Limitations: This safety classification applies only to preparations containing a combination of the two drugs bupipivacaine and adrenaline (epinephrine). The same ATC-code (N01BB51) can in some countries be used for different combinations of bupivacaine and other drugs which in theory may be porphyrinogenic. Please refer to the classification and monograph of each individual substance. If the combination contains a substance which is not classified (NC) or has been classified as porphyrinogenic (PSP, PRP or P), the safety classification of such a combination as PNP is no longer valid. Bupivacaine: Used uneventfully in more than 53 patients with latent or active acute porphyria. By clinical criteria the local anaesthetic bupivacaine is not porphyrinogenic. One report of increased porphyrinogenic activity following an operation where bupivacaine was used in epidural anaesthesia, but causality was not established. Bupivacaine is classified NP. Adrenalin (epinephrine): Endogenous catecholamine. Metabolism is not CYP-dependent. No data pointing to CYP-interaction. Epinephrine is classified NP.

Bupivacaine hydrochloride is a local anaesthetic of the amide type. Bupivacaine occurs as a 50:50 racemic mixture of the R- and S-enantiomers. Epinephrine is a catecholamine added for longer duration of local anaesthesia.

Local anaesthetic. Administration together with adrenalin (not porphyrinogenic) gives a slower release of the local anaesthetic, probably resulting in lower hepatic exposure / time unit and higher tolerance. There are conflicting references regarding bupivacaine but clinical experience points to of relative non- porphyrinogenicity. Recommended for first hand use.

Bupivacaine is principally metabolized to pipecolylxylidine (PPX) by N-dealkylation, probably in the liver. Bupivacaine is excreted in urine as small amounts of PPX, unchanged drug (5%), and other metabolites is yet unidentified. Rendic (2002) reports that bupivacaine is a substrate of CYP3A4 (major reaction), CYP1A2, CYP2C19 and 2D6 (minor reaction). Adrenalin (epinephrine) is an endogenous compound. It is very rapidly inactivated by processes which include uptake into adrenergic neurones, diffusion, and enzymatic degradation in the liver and body tissues. Metabolism involves monoamine oxidase (MAO) and catechol-O-methyl transferase (COMT).

Thunell, S., study to be published: 48 patients exposed to bupivacaine without porphyric adverse reaction reported. Peters: According to our experience not porphyrinogenic.

Used uneventfully in AIP woman during delivery (Aggarwal, N., Bagga, R. et al, 2002). Used uneventfully for epidural anaesthesia during delivery by woman with latent VP (Consolo, D., Ouardirhi, Y. et al, 2005). Used uneventfully twice over two years in the same patient (one epidural and one spinal injection), an AIP woman (McNeill, M.J. & Bennet, A., 1990). Used uneventfully in epidural anaesthesia to relieve postoperative pain in AIP patient presenting with elevated PBG (Messmer, M., Gerheuser, F. et al, 2004). Used uneventfully as epidural, during surgery and post operativly in VP woman (Minoda,Y., Yoshimine, K. et al, 1997). Used uneventfully as spinal epidural in AIP woman (Sahu, M.T., Rajaram, S. et al, 2006). Used uneventfully as epidural, during surgery and post operativly, in HCP man (Yamamori, Y., Sumi, M. et al, 1996). Used uneventfully as spinal anesthesia in VP man (Bohrer, H. & Schmidt, H., 1992). Listed as safe in review by James and Hift (James, M.F. & Hift, R.J., 2000). One report of increased porphyrinogenic activity following an operation where bupivacaine was used in epidural anaesthesia, but causality was not established (Ii, C., Tanaka, N. et al, 1993).

Bupivacaine (N01BB01): Uneventful use reported in 5 patients with acute porphyria.