Ropivacaine Hydrochloride 5 mg/mL Injection — NDC 70121-1734-7 (Billing 70121-1734-07)

12 CLINICAL PHARMACOLOGY

12.1Mechanism 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.

12.2Pharmacodynamics 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 mg ± 38 mg) was significantly higher than that of bupivacaine (99 mg ± 30 mg) while in the other study the doses were not different (115 mg ± 29 mg of ropivacaine and 103 mg ± 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 eff… [Excerpted — this section continues on DailyMed.]

12.1Mechanism 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.

12.3Pharmacokinetics 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 minutes ± 7 minutes and 4.2 hours ± 0.9 hour, 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 mcg/mL ± 0.3 mcg/mL. Table 7: Pharmacokinetic (Plasma Concentration-Time) Data From Clinical Trials Route Epidural Infusion * Epidural Infusion * Epidural Block † Epidural Block † Plexus Block ‡ Intravenous Infusion § Dose (mg) 1,493 ± 10 2,075 ± 206 1,217 ± 277 150 187.5 300 40 N 12 12 11 8 8 10 12 C max (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 # T max (min) n/a ♠ n/a n/a 43 ± 14 34 ± 9 54 ± 22 n/a AUC 0- (mg.h/L) 135.5 ± 50 145 ± 34 161 ± 90 7.2 ± 2 11.3 ± 4 13 ± 3.3 1.8 ±

0.6CL (L/h) 11.03 13.7 n/a 5.5 ± 2 5 ± 2.6 n/a 21.2 ± 7 t 1/2 (hour) ♥ 5 ± 2.5 5.7 ± 3 6 ± 3 5.7 ± 2 7.1 ± 3 6.8 ± 3.2 1.9 ± 0.5 * Continuous 72 hour epidural infusion after an epidural block with 5 mg/mL 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 intravenous infusion to volunteers (40 mg). ¶ C max measured at the end of infusion (i.e. at 72 hour). # C max measured at the end of infusion (i.e. at 20 minutes). ♠ n/a=not applicable ♥ t ½ is the true terminal elimination half-life.

On the other hand, t ½ follows absorption dependent elimination (flip-flop) after non-intravenous administration. 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 liters ± 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 intravenous 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 unboun… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics 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 mg ± 38 mg) was significantly higher than that of bupivacaine (99 mg ± 30 mg) while in the other study the doses were not different (115 mg ± 29 mg of ropivacaine and 103 mg ± 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.

14 CLINICAL STUDIES Ropivacaine was studied as a local anesthetic both for surgical anesthesia and for acute pain management [ see Dosage and Administration (2) ] . The onset, depth and duration of sensory block are, in general, similar to bupivacaine. However, the depth and duration of motor block, in general, are less than that with bupivacaine.

14.1Epidural Administration in Surgery There were 25 clinical studies performed in 900 patients to evaluate ropivacaine hydrochloride epidural injection for general surgery. Ropivacaine hydrochloride was used in doses ranging from 75 mg to 250 mg. In doses of 100 mg to 200 mg, the median (1st to 3rd quartile) onset time to achieve a T10 sensory block was 10 (5 to 13) minutes and the median (1st to 3rd quartile) duration at the T10 level was 4 (3 to 5) hours [ see Dosage and Administration (2.2) ] .

Higher doses produced a more profound block with a greater duration of effect.

14.2Epidural Administration in Cesarean Section A total of 12 studies were performed with epidural administration of ropivacaine hydrochloride for cesarean section. Eight of these studies involved 218 patients using the concentration of 5 mg/mL (0.5%) in doses up to 150 mg. Median onset measured at T6 ranged from 11 minutes to 26 minutes.

Median duration of sensory block at T6 ranged from 1.7 hours to 3.2 hours, and duration of motor block ranged from 1.4 hours to 2.9 hours. Ropivacaine hydrochloride provided adequate muscle relaxation for surgery in all cases. In addition, 4 active controlled studies for cesarean section were performed in 264 patients at a concentration of 7.5 mg/mL (0.75%) in doses up to 187.5 mg.

Median onset measured at T6 ranged from 4 minutes to 15 minutes. Seventy-seven to 96% of ropivacaine hydrochloride-exposed patients reported no pain at delivery. Some patients received other anesthetic, analgesic, or sedative modalities during the course of the operative procedure.

14.3Epidural Administration in Labor and Delivery A total of 9 double-blind clinical studies, involving 240 patients were performed to evaluate ropivacaine hydrochloride for epidural block for management of labor pain. When administered in doses up to 278 mg as intermittent injections or as a continuous infusion, ropivacaine hydrochloride produced adequate pain relief. A prospective meta-analysis on 6 of these studies provided detailed evaluation of the delivered newborns and showed no difference in clinical outcomes compared to bupivacaine.

There were significantly fewer instrumental deliveries in mothers receiving ropivacaine as compared to bupivacaine. Table 8: Labor and Delivery Meta-analysis: Mode of Delivery Delivery Mode Ropivacaine Hydrochloride n=199 Bupivacaine n=188 n % n % Spontaneous Vertex 116 58 92 49 Vacuum Extractor 26 33 }27* }40 Forceps 28 42 Cesarean Section 29 15 21 11 *p=0.004 versus bupivacaine.

14.4Epidural Administration in Postoperative Pain Management There were 8 clinical studies performed in 382 patients to evaluate ropivacaine hydrochloride 2 mg/mL (0.2%) for postoperative pain management after upper and lower abdominal surgery and after orthopedic surgery. The studies utilized intravascular morphine via PCA as a rescue medication and quantified as an efficacy variable. Epidural anesthesia with ropivacaine hydrochloride 5 mg/mL, (0.5%) was used intraoperatively for each of these procedures prior to initiation of postoperative ropivacaine hydrochloride.

The incidence and intensity of the motor block were dependent on the dose rate of ropivacaine hydrochloride and the site of injection. Cumulative doses of up to 770 mg of ropivacaine were administered over 24 hours (intraoperative block plus postoperative continuous infusion). The overall quality of pain relief, as judged by the patients, in the ropivacaine groups was rated as good or excellent (73% to 100%).

The frequency of motor block was greatest at 4 hours and decreased during the infusion period in all groups. At least 80% of patients… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Long-term studies in animals to evaluate the carcinogenic potential of ropivacaine have not been conducted. Mutagenesis Weak mutagenic activity was seen in the mouse lymphoma test. However, ropivacaine was negative in an in vitro Ames assay and an in vivo mouse micronucleus assay.

Impairment of Fertility No adverse effects on fertility or early embryonic development were reported in a 2-generational reproduction study in which female rats (F 0 ) were administered subcutaneous doses of 6.3, 12, and 23 mg/kg/day (equivalent to 0.08, 0.15, and 0.29 times the maximum recommended human dose (MRHD) of 770 mg/24 hours for epidural use, respectively, and 0.24, 0.45, and 0.88 times the MRHD of 250 mg for nerve block use, respectively, based on BSA comparisons and a 60 kg human) throughout the mating period and pregnancy, partus, and lactation.

13.2Animal Toxicology and/or Pharmacology The mean dosages of ropivacaine producing seizures, after intravenous infusion in dogs, nonpregnant and pregnant sheep were 4.9 mg/kg, 6.1 mg/kg and 5.9 mg/kg (HED: 5.3 mg/kg, 6.6 mg/kg, and 6.4 mg/kg, based on 75 kg sheep weight and 60 kg human weight), respectively. These doses were associated with peak arterial total plasma concentrations of 11.4 mcg/mL, 4.3 mcg/mL and 5 mcg/mL, respectively.