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ropivacaine hydrochloride injection, USP Clinical Pharmacology

12 CLINICAL PHARMACOLOGY

12.1 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.

12.2 Pharmacodynamics

Studies in humans have demonstrated that, unlike most other local anesthetics, the presence of epinephrine has no major effect on either the time of onset or the duration of action of ropivacaine. Likewise, addition of epinephrine to ropivacaine has no effect on limiting systemic absorption of ropivacaine.

Systemic absorption of local anesthetics can produce effects on the central nervous and cardiovascular systems. At blood concentrations achieved with therapeutic doses, changes in cardiac conduction, excitability, refractoriness, contractility, and peripheral vascular resistance have been reported. Toxic blood concentrations depress cardiac conduction and excitability, which may lead to atrioventricular block, ventricular arrhythmias and to cardiac arrest, sometimes resulting in fatalities. In addition, myocardial contractility is depressed and peripheral vasodilation occurs, leading to decreased cardiac output and arterial blood pressure.

Following systemic absorption, local anesthetics can produce central nervous system stimulation, depression or both. Apparent central stimulation is usually manifested as restlessness, tremors and shivering, progressing to convulsions, followed by depression and coma, progressing ultimately to respiratory arrest. However, the local anesthetics have a primary depressant effect on the medulla and on higher centers. The depressed stage may occur without a prior excited stage.

In 2 clinical pharmacology studies (total n=24) ropivacaine and bupivacaine were infused (10 mg/min) in human volunteers until the appearance of CNS symptoms, e.g., visual or hearing disturbances, perioral numbness, tingling and others. Similar symptoms were seen with both drugs. In 1 study, the mean ± SD maximum tolerated intravenous dose of ropivacaine infused (124 ± 38 mg) was significantly higher than that of bupivacaine (99 ± 30 mg) while in the other study the doses were not different (115 ± 29 mg of ropivacaine and 103 ± 30 mg of bupivacaine). In the latter study, the number of subjects reporting each symptom was similar for both drugs with the exception of muscle twitching which was reported by more subjects with bupivacaine than ropivacaine at comparable intravenous doses. At the end of the infusion, ropivacaine in both studies caused significantly less depression of cardiac conductivity (less QRS widening) than bupivacaine. Ropivacaine and bupivacaine caused evidence of depression of cardiac contractility, but there were no changes in cardiac output.

Clinical data in one published article indicate that differences in various pharmacodynamic measures were observed with increasing age. In one study, the upper level of analgesia increased with age, the maximum decrease of mean arterial pressure (MAP) declined with age during the first hour after epidural administration, and the intensity of motor blockade increased with age. However, no pharmacokinetic differences were observed between elderly and younger patients.

In non-clinical pharmacology studies comparing ropivacaine and bupivacaine in several animal species, the cardiac toxicity of ropivacaine was less than that of bupivacaine, although both were considerably more toxic than lidocaine. Arrhythmogenic and cardio-depressant effects were seen in animals at significantly higher doses of ropivacaine than bupivacaine. The incidence of successful resuscitation was not significantly different between the ropivacaine and bupivacaine groups.

12.3 Pharmacokinetics

Absorption

The systemic concentration of ropivacaine is dependent on the total dose and concentration of drug administered, the route of administration, the patient's 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 that 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 mcg/mL.

Table 7 Pharmacokinetic (Plasma Concentration-Time) Data From Clinical Trials
*
Continuous 72 hour epidural infusion after an epidural block with 5 or 10 mg/mL.
Epidural anesthesia with 7.5 mg/mL (0.75%) for cesarean delivery.
Brachial plexus block with 7.5 mg/mL (0.75%) ropivacaine.
§
20 minute IV infusion to volunteers (40 mg).
Cmax measured at the end of infusion (i.e., at 72 hr).
#
Cmax measured at the end of infusion (i.e., at 20 minutes).
Þ
n/a=not applicable
ß
t1/2 is the true terminal elimination half-life. On the other hand, t1/2 follows absorption-dependent elimination (flip‑flop) after non-intravenous administration.

Route

Epidural Infusion*

Epidural Infusion*

Epidural Block

Epidural Block

Plexus Block

IV Infusion§

Dose (mg)

1493±10

2075±206

1217±277

150

187.5

300

40

N

12

12

11

8

8

10

12

Cmax (mg/L)

2.4±1

2.8±0.5

2.3±1.1

1.1±0.2

1.6±0.6

2.3±0.8

1.2±0.2#

Tmax (min)

n/aÞ

n/a

n/a

43±14

34±9

54±22

n/a

AUC0-

(mg.h/L)

135.5±50

145±34

161±90

7.2±2

11.3±4

13±3.3

1.8±0.6

CL (L/h)

11.03

13.7

n/a

5.5±2

5±2.6

n/a

21.2±7

t1/2 (hr)ß

5±2.5

5.7±3

6±3

5.7±2

7.1±3

6.8±3.2

1.9±0.5

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 Warnings and Precautions (5.7)]. 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 α1-acid glycoprotein. An increase in total plasma concentrations during continuous epidural infusion has been observed, related to a postoperative increase of α1-acid glycoprotein. Variations in unbound, i.e., 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 Warnings and Precautions (5) and Use in Specific Population (8.1)].

Metabolism

Ropivacaine is extensively metabolized in the liver, predominantly by aromatic hydroxylation mediated by cytochrome P4501A to 3-hydroxy ropivacaine. After a single IV dose approximately 37% of the total dose is excreted in the urine as both free and conjugated 3-hydroxy ropivacaine. Low concentrations of 3‑hydroxy ropivacaine have been found in the plasma. Urinary excretion of the 4‑hydroxy ropivacaine, and both the 3-hydroxy N-de-alkylated (3-OH-PPX) and 4-hydroxy N-de-alkylated (4-OH-PPX) metabolites account for less than 3% of the dose. An additional metabolite, 2‑hydroxy‑methyl‑ropivacaine, has been identified but not quantified in the urine. The N-de-alkylated metabolite of ropivacaine (PPX) and 3-OH-ropivacaine are the major metabolites excreted in the urine during epidural infusion. Total PPX concentration in the plasma was about half as that of total ropivacaine; however, mean unbound concentrations of PPX were about 7 to 9 times higher than that of unbound ropivacaine following continuous epidural infusion up to 72 hours. Unbound PPX, 3-hydroxy and 4-hydroxy ropivacaine, have a pharmacological activity in animal models less than that of ropivacaine. There is no evidence of in vivo racemization in urine of ropivacaine.

Elimination

The kidney is the main excretory organ for most local anesthetic metabolites. In total, 86% of the ropivacaine dose is excreted in the urine after intravenous administration of which only 1% relates to unchanged drug. After intravenous administration ropivacaine has a mean ± SD total plasma clearance of 387 ± 107 mL/min, an unbound plasma clearance of 7.2 ± 1.6 L/min, and a renal clearance of 1 mL/min. The mean ± SD terminal half‑life is 1.8 ± 0.7 h after intravascular administration and 4.2 ± 1 h after epidural administration.

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