, egg lecithin, sodium oleate, soya-bean oil, sodium, water for injections 1.2. Indication Propofol Lipuro 1% (10 mg/ml) is a rapid-acting intravenous anaesthetic agent for: - induction and maintenance of general anaesthesia; - sedation of ventilated patients in an intensive care unit; - sedation for diagnostic or surgical procedures, alone or in combination with local or regional anaesthesia Dosage - General instructions: Propofol Lipuro 1% (10 mg/ml) should only be administered in a hospital establishment or in day centres that are properly equipped and only by anaesthetists-intensive care physicians. Circulatory and respiratory functions should be continuously monitored (e.g. by ECG, pulse oximetry) and all equipment needed for keeping the airways open and for artificial ventilation and other resuscitation equipment should be readily accessible at all times. When Propofol Lipuro 1% (10 mg/ml) is used for sedation during surgical interventions or diagnostic procedures, it should not be administered by the person who performs the surgical or diagnostic procedure. Other analgesic agents are usually needed in addition to Propofol Lipuro 1% (10 mg/ml). - Recommended dosage regimen and duration of treatment: Propofol Lipuro 1% (10 mg/ml) is administered by the intravenous route. The dosage administered is individually adjusted according to the clinical response. - General anaesthesia in adults: Induction: The dose of Propofol Lipuro 1% (10 mg/ml) should be titrated (20-40 mg propofol every 10 sec) according to the patient s response until clinical signs of narcosis are obtained. Most adult patients under 55 years of age will need 1.5 to 2.5 mg propofol per kg body weight. In patients over 55 years of age and in patients of ASA grade III and IV, particularly those with heart failure, the doses needed will be lower and the total dose of Propofol Lipuro 1% (10 mg/ml) can be reduced to 1 mg propofol per kg body weight. In these patients, slower rates of administration should be used (approximately 2 ml, i.e. 20 mg every 10 sec). Maintenance: The anaesthesia can be maintained by administering Propofol Lipuro 1% (10 mg/ml) either as a continuous infusion or as a repeated bolus. In cases of repeated bolus administration, increasing doses of 25 mg (2.5 ml Propofol Lipuro 1% (10 mg/ml)) to 50 mg (5 ml Propofol Lipuro 1% (10 mg/ml)) may be administered, according to clinical needs. For maintenance of anaesthesia by continuous infusion, the doses are usually 4-12 mg/kg/h. In elderly patients, patients in poor general health, patients of ASA grade III and IV, and hypovolaemic patients, the doses can be reduced according to the patient s clinical status and the anaesthetic technique employed. 2/8

3 - General anaesthesia in children over 1 month of age: Induction: For induction of anaesthesia, the dose of Propofol Lipuro 1% (10 mg/ml) should be slowly titrated according to the patient s response until clinical signs of narcosis are obtained. The dosage should be adjusted according to the child s age and body weight. Most patients over 8 years of age will need about 2.5 mg/kg body weight for induction of anaesthesia. For children under 8 years of age, the dose needed may be higher (2.5-4 mg/kg). As clinical data are not available, a lower dose is recommended in young children at high risk (ASA grade III or IV). Maintenance: For maintenance of general anaesthesia, a satisfactory level of anaesthesia is usually obtained with continuous infusion of doses of 9-15 mg/kg/h. Compared to older children, children under 3 years of age may require higher doses (though within the range recommended above). The dosage should be individually adjusted and special attention should be paid to the need for tailored analgesia. In the studies on the maintenance of anaesthesia in children under 3 years of age, the duration of use was usually about 20 min, with a maximum duration of 75 min. The duration of use should therefore not exceed 60 min, except where longer use is specifically indicated, e.g. in malignant hyperthermia, in which halogenated anaesthetics must be avoided. PROPOFOL Lipuro 1% (10 mg/ml) should not be used for inducing and maintaining anaesthesia in children under one month of age. - Sedation in adults on respiratory support in an intensive care unit: For sedation in patients requiring intensive care, it is recommended that PROPOFOL Lipuro 1% (10 mg/ml) be administered by continuous infusion. The infusion rate should be adjusted according to the required depth of sedation. For most patients, sufficient sedation is obtained with doses of 0.3 mg/kg/h to 4 mg/kg/h propofol. Propofol is contraindicated for sedation in patients aged 16 years and under in intensive care. Administration of propofol by targetcontrolled intravenous infusion (TCI method) is not recommended for sedation in an intensive care unit. - Sedation in adults during diagnostic or surgical procedures: To obtain sedation during surgical interventions or diagnostic procedures, the doses and rate of administration should be adjusted according to the clinical response. In most patients, the dose required for induction of sedation is 0.5 to 1 mg/kg for 1 to 5 min. Maintenance of sedation can be achieved by adjusting the dose of Propofol Lipuro 1% (10 mg/ml) infused according the desired depth of sedation. In most patients, the dose is between 1.5 and 4.5 mg/kg/h. A bolus of 10 to 20 mg (1 to 2 ml Propofol Lipuro 1% (10 mg/ml)) can be administered in addition, if the depth of sedation needs to be increased rapidly. In patients over 55 years of age and in patients of ASA grade III and IV, the dose of PROPOFOL Lipuro 1% (10 mg/ml) can be reduced and the rate of infusion decreased. PROPOFOL Lipuro 1% (10 mg/ml) should not be used for sedation in diagnostic or surgical procedures in children aged 16 years and under. Method and duration of administration: Method of administration: Propofol Lipuro 1% (10 mg/ml) is administered intravenously by injection or continuous infusion, either undiluted or diluted with a 5% glucose or 0.9% sodium chloride solution or a 0.18% sodium chloride and 4% glucose solution in PVC infusion bags or glass infusion bottles. Shake the container before use. Before use, the neck of the ampoule or the rubber stopper of the vial should be cleaned with medical alcohol (sprayed or on a compress). After 3/8

4 use, the opened containers should be discarded. Propofol Lipuro 1% (10 mg/ml) does not contain any antimicrobial preservative and may support microbial growth. Propofol Lipuro 1% (10 mg/ml) should therefore be withdrawn and administered aseptically with a sterile syringe or an infusion set immediately after the ampoule has been opened or the vial seal broken. Administration should take place immediately. Throughout the infusion, maintain asepsis when handling Propofol Lipuro 1% (10 mg/ml) and infusion equipment. Any medicine or liquid added to the infusion of Propofol Lipuro 1% (10 mg/ml) should be administered as close as possible to the vein. Propofol Lipuro 1% (10 mg/ml) should not be administered via an antimicrobial filter. The contents of an ampoule, vial of Propofol Lipuro 1% (10 mg/ml), and any syringe containing Propofol Lipuro 1% (10 mg/ml) are for single use in an individual patient. Any product left over after use should be thrown away. Infusion of undiluted Propofol Lipuro 1% (10 mg/ml): When Propofol Lipuro 1% (10 mg/ml) is administered by continuous infusion, a burette, dropcounter, syringe pump or volumetric infusion pump should always be used, to control the rate of infusion. In accordance with the established rules for the parenteral use of lipid emulsions, the duration of continuous infusion, by the same infusion system, of Propofol Lipuro 1% (10 mg/ml) should not exceed 12 h. The infusion line and reservoir of Propofol Lipuro 1% (10 mg/ml) should be discarded and replaced after 12 h at the latest. Any Propofol Lipuro 1% (10 mg/ml) left over after the end of the infusion or after a change of infusion equipment should be discarded. Infusion of diluted Propofol Lipuro 1% (10 mg/ml): When Propofol Lipuro 1% (10 mg/ml) is administered diluted, a burette, drop-counter, syringe pump or volumetric infusion pump should always be used, to control the rate of infusion and to avoid the risks of accidental uncontrolled infusion of large volumes of diluted Propofol Lipuro 1% (10 mg/ml). The maximum dilution should not exceed one volume of Propofol Lipuro 1% (10 mg/ml) to 4 volumes of a 5% glucose or 0.9% sodium chloride solution or a 0.18% sodium chloride and 4% glucose solution (minimum concentration: 2 mg propofol/ml). The dilution should be prepared aseptically immediately before administration and should be used within 6 h of its preparation. This medicine should not be mixed with other medicines, except those mentioned in the methods of disposal and other handling. To reduce pain on initial injection, Propofol Lipuro 1% (10 mg/ml) may be mixed with preservative-free lidocaine 1% (in the ratio of 20 volumes of Propofol Lipuro 1% (10 mg/ml) to 1 volume of 1% lidocaine solution for injection) [ ]. Before administering the muscle relaxants atracurium or mivacurium by the same line as already used for Propofol Lipuro 1% (10 mg/ml), the line should be flushed. Propofol can be administered by the TCI method (target-controlled intravenous infusion). In view of the various algorithms available on the market, please refer to the manufacturer s instructions for use for information on recommended doses. Duration of administration: Propofol Lipuro 1% (10 mg/ml) can be administered for up to 7 days at most. Methods of disposal and other handling: Any unused product or waste material should be disposed of in accordance with local recommendations. Shake the container before use. For single use. Any contents remaining after use should be thrown away [ ]. If two layers are observed after shaking, do not use the product. Propofol Lipuro 1% (10 mg/ml) should only be mixed with the following products: a 5% glucose or 0.9% sodium chloride solution or a 0.18% sodium chloride and 4% glucose solution, and a preservative-free 1% lidocaine injection [ ]. However, Propofol Lipuro 1% (10 mg/ml) may be administered at the same time as a 5% glucose or 0.9% sodium chloride solution or a 0.18% sodium chloride and 4% glucose solution by using a Y-tube positioned close to the injection site. 4/8

5 2 SIMILAR MEDICINAL PRODUCTS 2.1. ATC Classification (2005) N01 : Anaesthetics N01A : Anaesthetics, general N01AX : Other general anaesthetics N01AX10 : Propofol 2.2. Medicines in the same therapeutic category General anaesthetics containing propofol: - DIPRIVAN 2%, emulsion for injection, prefilled syringe - DIPRIVAN 200 mg/20 ml, emulsion for intravenous injection - DIPRIVAN 500 mg/50 ml, emulsion for intravenous injection - DIPRIVAN 500 mg/50 ml, emulsion for injection, prefilled syringe - DIPRIVAN 1g/100 ml, emulsion for intravenous injection - DIPRIVAN 2%, emulsion for injection - PROPOFOL DAKOTA PHARM 10 mg/ml, emulsion for intravenous injection - PROPOFOL FRESENIUS 10 mg/ml, emulsion for injection - PROPOFOL LIPURO 1%, emulsion for injection infusion - PROPOFOL LIPURO 2%, emulsion for injection or powder for infusion - PROPOFOL MERCK 20 mg/ml, emulsion for intravenous injection 2.3. Medicines with a similar therapeutic aim All general anaesthetics. They are hypnotics and sedatives (etomidate, midazolam - considered the standard benzodiazepine in intensive care), general anaesthetics (ketamine, particularly in paediatrics). All can be administered intravenously. 3 ANALYSIS OF AVAILABLE DATA 3.1. Efficacy The efficacy of PROPOL LIPURO has been established through use Adverse effects Since the Committee s last opinion on PROPOFOL LIPURO in 2002, the following studies have been published: -A randomised double-blind comparative study 1 included 50 ASA I-II patients, in induction therapy. One group of patients received PROPOFOL LIPURO and the other received DIPRIVAN. The primary endpoint was pain in the forearm. The patients were asked about the intensity of their pain 30, 60, and 120 sec after the injection of the product; the assessment was made using a visual analogue scale (VAS) running from 0 to 10. A catheter of gauge 20 or above was inserted in a forearm vein, after which an infusion of Ringer s acetate was started. For both groups, the plasma concentration 1 Suzuki H, Miyazaki H, Andoh T, Yamada Y. Acta Anaesthesiol Scand. Propofol formulated with long-/medium-chain triglycerides reduces the pain of injection by target controlled infusion May; 50(5): /8

6 to be reached was 4 µg/m. The number of patients not experiencing any pain was higher in the group treated with PROPOFOL LIPURO (11/22 versus 3/23 in the DIPRIVAN group, p < 0.005). -A randomised double-blind crossover study 2 compared PROPOFOL LIPURO with DIPRIVAN, in terms of pain at the injection site, at a subanaesthetic dose in 60 patients. The patients included were over 18 years of age and scheduled to undergo a gynaecological or maxillofacial surgical intervention. EMLA cream (lidocaine and prilocaine) was applied to the back of each patient s hand 1 to 2 hours before the surgery. The patients received the 2 test products 10 min apart, through a 22-gauge catheter. The pain was assessed on a VAS during the injection and then 1, 2, 3, and 5 min after the injection. The patients that received DIPRIVAN first then PROPOFOL Lipuro experienced significantly less pain with PROPOFOL LIPURO than with DIPRIVAN (median difference on VAS = 2 [0-2] at T0, p = and 3 [0-4] at 1 min, p < 0.001). In the patients that received PROPOFOL LIPURO first, there was no difference in pain intensity on the VAS (in both groups the score was zero in the 3rd measurement). -A controlled randomised double-blind study 3 compared the degree of discomfort caused by injection of PROPOFOL Fresenius with that caused by PROPOFOL LIPURO, in induction anaesthesia. One hundred and twenty adult ASA I-II patients were included (60 in each group). The injection was administered in the back of the hand using a syringe pump set to deliver 600 ml/h. The number of episodes of discomfort deemed moderate to severe was significantly lower in the PROPOFOL LIPURO group than in the PROPOFOL Fresenius group (20% vs 43%, p < 0.006); moderate to severe discomfort was reduced by 54% in the patients receiving PROPOFOL Lipuro. As regards severe discomfort, the number of episodes was significantly lower in the PROPOFOL LIPURO group than in the PROPOFOL Fresenius group (5% vs 17%, p < 0.04); the reduction was 70%. There was no significant difference in the incidence of postoperative nausea and vomiting in the two groups (incidence of 17% in the DIPRIVAN group versus 12% in the PROPOFOL LIPURO group). -A randomised crossover study 4 compared PROPOFOL LIPURO with DIPRIVAN in regard to pain at the injection site. Eighty adult ASA I-II patients were included in this study. These patients were to undergo planned ENT or plastic surgery. The product was injected into the back of each hand via a Teflon cannula. Each patient received two 3.0 ml intravenous boluses of the two products at a rate of 1 ml/sec, through each cannula, 5 min apart. The first product administered was DIPRIVAN in group A (n = 34) and PROPOFOL LIPURO in group B (n = 39). Each patient assessed his or her pain at the injection site using a VAS: the incidence of local pain on injection (VAS > 0) was 52% for PROPOFOL LIPURO and 71% for DIPRIVAN. Moderate to severe pain (VAS > 4) was observed in 10% of the cases with PROPOFOL LIPURO and in 36% of the cases with DIPRIVAN. The maximum intensity of pain caused by the injection was significantly lower after PROPOFOL LIPURO (median 1 [25 th percentile: 0; 75 th percentile: 2], min 0 max 6) than after DIPRIVAN (median 3 [0; 5], min 0, max: 9) (p < ). - A randomised study compared PROPOFOL LIPURO with propofol mixed with lidocaine 5. Two hundred ASA I-III patients scheduled for elective surgery under general anaesthesia who did not receive premedication were included. The patients received either PROPOFOL 2 Sun NC, Wong AY, Irwin MG. A comparison of pain on intravenous injection between two preparations of propofol. Anesth Analg. 2005;101(3): Allford MA, Mensah JA. Discomfort on injection: a comparison between two formulations of propofol. Eur J Anaesthesiol Nov;23(11): Liljeroth E, Akeson J. Less local pain on intravenous infusion of a new propofol emulsion. Acta Anaesthesiol Scand ;49(2): Kam E, Abdul-Latif MS, McCluskey A. Comparison of Propofol-Lipuro with propofol mixed with lidocaine 10 mg on propofol injection pain. Anaesthesia Dec;59(12): This study was financed by the company B Braun. 6/8

7 LIPURO without lidocaine or DIPRIVAN + lidocaine 10 mg by intravenous infusion into the back of the hand using a G20 catheter at a constant rate. The incidence of pain on injection was 38% (37/98) in the group that received PROPOFOL LIPURO without lidocaine and 36% (35/98) in the group that received DIPRIVAN + lidocaine 10 mg (difference not significant). - A randomised study compared 2 groups 6 : one group received PROPOFOL LIPURO and the other received DIPRIVAN. The 200 patients included were ASA I-II and were not premedicated. Each patient received a dose of 1.5 mg product per kg, administered into a forearm vein via a 20-gauge catheter at a rate of 200 mg/min. The assessment of the pain by the patient was measured as follows: 0 = no pain; 1 = discomfort; 2 = mild pain; 3 = moderate pain; 4 = severe pain. The intensity of the pain was lower (p < 0.01) in the PROPOFOL LIPURO group (see Table 1). Table 1 Pain DIPRIVAN, N (%) 39 (38.2) 16 (15.7) 21 (20.6) 18 (17.7) 8 (7.8) PROPOFOL LIPURO, N (%) 62 (63.3) 13 (13.3) 15 (15.3) 7 (7.1) 1 (1.0) 3.3. Conclusion The efficacy of propofol is recognized from use. The 6 phase III studies presented in the dossier and published from 2002 included 50 to 200 patients. Five studies showed a lower intensity of pain on injection in the patients receiving PROPOFOL LIPURO 1% as induction therapy than in those treated with propofol on its own. In a 6 th study (200 patients included), there was no difference between the local tolerability of PROPOFOL LIPURO and that of standard propofol (LCT emulsion 1 ) added to lidocaine. The studies supplied have methodological limitations and are hard to interpret, as the numbers included were small and the choice of endpoints debatable. This is because it is hard to assess induction-phase pain for a patient who is in the process of losing consciousness, particularly as the patient has no experience of this pain. The speed of (slow) injection needs to be standardised, but the speed of assessment and response of the patient cannot be standardised. It should also be stressed that, in 5 studies, pain on injection is significantly reduced but never eliminated entirely; there are still patients who felt injection pain under PROPOFOL LIPURO. A meta-analysis of the trials carried out in this area would be desirable; in particular, a search for a publication bias is required. For all of these reasons, it is not possible to conclude that PROPOFOL LIPURO is superior to propofol LCT emulsion 7. 6 Ohmizo H, Obara S, Iwama H. Mechanism of injection pain with long and long-medium chain triglyceride emulsive propofol. Can J Anaesth Jun-Jul;52(6): Long-chain triglycerides 7/8

8 4 TRANSPARENCY COMMITTEE CONCLUSIONS 4.1. Reassessment of actual benefit The actual benefit remains substantial Reassessment of the improvement in actual benefit (IAB) In the absence of proof of superiority of the tolerance of PROPOFOL LIPURO 1% in comparison with the other anaesthetic agents that contain propofol, PROPOFOL LIPURO 1% does not provide an improvement in actual benefit (IAB V) Therapeutic use PROPOFOL LIPURO 1% can be used for general anaesthesia, on its own or alongside other substances, depending on the nature and duration of the surgical intervention or for sedation Target population The target population is patients receiving general anaesthesia (induction and/or maintenance) or sedation in the case of ventilated patients in an intensive care unit or sedation for diagnostic or surgical procedures, alone or in combination with local or regional anaesthesia. According to the results of an epidemiological survey 8 carried out in 1996 at the instigation of the Société Française d Anesthésie et de Réanimation [French Society of Anaesthesia and Intensive Care], the number of anaesthetic procedures performed in France was 7,937,000 (95CI: +/- 387,000), with an annual incidence of 13.5 per 100 persons. Taking account of French demographic development, the number of anaesthetic procedures performed in 2007 can be considered to be nearly 8,400,000, which provides a rough estimate of the target population of PROPOFOL LIPURO. 8 French survey of anesthesia in Anesthesiology 1999 ; 91 (5) : /8