NDA 20-533/S-012 Page 3 721683-05 NAROPIN (ropivacaine HCl) Injection Rx only DESCRIPTION Naropin Injection contains ropivacaine HCl which is a member of the amino amide class of local anesthetics. Naropin Injection is a sterile, isotonic solution that contains the enantiomerically pure drug substance, sodium chloride for isotonicity and Water for Injection. Sodium hydroxide and/or hydrochloric acid may be used for pH adjustment. It is administered parenterally. Ropivacaine HCl is chemically described as S-(-)-1-propyl-2,6-pipecoloxylidide hydrochloride monohydrate. The drug substance is a white crystalline powder, with a molecular formula of C17H26N2OHClH2O, molecular weight of 328.89 and the following structural formula: At 25C ropivacaine HCl has a solubility of 53.8 mg/mL in water, a distribution ratio between n- octanol and phosphate buffer at pH 7.4 of 14:1 and a pKa of 8.07 in 0.1 M KCl solution. The pKa of ropivacaine is approximately the same as bupivacaine (8.1) and is similar to that of mepivacaine (7.7). However, ropivacaine has an intermediate degree of lipid solubility compared to bupivacaine and mepivacaine. Naropin Injection is preservative-free and is available in single dose containers in 2.0 (0.2%), 5.0 (0.5%), 7.5 (0.75%) and 10.0 mg/mL(1.0%) concentrations. The specific gravity of Naropin Injection solutions range from 1.002 to 1.005 at 25C. CLINICAL PHARMACOLOGY Mechanism of Action Ropivacaine is a member of the amino amide class of local anesthetics and is supplied as the pure S-(-)-enantiomer. Local anesthetics block the generation and the conduction of nerve impulses, presumably by increasing the threshold for electrical excitation in the nerve, by slowing the propagation of the nerve impulse, and by reducing the rate of rise of the action potential. In general, the progression of anesthesia is related to the diameter, myelination and conduction velocity of affected nerve fibers. Clinically, the order of loss of nerve function is as follows: (1) pain, (2) temperature, (3) touch, (4) proprioception, and (5) skeletal muscle tone. NDA 20-533/S-012 Page 4 Pharmacokinetics Absorption: The systemic concentration of ropivacaine is dependent on the total dose and concentration of drug administered, the route of administration, the patients hemodynamic/circulatory condition, and the vascularity of the administration site. From the epidural space, ropivacaine shows complete and biphasic absorption. The half-lives of the 2 phases, (mean SD) are 14 7 minutes and 4.2 0.9 h, respectively. The slow absorption is the rate limiting factor in the elimination of ropivacaine which explains why the terminal half-life is longer after epidural than after intravenous administration. Ropivacaine shows dose-proportionality up to the highest intravenous dose studied, 80 mg, corresponding to a mean SD peak plasma concentration of 1.9 0.3 g/mL. Table 1 Pharmacokinetic (plasma concentration-time) data from clinical trials Route Epidural Infusiona Epidural Infusiona Epidura l Blockb Epidural Blockb Plexus Blockc IV Infusiond Dose (mg) 149310 2075206 1217277 150 187.5 300 40 N 12 12 11 8 8 10 12 Cmax (mg/L) 2.41e 2.80.5e 2.31.1e 1.10.2 1.60.6 2.30.8 1.20.2f Tmax (min) n/ah n/a n/a 4314 349 5422 n/a AUC0- (mg.h/L) 135.550 14534 16190 7.22 11.34 133.3 1.80.6 CL (L/h) 11.03 13.7 n/a 5.52 52.6 n/a 21.27 T1/2 (hr) g 52.5 5.73 6.03 5.72 7.13 6.83.2 1.90.5 a Continuous 72 hour epidural infusion after an epidural block with 5 or 10 mg/mL. b Epidural anesthesia with 7.5 mg/mL (0.75%) for cesarean delivery. c Brachial plexus block with 7.5 mg/mL (0.75%) ropivacaine. d 20 minute IV infusion to volunteers (40 mg). e Cmax measured at the end of infusion (ie, at 72 hr). f Cmax measured at the end of infusion (ie, at 20 minutes). g t is the true terminal elimination half-life. On the other hand, t follows absorption-dependent elimination (flip-flop) after non-intravenous administration. h n/a=not applicable In some patients after a 300 mg dose for brachial plexus block, free plasma concentrations of ropivacaine may approach the threshold for CNS toxicity. (See PRECAUTIONS.) At a dose of greater than 300 mg, for local infiltration, the terminal half-life may be longer (30 hours). Distribution: After intravascular infusion, ropivacaine has a steady state volume of distribution of 41 7 liters. Ropivacaine is 94% protein bound, mainly to 1-acid glycoprotein. An increase in total plasma concentrations during continuous epidural infusion has been observed, related to a postoperative increase of 1-acid glycoprotein. Variations in unbound, ie, pharmacologically active, concentrations have been less than in total plasma concentration. Ropivacaine readily crosses the placenta and equilibrium in regard to unbound concentration will be rapidly reached. (See PRECAUTIONS, Labor and Delivery.) NDA 20-533/S-012 Page 5 Metabo