Ropivacaine Hydrochloride

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Ropivacaine Hydrochloride Prescribing Information

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Table 1: Dosage Recommendations
	mg/mL	(%)	mL	mg	min	hours
	Conc.		Volume	Dose	Onset	Duration
SURGICAL ANESTHESIA
Lumbar Epidural Administration Surgery	5	(0.5%)	15 to 30	75 to 150	15 to 30	2 to 4
	7.5	(0.75%)	15 to 25	113 to 188	10 to 20	3 to 5
	10	(1.0%)	15 to 20	150 to 200	10 to 20	4 to 6
Lumbar Epidural Administration Cesarean Section	5	(0.5%)	20 to 30	100 to 150	15 to 25	2 to 4
Lumbar Epidural Administration Cesarean Section	7.5	(0.75%)	15 to 20	113 to 150	10 to 20	3 to 5
Thoracic Epidural Administration Surgery	5	(0.5%)	5 to 15	25 to 75	10 to 20	n/a= Not Applicable
Thoracic Epidural Administration Surgery	7.5	(0.75%)	5 to 15	38 to 113	10 to 20	n/a
Major Nerve Block= The dose for a major nerve block must be adjusted according to site of administration and patient status. Supraclavicular brachial plexus blocks may be associated with a higher frequency of serious adverse reactions, regardless of the local anesthetic used [see Warnings and Precautions (5.7)] . (e.g., brachial plexus block)	5	(0.5%)	35 to 50	175 to 250	15 to 30	5 to 8
	7.5	(0.75%)	10 to 40	75 to 300	10 to 25	6 to 10
Field Block (e.g., minor nerve blocks and infiltration)	5	(0.5%)	1 to 40	5 to 200	1 to 15	2 to 6
LABOR PAIN MANAGEMENT
Lumbar Epidural Administration
Initial Dose	2	(0.2%)	10 to 20	20 to 40	10 to15	0.5 to 1.5
Continuous infusion= Median dose of 21 mg per hour was administered by continuous infusion or by incremental injections (top-ups) over a median delivery time of 5.5 hours.	2	(0.2%)	6 to 14 mL/h	12 to 28 mg/h	n/a	n/a
Incremental injections (top-up)	2	(0.2%)	10 to 15 mL/h	20 to 30 mg/h	n/a	n/a
POSTOPERATIVE PAIN MANAGEMENT
Lumbar Epidural Administration Continuous infusion= Cumulative doses up to 770 mg of Ropivacaine Hydrochloride over 24 hours (intraoperative block plus postoperative infusion); Continuous epidural infusion at rates up to 28 mg per hour for 72 hours have been well tolerated in adults, i.e., 2016 mg plus surgical dose of approximately 100 to 150 mg as top-up.	2	(0.2%)	6 to 14 mL/h	12 to 28 mg/h	n/a	n/a
Thoracic Epidural Administration Continuous infusion	2	(0.2%)	6 to 14 mL/h	12 to 28 mg/h	n/a	n/a
Infiltration (e.g., minor nerve block)	2	(0.2%)	1 to 100	2 to 200	1 to 5	2 to 6
Infiltration (e.g., minor nerve block)	5	(0.5%)	1 to 40	5 to 200	1 to 5	2 to 6

for Dosage Recommendations (

2.2 Dosage Recommendations

Table 1: Dosage Recommendations
	mg/mL	(%)	mL	mg	min	hours
	Conc.		Volume	Dose	Onset	Duration
SURGICAL ANESTHESIA
Lumbar Epidural Administration Surgery	5	(0.5%)	15 to 30	75 to 150	15 to 30	2 to 4
	7.5	(0.75%)	15 to 25	113 to 188	10 to 20	3 to 5
	10	(1.0%)	15 to 20	150 to 200	10 to 20	4 to 6
Lumbar Epidural Administration Cesarean Section	5	(0.5%)	20 to 30	100 to 150	15 to 25	2 to 4
Lumbar Epidural Administration Cesarean Section	7.5	(0.75%)	15 to 20	113 to 150	10 to 20	3 to 5
Thoracic Epidural Administration Surgery	5	(0.5%)	5 to 15	25 to 75	10 to 20	n/a= Not Applicable
Thoracic Epidural Administration Surgery	7.5	(0.75%)	5 to 15	38 to 113	10 to 20	n/a
Major Nerve Block= The dose for a major nerve block must be adjusted according to site of administration and patient status. Supraclavicular brachial plexus blocks may be associated with a higher frequency of serious adverse reactions, regardless of the local anesthetic used [see Warnings and Precautions (5.7)] . (e.g., brachial plexus block)	5	(0.5%)	35 to 50	175 to 250	15 to 30	5 to 8
	7.5	(0.75%)	10 to 40	75 to 300	10 to 25	6 to 10
Field Block (e.g., minor nerve blocks and infiltration)	5	(0.5%)	1 to 40	5 to 200	1 to 15	2 to 6
LABOR PAIN MANAGEMENT
Lumbar Epidural Administration
Initial Dose	2	(0.2%)	10 to 20	20 to 40	10 to15	0.5 to 1.5
Continuous infusion= Median dose of 21 mg per hour was administered by continuous infusion or by incremental injections (top-ups) over a median delivery time of 5.5 hours.	2	(0.2%)	6 to 14 mL/h	12 to 28 mg/h	n/a	n/a
Incremental injections (top-up)	2	(0.2%)	10 to 15 mL/h	20 to 30 mg/h	n/a	n/a
POSTOPERATIVE PAIN MANAGEMENT
Lumbar Epidural Administration Continuous infusion= Cumulative doses up to 770 mg of Ropivacaine Hydrochloride over 24 hours (intraoperative block plus postoperative infusion); Continuous epidural infusion at rates up to 28 mg per hour for 72 hours have been well tolerated in adults, i.e., 2016 mg plus surgical dose of approximately 100 to 150 mg as top-up.	2	(0.2%)	6 to 14 mL/h	12 to 28 mg/h	n/a	n/a
Thoracic Epidural Administration Continuous infusion	2	(0.2%)	6 to 14 mL/h	12 to 28 mg/h	n/a	n/a
Infiltration (e.g., minor nerve block)	2	(0.2%)	1 to 100	2 to 200	1 to 5	2 to 6
Infiltration (e.g., minor nerve block)	5	(0.5%)	1 to 40	5 to 200	1 to 5	2 to 6

The doses in the table are those considered to be necessary to produce a successful block and should be regarded as guidelines for use in adults. Individual variations in onset and duration occur. The figures reflect the expected average dose range needed. For other local anesthetic techniques standard current textbooks should be consulted.

When prolonged blocks are used, either through continuous infusion or through repeated bolus administration, the risks of reaching a toxic plasma concentration or inducing local neural injury must be considered. Experience to date indicates that a cumulative dose of up to 770 mg Ropivacaine Hydrochloride administered over 24 hours is well tolerated in adults when used for postoperative pain management: i.e., 2016 mg. Caution should be exercised when administering Ropivacaine Hydrochloride for prolonged periods of time, e.g., >70 hours in debilitated patients.

For treatment of postoperative pain, the following technique can be recommended: If regional anesthesia was not used intraoperatively, then an initial epidural block with 5 to 7 mL Ropivacaine Hydrochloride is induced via an epidural catheter. Analgesia is maintained with an infusion of Ropivacaine Hydrochloride, 2 mg/mL (0.2%). Clinical studies have demonstrated that infusion rates of 6 to 14 mL (12 to 28 mg) per hour provide adequate analgesia with nonprogressive motor block. With this technique a significant reduction in the need for opioids was demonstrated. Clinical experience supports the use of Ropivacaine Hydrochloride epidural infusions for up to 72 hours.

)

Risk Summary

There are no available human data on use of Ropivacaine Hydrochloride Injection in pregnant women to evaluate a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Local anesthetics may cause varying degrees of toxicity to the mother and fetus and adverse reactions include alterations of the central nervous system, peripheral vascular tone, and cardiac function

(see

Clinical Considerations

)

. No teratogenicity was observed at doses up to 0.3 times the maximum recommended human dose of 770 mg/24 hours for epidural use, and equal to the MRHD of 250 mg for nerve block use, based on body surface area (BSA) comparisons and a 60 kg human weight

(see

Animal data

)

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U. S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

Labor or Delivery

Local anesthetics, including ropivacaine, rapidly cross the placenta, and when used for epidural block can cause varying degrees of maternal, fetal, and neonatal toxicity

[see

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
Route	Epidural InfusionContinuous 72 hour epidural infusion after an epidural block with 5 or 10 mg/mL.		Epidural Infusion	Epidural BlockEpidural anesthesia with 7.5 mg/mL (0.75%) for cesarean delivery.	Epidural Block	Plexus BlockBrachial plexus block with 7.5 mg/mL (0.75%) ropivacaine.	IV Infusion20 minute IV infusion to volunteers (40 mg).
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 ± 1Cmax measured at the end of infusion (i.e., at 72 hr).	2.8 ± 0.5	2.3 ± 1.1	1.1 ± 0.2	1.6 ± 0.6	2.3 ± 0.8	1.2 ± 0.2Cmax measured at the end of infusion (i.e., at 20 minutes).
Tmax (min)	n/an/a=not applicable	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
t_1/2(hr)t½ is the true terminal elimination half-life. On the other hand, t½ follows absorption dependent elimination (flip-flop) after non-intravenous administration.	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-methylropivacaine, 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.

]

. The incidence and degree of toxicity depend upon the procedure performed, the type and amount of drug used, and the technique of drug administration. Adverse reactions in the parturient, fetus and neonate involve alterations of the central nervous system, peripheral vascular tone and cardiac function.

Maternal Adverse reactions

Maternal hypotension has resulted from regional anesthesia. Local anesthetics produce vasodilation by blocking sympathetic nerves. Therefore, during treatment of systemic toxicity, maternal hypotension or fetal bradycardia following regional block, the parturient should be maintained in the left lateral decubitus position if possible, or manual displacement of the uterus off the great vessels be accomplished. Elevating the patient's legs will also help prevent decreases in blood pressure. The fetal heart rate also should be monitored continuously, and electronic fetal monitoring is highly advisable.

Data

Animal data

No malformations were reported in embryo-fetal development toxicity studies conducted in pregnant New Zealand white rabbits and Sprague-Dawley rats. During gestation days 6 to 18, rabbits received daily subcutaneous doses of ropivacaine at 1.3, 4.2, or 13 mg/kg/day (equivalent to 0.03, 0.10, and 0.33 times the maximum recommended human dose (MRHD) of 770 mg/24 hours, respectively, and 0.10, 0.32, and 1.0 times the MRHD of 250 mg for nerve block use, respectively based on body surface area (BSA) comparisons and a 60 kg human weight). Rats received daily subcutaneous doses of 5.3, 11, and 26 mg/kg/day (equivalent to 0.07, 0.14, and 0.33 times the MRHD for epidural use, respectively, and 0.21, 0.43, and 1.0 times the MRHD for nerve block use, respectively, based on BSA comparisons) during GD 6 to 15.

No treatment-related effects on late fetal development, parturition, litter size, lactation, neonatal viability, or growth of the offspring were reported in a prenatal and postnatal reproductive and development toxicity study; however functional endpoints were not evaluated. Female rats were dosed daily subcutaneously from GD 15 to Lactation Day 20 at doses of 5.3, 11, and 26 mg/kg/day (equivalent to 0.07, 0.1, and 0.3 times the MRHD for epidural use, respectively, and 0.21, 0.43, and 1.0 times the MRHD for nerve block use, respectively), with maternal toxicity exhibited at the high dose.

No adverse effects in physical developmental milestones or in behavioral tests were reported in a 2-generational reproduction study, in which rats received daily subcutaneous doses of 6.3, 12, and 23 mg/kg/day (equivalent to 0.08, 0.15, and 0.29 times the MRHD for epidural use, respectively, and 0.24, 0.45, and 0.88 times the MRHD for nerve block use, respectively, based on BSA comparisons) for 9 weeks before mating and during mating for males, and for 2 weeks before mating and during mating, pregnancy, and lactation, up to day 42 post coitus for females. Significant pup loss was observed in the high dose group during the first 3 days postpartum, from a few hours up to 3 days after delivery compared to the control group, which was considered secondary to impaired maternal care due to maternal toxicity. No differences were observed in litter parameters, or fertility, mean gestation time, or number of live births were observed between the control (saline) and treatment groups

[see

13.1 Carcinogenesis, 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 (F0) 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.

]

Delay in proper management of dose-related toxicity, underventilation, and/or altered sensitivity may lead to the development of acidosis, cardiac arrest and, possibly, death. (
5.1 General Warnings and Precautions
Prior to receiving major blocks the general condition of the patient should be optimized and the patient should have an IV line inserted. All necessary precautions should be taken to avoid intravascular injection. Local anesthetics should only be administered by clinicians who are well versed in the diagnosis and management of dose-related toxicity and other acute emergencies which might arise from the block to be employed, and then only after insuring the
immediate (without delay)
availability of oxygen, other resuscitative drugs, cardiopulmonary resuscitative equipment, and the personnel resources needed for proper management of toxic reactions and related emergencies
[see Adverse Reactions (6)and Overdosage (10.1)]
. Delay in proper management of dose-related toxicity, underventilation from any cause, and/or altered sensitivity may lead to the development of acidosis, cardiac arrest and, possibly, death.
The safe and effective use of local anesthetics depends on proper dosage, correct technique, adequate precautions and readiness for emergencies.
Resuscitative equipment, oxygen and other resuscitative drugs should be available for immediate use
[see Adverse Reactions (6)]
. The lowest dosage that results in effective anesthesia should be used to avoid high plasma levels and serious adverse events. Injections should be made slowly and incrementally, with frequent aspirations before and during the injection to avoid intravascular injection. When a continuous catheter technique is used, syringe aspirations should also be performed before and during each supplemental injection. During the administration of epidural anesthesia, it is recommended that a test dose of a local anesthetic with a fast onset be administered initially and that the patient be monitored for central nervous system and cardiovascular toxicity, as well as for signs of unintended intrathecal administration before proceeding. When clinical conditions permit, consideration should be given to employing local anesthetic solutions, which contain epinephrine for the test dose because circulatory changes compatible with epinephrine may also serve as a warning sign of unintended intravascular injection. An intravascular injection is still possible even if aspirations for blood are negative. Administration of higher than recommended doses of Ropivacaine Hydrochloride to achieve greater motor blockade or increased duration of sensory blockade may result in cardiovascular depression, particularly in the event of inadvertent intravascular injection. Tolerance to elevated blood levels varies with the physical condition of the patient. Debilitated, elderly patients and acutely ill patients should be given reduced doses commensurate with their age and physical condition. Local anesthetics should also be used with caution in patients with hypotension, hypovolemia or heart block.
Solutions of Ropivacaine Hydrochloride should not be used for the production of obstetrical paracervical block anesthesia, retrobulbar block, or spinal anesthesia (subarachnoid block) due to insufficient data to support such use. Intravenous regional anesthesia (bier block) should not be performed due to a lack of clinical experience and the risk of attaining toxic blood levels of ropivacaine.
It is essential that aspiration for blood, or cerebrospinal fluid (where applicable), be done prior to injecting any local anesthetic, both the original dose and all subsequent doses, to avoid intravascular or subarachnoid injection. However, a negative aspiration does not ensure against an intravascular or subarachnoid injection.
)
In performing Ropivacaine Hydrochloride blocks, unintended intravenous injection is possible and may result in cardiac arrhythmia or cardia arrest. (
5.2 Unintended Intravenous Injection
In performing Ropivacaine Hydrochloride blocks, unintended intravenous injection is possible and may result in cardiac arrhythmia or cardiac arrest. The potential for successful resuscitation has not been studied in humans. There have been rare reports of cardiac arrest during the use of Ropivacaine Hydrochloride for epidural anesthesia or peripheral nerve blockade, the majority of which occurred after unintentional accidental intravascular administration in elderly patients and in patients with concomitant heart disease. In some instances, resuscitation has been difficult. Should cardiac arrest occur, prolonged resuscitative efforts may be required to improve the probability of a successful outcome.
Ropivacaine Hydrochloride should be administered in incremental doses. It is not recommended for emergency situations, where a fast onset of surgical anesthesia is necessary. Historically, pregnant patients were reported to have a high risk for cardiac arrhythmias, cardiac/circulatory arrest and death when 0.75% bupivacaine (another member of the amino amide class of local anesthetics) was inadvertently rapidly injected intravenously.
)
Intra-articular infusions of local anesthetics may cause chondrolysis. Ropivacaine Hydrochloride is not approved for this use. (
5.3 Intra-Articular Infusions and Risk of Chondrolysis
Intra-articular infusions of local anesthetics following arthroscopic and other surgical procedures is an unapproved use, and there have been post-marketing reports of chondrolysis in patients receiving such infusions. The majority of reported cases of chondrolysis have involved the shoulder joint; cases of gleno-humeral chondrolysis have been described in pediatric and adult patients following intra-articular infusions of local anesthetics with and without epinephrine for periods of 48 to 72 hours. There is insufficient information to determine whether shorter infusion periods are not associated with these findings. The time of onset of symptoms, such as joint pain, stiffness and loss of motion can be variable, but may begin as early as the 2nd month after surgery. Currently, there is no effective treatment for chondrolysis; patients who experienced chondrolysis have required additional diagnostic and therapeutic procedures and some required arthroplasty or shoulder replacement.
).
Signs of methemoglobinemia may occur. (
5.4 Risk of Methemoglobinemia
Cases of methemoglobinemia have been reported in association with local anesthetic use. Although all patients are at risk for methemoglobinemia, patients with glucose-6-phosphate dehydrogenase deficiency, congenital or idiopathic methemoglobinemia, cardiac or pulmonary compromise, infants under 6 months of age, and concurrent exposure to oxidizing agents or their metabolites are more susceptible to developing clinical manifestations of the condition. If local anesthetics must be used in these patients, close monitoring for symptoms and signs of methemoglobinemia is recommended.
Signs of methemoglobinemia may occur immediately or may be delayed some hours after exposure, and are characterized by a cyanotic skin discoloration and/or abnormal coloration of the blood. Methemoglobin levels may continue to rise; therefore, immediate treatment is required to avert more serious central nervous system and cardiovascular adverse effects, including seizures, coma, arrhythmias, and death. Discontinue Ropivacaine Hydrochloride and any other oxidizing agents. Depending on the severity of the signs and symptoms, patients may respond to supportive care, i.e., oxygen therapy, hydration. A more severe clinical presentation may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
)

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