Bupivacaine hydrochloride

Bupivacaine hydrochloride DE/W/042/pdWS/001 Page 1/54

Rapporteur’s Public Assessment Report

for paediatric studies submitted in accordance with Article 45 of Regulation (EC) No1901/2006, as

amended

Bupivacaine hydrochloride

Bupivacaine hydrochloride + adrenaline

Marcaine®, Carbostesin®

DE/W/042/pdWS/001

Rapporteur: Germany (DE)

Finalisation procedure: 31.10.2012

Date of finalisation of PAR: 23.11.2012


ADMINISTRATIVE INFORMATION

Invented name of the medicinal product(s):

See section VIII

INN (or common name) of the active substance(s):

Bupivacaine hydrochloride

MAH (s): See section VIII

Pharmaco-therapeutic group (ATC Code):

N01BB01

Pharmaceutical form(s) and strength(s):

Solution for injection 1,25 mg/ml



Solution for injection 5 mg/ml


Hyperbaric solution for injection 5 mg/ml

Solution for injection 5 mg/ml + 5 mcg/ml adrenaline

Solution for injection 7,5 mg/ml+ 5 mcg/ml adrenaline


TABLE OF CONTENTS

I. Executive Summary ....................................................................................................... 4

II. Recommendation ........................................................................................................... 5

III. INTRODUCTION ............................................................................................................. 5

IV. SCIENTIFIC DISCUSSION .............................................................................................. 5

IV.1 Information on the pharmaceutical formulation used in the clinical study(ies) ......... 5

IV.2 Non-clinical aspects .................................................................................................................. 6

IV.3 Clinical aspects ............................................................................................................................ 6

V. Rapporteur’s Overall Conclusion AND RECOMMENDATION ................................... 22

VI. Assessment of response to questions ....................................................................... 23

VII. Final Rapporteur’s Overall Conclusion AND RECOMMENDATION .......................... 46

VIII. List of Medicincal products and marketing authorisation holders involved ........... 54


I. EXECUTIVE SUMMARY SmPC and PL changes are proposed in sections 4.1 and 4.2 Summary of outcome

No change

Change

New study data: <section(s) xxxx, xxxx>

New safety information: <section(s) xxxx, xxxx>

Paediatric information clarified: section(s) 4.1, 4.2, 4.3, 4.4, 4.8

New indication: <section(s) 4.1, 4.2>


II. RECOMMENDATION See section VII.

III. INTRODUCTION Bupivacaine is a long-acting amino-amide type of local anaesthetic agent that is well established and in widespread use for various types of local and regional nerve blockade. Marcaine® (Carbostesin®) has been marketed in the EU since 1966 and was initially approved in Denmark. New sponsored studies or data that relate to the paediatric use of bupivacaine in accordance with Article 45 of the Regulation (EC) No 1901/2006, as amended on medicinal products for paediatric use have not been submitted. An evaluation of published data covering the period 1992 to 2011 was presented by one MAH (AstraZeneca) together with a short critical expert overview. The MAH proposed the following regulatory action: Amendments to be included in SPC and PL. In addition, the following documentation has been included as per the procedural guidance:

- A line listing; - An annex including SPC wording of section 4.2 related to the paediatric use of the

medicinal product (wording for section 4.1 and related PL was missing).

IV. SCIENTIFIC DISCUSSION

IV.1 Information on the pharmaceutical formulation used in the clinical study(ies)

Carbostesin® solution for injection is available in two different concentrations: 0,25% and 0,5% (2,5 and 5 mg/ml). Carbostesin® 0,25% and 0,5% solution for injection are indicated for local and regional nerve blocks. At present dose recommendations are given for adults and adolescents older than 15 years. Furthermore, a hyperbaric 5 mg/ml bupivacaine solution for injection containing Glucose is on the market. It is approved only for spinal anaesthesia. Up to now (in DE) hyperbaric Carbostesin® is not approved for children, in section 4.3 spinal anaesthesia is not recommended in adolescents and adults up to 30 years. This accounts also for the isobaric 0,5% solution for injection. A separate paediatric formulation is not marketed.


IV.2 Non-clinical aspects Not applicable

IV.3 Clinical aspects

1. Introduction

The MAH submitted no study reports. The MAH submitted a number of published articles (see below). Since bupivacaine has been approved decades ago, product information does not reflect the current state of knowledge. Numerous publications of the last 20 years provide additional information as regards the use of bupivacaine in children.

2. Published articles

Field block – local infiltration Local anaesthetic infiltration with bupivacaine is in widespread use in paediatric patients. The submitted published articles demonstrate that local infiltration of bupivacaine has been studied in a variety of surgical procedures, the most common being hernia repair and adenotonsillectomy. Anand P, Wilson R, Sheehy EC. Intraligamental analgesia for post-operative pain control in children having dental extractions under general anaesthesia. Eur.J.Paediatr.Dent. 2005;6(1):10-15. 30 children aged 10-13,5 y undergoing dental extraction of permanent molars under general anaesthesia received ILA (intraligamental local analgesia) for postoperative pain control with bupivacaine 0,5% (+ epinephrine 1;200000), 0,2 ml per root of each tooth, randomly assigned to one side of the mouth. The contralateral control side received no ILA. The observer was blinded. VAS scores were not significantly different between the experimental and control sides, but 63% found that pain control was better on the side with ILA. Anatol TI, Pitt-Miller P, Holder Y. Trial of three methods of intraoperative bupivacaine analgesia for pain after paediatric groin surgery. Can.J.Anaesth. 1997;44(10):1053-1059. 183 children aged 5-12 years undergoing groin surgery (herniotomy, orchidopexy, hydrocele) under general anaesthesia received bupivacaine 0,5% (2 mg/kg) for postoperative pain control. They were randomized to three groups: A received wound infiltration, B regional nerve blockade, C combination of both. 168 patients (A: 61, B: 55, C: 52) could be evaluated. No differences could be detected between groups as regards pain scores (CHEOPS). 80% of all patients met the criteria of satisfactory pain control (CHEOPS < 6). None ot the techniques enjoyed any apparent advantage. Bültmann M, Streich R, Risse A, Falke KJ, Pappert D. Wound infiltration with different concentrations of bupivacaine for postoperative pain relief in children after hernioplasty. Anaesthesist 1999;48(7):439-443. This prospective, randomized, double-blind pilot study in 29 children aged 3-13 years undergoing hernia repair under general anaesthesia aimed to define the appropriate concentration of local anaesthetic for posthernioplastic analgesia. Patients received 0,2 ml/kg bupivacaine either 0,125% (n= 10), 0,25% (n= 10) or 0,5% (n= 9) for intraoperative instillation before wound closure. The 0,5% group tended to have less pain. Patients from the other groups


required earlier supplementary analgesics. Results are not statistically significant and have to be confirmed in a larger study cohort. Dahl V, Raeder JC, Erno PE, Kovdal A. Pre-emptive effect of pre-incisional versus post-incisional infiltration of local anaesthesia on children undergoing hernioplasty. Acta Anaesthesiol.Scand. 1996;40(7):847-851. 50 children aged 2-10 y undergoing hernia repair were randomly assigned to two groups receiving either bupivacaine 0,25% 1 mg/kg infiltration after induction of general anaesthesia and infiltration with the same volume of normal saline after surgery or vice versa. Children receiving bupivacaine pre incision needed significantly less halothane during the procedure compared with the post-incisional group and had significantly lower OPS paine score 30 min after surgery. However, no differenceds between groups were ovserved regarding the need for additional analgesic medication. Sajedi P, Nazem M, Kaznavi K. Effect of pre vs. post incision inguinal field block on postoperative pain after pediatric herniorrhapy, a different approach. J.Res.Med.Sci. 2007;12(1):1-6. 40 children aged 1-10y undergoing hernia repair were randomly assigned to two groups receiving either bupivacaine 0,25% 0,5 mg/kg infiltration 20 min before incision of skin and infiltration with the same volume of normal saline at the end of skin suture or vice versa. Postoperative pain scores were significantly lower in the first group. Mean dosage of acetaminophen administration was significantly higher in the second group. In conclusion pre-surgical infiltration of bupivacaine in the surgical field is a useful method in decreasing post surgical wound pain up to 24 h. Demiraran Y, Ilce Z, Kocaman B, Bozkurt P. Does tramadol wound infiltration offer an advantage over bupivacaine for postoperative analgesia in children following herniotomy? Paediatr.Anaesth. 2006;16(10):1047-1050. 75 children aged 1-6 y undergoing hernia repair were randomly assigned to 3 groups: T received wound infiltration with 2 mg/kg tramadol in 0,2 ml/kg normal saline, B wound infiltration with bupivacaine 0,25% 0,2 ml/kg, I received i.m. injection of tramadol 2 mg/kg 20 min before end of the surgery. No side effects were recorded in any group. Postoperative pain scores were significantly higher in group B and I at 1, 4 and 8 h. Average time to first analgesic requirement was significantly longer in group T. In conclusion wound infiltration with tramadol may be a good choice for postoperative analgesia. Isaac LA, McEwen J, Hayes JA, Crawford MW. A pilot study of the rectus sheath block for pain control after umbilical hernia repair. Paediatr.Anaesth. 2006;16(4):406-409. 14 children aged 1-8 y undergoing umbilical hernia repair were randomly assigned to receive either a rectus sheath block or local wound infiltration at completion of surgery. Each analgesic technique was performed with 0,8ml/kg bupivacaine 0,25% with epinephrine 1:200 000. A blind observer registered no differences in postoperaitive pain or sedation scores or comsumption of total rescue morphine and no complications related to either analgesic technique. In conclusion rectus sheath block has no advantage over wound infiltration. Machotta A, Risse A, Bercker S, Streich R, Pappert D. Comparison between instillation of bupivacaine versus caudal analgesia for postoperative analgesia following inguinal herniotomy in children. Paediatr.Anaesth. 2003;13(5):397-402. In this prospective, randomized single blind study 58 children aged 0-5 y undergoing unilateral hernia repair received either caudal analgesia (n=30) with 1 ml/kg bupivacaine 0,25% or wound infiltration (n=28) with 0,2 ml/kg bupivacaine 0,5% at the end of surgery. There were no statistically significant differences between groups regarding postoperative pain scores, need for


additional analgesia, discharge time form the PACU. No complications were observed. In conclusion wound infiltration is as effectrive as caudal block after hernia repair. Okur H, Kucukaydin M, Muhtaroglu S, Kazez A. Effects of bupivacaine infiltration on beta-endorphin and cortisol release and postoperative pain following inguinal herniorrhaphy in children. Pediatr.Surg.Int. 1996;11(1):41-44. 30 children aged 1 mo to 2 y undergoing inguinal hernia repair under general anesthesia were randomized tnto three groups: 1 wound infiltration with bupivacaine 0,25% 0,5 ml/kg prior to surgery, 2: after hernia repair but before skin closure, 3: control group without local analgesia. Postoperative pain scores were not statistically different upon PACU arrival, but infiltratec patients achieved a pain score of 0 much more quickly than the control group (p< 0.05). In the control group beta-endorphin (BE) increased significantly at the end of the operation, but no significant elevation was found in the infiltration groups. Plasma cortisol increased in all groups, but significantly only in the control group. These findings suggest that wound infiltration with bupivacaine decreases the stress response to surgery and postoperative pain. Wright JE. Controlled trial of wound infiltration with bupivacaine for postoperative pain relief after appendicectomy in children. Br.J.Surg. 1993;80(1):110-111. In this double-blind controlled trial 60 children aged 5-14 y undergoing appendectomy were randomized to receive either wound infiltration with bupivacaine 0,25% (n=24) or normal saline (n=28)0,5 ml/kg. In the immediate postoperative period significantly less pain was measured in the treated group. Fischer CG, Lloyd S, Kopcha R, Warden GD, McCall JE. The Safety of Adding Bupivacaine to the Subcutaneous Infiltration Solution Used for Donor Site Harvest. J.Burn Care Rehabil. 2003;24(6):361-364. 14 children aged 2-18 y with acute burns requiring split thickness skin grafts were enrolled to receive bupivacaine infiltration of donor sites. Mean concentration of bupivacain infused was 0,05 mg/ml and total dose infused was 1,86 ± 0,21 mg/kg. Purpose of this study was to demonstate that bupivacaine at a dose of slightly less than 1.9 mg/kg added to donor site infiltration solution containing epinephrine is unlikely to produce systemic toxicity. No blood level approached the toxic range and no patient demonstrated any clinical signs of toxicity. Tirotta CF, Munro HM, Salvaggio J, Madril D, Felix DE, Rusinowski L, et al. Continuous incisional infusion of local anesthetic in pediatric patients following open heart surgery. Paediatr.Anaesth. 2009;19(6):571-576. In this prospective randomized double blind study 72 children aged 3 mo to 16 y undergoing open heart surgery were assigned to receive either levobupivacaine 0,25% or bupivacaine 0,25% or saline delivered subcutaneously via continuous incisional infusion for 72h. Dosed at a maximum rate of 0,4 mg/kg/h treatment groups reduced postoperative analgesic requirement and sedative use in pediatric patients.

The majority of the presented published articles studied small populations of children mostly above 1 year of age undergoing groin surgery. Studies have been prospective and study design was in part randomized and blinded. Bupivacaine (0,25-0,5%) was administered at doses between 0,5 and 2,5 mg/kg for wound infiltration in more than 300 paediatric patients. Across studies analgesic efficacy can be assumed for wound infiltration with bupivacaine. No safety signals could be derived from the studies.

Sun J, Wu X, Meng Y, Jin L. Bupivacaine versus normal saline for relief of post-adenotonsillectomy pain in children: a meta-analysis. Int.J.Pediatr.Otorhinolaryngol. 2010 Apr;74(4):369-373.


In this meta-analysis 7 random controlled studies were included. The included patient populations were small and quality of the studies was mainly low.

Children undergoing adenotonsillectomy under general anaesthesia were injected either bupivacaine or placebo (saline) into the tonsillar region immediately or after the removal of the tonsils. Pain intensity and analgesic requirement was significantly lower in the bupivacaine treated children than in the placebo group. No statistical difference was detected between groups as regards complications In total, 142 paediatirc patients aged 2-18 years received bupivacaine or levobupivacaine for local infiltration in the tonsillar region. The majority (84 children) received bupivacaine 0,25% at a dose of 3-5 ml. Akoglu E, Akkurt BCO, Inanoglu K, Okuyucu S, Dagli S. Ropivacaine compared to bupivacaine for post-tonsillectomy pain relief in children: A randomized controlled study. Int.J.Pediatr.Otorhinolaryngol. 2006;70(7):1169-1173. 46 children aged 2-12 years undergoing tonsillectomy were randomly assigned to receive 3-5 ml bupivacaine 0,25%(n=16), ropivacaine 0,2%(n=15) or saline (n=15). Pain scores and analgesic requirements were significantly lower in the treatment groups compared to the control group. Inanoglu K, Akkurt BCO, Turhanoglu S, Okuyucu S, Akoglu E. Intravenous ketamine and local bupivacaine infiltration are effective as part of a multimodal regime for reducing post-tonsillectomy pain. Med.Sci.Monit. 2009;15(10):R539-R543. 90 children aged 2-12 years undergoing tonsillectomy were enrolled in this randomized controlled double blind study. Group I received iv and peritonsillar saline, group II iv saline and peritonsillar bupivacaine 0,25% and group III iv ketamine 0,5 mg/kg and peritonsillar bupivacaine 0,25% (3-5 ml or 7,5-12,5 mg) per tonsil. Pain scores and analgesic requirements were significantly lower in the treatment groups compared to the control group. Kasapoglu F, Kaya FN, Tuzemen G, Ozmen OA, Kaya A, Onart S. Comparison of peritonsillar levobupivacaine and bupivacaine infiltration for post-tonsillectomy pain relief in children: Placebo-controlled clinical study. Int.J.Pediatr.Otorhinolaryngol. 2011 March 2011;75(3):322-326. 60 children (mean age 6.4-6.7) undergoing elective tonsillectomy or adenotonsillectomy under general anaesthesia were randomly allocated to receive peritonsillar infiltration of 5 ml per tonsil either 0,25% levobupivacaine with epinephrine 1:200 000, 0,25% bupivacaine with epinephrine 1:200 000 or with normal saline. Pain scores and analgesic requirements were significantly lower in the treatment groups compared to the control group.


Molliex S, Haond P, Baylot D, Prades JM, Navez M, Elkhoury Z, et al. Effect of pre- vs postoperative tonsillar infiltration with local anesthetics on postoperative pain after tonsillectomy. Acta Anaesthesiol.Scand. 1996;40(10):1210-1215. 68 patients aged 8-65y undergoing tonsillectomy under general anaesthesia were randomly allocated to either receive peritonsillar infiltration with 0,25% bupivacaine or normal saline before incision or to receive 0,25% bupivacaine after the completion of surgery but before the patients were awakened form anaesthesia. In total 24 paediatric patients aged 8-15 years were included (9 / 7 / 8 in group 1 / 2 / 3) receiving < 6 ml bupivacaine. Pain scores and analgesic requirements were significantly lower in the treatment groups compared to the control group. Schoem SR, Watkins GL, Kuhn JJ, Thompson DH. Control of early postoperative pain with bupivacaine in pediatric tonsillectomy. Ear Nose Throat J. 1993;72(8):560-563. A prospective randomized double blind study was conducted in 50 paediatric patients aged 3-16 years undergoing tonsillectomy under general anaesthesia. After tonsil resection either 0,5% bupivacaine 1 mg/kg or saline was injected into each fossa. No significant difference in pain levels or analgesic requirements could be detected between groups. Stuart JC, MacGregor FB, Cairns CS, Chandrachud H. Peritonsillar infiltration with bupivacaine for paediatric tonsillectomy. Anaesth.Intensive Care 1994;22(6):679-682. 42 children aged 2-12 years scheduled for elective adenotonsillectomy were randomized to receive peritonsillar infiltration follwing induction of anaesthesia with either 0,25% bupivacaine or normal saline, 0,5 ml/kg to a maximum of 10 ml. Peritonsillar infiltration with bupivacaine was better than placebo in reducing pain experienced in the initial recovery period following tonsillectomy, but in the medium to long term it made no difference. Unal Y, Pampal K, Korkmaz S, Arslan M, Zengin A, Kurtipek O. Comparison of bupivacaine and ropivacaine on postoperative pain after tonsillectomy in paediatric patients. Int.J.Pediatr.Otorhinolaryngol. 2007;71(1):83-87. 60 children aged 4-17 yearsundergoing tonsillectomy under general anaesthesia were randomly allocated to three groups: bilateral peritonsillar infiltration with 3-5 ml bupivacaine 0,25%, ropivacaine 0,2% or normal saline (each containing 1: 200 000 epinephrine). Pain scores and analgesic requirements were significantly lower in the treatment groups compared to the control group. However, bupivacaine did not control postoperative pain completely. Wong AK, Bissonnette B, Braude BM, Macdonald RM, St-Louis PJ, Fear DW. Post-tonsillectomy infiltration with bupivacaine reduces immediate postoperative pain in children. Can.J.Anaesth. 1995;42(9):770-774. 43 children aged 2-10 years were randomized into three groups after tonsillectomy was performed. To receive either normal saline spray (0,5 ml/kg), bupivacaine 0,5% with 1 : 200 000 epinephrine peritonsillar infiltration or bupivacaine 0,5% with 1:200 000 epinephrine spray to both tonsillar beds (2 mg/kg). Peritonsillar infiltration of bupivacaine provided significantly superior immediate postoperative analgesia and lower opioid requirements compared to bupivacaine spray or placebo.

Including the metaanalysis of Sun et al. in total more than 300 paediatric patients aged 2 years and older have been treated with bupivacaine infiltrations in the tonsillar region. No safety concerns could be derived from the published articles. The majority of patients (more than 230 children) has been treated with 3-5 ml bupivacaine 0,25% (7,5 – 12,5 mg) per tonsil. Bupivacaine 0,5% has been used at doses of 1-2 mg/kg in 72 patients. Epinephrine has been added to the solutions for injection at 1:200 000 in 3 studies without generating any safety concerns (n=163, including control groups)


Peripheral nerve blocks The use of peripheral nerve blocks in children is gaining considerable interest. However, success rate is variable, depending on the technique used and also of the experience of the anaesthetist. The following publications demonstrate that bupivacaine is in widespread use for peripheral nerve blocks also in paediatric patients. Ilioinguinal-iliohypogastric block Anatol TI, Pitt-Miller P, Holder Y. Trial of three methods of intraoperative bupivacaine analgesia for pain after paediatric groin surgery. Can.J.Anaesth. 1997;44(10):1053-1059. 183 children aged 5-12 years undergoing groin surgery (herniotomy, orchidopexy, hydrocele) under general anaesthesia received bupivacaine 0,5% (2 mg/kg) for postoperative pain control. They were randomized to three groups: A received wound infiltration, B regional nerve blockade, C combination of both. 168 patients (A: 61, B: 55, C: 52) could be evaluated. No differences could be detected between groups as regards pain scores (CHEOPS). 80% of all patients met the criteria of satisfactory pain control (CHEOPS < 6). None ot the techniques enjoyed any apparent advantage. Bhattarai BK, Rahman TR, Sah BP, Tuladhar UR. Analgesia after inguinal herniotomy in children: combination of simplified (Single Puncture) ilioinguinal and iliohypogastric nerve blocks and wound infiltration vs. caudal block with 0.25% bupivacaine. Kathmandu Univ.Med.J.(KUMJ) 2005;3(3):208-211. 60 children aged 1-14 years undergoing herniotomy were randomly allocated to receive either ilioinguinal –iliohypogastric nerve block with 0,5 ml/kg of 0,25% bupivacaine combined with small amount of the solution (0,1 ml/kg) infiltrated alon the wound margin or caudal block with 1 ml/kg of 0,25% bupivacaine. At the end of surgery under general anaesthesia. No significant differences in frequency of complications or acceptance of the techniques by parents and children were observed, however, duration was (not significantly) longer in the first group. Jagannathan N, Sohn L, Sawardekar A, Ambrosy A, Hagerty J, Chin A, et al. Unilateral groin surgery in children: Will the addition of an ultrasound-guided ilioinguinal nerve block enhance the duration of analgesia of a single-shot caudal block? Paediatr.Anaesth. 2009;19(9):892-898. In this double blind randomized controlled trial 50 children aged 1-6 years scheduled for unilateral inguinal hernia repair, hydrocelectomy, orchidopexy or orchiectomy were randomized to receive either ilioinguinal nerve block with 0,1 ml/kg of normal saline or an US guided nerve block with 0,1 ml/kg of 0,25% buipvacaine with 1:200 000 epinephrine at the conclusion of the surgery. After induction of anaesthesia but prior to surgical incision, all patients received caudal anaesthesia with 0,7 ml/kg of 0,125% bupivacaine with 1 : 200 000 epinephrine. 46 patients completed the study. The addition of an US-guided ilioinguinal nerve block to a single-shot caudal block decreases the severity of pain after paediatric groin surgery and reduced time to first rescue medication, however, not significantly. Kaabachi O, Zerelli Z, Methamem M, Ben Abdelaziz A, Moncer K, Toumi M. Clonidine administered as adjuvant for bupivacaine in ilioinguinal- iliohypogastric nerve block does not prolong postoperative analgesia. Paediatr.Anaesth. 2005;15(7):586-590. 98 children aged 1-12 years scheduled for elective outpatient herniorraphy or orchidopexy were randomly allocated to receive an iioinguinal-iliohypogastric nerve block with 0,3 ml/kg bupivacaine 0,25% etiher with or without 1 µg/kg clonidine. The study could not demonstrate any advantage in addition of clonidin.


Kundra P, Sivashanμgam T, Ravishankar M. Effect of needle insertion site on ilioinguinal-iliohypogastric nerve block in children. Acta Anaesthesiol.Scand. 2006;50(5):622-626. 132 children aged 2-12 years undergoing elective unilateral hernia repair were randomly allocated into four groups to receive no block, ILIH block at 1 cm inferiomedial (IM) , medial (M) and 2 cm superiomedial (SM) to the anterior superior iiac spine. Blocks were performed with 0,25 ml/kg bupivacaine 0,25% after induction of anaesthesia. Needle entry sites do not have a bearing on success of the ILIH nerve block. All treatment groups had significantly lower requirements for supplementary analgesics. Smith T, Moratin P, Wulf H. Smaller children have greater bupivacaine plasma concentrations after ilioinguinal block. Br.J.Anaesth. 1996;76(3):452-455. 31 children undergoing elective surgery for inguinal hernia, hydrocele or orchidopexy under general anesthesia. Ilioinguinal block was performed with bupivacaine 0,5% at a dose of 0,25 ml/kg (1,25 mg/kg) prior to surgery. Blood samples were taken during the first hour after the block. Significantly higher plasma concentrations of bupivacaine were measured in children with a body weight of 10-15 kg (14 children) compared to children with a higher (15-30 kg) body weight (17 children).

There were no complications and no side effects attributable to systemic toxicity of bupivacaine. Although the dose of 1.25 mg/kg was considerably less than the maximum recommended dose of 2 mg/kg, the 10-15 kg group had unexpectedly high plasma bupivacaine concentrations, the highest bordering on the generally accepted tocic range for adults of <4mg/l (proposed by Jordfeldt et al. in 1968 based on toxicity studies in dogs). The authors recommend not to exceed a total dose of bupivacaine 1.25 mg/kg in the perioperative period when performing ilioinguinal blocks in children less than 15 kg. Trotter C, Martin P, Youngson G, Johnston G. A comparison between ilioinguinal-iliohypogastric nerve block performed by anaesthetist or surgeon for postoperative analgesia following groin surgery in children. Paediatr.Anaesth. 1995;5(6):363-367. 52 children (23 < 2 years, 29 > 2 years) scheduled for herniotomy, orchidopexy or hydrocele repair were randomly allocated to receive ilioinguinal-iliohypogastric nerve blocks with bupivacaine 0,25% 0,5ml/kg either pwerformed percutaneaously by the anaesthetist after the


induction of general anaesthesia or intraoperatively under direct visio by the surgeon. No statistical significant differences in pain scores could be detected. Tsuchiya N, Ichizawa M, Yoshikawa Y, Shinomura T. Comparison of ropivacaine with bupivacaine and lidocaine for ilioinguinal block after ambulatory inguinal hernia repair in children. Paediatr.Anaesth. 2004;14(6):468-470. 30 children aged 1- 8 years undergoing inguinal hernia repair were assigned randomly to receive 0,5 ml/kg of either ropivacaine 0,2%, bupivacaine 0,25% or lidocaine 1% for ilioinguinal block. Bupivacaine and ropivacaine were more effective than lidocaine in the prevention of postoperative pain. However, the need for supplementary analgesics was not different between the three groups.

In the above presented studies ilioinguinal block was performed in 289 paediatric patients above 1 year or age with bupivacaine 0,25% at a dose of 0,1-0,5 ml/kg equivalent to 0,25-1,25 mg/kg. In 138 patients, mostly above 5 years of age, bupivacaine 0,5% was used at a dose of 1,25 to 2 mg/kg. Across studies nerve block was effective and no major safety concerns could be detected.

Infra-orbital block Jonnavithula N, Durga P, Kulkarni DK, Ramachandran G. Bilateral intra-oral, infra-orbital nerve block for postoperative analgesia following cleft lip repair in paediatric patients: Comparison of bupivacaine vs bupivacaine-pethidine combination. Anaesthesia 2007 Jun 2007;62(6):581-585. Prospective, double blind controlled trial: 40 patients aged 5-60 months undergoing cleft lip repair were randomly allocated to receive either bupivacaine 0,25% (1 ml on each side) alone for bilateral infra-orbital nerve block or bupivacaine with pethidine 0,25 mg/kg. Intra-oral, infra orbital nerve block was safe and easy to perform eith high success rates and minimal complications. Addition of pethidine as an adjunct significantly prolonged the duration of postoperative analgesia without any adverse effects. Palatal block Jonnavithula N, Durga P, Madduri V, Ramachandran G, Nuvvula R, Srikanth R, et al. Efficacy of palatal block for analgesia following palatoplasty in children with cleft palate. Paediatr.Anaesth. 2010;20(8):727-733. This prospective randomized controlled study was performed in 45 children aged below 5 years undergoing cleft palatoplasty under general anaesthesia. Children were randomly assigned to receive either no block, injection of normal saline 0,5 ml or bupivacaine 0,25% 0,5 ml for palatal block. The block had no anaesthetic sparing effect. Mean pain scores were significantly lower, time to first demand of analgesia was lower and number of demands of rescue analgesia was significantly less in the bupivacaine group. Palatal block is technically simple safe end effectively. Subpubic block Atallah MM, Saied MMA, Yahya R, Ghaly AM. Presurgical analgesia in children subjected to hypospadias repair. Br.J.Anaesth. 1993;71(3):418-421. 30 children aged 2-10 years undergoing repair of hypospadieas were allocated randomly in a double blind placebo controlled study to receive either lumbar extradural analgesia using 0,5% bupivacaine 1 mg/kg plus morphine 50 µg/kg, morphine 100µg/kg i.m. or subpubic block using 0,5% bupivacaine 0,5 mg/kg for each side. Children given extradural analgesia had more stable


haemodynamic variables and smaller catecholamine concentrations and needed less anaesthetic supplementation with no analgesic requirement in the postoperative period. In children with subpubic block, no nausea or vomiting was observed. Penile block Chhibber AK, Perkins FM, Rabinowitz R, Vogt AW, Hulbert WC. Penile block timing for postoperative analgesia of hypospadias repair in children. J.Urol. 1997;158(3 SUPPL):1156-1159. 98 boys aged 6 months to 12 years undergoing hypospadias repair under general anesthesia were randomly assigned to receive a penile block with the same total dose (0,5 ml/kg) of bupivacaine 0,5% at the completion of surgery, before the incision or before and at the completion of surgery. Conclusion: Two penile blocks performed at the beginning and conclusion of hypospadias repair provide significantly better postoperative pain control than 1 penile block done before or after surgery. Choi WY, Irwin mg, Hui TW, Lim HH, Chan KL. EMLA cream versus dorsal penile nerve block for postcircumcision analgesia in children. Anesth.Analg. 2003;96(2):396-399. In this prospective, randomized doubleblind trial 63 boys aged 2-12 years were randomly assigned to receive preoperative application of 2-4 g EMLA cream and normal saline dorsal penile block or placebo cream and bupivacaine 0,5% 0,2 ml/kg dorsal penile nerve block for postcircumcision analgesia. There were no local or systemic complications related to either technique. No difference in pain scores was detected between groups, but bupivacaine blocks resulted in significantly longer analgesia. Gauntlett I. A comparison between local anaesthetic dorsal nerve block and caudal bupivacaine with ketamine for paediatric circumcision. Paediatr.Anaesth. 2003;13(1):38-42. 60 boys aged 1-10 years undergoing elective circumcision were given either caudal 0,5 ml/kg bupivacaine 0,15% with ketamine 0,5 mg/kg or dorsal nerve block of the penis with bupivacaine 0,5% (3-5 ml with an extra 1 ml for the subcutaneous injection) as a supplement to general anaesthesia. There was no difference between the groups in time to first requirement for analgesia or number of analgesic requirements or PONV. However, almost half the boys in the caudal group had motor weakness and there was a significant increase in time to first micturition in this group, so in conclusion the technique does not confer any advantage over a dorsal nerve block. Stolik-Dollberg OC, Dollberg S. Bupivacaine versus lidocaine analgesia for neonatal circumcision. BMC Pediatr. 2005;5. 38 neonates received DPNB analgesia with either lidocaine 1% 4-5 mg/kg or bupivacaine 1,5-2 mg/kg. Patients with bupivacaine block needed significantly less acetaminophen postoperatively. Weksler N, Atias I, Klein M, Rosenztsveig V, Ovadia L, Gurman GM. Is penile block better than caudal epidural block for postcircumcision analgesia? J.Anesth. 2005;19(1):36-39. 100 boys aged 3-8 years undergoing circumcision under general anaesthesia were allocated randomly to receive either penile block with bupivacaine 0,5% (0,2 ml/kg per compartment with additional 0,1 ml/kg into the dorsal aspect of the penis) or caudal block with bupivacaine 0,25% 1 ml/kg. Penile block shortened the induction-incision time and enabled earlier discharge home compared with caudal block. Penile and caudal block are equally effective for postcircumcision analgesia and neither is associated with serious complications.


Penile blocks have been performed with bupivacaine 0,5% in a total of 230 paediatric patients including 19 neonates. Across studies blocks have been efficaous and safe. Bupivacaine 0,5% has been used at total doses of 0,2-0,5 ml/kg equivalent to 1-2,5 mg/kg.

Rectus sheath block Isaac LA, McEwen J, Hayes JA, Crawford MW. A pilot study of the rectus sheath block for pain control after umbilical hernia repair. Paediatr.Anaesth. 2006;16(4):406-409. 14 children aged 1-8 y undergoing umbilical hernia repair were randomly assigned to receive either a rectus sheath block or local wound infiltration at completion of surgery. Each analgesic technique was performed with 0,8ml/kg bupivacaine 0,25% with epinephrine 1:200 000. A blind observer registered no differences in postoperaitive pain or sedation scores or comsumption of total rescue morphine and no complications related to either analgesic technique. In conclusion rectus sheath block has no advantage over wound infiltration. Sciatic block Vas L. Continuous sciatic block for leg and foot surgery in 160 children. Paediatr.Anaesth. 2005;15(11):971-978. 160 patients aged 4 months to 12 years were given continuous sciatic block (bupivacaine 0,25% 0,75 ml/kg) plus single shot 3-in1 block (bupivacaine 0,25% 0,25 ml/kg) against tourniquet pain for leg and foot surgery under general anaesthesia. 82% of patients showed no response to surgery, block was considered to have failed in 4% of patients. A total of 154 patients had good postoperative pain relief for 72 h with continuous infusion of 0,05% bupivacaine at 0,3 mg/kg/h. Intrathecal block Over the last decades spinal anaesthesia is in increasing use in paediatric patients of all ages. The submitted published articles demonstrate that intrathecal application of bupivacaine has been studied prospectively in numerous paediatric patient populations. Batra YK, Lokesh VC, Panda NB, Rajeev S, Rao KLN. Dose-response study of intrathecal fentanyl added to bupivacaine in infants undergoing lower abdominal and urologic surgery. Paediatr.Anaesth. 2008;18(7):613-619. 58 infants (mean age between 6,33 ± 3.5 and 7.43 ± 2.9 months) undergoing lower abdominal and urologic procedures were randomized to receive either plain 0,5% hyperbaric bupivacaine (0,5 mg/kg for <5kg, 0,4 mg/kg for 5-10kg), or bupivacaine added with 0,25, 0,5 or 1µg/kg fentanyl respectively for spinal anaesthesia, placed under propofol sedation. The addition of 1µg/kg fentanyl significantly increased the duration of spinal anaesthesia and significantly less rescue analgesics were required. No significant differences were detected in the other groups. Batra YK, Rajeev S, Panda NB, Lokesh VC, Rao KLN. Intrathecal neostigmine with bupivacaine for infants undergoing lower abdominal and urogenital procedures: Dose response. Acta Anaesthesiol.Scand. 2009;53(4):470-475. 75 infants aged 1-12 months undergoing lower abdominal and urogenital procedures were randomized to receive either plain 0,5% hyperbaric bupivacaine (0,5 mg/kg for <5kg, 0,4 mg/kg for 5-10kg),, or bupivacaine with 0,25, 0,5, 0,75 or 1µg/kg of neostigmine respectively for spinal anaesthesia under propofol sedation. Two children failed to reach spinal blockade. Addition of 0,5, 0,75 and 1µg/kg neostigmin prolonged spinal anaesthesia duration without a significant between 0,75 and 1 µg.


Batra YK, Rakesh SV, Panda NB, Lokesh VC, Subramanyam R. Intrathecal clonidine decreases propofol sedation requirements during spinal anesthesia in infants. Paediatr.Anaesth. 2010;20(7):625-632. In this prospective double-blind study 65 infants aged 2-11 months undergoing elective lower abdominal surgery were randomly assigned to receive either hyperbaric bupivacaine 0,5% (0,5 mg/kg for <5kg, 0,4 mg/kg for 5-10kg), bupivacaine with 1µg/kg clonidine, bupivacaine with 1µg/kg fentanyl or bupivacaine with both for spinal anaesthesia administered under propofol sedation. The requirement of propofol sedation reduces with intrathecal adjuvants, significantly when clinidine is administered. Frawley G, Smith KR, Ingelmo P. Relative potencies of bupivacaine, levobupivacaine, and ropivacaine for neonatal spinal anaesthesia. Br.J.Anaesth. 2009;103(5):731-738. 151 infants of <55 weeks post menstual age undergoing inguinal hernia repair under spinal anaesthesia were enrolled. Either bupivacaine, levobupivacaine or ropivacaine were administered. To estimate ED50 (in 81 patients) doses to be administered were determined according to Dixon’s up-down sequential allocation method starting with 0,25 ml/kg of the 0,5% local anaesthetic (1,25 mg/kg). In phase 2, four dose levels above the calculated ED50 were defined as a dose escalation. ED50 estimates were 0,3 mg/kg for bupivacaine, 0,55 mg/kg for levobupivacaine and 0,50 mg/kg for ropivacaine. ED95 estimates were 0,96 mg/kg for bupivacaine, 1,18 mg/kg for levobupivacaine and 0,99 mg/kg for ropivacaine. Bupivacaine is estimated to be more potent than either ropivacaine or levobupivacaine , the potency difference, hoever, is less marked at the ED95. An appropriate dose for infant spinal anaesthesia is 1 mg/kg of isobaric 0,5% bupivacaine and ropivacaine and 1,2 mg/kg of isobaric levobupivacaine. At these doses, duration of surgical anaesthesia should last approximately 80 min.Although no adverse events or excessively high blocks were encountered in this study, caution is warranted in exceeding these doses. Hermanns H, Stevens MF, Werdehausen R, Braun S, Lipfert P, Jetzek-Zader M. Sedation during spinal anaesthesia in infants. Br.J.Anaesth. 2006;97(3):380-384. 20 unpremedicated preterm infants underwent surgery under spinal anaesthesia with hyperbaric bupivacaine 0,5% 1 mg/kg with epinephrine 10µg/kg. BIS was recorded to assess sedation, which was at least as pronounced as in adults. The sedative effect of spinal anaesthesia should be kept in mind when additional sedatives are administered. Hesselgard K, Stromblad LG, Reinstrup P. Morphine with or without a local anaesthetic for postoperative intrathecal pain treatment after selective dorsal rhizotomy in children. Paediatr.Anaesth. 2001;11(1):75-79. 12 children aged 3-6 years received either intermittent IT morphine 5 µg/kg four times a day or continuous infusion of bupivacaine 40µg/kg/h and morphine 0,6µg/kg/h for postoperative pain control after dorsal rhizotomy. The continuous application of bupivacaine and morphine was superior in the treatment of pain. Imbelloni LE, Vieira EM, Sperni F, Guizellini RH, Tolentino AP. Spinal anesthesia in children with isobaric local anesthetics: Report on 307 patients under 13 years of age. Paediatr.Anaesth. 2006;16(1):43-48. 307 children aged 0-12 years were scheduled for spinal anaesthesia with enantiomeric mixture of bupivacaine (S75:25R) 0,5 mg/kg or racemic bupivacaine 0,5% 0,5 mg/kg or lidocaine 2% 2 mg/kg. 32 patients <2 years, 140 of the age 2-6 years and 135 at the age 6-13 years have been included.


Spinal anaesthesia was successful in 98% and there were no incidences of recognizable spinal cord injury. Imbelloni LE, Vieira EM, Beato L, Zapatta C. Isobaric 0.5% bupivacaine for spinal anesthesia in pediatric outpatient surgery of 6 to 12 year old children. A prospective study. Rev.Bras.Anestesiol. 2002;52(4):402-409. 40 children aged 6-12 years undergoing spinal anaesthesia with 0,5 mg/kg of 0,5% isobaric plain bupivacaine were evaluated. Onset time was 2.6 ± 1,28 min, analgesia duration was 4.51 ± 0,89 h, time for ambulation was 4.04 ± 0,83 h, PACU stay was 44.39 ± 43.13 min, motor block duration was 2,5 ± 0,83 h, sensory block level varied form T9 to T4. Motor block onset was less than 3 min. Over 70% recovered to motor block 3 or 2 at surgery completion. No patient showed oxygen desaturation or hypotension. Bradycardia was observed in two patients. There were no postdural puncture headache (PDPH) or transient neurological symptoms. Jetzek-Zader M, Hermanns H, Freynhagen R, Lipfert P, Stevens MF. Increase in Skin Temperature After Spinal Anesthesia in Infants. Reg.Anesth.Pain Med. 2006;31(6):519-522. In 15 infants of postconceptual age 45.0 ± 4.8 weeks, weight 4.0 ± 1.2 kg, scheduled for inguinal hernia repair under spinal anaesthesia, skin temperature at T4 level and at plantar foot was measured. Spinal anaesthesia was induced with 0,5% hyperbaric bupivacaine 1 mg/kg with 10µg/kg adrenaline added. A significant increase in skin temperature of the feet within 10 min as a sign of sympatholysis was observed, blood pressure decreased but remained within the normal range, despite sympatholysis. Kokki H, Hendolin K, Vainio J, Partanen J. Comparison of spinal anaesthesia with general anaesthesia for paediatric surgery. Anaesthesist 1992;41(12):765-768. 40 children aged 2-5 years were randomly assigned to receive either spinal or general anaesthesia. Spinal anaesthesia was performed with bupivacaine 0,5% at a dose of 0,5 mg/kg. Time spent in the operation room was shorter in the spinal anaesthesia group, after general anaesthesia arterial desaturation was detected in 11 of the 20 patients. After spinal anaesthesia three patients were restless. Kokki H, Hendolin H, Turunen M. Postdural puncture headache and transient neurologic symptoms in children after spinal anaesthesia using cutting and pencil point paediatric spinal needles. Acta Anaesthesiol.Scand. 1998;42(9):1076-1082. In this open randomised parallel group prospective study puncture quality, success rate and postpuncture characteristics in 200 children aged 2-128 months were studied. Patients were sedated with thiopentone or propofol. Spinal anaesthesia was performed with bupivacaine 0,5% 0,3-0,5 mg/kg. Success rate of SA was 91%. Spinal block was completed in less than 3 min in


96% of the cases. 17 children developed headache, 10 were classified as PDPH, which is common in children, 10 children developed low back pain, 3 signs of transient radicular irritation. Kokki H, Tuovinen K, Hendolin H. Spinal anaesthesia for paediatric day-case surgery: A double-blind, randomized, parallel group, prospective comparison of isobaric and hyperbaric bupivacaine. Br.J.Anaesth. 1998;81(4):502-506. In a prospective double blind, randomized parallel group study 100 children aged 2-115 months were assigned to receive either isobaric or hyperbaric bupivacaine 0,5% at a dose of 0,3-0,5 mg/kg for spinal anaesthesia. Success rate of the block was greater with hyperbaric bupivacaine (96% versus 82%). 5 children developed a mild, position dependent headache. Kokki H, Heikkinen M, Turunen M, Vanamo K, Hendolin H. Needle design does not affect the success rate of spinal anaesthesia or the incidence of postpuncture complications in children. Acta Anaesthesiol.Scand. 2000;44(2):210-213. This randomised parallel group and prospective study investigated 215 children aged 1-18 y receiving spinal anaesthesia with different needle types. Hyperbaric bupivacaine 0,5% was administered at a dose of 0,3-0,4 mg/kg. Success rate of spinal anaesthesia was 97%. 24 children developed a headache, 8 were classified as PDPH. 9 children developed signs of transient radicular irritation. Kokki H, Hendolin H. No difference between bupivacaine in 0.9% and 8% glucose for spinal anaesthesia in small children. Acta Anaesthesiol.Scand. 2000;44(5):548-551. Two hyperbaric bupivacaine solutions in 0,9% and in 8% glucose for spinal anaesthesia were investigated in 60 children aged 1-7 years in a double blind randomised parallel group study. Bupivacaine 0,5% in either 0,9 or 8% glucose was injected at a dose of 0,4 mg/kg. Success rate, spread and duration of sensory block and adverse effects were similar in both groups. Kokki H, Hendolin H. Hyperbaric bupivacaine for spinal anaesthesia in 7-18 yr old children: Comparison of bupivacaine 5 mg/ml in 0.9% and 8% glucose solutions. Br.J.Anaesth. 2000;84(1):59-62. In a prospective double blind, randomized parallel group study 107 children aged 7-18 years were assigned to receive hyperbaric (either in 0,9 or in 8% glucose) bupivacaine 0,5% at a dose of 0,3 mg/kg for spinal anaesthesia. Success rate, spread and duration of sensory block and adverse events were similar in both groups. Somri M, Gaitini LA, Vaida SJ, Malatzkey S, Sabo E, Yudashkin M, et al. The effectiveness and safety of spinal anaesthesia in the pyloromyotomy procedure. Paediatr.Anaesth. 2003;13(1):32-37. 25 infants aged 1-5 weeks undergoing pyloromyotomy were administered spinal anaesthesia with bupivacaine 0,5% at a dose of 0,8 mg/kg. Sensory levels ranged between T3 and T5. The authors proposed that spinal anaesthesia is an slternative option to general anaesthesia in infants undergoing pyloromyotomy.

The above published articles present a total number of 1116 paediatric patients of all ages undergoing spinal anaesthesia with bupivacaine 0,5%. Of these, at least 370 patients have been


< 1 year, with 50 patients < 4 months and 25 in the range of 1-5 weeks. 20 preterm infants have been included as well. Anaesthesia was performed with either isobaric or hyperbaric bupivacaine at doses between 0,3 and 1 mg/kg. Children < 1 year received higher doses (0,8 – 1 mg/kg). Epinephrine was added only in two studies in a total of 35 patients. Across studies, spinal anaesthesia was effective and safe.

3. Discussion on clinical aspects and conclusion

From the presented extract of published literature of the last decades it can be derived that bupivacaine is in widespread use in paediatric patients. At present, product information (SmPC and PL) does not reflect the current state of knowledge and has to be updated. We agree to the MAH that there is sufficient evidence in the literature to support the proposed additional paediatric indications for bupivacaine 2,5 and 5 mg/ml solution for injection:

local infiltration

peripheral nerve block Across studies local infiltration techniques and peripheral nerve blocks have been efficacious and safe in children above 1 year of age. However, it should be very clearly stated in SmPC/PL that depending of age and site of injection concentration and amount of solution for injection should be determined. We also agree to the MAH to introduce an additional indication

spinal anaesthesia for bupivacaine 5 mg/ml and hyperbaric bupivacaine 5 mg/ml solution for injection. Throughout published articles it was demonstated that spinal anaesthesia with bupivacaine could be performed efficaciously and safe in children of all ages. No conclusions should be drawn during this worksharing procedure as regards the paediatric use of bupivacaine with the addition of epinephrine.

Proposal of the MAH for the wording to be introduced for children:

It would be helpful to compare the complete CCDS with the proposed changes as the national SmPC version might differ slightly .A proposal for the wording in sections 4.1, 4.3, 4.4 and 4.8 is missing or a statement about no changes required. A proposal for the PL wording is missing as well.

Section 4.2:

Paediatric patients 1 to 12 years of age The doses in the table should be regarded as guidelines for use in paediatrics. Individual variations occur.

In children with a high body weight a gradual reduction of the dosage is often necessary and should be

based on the ideal body weight. Standard textbooks should be consulted for factors affecting specific

block techniques and for individual patient requirements. The duration may be prolonged with the

adrenaline-containing solutions.

N.B. Risk of systemic effects of adrenaline with large volumes of adrenaline containing solutions should

be considered.


Dosage recommendations for children

Conc.

mg/ml

Volume

ml/kg

Dose

mg/kg

Onset

min

Duration of

effect

hours

ACUTE PAIN MANAGEMENT (per-and

postoperative)

Caudal Epidural Administration

2.5 0.6-0.8 1.5-2 20-30 2-6

Lumbar Epidural Administration

2.5 0.6-0.8 1.5-2 20-30 2-6

Thoracic Epidural Administration

2.5 0.6-0.8 1.5-2 20-30 2-6

Field Block

(eg, minor nerve blocks and infiltration)

2.5 0.5-2.0

5.0 0.5-2.0

Peripheral Nerve Blocks

(e.g ilioinguinal –iliohypogastric)

2.5 0.5-2.0

5.0 0.5-2.0

In children the dosage should be calculated on a weight basis up to 2 mg/kg.

As bupivacaine is already in widespread use for local infiltration techniques also in children it can be agreed to add the indication “Field block” for children > 1 year of age with a maximum dose of 2 mg/kg. The addition of epinephrine to paediatric local anaesthetic techniques should not be discussed during this worksharing procedure. At present the database does not seem to be very extended. A separate discussion for the combined medicinal products is required. Peritonsillar infiltration has only been performed in children > 2 years of age.

Most of the studies have been performed with bupivacaine 0,25% for ilioinguinal-iliohypogastric blockade in children > 1 year at doses between 0,25-1,25 mg. Furthermore, it has to be taken into consideration the study of Smith et al., who described an unexpected high plasma level in small children (10-15 kg) after administration of bupivacaine 0,5% at a dose of 1,25 mg/kg.

Section 4.2: (Spinal anaesthesia)

Adults and children above 12 years of age

Dosage recommendations

Conc.

mg/ml

Dose Onset

(min)

Duration (h)

ml mg

MARCAINE Spinal

Lower limb, including hip

surgery

5.0 2-4 10-20 5-8 1.5-4


Conc.

mg/ml

Dose Onset

(min)

Duration (h)

ml mg

7.5 1-2.5 7.5-18.5 5-8 1.5-4

MARCAINE Spinal Heavy

Urological 5.0 1.5-3 7.5-15 5-8 2-3

Lower abdominal surgery

(incl. caesarean section), lower

limb, including hip surgery

5.0 2-4 10-20 5-8 1.5-3

Urological 7.5 1.5-3 11.25-22.5 5-8 2-3

Lower abdominal surgery

(incl. caesarean section), lower

limb, including hip surgery

7.5 1.5-3 11.25-22.5 5-8 2-3

Children up to 40 kg

MARCAINE Spinal 5 mg/ml and MARCAINE Spinal Heavy 5 mg/ml may be used in children.

One of the differences between small children and adults is a relatively high CSF volume in infants and

neonates, requiring a relatively larger dose/kg to produce the same level of block as compared to adults

Table 1 Dosage recommendations in children

Body weight (kg) Dose (mg/kg)

<5 0.40-0.50 mg/kg

5 to 15 0.30-0.40 mg/kg

15 to 40 0.25-0.30 mg/kg

In section 4.1 and 4.2 age limits should be specified. According to the studies of Frawley, Hermanns; Jetzek-Zader and Somri in infants < 1 year higher doses have been studied for spinal anaesthesia.

4. Request for supplementary information (RMS)

Comparison of the complete CCDS with the proposed changes should be provided as the national SmPC versions might differ.

A proposal for the wording in sections 4.1, 4.3, 4.4 and 4.8 or a statement about no changes required should be provided.

In section 4.1 and 4.2 age limits should be specified.

A proposal for the PL wording should be provided.

Revision of the proposed wording should take into account the comments of Section IV.3. It should be very clearly stated that depending of age and site of injection concentration and amount of solution for injection should be determined for local infiltration and peripheral nerve blocks

Wording should be clearly attributed to the three different medicinal products


V. RAPPORTEUR’S OVERALL CONCLUSION AND RECOMMENDATION

Overall conclusion Many published articles of the last years provide information about well established use of bupivacaine in paediatric patient populations which should be reflected by the product information. Recommendation Based on the data submitted, the MAH should provide a revision of the proposed wording for SPC and PL1 as part of this worksharing procedure. (see section IV.4 “Request for supplementary information”) Comments Member States IE, HU and SE endorse the Rapporteur’s overall conclusion without further comments. UK agrees with the overall conclusions of the Rapporteur but has the following points for consideration by the Rapporteur and other MS before adopting final recommendations for the SmPC and proposes to address the following additional questions for clarification to the MAHs : General points (as required) This European paediatric work-sharing procedure is reviewing the available data with the intention of updating the SmPC paediatric indications and posology. As such, the information should reflect the anaesthetic practices across Europe and provide a safe framework of guidance for medical practitioners. The MHRA notes that there is a significant body of literature with data on the use of Bupivacaine not only in spinal anesthesia but also in caudal and epidural administration which across Europe is one of its major paediatric uses. This information should be discussed and therefore the MAH is requested to review the available data and propose appropriate SmPC recommendations to reflect this use of Bupivacaine in the paediatric population. The MHRA notes that the addition of epinephrine to paediatric local anaesthetic techniques was not discussed during this work-sharing procedure. However the MHRA believes there is the need to review this combined use as it is often used in paediatric anaesthesia in order to increase the duration of the block particularly in very vascular areas. Specific points (as required) Regarding the dosage recommendations in section 4.2 the MHRA is concerned about the proposed wording. Particularly in the table on page 20/23 of the AR, the maximum dose of bupivacaine by caudal, lumbar and thoracic epidural routes is given as the same. However giving this dose as a single shot at the thoracic level rather than incrementally, is considered to be dangerous, with an increased risk of central hypotension and other severe adverse events. The MHRA is of the view that the dosing proposals should be reviewed in order to emphasize the need to give drugs incrementally particularly in the lumbar and thoracic epidural routes as well as the safety support and environment needed for administration. Regarding the use of Bupivacaine in spinal surgery, the MHRA notes that the 2.5mg/ml formulation is also often used in spinal anaesthesia in children apart from the hyperbaric 5mg/ml and as the rapporteur identified there is a wide variety of doses reported in the literature. The

1 Directly linked to the study(ies) submitted


MHRA supports rapporteur’s request for clarity of the indications and posology proposed in the SmPC of all Bupivacaine products.

NL agrees with the overall conclusion of the Rapporteur but has one additional comment which concerns the use of the available products in neonates with low body weight: The company is requested to consider the applicability of the product to children with a low bodyweight i.e. preterm and dysmature neonates and to take appropriate measures, e.g. by the development of lower concentration or a minimum body weight in the SPC. The administration of a 0,40 mg/kg dose with a 5 mg/ml concentration equals the administration of 0,08 ml/kg. In accordance with the draft guideline on the pharmaceutical development of medicines for paediatric use, dosing volumes should not be smaller than 0.1 ml using an appropriate 1.0 ml syringe i.e. the child should at least weigh 1,25 kg. It is noted that the guideline is still under public consultation and the minimum volume may be changed in view of stakeholders’ comments. FR does not agree with the Rapporteur’s conclusions on the following indication: In children, local infiltration with bupivacaine requires large doses; due to the toxicity of this local anaesthetic agent, it should not be used. The use of ropivacaine or levobupivacaine is recommended as they are less toxic. Summary of request for supplementary information by Member States

Dose recommendations for different locations of epidural anaesthesia in children should be discussed according to the available literature.

Dose recommendations for spinal anaesthesia as regards the various concentrations of bupivacaine should be discussed regarding available literature.

A separate review of literature about indications and dose recommendations for the combination product bupivacaine and epinephrine should be presented.

The company is requested to consider the applicability of the product to children with a low bodyweight i.e. preterm and dysmature neonates taking into account the draft guideline on the pharmaceutical development of medicines for paediatric use.

Safety of bupivacaine for local infiltration in children should be discussed.

VI. ASSESSMENT OF RESPONSE TO QUESTIONS

Spinal anaesthesia The MAH lined out that in general, paediatric dosing for intrathecal anaesthesia is related to weight. This is described in textbooks (Brown & Fisk 1990) and recently published literature (Kokki H. 2012). Therefore, no age limit is specified in the SmPC text proposal for Marcaine Spinal/Spinal heavy. According to the studies of Frawley et al 2009, Fösel et al 1994, Hermanns et al 2006, Jetzek-Zader et al 2006 and Somri et al 2003 in infants < 1 year higher doses have been studied for spinal anaesthesia than those recommended by the MAH. Infants have larger spinal fluid volume (4ml/kg compared with 2 ml/kg in the adult); thus require a relatively larger dose/kg to produce the same level of block (Brown & Fisk 1990). Although doses up to 1.2 mg/kg have been suggested for neonates, the MAH’s opinion is that the safety of these higher doses


injected intrathecally has not been established. This is also confirmed by recent literature (Kokki H. 2012). The MAH recommends that the lowest dose required for adequate anaesthesia should be used in order to minimize the risks in the paediatric population. The MAH recognizes that regional anaesthetic procedures in neonates are, and should be, performed by qualified clinicians who are familiar with this special population and the technique. The doses in section 4.2 in the prescribing information for Marcaine Spinal/Spinal heavy correspond to the dose recommendations in the currently approved SmPCs in the countries in EU where Marcaine Spinal/Spinal heavy is approved for paediatric use. The dosage recommendations should be regarded as guidelines rather than minimum and maximum doses. As regards the use of a 2.5mg/ml formulation for paediatric spinal anaesthesia the MAH has evaluated recently published material focusing on bupivacaine in paediatric anaesthesia covering the period 1992 to 2011. The literature search generated 19 publications in which bupivacaine was used for intrathecal anaesthesia. In 18 of those studies bupivacaine at a concentration of 5mg/mL was used (Batra et al 2008, Batra et al 2009, Batra et al 2010, Frawley et al 2009, Fösel et al 1994, Hermanns et al 2006, Imbelloni et al 2002, Imbelloni et al 2006, Jetzek-Zader et al 2006, Kokki et al 1992 – 2002 (7 studies in total), Somri et al 2003 and Vila et al 2002). Hyperbaric bupivacaine and isobaric bupivacaine was used in 10 studies respectively. Two studies used both isobaric and hyperbaric bupivacaine. From the Hesselgard et al 2001 publication it is not possible to determine the concentration used (40μg/kg/h) or whether the solution was iso- or hyperbaric. During this evaluation the MAH has not identified any study that used a lower concentration of bupivacaine than 5 mg/ml for intrathecal anaesthesia and therefore bupivacaine 2.5 mg/ml cannot be recommended for intrathecal anaesthesia. Preterm neonates: Although spinal anaesthesia in neonates with a weight below 1.25 kg is rarely performed, and if so, by specialists skilled in neonatal regional anaesthetic procedures, it is important that anaesthetic drugs are available to this population. In the SmPC text proposal for Marcaine Spinal/Spinal heavy it has been emphasized that paediatric regional anaesthetic procedures should be performed by qualified clinicians who are familiar with this population and the technique. Furthermore, it has been clarified that the recommended doses should be regarded as guidelines for use in paediatrics. Four studies (Fösel et al 1994, Hermanns et al 2006, Jetzek-Zader et al 2006, Vila et al 2002), in which bupivacaine 5 mg/ml has been used in neonates for intrathecal anaesthesia, have been identified in the published material covering the period 1992 to 2011. Fösel et al and Vila et al studied the neonates with the lowest body weights. Fösel et al studied 10 former pre-term neonates, gestational age 38 - 48 weeks and with a weight of 2.7 – 3.2 kg on the day of surgery. Spinal anaesthesia, using bupivacaine in a concentration of 5mg/mL with or without adrenaline 1:200 000, was administered in a volume of 0.6 ml to each neonate (Fösel et al 1994). In spite of the large bupivacaine dose used, they conclude that the haemodynamic parameters in this age group remain stable. The result from a study performed by Vila et al 2002 indicate that in preterm infants sedated with nitrous oxide, spinal anaesthesia for inguinal herniotomy performed with isobaric bupivacaine 0.5% with adrenaline 1:200 000 at a dose 1.0 mg/kg in the lateral or sitting position is equally effective and is associated with minimal side effects. The 30 pre-term neonates included in their study had a weight of 1.7 – 3.1 kg and a postconceptual age 34-37 weeks at the time of surgery. The doses used for spinal anaesthesia in this particular population are higher than what the MAH recommends. During this evaluation, the MAH has not identified any study in which neonates with a lower weight has been subjected to spinal anaesthesia with bupivacaine.


Infants have larger spinal fluid volume (4 ml/kg compared with 2 ml/kg in the adult); thus require relatively larger dose/kg to produce the same level of block (Brown & Fisk 1990). Hence, furnishing infants with a lower concentration e.g. 2.5 mg/ml bupivacaine, necessitates a larger injected volume and has the potential to result in a high level dermatomal block but an insufficiently dense sensory block. Given the above, the MAH has not suggested a minimum body weight in the SmPC text proposal for Marcaine Spinal/Spinal heavy and does not recommend a lower concentration than 5 mg/mL to be used for intrathecal anaesthesia in neonates. References: T.C. K Brown & G.C Fisk: Anaesthesia for Children, second edition 1990 (p 306), Blackwell Scientific Publications ISBN 0-632-03023-2). Frawley G, Smith KR, Ingelmo P. Relative potencies of bupivacaine, levobupivacaine, and ropivacaine for neonatal spinal anaesthesia. Br.J.Anaesth. 2009;103(5):731-738. Fösel Th, Wilhelm W, Grüez V, Molter G. Spinalanästhesie in Säuglingsalter mit Bupivacain 0.5%. Anaesthetist 1994;43: 26-29 Kokki, H. Spinal blocks. Pediatric Anesthesia 2012; 22: 56-64

The MAH submitted proposals for a paediatric SPC and PL wording based on the complete Company Core Data Sheet for: (According to the MAH acute spinal anasthesia is licensed with dose recommendations in the SmPCs for children up to 40 kg in several EU countries, proposed SmPC changes are underlined, children > 12 years are included in the recommendations for adults)

Marcaine Spinal 5 mg/ml, solution for injection

Marcaine Spinal 7.5 mg/ml, solution for injection

Marcaine Spinal Heavy 5 mg/ml, solution for injection

Marcaine Spinal Heavy 7.5 mg/ml, solution for injection 4.1 Therapeutic indications

(no text proposal specifying age limits) 4.2 Posology and method of administration

Neonates, infants and children up to 40 kg

MARCAINE Spinal 5 mg/ml and MARCAINE Spinal Heavy 5 mg/ml may be used in children.

One of the differences between small children and adults is a relatively high CSF

volume in infants and neonates, requiring a relatively larger dose/kg to produce the

same level of block as compared to adults.

Paediatric regional anaesthetic procedures should be performed by qualified

clinicians who are familiar with this population and the technique.

The doses in the table should be regarded as guidelines for use in paediatric

patients.

Individual variations occur. Standard textbooks should be consulted for factors

affecting specific block technique and for individual patient requirements. The

lowest dose required for adequate anaesthesia should be used.

Table Dosage recommendations in neonates, infants and children


4.3 Contraindications (no specific contraindications proposed for paediatric patients) 4.4 Special warnings and special precautions for use (no specific warnings proposed for paediatric patients) 4.8 Undesirable effects

(no specific text proposed for paediatric patients) PL: no specific text proposed for paediatric patients

As no data for the 7.5 mg/ml solution for injection is available for children < 12 years, the following wording is regarded as appropriate: SmPC: Section 4.1 <TRADENAME> is indicated in adults and children > 12 years of age. Section 4.2 The safety and efficacy of <TRADENAME> in children < 12 years of age have not been established. No data are available. For children < 12 years of age use of the 5 mg/ml strength is recommended. Section 4.3 (No specific contraindications were identified for paediatric patients) Section 4.4 (No specific warnings were identified for paediatric patients) Section 4.8 Adverse drug reactions in children are similar to those in adults.

In the latest review article about spinal anaesthesia in children (Kokki 2012) the following recommendations were given:


The author himself uses isobaric bupivacaine at a dose of 0.5 mg/kg for body weight 5-10 kg, 0.4 mg/kg for 11-19 kg and 0.3 mg/kg for >20 kg, which is slightly higher than the doses recommended by the MAH. Kokki pointed out that safety of much higher doses suggested by other authors (up to 1.2 mg/kg) has not been established. Across reviewed articles (see Section IV.3.2.) most infants <5 kg received 0.5mg/kg bupivacaine. According to the MAH, the proposed dosing scheme is already licenced in several EU countries. Thus, the proposed wording for the 5 mg/ml solution for injection can be accepted as follows: SmPC: Section 4.1 <TRADENAME> is indicated in adults and children of all ages Section 4.2 Neonates, infants and children up to 40kg MARCAINE Spinal 5 mg/ml and MARCAINE Spinal Heavy 5 mg/ml may be used in children. One of the differences between small children and adults is a relatively high CSF volume in infants and neonates, requiring a relatively larger dose/kg to produce the same level of block as compared to adults. Paediatric regional anaesthetic procedures should be performed by qualified clinicians who are familiar with this population and the technique. The doses in the table should be regarded as guidelines for use in paediatric patients. Individual variations occur. Standard textbooks should be consulted for factors affecting specific block technique and for individual patient requirements. The lowest dose required for adequate anaesthesia should be used. Table: Dosage recommendations in neonates, infants and children

Section 4.3 (No specific contraindications were identified for paediatric patients) Section 4.4 (No specific warnings were identified for paediatric patients) Section 4.8 Adverse drug reactions in children are similar to those in adults.

Epidural anaesthesia

As Marcaine injection (bupivacaine) has been marketed in the EU since 1966 (first approved in Denmark) including usage in paediatrics there is extensive clinical experience of this product for epidural use. The current prescribing information for epidural administration in children is in


accordance with clinical textbook recommendations (Broadman and Rice 1998, Willis J. 1998) and corresponds to the dose recommendations in the currently approved SmPCs in 14 of the countries in EU where Marcaine injection is marketed. Therefore the MAH considers a review of the available published data for epidural administration to add no value. The MAH agrees that the dose should be administered incrementally, particularly in the lumbar and thoracic epidural routes. The following text is suggested in the SmPC text proposal for Marcaine injection in order to clarify the administration “In order to avoid intravascular injection, aspiration should be repeated prior to and during administration of the main dose. This should be injected slowly or in incremental doses, particularly in the lumbar and thoracic epidural routes, constantly and closely observing the patient’s vital functions.”

Field blocks/Local anaesthesia

The MAH has evaluated published controlled studies for bupivacaine in paediatric use covering the period 1992 to 2011. No safety signals with regards to bupivacaine for local infiltration could be derived from these studies. A search of the MAH’s global safety database was conducted through 06 December 2011, to identify adverse event reports relating to bupivacaine use and local infiltration in children (<18 years of age). This search yielded 23 case reports. In the majority of these reports, the events described may have been due to improper technique of administration, underlying medical history or complications from the surgical procedure itself. Additionally, some of these reports did not contain the information that would be needed to assess causality. Following a review of these reports the MAH believes that local infiltration with bupivacaine in children and adolescents is safe when used as indicated in the SmPC text proposal. In the paediatric work-sharing DE/W/027/pdWS/001 for ropivacaine hydrochloride the MAH suggested that single infiltration with Naropin offer a less complicated technique and therefore is a valid option, but the conclusion from the procedure was that the database is too small to derive safety and efficacy for this paediatric indication. The available published literature for bupivacaine present a similar profile as ropivacaine when used for local infiltration in paeditric patients.

Fixed combination bupivacaine and adrenaline

A separate Clinical Overview has been compiled evaluating published results from studies in which bupivacaine with adrenaline has been utilised. Rationale for the fixed combination: Adrenaline (epinephrine) is a powerful vasoconstrictor added frequently to local anaesthetics to reduce their systemic absorption and to maintain a greater local concentration of the anaesthetic at its intended site of action. A reduced risk of bupivacaine-related adverse events and an extension of the duration of analgesia can be expected. Furthermore, inadvertent intravascular injections are expected to be detected earlier by means of cardiovascular responses to adrenaline. Pharmacokinetics According to Tucker and Mather 1998 the threshold total plasma bupivacaine concentration for significant CNS toxicity is in the range 2 to 4 µg/ml (age not specified). Doyle E, Morton NS, McNicol LR. Plasma bupivacaine levels after fascia iliaca compartment block with and without adrenaline. Paediatric Anaesthesia 1997;7(2):121-124.


20 chlidren aged 1-14 y undergoing unilateral removal of a femoral plate under general anaesthesia were randomly allocated to receive either plain bupivacaine (P) 0,25% (2 mg/kg) or bupivacaine 0.25% with 1:200 000 adrenaline (A) for a fascia iliaca compartment block. Venous blood samples were taken at 5, 10, 15, 20, 25, 30, 40, 50 and 60 min after injection. Plasma concentrations of bupivacaine were well within the acceptable limits. In all subjects an adequate block was produced. Median Cmax was significantly higher in group P (1,1 vs 0,35 µg/ml), Tmax was shorter in group P (20 min vs 45 min) and median time to first analgesia was 9,75 vs 10,5 h. The authors concluded that the addititon of adrenaline reduces the maximum plasma concentration of bupivacaine but does not appear to prolong the duration of the block. Breschan C, Hellstrand E, Likar R, Lönnqvist PA. Bupivacaine plasma concentrations associated with clinical and electroencephalographic signs of early central nervous system toxicity in infants during awake caudal anaesthesia. Anaesthesist 1998;47(4):290-294. 7 awake infants, postconceptual age 36-52 w, 2,3 – 4,7 kg, undergoing hernia repair received a caudal block with bupivacaine 3.1 mg/kg with epinephrine 5 µg/ml . In two patients EEG showed suspect epileptic activity associated with clinical signs of early central nervous system toxicity. Bupivacaine plasma concentrations ranged from 0.56-1.62 µg/ml. For safety reasons the study was stopped prematurely. The authors concluded that the lower level of alpha-1 acidglyco-protein might be associated with a higher unbound, free concentration of bupivacain in small infants and recommend not to exceed a dose of 2 mg/ml at maximum in caudal blocks at this age. Sprunger JK, Reese CT, Decter RM. Can standard open pediatric urological procedures be performed on an outpatient basis? Journal of Urology 2001;166(3):1062-1064. 45 of 51 patients aged 2 mo to 13 years undergoing open urological procedures under general anaesthesia received caudal block with 1 ml/kg bupivacaine 0.25% with adrenaline 1:200000. The wound was infiltrated before closure with 1 ml/kg 0.25% bupivacaine. In 5 patients blood samples were obtained 1 h after wound infiltration. The average level was 0.87µg/ml bupivacaine. Cheung SLW, Booker PD, Franks R, Pozzi M. Serum concentrations of bupivacaine during prolonged continuous paravertebral infusion in young infants. British Journal of Anaesthesia 1997;79(1):9-13. 22 infants aged 1 day to 20.4 weeks (>37 gestational week, > 2 kg bodyweight) undergoing thoracotomy for various cardiac procedures were treated with prolonged continuous paravertebral infusion of bupivacain for the management of post-thoracotomy pain. Immediately before chest closure, 0.25% bupivacaine 1.25 mg/kg was given into an extrapleural prarvertebral catheter. Subsequently, 0.125% bupivacaine with adrenaline 1:400 000 was infused at a rate of 0.2ml/kg/h for 48 h. There were no major complications relating to the technique and paravertebral block was an effective method to provide analgesia. Mean maximum serum bupivacaine concentration measured at any time after starting the infusion was 1.65 (0.47) µg/ml. 3 patients had maximum bupivacaine concentrations above 3 µg/ml at 30, 42 and 48 h. No clinical signs of toxicity could be observed. Wong AK, Bissonnette B, Braude BM, Macdonald RM, St-Louis PJ, Fear DW. Post-tonsillectomy infiltration with bupivacaine reduces immediate postoperative pain in children. Can.J.Anaesth. 1995;42(9):770-774. 43 children aged 2-10 years were randomized into three groups after tonsillectomy was performed. To receive either normal saline spray (0,5 ml/kg), bupivacaine 0,5% with 1 : 200 000 epinephrine peritonsillar infiltration or bupivacaine 0,5% with 1:200 000 epinephrine spray to both tonsillar beds (2 mg/kg). Peritonsillar infiltration of bupivacaine provided significantly superior immediate postoperative analgesia and lower opioid requirements compared to


bupivacaine spray or placebo. Blood samples were drawn at 5, 10, 15, 30 and 60 min following bupivacaine administration. Mean Plasma concentration was higher in patients receiving submucosal infiltration than in those receiving topical spray (0,54 vs 0,19 µg/ml, p <0.05), but well below the toxic range in all patients.

Only limited paediatric data is available comparing PK of plain bupivacaine with bupivacaine and adrenaline. Regarding epidural administration there is only one comparative study (Hansen 2001) in infants < 15 months indicating comparable Cmax and Tmax between groups being in accordance with data for adults (Abdel-Salem 1975). A significantly elevated prolonged terminal half life and elevated Cmax after 6h suggested prolongation of systemic absorption of bupivacaine in conjunction with adrenaline (in small infants). Regarding peripheral nerve blocks only one comparative study (Doyle 1997) in children < 14 years undergoing fascia iliaca compartment block indicated that the addition of adrenaline reduces the maximum plasma concentration of bupivacaine but does not appear to prolong the duration of the block concurring with data in adults (Wildsmith et al 1977). In SPC section 5.2 the current paediatric CCDS-wording for both plain bupivacaine and bupivacaine with adrenaline is: In children the pharmacokinetics is similar to that in adults. It seems sensible to add the fact that PK data in children is limited, at least for the combination with adrenaline.

Caudal / Epidural single injection The following studies have reported on single caudal/epidural injection of bupivacaine with adrenaline in paediatric patients: Controlled trials: Blanco D, Mazo V, Ortiz M, Fernandez-Llamazares J, Vidai F. Spread of local anesthetic into the epidural caudal space for two rates of injection in children. Regional Anesthesia 1996; 21(5):442-445. 79 ASA I children scheduled for minor surgery under general anaesthesia randomly received caudal anaesthesia with either 1ml/kg of 0.25% bupivacaine with 1:200 000 eipnephrine at 1 ml/s or at 1 ml per 10s. 20 children were 0-12mo, 30 were 13-36 mo and 29 were 37 – 72 mo old. Level of analgesia was not affected by the rate of injection. Gadiyar V, Gallagher TM, Crean PM, Taylor RH. The effect of a combination of rectal diclofenac and caudal bupivacaine on postoperative analgesia in children. Anaesthesia 1995; 50(9):820-822. 39 ASA I-II children aged 5,3 ± 2,14 y undergoing inguinal or penoscrotal surgery under general anaesthesia randomly received either caudal block with 0.125% bupivacaine 1 ml/kg and adrenaline 1:400 000 or caudal block in combination with rectally administered diclofenac 1 mg/kg. The need for supplementary analgesia (paracetamol) during the first 24 h postoperatively was higher in the group with caudal block alone. Jamali S, Monin S, Begon C, Dubousset AM, Ecoffey C. Clonidine in pediatric caudal anesthesia. Anesthesia and Analgesia 1994;78(4):663-666. 45 children aged 1-7 yr undergoing subumbilical surgery under general anaesthesia received caudal anaesthesia at random with either plain bupivacaine 0.25% 1 ml/kg (BG) or in addition with clonidine 1 µg/kg (CG) or epinephrine 1:200 000 (EG). Duration of postoperative analgesia was significantly increased by the addition of clonidin, but not by the addition of epinephrine.


Pathania J, Thakur JR, Sodhi SS. Comparison of efficacy and duration of caudal analgesia produced by bupivacaine alone and in combination with adrenaline and ketamine in children. Journal of Anaesthesiology Clinical Pharmacology 2003; 19(2):207-211. 60 ASA I children aged 3-12 y undergoing lower abdominal and genitourinary surgery under general anaesthesia received caudal anaesthesia at random with either plain bupivacaine 0.25% 1ml/kg or in addition with adrenaline 1:200 000 or ketamine 0.5 mg/kg. Quality and duration of analgesia was not significantly different between groups. Schrock CR, Jones MB. The dose of caudal epidural analgesia and duration of postoperative analgesia. Paediatric Anaesthesia 2003;13(5):403-408. 54 ASA I-II children aged 1-6 y undergoing elective inguinal herniorraphy under general anaesthesia received caudal anaesthesia at random with three doses of bupivacaine 0.25% addition with adrenaline 1:200 000: 0.7, 1 or 1.3 ml/kg. Duration of analgesia was not significantly different between groups. Fisher QA, McComiskey CM, Hill JL, Spurrier EA, Voigt RE, Savarese AM, et al. Postoperative voiding interval and duration of analgesia following peripheral or caudal nerve blocks in children. Anesthesia and Analgesia 1993;76(1):173-177. 82 ASA I-II children aged 6 mo – 10y undergoing herniorraphy or orchidopexie under general anaesthesia received randomly caudal anaesthesia with either plain bupivacain 0,25% 0,75 ml/kg or in addition with 1:200 000 epinephrine or ilioinguinal-iliohypogastric nerve block (bupivacain 0,25% 0,75 ml/kg with 1:200 000 epinephrine) through the wound by the surgeon. 8 patients were excluded from further analysis due to pain within half an hour after surgery. Postoperative analgesia and time to micturation did not deffer significantly between groups. Klimscha W, Chiari A, Michalek-Sauberer A, Wildling E, Lerche A, Lorber C, et al. The efficacy and safety of a clonidine/bupivacaine combination in caudal blockade for pediatric hernia repair. Anesthesia and Analgesia 1998;86(1):54-61. In this prospective randomized double-blind placebo-controlled study 58 children aged 38 ± 2 months undergoing hernia repair under general anaesthesia received caudal anaesthesia with either 0,75 ml/kg placebo (normal saline), plain bupivacaine 0.25%, bupivacaine 0.25% with epinephrine 1:200 000, bupivacaine 0.25% with clonidine 1 µg/kg or bupivacaine 0.25% with clonidine 2 µg/kg. Duration of analgesia was significantly longer in the clonidine-groups compared to placebo, bupivacaine and bupivacaine with epinephrine. Cook B, Grubb DJ, Aldridge LA, Doyle E. Comparison of the effects of adrenaline, clonidine and ketamine on the duration of caudal analgesia produced by bupivacaine in children. British Journal of Anaesthesia 1995; 75(6):698-701. 60 boys aged 1-10 y undergoing orchidopexy under general anaesthesia received randomly caudal anaesthesia with either 0.25% bupivacaine 1 ml/kg and adrenaline 1:200 000 (A), clonidine 2µg/kg (C) or ketamine 0.5 mg/kg (K). The median duration of analgesia was significantly longer in group K compared to C and A and also significantly longer in group C compared to A. Deng M, Wang X, Wang L, Zheng S. The hemodynamic effects of newborn caudal anesthesia assessed by transthoracic echocardiography: A randomised, double-blind, controlled study. Paediatric Anaesthesia 2008;18(11):1075-1081. In this controlled double-blind study, 30 ASA I-II full term newborn infants undergoing lowerabdominal or urinary tract surgery under general anaesthesia with sevofluran, received either no (GA), caudal block with plain 0.2% Bupivacaine (1.25 ml/kg) (GA+CP) or with 0.2%


Bupivacaine (1.25 ml/kg) plus epinephrine 1:200 000 (GA+CA). Haemodynamic variables did not differ significantly between groups. Gouyet I, Dubois MC, Murat I, Saint-Maurice C. Comparison of two anesthesia techniques on perioperative insulin response to i.v. glucose infusion in children. Acta Anaesthesiologica Scandinavica 1993;37(1):12-16. 20 children aged 1-9 y undergoing minor genitourinary surgery of less than 2h duration under general anaesthesia randomly received epidural anaesthesia with 0.25% bupivacaine 0.75 ml/kg plus adrenaline 1:200 000 or not. Defined perioperative glucose infusion produced a similar increase in blood glucose in both groups, but insulin secretion was significantly greater in the group receiving regional anaesthesia. Marhofer P, Krenn CG, Plochl W, Wallner T, Glaser C, Koinig H, et al. S(+)-ketamine for caudal block in paediatric anaesthesia. British Journal of Anaesthesia 2000; 84(3):341-345. In this prospective randomized double blind study 49 children aged 3 mo to 6 yr undergoing hernia repair under general anaesthesia were given a caudal injection (0.75 ml/kg) of either ketamine 0.5 mg/kg (K1), ketamine 1.0 mg/kg (K2) or 0.25% bupivacaine with epinephrine 1 : 200 000 (B). Mean duration of analgesia was significantly longer in groups B and K2. Menezes M, Gozzani J. Postoperative analgesia in pediatric patients: Comparative study among local anesthetics, opioids and non-steroidal anti-inflammatory drugs. Revista Brasileira De Anestesiologia 2002;52(2):175-184. 100 ASA I-III children aged 2-12 y undergoing lower limb, urogenital or infraumbilical surgery under general anaesthesia received either 0.25% bupivacaine with 1:400 000 epinephrine (0.5-1.0 ml/kg) (B), fentanyl 1,5µg/kg in 10 ml saline (F), morphine 30µg/kg in 10 ml saline (M), sufentanil 0.3µg/kg in 10 ml saline (S) for caudal analgesia or 1mg/kg diclofenac rectally. Analgesia was longer in group S with significance to D and B. D had a very high need for analgesics during the first 4 h. Side effects were more frequent in patients with opioids. Splinter WM, Reid CW, Roberts DJ, Bass J. Reducing pain after inguinal hernia repair in children: Caudal anesthesia versus ketorolac tromethamine. Anesthesiology 1997;87(3):542- 546. In this randomized single-blinded investigation 164 children aged 2-6 y undergoing elective outpatient inguinal hernia repair under general anaesthesia were randomly assigned to receive caudal analgesia with 1 ml/kg 0.25% bupivacaine plus 1:200 000 epinephrine or intravenous ketorolac 1 mg/kg immediately after induction of anaesthesia. Both groups received additional field blocks with 0.25% bupivacaine under direct vision during surgery. Pain at home was significantly less in the ketorolac group, these patients had also a lower incidence of vomiting and micturated earlier. Splinter WM, Bass J, Komocar L. Regional anaesthesia for hernia repair in children: Local vs caudal anaesthesia. Canadian Journal of Anaesthesia 1995; 42(3): 197-200 In this randomized, single blind investigation 202 ASA I-II children aged 1-13y undergoing inguinal hernia repair under general anaesthesia received either caudal anaesthesia (1 ml/kg bupivacaine 0.2% plus 5µg/ml adrenaline) or ilioinguinal and iliohypogastric nerve block plus subcutaneous injection by the surgeon (up to 0.3 ml/kg bupivacaine 0.25% plus 5µg/kg adrenaline). No significant differences regarding postoperative outcome could be observed. Campbell FA, Fear DW, Bissonnette B, Yentis SM. Analgesic efficacy and safety of a caudal bupivacaine-fentanyl mixture in children. Canadian Journal of Anaesthesia 1992;39(7):661- 664.


34 ASA I-II children aged 1-11 y undergoing urological surgery under general anaesthesia randomly received a caudal injection of 1 ml/kg bupivacaine 0.125% with epinephrine 1:400 000 and 1 ml normal saline with or without 1 µg/kg fentanyl. Pain and sedation scores die not deffer between groups. In conclusion the addition of fentanyl showed no advantage. Joshi W, Connelly NR, Dwyer M, Schwartz D, Kilaru PR, Reuben SS. A comparison of two concentrations of bupivacaine and adrenaline with and without fentanyl in paediatric inguinal herniorrhaphy. Paediatric Anaesthesia 1999;9(4):317-320. 56 ASA I-II children aged 6 mo – 6 y undergoing hernia repair under general anaesthesia randomly received randomly, but not blinded 1 ml/kg bupivacaine 0.125% or 0.25% all plus epinephrine 1:200 000 with or without 1µg/kg fentanyl. No difference in pain scores, but significantly more patients with 0.125% plain bupivacaine received iv fentanyl. As significantly more patients with 0.25% bupivacaine, with and without epidural fentanyl had a higher incidence of vomiting, the authors recommend the use of bupivacaine 0.125% bupivacaine with fentanyl. Lawhorn CD, Stoner JM, Schmitz ML, Brown J, R.E, Stewart FW, Volpe P, et al. Caudal epidural butorphanol plus bupivacaine versus bupivacaine in pediatric outpatient genitourinary procedures. Journal of Clinical Anesthesia 1997;9(2):103-108. In this randomized, double-blind, controlled study, 200 ASA I-II male patients aged 6 mo to 10 y undergoing genitourinary surgery under general anaesthesia received caudal block with 0.75 ml/kg bupivacaine 0.25% with 1:200 000 epinephrine either with or without 30 µg/kg butorphanol. Patients with butorphanol needed significantly less postoperative analgesia. Santhosh Kumar TP, Jacob R. A comparison of caudal epidural bupivacaine with adrenaline and bupivacaine with adrenaline and pethidine for operative and postoperative analgesia in infants and children. Anaesthesia and Intensive Care 1993;21(4):424-428. 50 ASA I children aged 6 mo to 12y undergoing elective surgery below segmental level of T-10 under general anaesthesia randomly received caudal analgesia with 0.5-0.75 ml/kg bupivacaine plus 1:200 000 adrenaline with or without 0.5 mg/kg pethidine. Though children receiving pethidine had a longer duration of analgesia and sedation the high incidence of vomiting and delay in urination observed precludes the routine use. Tripi PA, Palmer JS, Thomas S, Elder JS. Clonidine increases duration of bupivacaine caudal analgesia for ureteroneocystostomy: A double-blind prospective trial. Journal of Urology 2005;174(3):1081-1083. 35 ASA I – II children aged 1 – 10 y undergoing ureteroneocystostomy under general anaesthesia randomly received caudal block with 0.125% bupivacaine plus 1:400 000 epinephrine with or without 1 µg/kg clonidine. The addition of clonidine significantly increased duration of caudal analgesia and decreased postoperative morphine requirements. Malviya S, Fear DW, Roy WL, Lerman J. Adequacy of caudal analgesia in children after penoscrotal and inguinal surgery using 0.5 or 1.0 ml kg-1 bupivacaine 0.125%. Canadian Journal of Anaesthesia 1992;39(5 I):449-453. In this prospective, randomized, double-blind study 80 ASA I – II children aged 1-10 y undergoing penoscrotal and inguinal surgery under general anaesthesia received a caudal block with either 0.5 ml/kg or 1.0 ml/kg bupivacaine 0.125% with 1:200 000 epinephrine. ‘Analgesia and aupplemental analgesic requirements did not differ between groups. Ho JWS, Khambatta HJ, Pang LM, Siegfried RN, Sun LS. Preemptive analgesia in children: Does it exist? Regional Anesthesia 1997; 22(2):125-130. In this randomised observer blinded study 51 patients aged 1-6 y undergoing minor elective ilioinguinal surgery under general anaesthesia either received a preincisional caudal block with


0.6ml/kg bupivacaine 0.25% plus 1:200 000 epinephrine or a postincisional one after surgery. Postoperative pain scores did not differ between groups. *Hansen TG, Morton NS, Cullen PM, Watson DG. Plasma concentrations and pharmacokinetics of bupivacaine with and without adrenaline following caudal anaesthesia in infants. Acta Anaesthesiologica Scandinavica 2001; 45(1):42-47. Uncontrolled studies *Breschan C, Hellstrand E, Likar R, Lönnqvist PA. Bupivacaine plasma concentrations associated with clinical and electroencephalographic signs of early central nervous system toxicity in infants during awake caudal anaesthesia. Anaesthesist 1998;47(4):290-294. Freid EB, Bailey AG, Valley RD. Electrocardiographic and hemodynamic changes associated with unintentional intravascular injection of bupivacaine with epinephrine in infants. Anesthesiology 1993;79(2):394-398. Case reports of unintentional intravascular injection of 0.5 ml 0.25-0.375% bupivacaine plus 5µg/ml epinephrine in 4 neonates (1800 – 3400 g) and one 2 month old infant (4 kg) receiving caudal anaesthesia showing ST-T changes and relative bradycardia immediately after injection and resolving rapidly. Krishna HM, Sehgal R, Kumar R. Heart rate changes with test dose and total dose during caudal epidural block in children as a test to predict correct needle placement. Journal of Anaesthesiology Clinical Pharmacology 2004; 20(3):283-286. 50 ASA I-II children aged 0.3-12 y undergoing infra-umbilical surgery under general anaesthesia received caudal epidural 0.1 ml/kg 0.25% bupivacaine plus 5µg/kg epinephrine as test dose followed by 1 ml/kg 0.25% bupivacaine. Caudal block was successful in 45 patients and associated with a significant decrease in heart rate following test dose injection. Larousse E, Asehnoune K, Dartayet B, Albaladejo P, Dubousset AM, Gauthier F, et al. The hemodynamic effects of pediatric caudal anesthesia assessed by esophageal Doppler. Anesthesia and Analgesia 2002;94(5):1165-1168. In 10 ASA I-II children aged 2 mon to 5 y undergoing lower abdominal surgery under general anaesthesia haemodynamic effects of caudal anaesthesia 1 ml/kg 0.25% bupivacaine plus 1 : 200000 epinephrine were investigated by transesophageal Doppler. Heart rate and mean arterial blood pressure were unchanged by caudal anaesthesia, but descending aortic blood flow was significantly increased. Monsel A, Salvat-Toussaint A, Durand P, Haas V, Baujard C, Rouleau P, et al. The transesophageal Doppler and hemodynamic effects of epidural anesthesia in infants anesthetized with sevoflurane and sufentanil. Anesthesia and Analgesia 2007; 105(1):46-50. 14 ASA I-II infants <10 kg undergoing abdominal surgery under general anaesthesia haemodynamic effects of caudal anaesthesia with 0.75 ml/kg 0.25% bupivacaine plus 1 : 200000 epinephrine were investigated by transesophageal Doppler. Heart rate, stroke volume, mean arterial blood pressure and systemic vascular resistance were significantly decreased by caudal anaesthesia, while CO remained unchanged. *Sprunger JK, Reese CT, Decter RM. Can standard open pediatric urological procedures be performed on an outpatient basis? Journal of Urology 2001;166(3):1062-1064.


Valois T, Otis A, Ranger M, Muir JG. Incidence of self-limiting back pain in children following caudal blockade: An exploratory study. Paediatric Anaesthesia 2010; 20(9):844-850. In this prospective observational study in 135 children < 18 y the incidence of back pain following caudal anaesthesia was reported 4.7% on postoperative day 2 and 1.1% on postoperative day 15. Most patients (n=111) received 0.25% bupivacaine plus 1:200 000 epinephrine or 0.125% bupivacaine plus epinephrine (1: 200 000 or 1:400 000) (n=23). Mean volume injected was 11.7 ± 5.45 ml. Ved SA, Pinosky M, Nicodemus H. Ventricular tachycardia and brief cardiovascular collapse in two infants after caudal anesthesia using a bupivacaine-epinephrine solution. Anesthesiology 1993; 79(5):1121-1123. Two case reports of ventricular tachycardia and brief cardiovascular collapse after caudal anaesthesia with 1 ml/kg 0.25% bupivacaine plus epinephrine 1:200 000 in infants aged 4 and 10 months. The immediate onset and rapid resolution of the symptoms with or without treatment indicate inadvertent intravascular or intraosseous injection. Webster AC, McKishnie JD, Watson JT, Reid WD. Lumbar epidural anaesthesia for inguinal hernia repair in low birth weight infants. Canadian Journal of Anaesthesia 1993;40(7):670- 675. The authors report of 18 cases gestational age 26 ± 2.6 weeks most with bronchopulmonary dysplasia being oxygen-dependent. For inguinal hernia repair epidural good operating condions were achieved with bupivacaine 0.25% with or without epinephrine 1:200 000, (0.75)-1 ml/kg. *see above paragraph Pharmacokinetics Textbooks Brown TCK, Fisk GC. Anaesthesia for children. 2nd ed. Oxford: Blackwell Scientific Publications; 1992:p. 44-46. In Chapter 2 with reference to 3 publications (not provided) it is described that adrenaline increases the duration of action of local anaesthetics by 50-100% in infants, it also decreases peak blood levels. Dalens BJ. In: Paediatric regional anaesthesia. Boca Raton: CRC Press; 1990: p405-406. With reference to a (not provided) publication for caudal paediatric anaesthesia, the addition of 1:200 000 or 1:400 000 epinephrine is desirable, since it reduces the danger of systemic toxicity, it may increase duration and extent of analgesia and allows early detection of iv injection of the given dose.

In summary, 22 controlled clinical trials were conducted using bupivacaine in combination with adrenaline/epinephrine for caudal anaesthesia in children. In these trials more than 1000 children received a single epidural injection of bupivacaine plus adrenaline. The majority of the studies included children older than 1 year of age, however, across all trials age ranged between full term neonate (Deng 2008) and 12 years. Mostly 0.25% bupivacaine was used (range 0.125-0.25%) with 1:200 000 (5 µg/ml) epinephrine (range 1:400 000 – 1:200 000) at a dose of 1 ml/kg (range 0.5 - 1.3 ml/kg). Regarding the optimal dose and volume for a single–dose caudal block two trials (Malviya 1992, Schrock 2003) could not find differences is analgesic efficacy between various test doses. Studies were partially designed to compare the effects of bupivacaine plus epinephrine to plain bupivacaine (Fisher 1993, Jamali 1994, Klimscha 1998, Pathania 2003) but none could observe a significant group difference as regards analgesia and time to micturation.


A number of studies were designed to investigate a potential benefit of the addition of opioids or other substances to epidurally given bupivacain plus epinephrine (Campbell 1992, Joshi 1999, Lawhorn 1997, Santosh 1993, Tripi 2005), suggesting that the use of bupivacaine plus epinephrine for caudal anaesthesia is well established. Other studies (Jamali 1994, Pathania 2003, Cook 1995, Klimscha 1998, Mayrhofer 2000, Menzes 2002, Splinter 1997) compared the efficacy of caudal bupivacaine plus epinephrine with other analgesic agents either given epidurally, i.v. or rectally, also suggesting that the use of bupivacaine plus epinephrine for caudal anaesthesia is well established. In spite of the findings that some of the comparative groups showed longer analgesia, throughout all published trials safety and efficacy of epidural bupivacaine and epinephrine was not doubted. At least in two textbooks for paediatric (regional) anaesthesia the addition of epinephrine to caudal anaesthesia is described and recommended (Brown, Dalens). Also in the 9 presented uncontrolled trials the predominantly used combination was 0.25% bupivacaine plus 1:200 000 epinephrine. Studies designed to investigate the incidence of back pain after caudal anaesthesia (Valois 2010) or early indicators for a successful caudal anaesthesia (Krishna 2004) suggest again that the use of bupivacaine plus epinephrine for caudal anaesthesia is well established. Overall, only few reports of adverse events could be found in the 31 reviewed publications in a total of approximately 1300 patients, most of them concerning postoperative nausea and/or vomiting. The incidence of PONV, however, is confounded by the fact that almost all of the investigated patients underwent general anaesthesia and or received opioids as well. A number of studies reported changes in haemodynamic parameters, which are commonly associated with the physiological effects of epidural anaesthesia or with inadvertent intravenous injection of local anaesthetics or adrenaline. In conclusion no major safety issues concerning single epidural application of bupivacaine plus epinephrine in the dose range described above can be derived from the reviewed literature.

Caudal / Epidural intermittent bolus injection or continuous infusion The following studies have reported on caudal/epidural intermittent bolus injection or continuous infusion of bupivacaine with adrenaline in paediatric patients: Controlled trials: Løvstad RZ, Støen R. Postoperative epidural analgesia in children after major orthopaedic surgery: A randomised study of the effect on PONV of two anaesthetic techniques: Low and high dose i.v. fentanyl and epidural infusions with and without fentanyl. Acta Anaesthesiologica Scandinavica 2001;45(4):482-488. 42 ASA I-II children undergoing proximal osteotomy of the femur were randomized to receive one of the following anaesthetic regimen: PBA: propofol anaesthesia and epidural bupivacaine 1.5 mg/ml, adrenaline 2µg/ml SBA: sevoflurane anaesthesia and epidural bupivacaine 1.5 mg/ml, adrenaline 2µg/ml SBAF: sevoflurane anaesthesia and epidural bupivacaine 1 mg/ml, adrenaline 2µg/ml and fentanyl 2µg/ml A satisfactory postoperative analgesia could be achieved with both epidural mixtures, but significantly more PONV in the fentanyl-group. Uncontrolled trials: Courreges P, Lecoutre D, Poddevin F, Bayart R. Epidural anesthesia in children under 3 months of age. Apropos of 49 cases. Cahiers d'Anesthesiologie 1996;44(5):403-408. In this publication reports retrospectively about 45 patients (32 ± 28 days) receiving epidural postoperative analgesia with 0.125%- 0.25% bupivacaine plus epinephrine 1:200 000


Lönnqvist PA, Olsson GL. Paravertebral vs epidural block in children. Effects on postoperative morphine requirement after renal surgery. Acta Anaesthesiologica Scandinavica 1994;38(4):346-349. 35 paediatric patients (age range 1-146 mo) undergoing renal surgery under general anaesthesia were compared retrospectively regarding quality of analgesia provided by either lumbar epidural blockade (EDA, n=20) or continuous thoracic blockade (PVB, n=15). The blocks were initiated and maintained by intermittent bolus injections during operation using bupivacaine 0.25% with epinephrine 5µg/ml, starting at 0.75 ml/kg (EDA) and 0.5 ml/kg (PVB) followed by susbsequent half the initial bolus doses for both. The need for supplemental morphine administration was significantly lower in the PVB group. McCloskey JJ, Haun SE, Deshpande JK. Bupivacaine toxicity secondary to continuous caudal epidural infusion in children. Anesthesia and Analgesia 1992;75(2):287-290. The authors report about 3 cases of continuous postoperative epidural infusion of 0.25% bupivacaine plus epinephrine 1 :200 000, max. infusion rate 2.5 mg/kg/h leading to haemodynamic alterations and generalized tonic-clonic seizures several hours after start of the infusion. High bupivacaine plasma levels could be measured.

Four different reports about caudal epidural continuous infusion or intermittent bolus injections of bupivacaine plus epinephrine in a total of 125 paediatric patients were reviewed. The reported settings were not comparable, thus these data supported are considered to be insufficient to derive any recommendations.

Spinal/intrathecal block The following studies have reported on spinal/intrathecal administration of bupivacaine with adrenaline in paediatric patients: Controlled trials: Fösel T, Wilhelm W, Grüness V, Molter G. Spinal anaesthesia in former pre-term infants with bupivacaine 0.5%. Effect of added epinephrine on duration and haemodynamics. Anaesthesist 1994;43(1):26-29. In ten former preterm infants (postgestational age 38-48 weeks, 2.1 – 3.22 kg) scheduled for inguinal hernia repair spinal anaesthesia was performed with 0.6 ml bupivacaine 0.5% (first 5 patients) or 0.6 ml bupivacaine 0.5% plus epinephrine 1:200000. Haemodynamic parameters did not differ at any time between groups, but duration of anaesthesia (defined as time from injection to first movement of the legs after stimulation) was significantly longer in patients receiving epinephrine 50 [37-85] min vs 95 [60 – 120] min. Vila R, Lloret J, Munar F, Vinzo J. Spinal anaesthesia for inguinal herniotomy in preterminfants sedated with nitrous oxide: A comparison of lumbar puncture in the lateral or sitting position. Anaesthesia 2002;57(12):1164-1167. 30 preterm infants undergiong inguinal herniotomy randomly received spinal anaesthesia either in sitting or in lateral position both performed with isobaric 1 mg/kg bupivacaine 0.5% with epinephrine 1 :200 000. No significant differences could be observed between groups. Dermatomal block heights were between T4 and T7, the range of motor block was 50-85 min. Uncontrolled trials: Hermanns H, Stevens MF, Werdehausen R, Braun S, Lipfert P, Jetzek-Zader M. Sedation during spinal anaesthesia in infants. British Journal of Anaesthesia 2006;97(3):380-384.


Spinal anaesthesia was performed in 20 infants aged 5-24 weeks (gestational age at birth 24-40 week) with 1 mg/kg hyperbaric bupivacaine 0.5% with epinephrine 10µg/ml. No additional sedatives or anaesthetics were administered. Sedation was evaluated using BIS (bispectral index) and SEF95 (spectral edge frequency) and suggest that sedation after spinal anaesthesia ini infants is at least as pronounced as in adults. Jetzek-Zader M, Hermanns H, Freynhagen R, Lipfert P, Stevens MF. Increase in Skin Temperature After Spinal Anesthesia in Infants. Regional Anesthesia and Pain Medicine 2006;31(6):519-522. Spinal anaesthesia was performed at L4/5 in 15 infants, postconceptual age 45 ± 4.8 weeks with 1 mg/kg hyperbaric bupivacaine 0.5% with 10 µg/ml epinephrine. A significant increase in skin temperature of the feet within 10 min as a sign of sympatholysis was measured whereas trunk temperature remained constant.

Four studies investigating in total 70 paediatric patients, mostly preterm or former preterm infants, receiving spinal anaesthesia with bupivacaine and epinephrine were reviewed. Most infants received 1 ml/kg hyperbaric or isobaric bupivacaine 0.5% with epinephrine 5-10µg/ml. Studies in older children were not presented. In summary, the data is regarded as insufficient to support the inclusion of spinal anaesthesia as a paediatric indication for bupivacaine with adrenaline.

Peripheral nerve block The following studies have reported on peripheral nerve blocks with bupivacaine plus adrenaline in paediatric patients: Controlled trials: Doyle E, Morton NS, McNicol LR. Plasma bupivacaine levels after fascia iliaca compartment block with and without adrenaline. Paediatric Anaesthesia 1997; 7(2):121-124. see above paragraph Pharmacokinetics Isaac LA, McEwen J, Hayes JA, Crawford MW. A pilot study of the rectus sheath block for pain control after umbilical hernia repair. Paediatric Anaesthesia 2006; 16(4):406-409. 14 ASA I-II children aged 1-8 y undergoing repair of umbilical or paraumbilical hernia were randomly assigned to receive either a rectus sheath block or a local infiltration into the surgical wound with 0.8ml/kg of 0.25% bupivacaine with epinephrine 1:200 000. The total postoperative morphine consumption did not differ between groups. Jagannathan N, Sohn L, Sawardekar A, Ambrosy A, Hagerty J, Chin A, et al. Unilateral groin surgery in children: Will the addition of an ultrasound-guided ilioinguinal nerve block enhance the duration of analgesia of a single-shot caudal block? Paediatr.Anaesth. 2009;19(9):892-898. see above Section IV.3.2.Peripheral Nerve Block Matsota P, Livanios S, Marinopoulou E. Intercostal Nerve Block with Bupivacaine for postthoracotomy pain relief in children. European Journal of Pediatric Surgery 2001; 11(4):219- 222. 20 ASA I-II children aged 5-12 y undergoing thoracotomy under general anaesthesia randomly received either 3 mg/kg 0.25% bupivacaine plus epinephrine 1:200 000 directly injected intercostally by the surgeon or i.v. meperidine 1mg/kg. The mean duration of postoperative analgesia was significantly longer in children with an intercostal nerve block. Children receiving meperidine had a significantly higher incidence of PONV.


Splinter WM, Bass J, Komocar L. Regional anaesthesia for hernia repair in children: Local vs caudal anaesthesia. Canadian Journal of Anaesthesia 1995; 42(3): 197-200 see above: paragraph Caudal / Epidural single injection Suresh S, Barcelona SL, Young NM, Seligman I, Heffner CL, Cote CJ. Postoperative pain relief in children undergoing tympanomastoid surgery: Is a regional block better than opioids? Anesthesia and Analgesia 2002;94(4):859-862. In this prospective, randomized, double blind study, the overall incidence of postoperative vomiting was reduced by a great auricular nerve block (2 ml 0.25% bupivacaine with epinephrine 1:200 000) in comparison to an i.v. injection of 0.1 mg morphine sulphate in 40 ASA I-II children aged 2-18y undergoing tympanomastoid surgery under general anaesthesia. Suresh S, Barcelona SL, Young NM, Heffner CL, Cote CJ. Does a Preemptive Block of the Great Auricular Nerve Improve Postoperative Analgesia in Children Undergoing Tympanomastoid Surgery? Anesthesia and Analgesia 2004; 98(2):330-333. In this prospective, randomized, observer blind study, an influence of a preemptive great auricular nerve block performed before surgical incision in addition to a great auricular nerve block (2 ml 0.25% bupivacaine with epinephrine 1:200 000) performed 1 h before completion of surgery in 40 ASA I-II children aged 2-18y undergoing tympanomastoid surgery under general anaesthesia could not be observed. Uncontrolled trials: Cheung SLW, Booker PD, Franks R, Pozzi M. Serum concentrations of bupivacaine during prolonged continuous paravertebral infusion in young infants. British Journal of Anaesthesia 1997;79(1):9-13. see above paragraph Pharmacokinetics Semsroth M, Plattner O, Horcher E. Effective pain relief with continuous intrapleural bupivacaine after thoracotomy in infants and children. Paediatric Anaesthesia 1996;6(4):303-310. 22 children aged 6 months to 10 y undergoing elective lateral thoracotomy under general anaesthesia were inserted an intrapleural catheter under direct vision during surgery. An intrapleural infusion of bupivacaine 0.25% with adrenaline provided safe and suitable postoperative pain relief for 24 h.

Only a few reports (7 controlled and 2 uncontrolled) about studies investigating the use of bupivacaine in combination with epinephrine for peripheral nerve blocks children have been provided. Investigated patient populations were mostly very small and a variety of blocks were studied in different dose regimen, so that in summary, no recommendations regarding paediatric peripheral blocks with bupivacaine and epinephrine can be derived from the literature.

Local infiltration/Field block The following studies have reported on field blocks with bupivacaine plus adrenaline in paediatric patients: Controlled trials: Anand P, Wilson R, Sheehy EC. Intraligamental analgesia for post-operative pain control in children having dental extractions under general anaesthesia. European Journal of Paediatric Dentistry 2005; 6(1):10-15.


30 ASA I-II children >6 y of age undergoing symmetrical extractions of permanent teeth under general anaesthesia received intraligamental local analgesia (ILA) with bupivacaine 0.5% plus adrenaline 1:200 000 (0.2 ml per root) for postoperative pain control randomised on one side of the mouth. The contralateral side was the control. ILA was observed to be a useful and safe adjunct for postoperative pain control in these patients. *Isaac LA, McEwen J, Hayes JA, Crawford MW. A pilot study of the rectus sheath block for pain control after umbilical hernia repair. Paediatric Anaesthesia 2006; 16(4):406-409. 14 ASA I-II children aged 1-8 y undergoing repair of umbilical or paraumbilical hernia were randomly assigned to receive either a rectus sheath block or a local infiltration into the surgical wound with 0.8ml/kg of 0.25% bupivacaine with epinephrine 1:200 000. The total postoperative morphine consumption did not differ between groups. see above Section IV.3.2. Field Block Kasapoglu F, Kaya FN, Tuzemen G, Ozmen OA, Kaya A, Onart S. Comparison of peritonsillar levobupivacaine and bupivacaine infiltration for post-tonsillectomy pain relief in children: Placebo-controlled clinical study. International Journal of Pediatric Otorhinolaryngology 2011; 75(3):322-326. 60 children undergoing elective tonsillectomy or adenotonsillectomy under general anaesthesia randomly received either 5 ml 0.25% levobupivacaine plus epinephrine 1:200 000, 0.25% bupivacaine plus epinephrine 1:200 000 or normal saline for peritonsillar infiltration before incision. Patients receiving local anaesthetics had significantly less postoperative pain during the first hour compared to placebo and time to first analgesia was significantly longer. Strub KA, Tschopp K, Frei F, Kern C, Erb T. Local infiltration of epinephrine and bupivacaine in tonsillectomy. HNO 1996; 44(12):672-676. In a prospective randomized double-blind trial on 103 children undergoing tonsillectomy under general anaesthesia received either peritonsillar injection of 0.4 ml/kg normal saline, epinephrine 1:200 000 or epinephrine 1:200 000 combined with 0.25% bupivacaine. Analysis of the postoperative pain scores did not reveal any significant differences among groups, but epinephrine significantly reduced blood loss. Wong AK, Bissonnette B, Braude BM, Macdonald RM, St-Louis PJ, Fear DW. Post-tonsillectomy infiltration with bupivacaine reduces immediate postoperative pain in children. Can.J.Anaesth. 1995;42(9):770-774. 43 children aged 2-10 years were randomized into three groups after tonsillectomy was performed. To receive either normal saline spray (0,5 ml/kg), bupivacaine 0,5% with 1 : 200 000 epinephrine peritonsillar infiltration or bupivacaine 0,5% with 1:200 000 epinephrine spray to both tonsillar beds (2 mg/kg). Peritonsillar infiltration of bupivacaine provided significantly superior immediate postoperative analgesia and lower opioid requirements compared to bupivacaine spray or placebo. Blood samples were drawn at 5, 10, 15, 30 and 60 min following bupivacaine administration. Mean Plasma concentration was higher in patients receiving submucosal infiltration than in those receiving topical spray (0,54 vs 0,19 µg/ml, p <0.05), but well below the toxic range in all patients. see above Section IV.3.2. Field Block Uncontrolled trials: Suraseranivongse S, Chowvanayotin S, Pirayavaraporn S, Kongsayreepong S, Gunnaleka P, Kraiprasit K, et al. Effect of bupivacaine with epinephrine wound instillation for pain relief after pediatric inguinal herniorrhaphy and hydrocelectomy. Regional Anesthesia and Pain Medicine 2003; 28(1):24-28.


In a double-blind study 103 ASA I-II children aged 1-12 y undergoing inguinal herniorrhaphy and hydrocelectomy under general anaesthesia randomly received either ilioinguinal and iliohypogastric block (0.5 ml/kg 0.25% bupivacaine with epinbephrine) or local wound instillation with either 0.25 ml/kg normal saline or 0.5% bupivacaine plus 5 µg/ml epinephrine remaining either 20 or 60 s in the wound. Compared to placebo, all groups receiving local anaesthetics had significantly better postoperative analgesia (requiring less analgesics, longer time to first analgesic).

Only a few reports (5 controlled and 1 uncontrolled) about studies investigating the use of bupivacaine in combination with epinephrine for local infiltration techniques in children have been provided. Investigated patient populations were mostly very small and a variety of blocks were studied in different dose regimen, so that in summary, no recommendations regarding local infiltration with bupivacaine and epinephrine can be derived from the literature.

Other techniques Controlled trials: Andrzejowski J, Lamb L. The effect of swabs soaked in bupivacaine and epinephrine for pain relief following simple dental extractions in children. Anaesthesia 2002; 57(3):281-283. 133 ASA I-II children aged 5-12 y undergoing dental extractions under general anaesthesia randomly received either dental rolls soaked in bupivacaine 0.25% with 1:200 000 epinephrine or placebo rolls after surgery. No post-operative analgesic benefit could be observed for topical applied bupivacaine. Greengrass SR, Andrzejowski J, Ruiz K. Topical bupivacaine for pain control following simple dental extractions. British Dental Journal 1998; 184(7):354-355. 48 children aged 7-15 y undergoing dental extractions under general anaesthesia randomly received either dental rolls soaked in bupivacaine 0.25% with 1:200 000 epinephrine or placebo rolls after surgery. A significant reduction in pain could be observed for topical applied bupivacaine. Quirke W, Bhaskar K, Choonara I. A clinical trial of topical application of bupivacaine to reduce post-operative pain in children following dental extractions. Paediatric and Perinatal Drug Therapy 2005; 6(4):197-199. 48 children aged 4-13 y undergoing dental extractions under general anaesthesia randomly received either dental rolls soaked in bupivacaine 0.25% with 1:200 000 epinephrine or placebo rolls after surgery. No post-operative analgesic benefit could be observed for topical applied bupivacaine.

Two of the three studies with topical applied bupivacaine could not observe an increased analgesic effect compared to placebo.

The MAH submitted proposals for a paediatric SmPC and PL wording based on the complete Company Core Data Sheet for Marcaine injection. (According to the MAH acute pain management is licensed with dose recommendations in the SmPCs for children aged 1-12 years in several EU countries, proposed SmPC changes are underlined, children > 12 years are included in the recommendations for adults)


MARCAINE 1.25 mg/ml, solution for injection/infusion

MARCAINE 2.5 mg/ml, solution for injection/infusion

MARCAINE 3.75 mg/ml, solution for injection

MARCAINE 5.0 mg/ml, solution for injection

MARCAINE 7.5 mg/ml, solution for injection MARCAINE 2.5mg/ml + 5 microg/ml adrenaline, solution for injection

MARCAINE 5.0 mg/ml + 5 microg/ml adrenaline, solution for injection

MARCAINE 7.5 mg/ml + 5 microg/ml adrenaline, solution for injection

4.1 Therapeutic indications

Surgical anaesthesia in adults and children above 12 years of age

Acute pain management in adults, infants and children above 1 year of age 4.2 Posology and method of administration Paediatric patients 1 to 12 years of age

Paediatric regional anaesthetic procedures should be performed by qualified

clinicians who are familiar with this population and the technique.

The doses in the table should be regarded as guidelines for use in paediatrics.

Individual variations occur. In children with a high body weight a gradual reduction

of the dosage is often necessary and should be based on the ideal body weight.

Standard textbooks should be consulted for factors affecting specific block

techniques and for individual patient requirements. The lowest dose required for

adequate analgesia should be used. The duration may be prolonged with the adrenaline-containing solutions.

N.B. Risk of systemic effects of adrenaline with large volumes of adrenaline containing solutions should

be considered.


Conc.

mg/ml

Volume

ml/kg

Dose

mg/kg

Onset

min

Duration of

effect

hours


postoperative)


2.5 0.6-0.8 1.5-2 20-30 2-6


2.5 0.6-0.8 1.5-2 20-30 2-6

Thoracic Epidural Administration

2.5 0.6-0.8 1.5-2 20-30 2-6

Field Block


2.5 0.5-2.0

5.0 0.5-2.0



2.5 0.5-2.0 a)


Conc.

mg/ml

Volume

ml/kg

Dose

mg/kg

Onset

min

Duration of

effect

hours

5.0 0.5-2.0 a)

a) The onset and duration of peripheral nerve blocks depend on the type of block and the

dose administered.

In children the dosage should be calculated on a weight basis up to 2 mg/kg.

In order to avoid intravascular injection, aspiration should be repeated prior to and

during administration of the main dose. This should be injected slowly in incremental

doses, particularly in the lumbar and thoracic epidural routes, constantly and

closely observing the patient’s vital functions.

Peritonsillar infiltration has been performed in children above 2 years of age with

bupivacaine 2.5 mg/ml at a dose of 7.5-12.5mg per tonsil. The addition of adrenaline

reduced blood loss.

Ilioinguinal-iliohypogastric blocks have been performed in children aged 1 year or

older with bupivacaine 2.5 mg/ml at a dose of 0.1-0.5 ml/kg equivalent to 0.25-1.25

mg/kg. Children aged 5 years or older have received bupivacaine 5 mg/ml at a dose of

1.25-2 mg/kg.

For penile blocks bupivacaine 5 mg/ml has been used at total doses of 0.2-0.5 ml/kg

equivalent to 1-2.5 mg/kg. Adrenaline containing solutions should not be used for penile block. 4.3 Contraindications

(No specific contraindications were identified for paediatric patients.) 4.4 Special warnings and special precautions for use

(Epidrual anaesthesia): Children should be given doses commensurate with their age

and weight.

Paediatric population

The use of bupivacaine for intra-articular block in children 1 to 12 years of age has

not been documented.

The use of bupivacaine for major nerve block in children 1 to 12 years of age has not

been documented.

4.8 Undesirable effects

Paediatric population

In children, early signs of local anaesthetic toxicity may be difficult to detect in

cases where the block is given during sedation or general anaesthesia. 5.2 Pharmacokinetic properties

In children the pharmacokinetics is similar to that in adults.


The recommendations for the SmPC wording should take into account the latest Guideline on SmPC 2009. Plain bupivacaine solutions: Section 4.1: Throughout the literature reviewed regarding the use of bupivacaine in the paediatric population, 7.5 mg/ml solution for injection could not be identified as being (safely) used or recommended in paediatric anaesthesia. Section 4.2: Proposed wording to be added: The safety and efficacy of <TRADENAME> in children < 1 year of age have not been established. Only limited data are available. Safety and efficacy of intermittent epidural bolus injection or continuous infusion have not been established. Only limited data is available. Section 4.8 Proposed wording to be added: Adverse drug reactions in children are similar to those in adults.

Epinephrine containing solutions: Section 4.1 From the reviewed literature only evidence for the use of bupivacaine 1.25 - 2.5 mg/ml + 2.5 - 5µg/ml adrenaline for caudal block in children > 1 year of age could be derived. Regarding other anaesthetic techniques, the investigated paediatric population were mostly very small and a variety of different applications were studied, so that no reliable recommendations can be derived from the literature. Very limited paediatric data is available for the 5mg/ml and none 7.5 mg/ml solution for injection for any anaesthetic technique. Section 4.2 Bupivacaine 1.25 - 2.5 mg/ml + 2.5 - 5µg/ml adrenaline was used in more than 1000 children at a dose range of 0.5- 1.3 ml/kg, mostly at a dose of 1 ml/kg for caudal anaesthesia. The proposed recommendations of 0.6-0.8 ml/kg aiming at a dose of 1.5-2.0 mg/kg are within this range and maybe extended to 1 ml/kg. Proposed wording to be added: The safety and efficacy of <TRADENAME> in children < 1 year of age have not been established. Only limited data are available. Section 4.4 Proposed wording to be added: Adrenaline containing solutions should not be used for penile block. Section 4.8 Proposed wording to be added: Adverse drug reactions in children are similar to those in adults.


Proposed Update of the PLs will be assessed once the wording for the SmPCs is agreed on. CMS comments on Day 90 Finalised pdAR: NL agrees with the rapporteur's overall conclusion and SmPC recommendations. General comment: although a warning against penile block when adrenaline is applied is already included in the SPC for adults, there can be no harm in repeating this for the pediatric population.

Assessor’s comment: Standard textbooks of anaesthesia regard injection of adrenaline containing local anaesthetics in areas of end arteries (e.g. penile block, Oberst block) as a contraindication due to the risk of ischemic tissue necrosis.

The UK agrees with the rapporteur's overall conclusion and SmPC recommendations. However the UK's point regarding thoracic epidural administration is not resolved (pg 42-43/46). While the proposed SmPC correctly recommends incremental administration to try to detect intravascular injection, it still does not discriminate between administration of epidural anaesthesia at the lower end of the space (caudal/lumbar)a and the upper end of the space (thoracic). Administration of a full dose as in the recommendations as single bolus injection (0.6-0.8ml/kg) at a thoracic epidural level may result in severe hypotension, respiratory impairment as the diaphragmatic muscles become paralysed (cervical level C3,4,5), and bradycardia (T1-4 cardiac sympathetic block) is a very real possibility. In our views the SmPC should contain a warning that all thoracic epidural blocks need to be given by incremental dosage until the desired level of anaesthesia is achieved. The UK strongly feels that the single dose administration of 0.6-0.8mg/kg may lead to these very severe complications,independent of inadvertent intravenous or subarachnoid administration has occurred. The CMS comments have been taken into account in the final recommendations which are split according to strength of bupivacaine and the addition of epinephrine. MAH’s comments on Final pdAR: A final text recommendation for intrathecal use of bupivacaine in paediatric patients is missing.

Assessor’s comment: This has been omitted by mistake and is now included in the final recommenendations.

The final text recommendation “Adrenaline containing solutions must not be used for penile block” in section 4.2 for <TRADENAME> 1.25 mg/ml, 2.5 mg/ml, 3.75 mg/ml, 5.0 mg/ml, solution for injection (without adrenaline) is not relevant for solutions without adrenaline.

Assessor’s comment: In section 4.2 the text recommendation has been deleted, however, a similar recommendation (see Section VII) for section 4.3 (all strengths, with and without adrenaline) remains for all formulations due to the potential severity of an injection of adrenaline containing solutions in areas of end arteries.

Regarding the final text recommendation for the therapeutic indications for bupivacaine 1.25 – 2.5 mg/ml + 2.5 – 5 microgram/ml adrenaline “caudal block” refers to the route of administration which can be used for both surgical anaesthesia and acute pain management. Therefore the wording should be clarified to the prescriber as follows: “acute pain management in adults, infants and children above 1 year of age”.


The MAH proposed dose recommendations equal to those for plain bupivacaine also for lumbar and thoracic epidural anaesthesia for section 4.2.

Assessor’s comment: To be in line with the plain bupivacaine solutions, the proposal for section 4.1 is supported. Although from the literature dose recommendations can mainly be derived for caudal epidural anaesthesia in children, the argumentation of the MAH can be followed in terms of non restricting the use to the caudal epidural route only.

VII. FINAL RAPPORTEUR’S OVERALL CONCLUSION AND RECOMMENDATION

Overall conclusion

Many published articles of the last years provide information about the well established use of bupivacaine in parts of the paediatric patient population. The paediatric information given in SmPC and PL should be clarified according to the review of the publications, especially regarding different strengths of bupivacaine and the addition of epinephrine.

Recommendation

Type IB variation to be requested from the MAH within 60 days.


<TRADENAME> 7.5 mg/ml, solution for injection 4.1 Therapeutic indications


Acute pain management in adults and children above 12 years of age

Note: Throughout the literature reviewed regarding the use of bupivacaine in the paediatric population, 7.5 mg/ml solution for injection could not be identified as being (safely) used or recommended in paediatric anaesthesia. As for other local anaesthetics, recommendations for the adolescent population above 12 years remain included in the information for adults.

4.2 Posology and method of administration Paediatric patients The safety and efficacy of <TRADENAME> in children aged < 12 years have not been established. Only limited data are available. Lower strengths may be more appropriate for administration to children aged 1 – 12 years. 4.4 Special warnings and special precautions for use The safety and efficacy of <TRADENAME> in children aged < 12 years have not been established. <TRADENAME> 1.25 mg/ml, solution for injection/infusion <TRADENAME> 2.5 mg/ml, solution for injection/infusion <TRADENAME> 3.75 mg/ml, solution for injection <TRADENAME> 5.0 mg/ml, solution for injection



Acute pain management in adults, infants and children above 1 year of age 4.2 Posology and method of administration Paediatric patients 1 to 12 years of age Paediatric regional anaesthetic procedures should be performed by qualified clinicians who are familiar with this population and the technique. The doses in the table should be regarded as guidelines for use in paediatrics. Individual variations occur. In children with a high body weight a gradual reduction of the dosage is often necessary and should be based on the ideal body weight. Standard textbooks should be consulted for factors affecting specific block techniques and for individual patient requirements. The lowest dose required for adequate analgesia should be used.


Conc.

mg/ml

Volume

ml/kg

Dose

mg/kg

Onset

min

Duration of

effect

hours


postoperative)


Conc.

mg/ml

Volume

ml/kg

Dose

mg/kg

Onset

min

Duration of

effect

hours


2.5 0.6-0.8 1.5-2 20-30 2-6


2.5 0.6-0.8 1.5-2 20-30 2-6

Thoracic Epidural Administrationb)

2.5 0.6-0.8 1.5-2 20-30 2-6

Field Block


2.5 0.5-2.0

5.0 0.5-2.0



2.5 0.5-2.0 a)

5.0 0.5-2.0 a)

a)The onset and duration of peripheral nerve blocks depend on the type of block and the dose administered. b)Thoracic epidural blocks need to be given by incremental dosage until the desired level of anaesthesia is achieved.

In children the dosage should be calculated on a weight basis up to 2 mg/kg. In order to avoid intravascular injection, aspiration should be repeated prior to and during administration of the main dose. This should be injected slowly in incremental doses, particularly in the lumbar and thoracic epidural routes, constantly and closely observing the patient’s vital functions. Peritonsillar infiltration has been performed in children above 2 years of age with bupivacaine 2.5 mg/ml at a dose of 7.5-12.5mg per tonsil. Ilioinguinal-iliohypogastric blocks have been performed in children aged 1 year or older with bupivacaine 2.5 mg/ml at a dose of 0.1-0.5 ml/kg equivalent to 0.25-1.25 mg/kg. Children aged 5 years or older have received bupivacaine 5 mg/ml at a dose of 1.25-2 mg/kg. For penile blocks bupivacaine 5 mg/ml has been used at total doses of 0.2-0.5 ml/kg equivalent to 1-2.5 mg/kg. The safety and efficacy of <TRADENAME> in children < 1 year of age have not been established. Only limited data are available. Safety and efficacy of intermittent epidural bolus injection or continuous infusion have not been established. Only limited data is available. 4.4 Special warnings and special precautions for use The use of bupivacaine for intra-articular block in children 1 to 12 years of age has not been documented.


The use of bupivacaine for major nerve block in children 1 to 12 years of age has not been documented. <TRADENAME >SPINAL 5.0 mg/ml, solution for injection <TRADENAME >SPINAL Heavy 5.0 mg/ml, solution for injection 4.1 Therapeutic indications Spinal anaesthesia in adults and children of all ages 4.2 Posology and method of administration Neonates, infants and children up to 40kg MARCAINE Spinal 5 mg/ml and MARCAINE Spinal Heavy 5 mg/ml may be used in children. One of the differences between small children and adults is a relatively high CSF volume in infants and neonates, requiring a relatively larger dose/kg to produce the same level of block as compared to adults. Paediatric regional anaesthetic procedures should be performed by qualified clinicians who are familiar with this population and the technique. The doses in the table should be regarded as guidelines for use in paediatric patients. Individual variations occur. Standard textbooks should be consulted for factors affecting specific block technique and for individual patient requirements. The lowest dose required for adequate anaesthesia should be used. Table: Dosage recommendations in neonates, infants and children

4.8 Undesirable effects Adverse drug reactions in children are similar to those in adults, however, in children, early signs of local anaesthetic toxicity may be difficult to detect in cases where the block is given during sedation or general anaesthesia. 5.2 Pharmacokinetic properties In children the pharmacokinetics is similar to that in adults. <TRADENAME> 5.0 mg/ml + 5 microg/ml adrenaline, solution for injection <TRADENAME> 7.5 mg/ml + 5 microg/ml adrenaline, solution for injection 4.1 Therapeutic indications


Acute pain management in adults and children above 12 years of age

Note: Very limited paediatric data is available for the 5mg/ml and none 7.5 mg/ml solution for injection for any anaesthetic technique. As for other local anaesthetics, recommendations for the adolescent population above 12 years remain included in the information for adults.


4.2 Posology and method of administration Paediatric patients The safety and efficacy of <TRADENAME> in children aged < 12 years have not been established. Only limited data are available. Lower strengths may be more appropriate for administration to children aged 1 – 12 years. 4.4 Special warnings and special precautions for use The safety and efficacy of <TRADENAME> in children aged < 12 years have not been established. <TRADENAME> 1.25 - 2.5mg/ml + 2.5 - 5 microg/ml adrenaline, solution for injection



Acute pain management in adults, infants and children above 1 year of age

Note: From the reviewed literature only evidence for the use of bupivacaine 1.25 - 2.5 mg/ml + 2.5 - 5µg/ml adrenaline for caudal epidural block in children > 1 year of age could be derived. Regarding other anaesthetic techniques, the investigated paediatric population were mostly very small and a variety of different applications were studied, so that no reliable recommendations can be derived from the literature. As for other local anaesthetics, recommendations for the adolescent population above 12 years remain included in the information for adults.

4.2 Posology and method of administration Paediatric patients 1 to 12 years of age Paediatric regional anaesthetic procedures should be performed by qualified clinicians who are familiar with this population and the technique. The doses in the table should be regarded as guidelines for use in paediatrics. Individual variations occur. In children with a high body weight a gradual reduction of the dosage is often necessary and should be based on the ideal body weight. Standard textbooks should be consulted for factors affecting specific block techniques and for individual patient requirements. The lowest dose required for adequate analgesia should be used. The duration may be prolonged with the adrenaline-containing solutions. N.B. Risk of systemic effects of adrenaline with large volumes of adrenaline containing solutions should be considered.

Dosage recommendations for children 1 to 12 years of age

Conc.

mg/ml

Volume

ml/kg

Dose

mg/kg

Onset

min

Duration of

effect

hours


postoperative)


Conc.

mg/ml

Volume

ml/kg

Dose

mg/kg

Onset

min

Duration of

effect

hours

Caudal, lumbar and thoracic Epidural

Administration

2.5 0.6-0.8 1.5-2 20-30 2-6

In order to avoid intravascular injection, aspiration should be repeated prior to and during administration of the main dose. This should be injected slowly in incremental doses, particularly in the lumbar and thoracic epidural routes, constantly and closely observing the patient’s vital functions. Thoracic epidural blocks need to be given by incremental dosage until the desired level of anaesthesia is achieved. The safety and efficacy of <TRADENAME> in children < 1 year of age have not been established. Only limited data are available. Safety and efficacy of intermittent epidural bolus injection or continuous infusion have not been established. Only limited data is available. 4.4 Special warnings and special precautions for use The safety and efficacy of <TRADENAME> in children < 1 year of age have not been established. Only limited data are available. <TRADENAME> <all strengths>, solution for injection <TRADENAME> <all strengths> + 2.5 - 5 microg/ml adrenaline, solution for injection 4.3 Contraindications Injection of adrenaline containing bupivacaine in areas of end arteries (e.g. penile block, Oberst block) may cause ischemic tissue necrosis.

Note: No specific contraindications were identified for paediatric patients.

4.4 Special warnings and special precautions for use Paediatric population For Epidural anaesthesia children should be given incremental doses commensurate with their age and weight as especially epidural anaesthesia at a thoracic level may result in severe hypotension and respiratory impairment. 4.8 Undesirable effects Paediatric population Adverse drug reactions in children are similar to those in adults, however, in children, early signs of local anaesthetic toxicity may be difficult to detect in cases where the block is given during sedation or general anaesthesia. 5.2 Pharmacokinetic properties In children the pharmacokinetics is similar to that in adults.


Likewise the following wording for the paediatric population is recommended to be introduced in the PLs of the different strengths: <TRADENAME> 7.5 mg/ml, solution for injection 1. What /../ is and what it is used for /../ is used in adults and children above 12 years to numb (anaesthetise) parts of the body. It is used to stop pain happening or to provide pain relief. It can be used to:

Numb parts of the body during surgery

Relieve pain 2. What you need to know before you /../ is given to you: Warnings and precautions The safety and efficacy of /../ in children aged < 12 years of age have not been established.. Other strengths may be more appropriate. <TRADENAME> 1.25 mg/ml, solution for injection/infusion <TRADENAME> 2.5 mg/ml, solution for injection/infusion <TRADENAME> 3.75 mg/ml, solution for injection <TRADENAME> 5.0 mg/ml, solution for injection

1. What /../ is and what it is used for /../ is used to numb (anaesthetise) parts of the body. It is used to stop pain happening or to provide pain relief. It can be used to:

Numb parts of the body during surgery in adults and children above 12 years

Relieve pain in adults, infants and children above 1 year of age

2. What you need to know before you /../ is given to you: Warnings and precautions In children < 12 years as some injections of /../ in order to numb parts of the body during surgery are not established in younger children. /../ is not established in children < 1 year. <TRADENAME >SPINAL 5.0 mg/ml, solution for injection <TRADENAME >SPINAL Heavy 5.0 mg/ml, solution for injection 1. What /../ is and what it is used for /../ is used to numb (anaesthetise) parts of the body during surgery in adults and children of all ages. 3. How to use /../ Use in children and adolescents /../ is injected slowly into the spinal channel (part of the spine) by an anaesthesiologist experienced in paediatric anaesthetic techniques. Dosage depends on the age and weight of the patient and will be determined by the anaesthesiologist. 4. Possible side effects Additional side effects in children and adolescents Adverse drug reactions in children are similar to those in adults.


<TRADENAME> 5.0 mg/ml + 5 microg/ml adrenaline, solution for injection <TRADENAME> 7.5 mg/ml + 5 microg/ml adrenaline, solution for injection 1. What /../ is and what it is used for /../ is used in adults and children above 12 years to numb (anaesthetise) parts of the body. It is used to stop pain happening or to provide pain relief. It can be used to:

Numb parts of the body during surgery

Relieve pain 2. What you need to know before you /../ is given to you: Warnings and precautions The safety and efficacy of /../ in children aged < 12 years of age have not been established.. Other strengths may be more appropriate. <TRADENAME> 1.25 - 2.5mg/ml + 2.5 - 5 microg/ml adrenaline, solution for injection 1. What /../ is and what it is used for /../ is used to numb (anaesthetise) parts of the body. It is used to stop pain happening or to provide pain relief. It can be used to:

Numb parts of the body during surgery in adults and children above 12 years

Relieve pain in adults, infants and children above 1 year of age 2. What you need to know before you /../ is given to you: Warnings and precautions The safety and efficacy of /../ in children aged < 1 year of age have not been established. <TRADENAME> <all strengths>, solution for injection <TRADENAME> <all strengths> + 2.5 - 5 microg/ml adrenaline, solution for injection 2. What you need to know before you /../ is given to you: Do not use adrenaline containing /../ for special techniques (e.g. penile block, Oberst block) to numb parts of the body where areas with end arteries are affected. 3. How to use /../ Use in children and adolescents Depending on the type of required analgesia /../ is injected slowly either into the epidural space (part of the spine) or other parts of the body by an anaesthesiologist experienced in paediatric anaesthetic techniques. Dosage depends on the age and weight of the patient and will be determined by the anaesthesiologist. 4. Possible side effects Additional side effects in children and adolescents Adverse drug reactions in children are similar to those in adults.


Request for supplementary information Not applicable

VIII. LIST OF MEDICINCAL PRODUCTS AND MARKETING AUTHORISATION HOLDERS INVOLVED

MAH MS

Name of the medicinal product

Strength Pharmaceutical form

AS

AstraZeneca UK Ltd

CZ Marcaine 0,5%

5 mg/ml solution for injection

bupivacaine hydrochloride

AstraZeneca UK Ltd

CZ Marcaine Spinal 0,5%



AstraZeneca UK Ltd

CZ Marcaine Spinal 0,5% Heavy



Documents

Bupivacaine hydrochloride