Amides

Ropivacaine Hydrochloride

Approved 15 Jun 2018InjectionSolution

The FDA lists this product in 60 strengths and forms.

Indications

Ropivacaine hydrochloride injection is indicated for the production of local or regional anesthesia for surgery and for acute pain management. Surgical Anesthesia : epidural block for surgery including cesarean section; major nerve block; local infiltration Acute Pain Management : epidural continuous infusion or intermittent bolus, e.g., postoperative or labor; local infiltration Ropivacaine hydrochloride injection is an amide local anesthetic indicated in adults for the production of local or regional anesthesia for surgery and for acute pain management.

Surgical Anesthesia : epidural block for surgery including cesarean section; major nerve block; local infiltration Acute Pain Managemen t: epidural continuous infusion or intermittent bolus, e.g., postoperative or labor; local infiltration

Contraindications

Ropivacaine hydrochloride injection is contraindicated in patients with a known hypersensitivity to ropivacaine or to any local anesthetic agent of the amide type. History of hypersensitivity to local anesthetics of the amide type. (4)

Warnings and precautions

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) In performing Ropivacaine hydrochloride injection blocks, unintended intravenous injection is possible and may result in cardiac arrhythmia or cardia arrest. (5.2) Intra-articular infusions of local anesthetics may cause chondrolysis. Ropivacaine hydrochloride injection is not approved for this use.

(5.3). Signs of methemoglobinemia may occur. (5.4)

5.1General 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 )].

Indications

Warnings and precautions

(5.3). Signs of methemoglobinemia may occur. (5.4)

5.1General Warnings and Precautions Prior

Interactions

Patients who are administered local anesthetics are at increased risk of developing methemoglobinemia when concurrently exposed to the following drugs, which could include other local anesthetics [see Warnings and Precautions ( 5.4 )] : Examples of Drugs Associated with Methemoglobinemia Class Examples Nitrates/Nitrites nitric oxide, nitroglycerin, nitroprusside, nitrous oxide Local anesthetics articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, tetracaine Antineoplastic agents cyclophosphamide, flutamide, hydroxyurea, ifosfamide, rasburicase Antibiotics dapsone, nitrofurantoin, para-aminosalicylic acid, sulfonamides Antimalarials chloroquine, primaquine Anticonvulsants Phenobarbital, phenytoin, sodium valproate Other drugs acetaminophen, metoclopramide, quinine, sulfasalazine Ropivacaine hydrochloride injection should be used with caution in patients receiving other local anesthetics or agents structurally related to amide- type local anesthetics, since the toxic effects of these drugs are additive.

Cytochrome P4501A2 is involved in the formation of 3-hydroxy ropivacaine, the major metabolite. In vivo, the plasma clearance of ropivacaine was reduced by 70% during coadministration of fluvoxamine (25 mg bid for 2 days), a selective and potent CYP1A2 inhibitor. Thus strong inhibitors of cytochrome P4501A2, such as fluvoxamine, given concomitantly during administration of ropivacaine hydrochloride injection, can interact with ropivacaine hydrochloride injection leading to increased ropivacaine plasma levels.

Caution should be exercised when CYP1A2 inhibitors are coadministered. Possible interactions with drugs known to be metabolized by CYP1A2 via competitive inhibition such as theophylline and imipramine may also occur. Coadministration of a selective and potent inhibitor of CYP3A4, ketoconazole (100 mg bid for 2 days with ropivacaine infusion administered 1 hour after ketoconazole) caused a 15% reduction in in vivo plasma clearance of ropivacaine.

Specific trials studying the interaction between ropivacaine and class III antiarrhythmic drugs (e.g., amiodarone) have not been performed, but caution is advised [see Warnings and Precautions ( 5.13 )] . Agents structurally related to amide-type local anesthetics: Concurrent use may cause additive effects. (7)

Pregnancy and breastfeeding

8.1Pregnancy 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 Clinical Pharmacology ( 12 )] .

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 Carcinogenesis, Mutagenesis, Impairment of Fertility ( 13.1 )] .

Adverse reactions

Reactions to ropivacaine are characteristic of those associated with other amide-type local anesthetics. A major cause of adverse reactions to this group of drugs may be associated with excessive plasma levels, which may be due to overdosage, unintentional intravascular injection or slow metabolic degradation. The reported adverse events are derived from clinical studies conducted in the U.S. and other countries. The reference drug was usually bupivacaine.

The studies used a variety of premedications, sedatives, and surgical procedures of varying length. A total of 3,988 patients have been exposed to ropivacaine hydrochloride injection at concentrations up to 1% in clinical trials. Each patient was counted once for each type of adverse event. Because clinical trials are conducted under widely conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Incidence ≥ 5% For the indications of epidural administration in surgery, cesarean section, postoperative pain management, peripheral nerve block, and local infiltration, the following treatment-emergent adverse events were reported with an incidence of ≥ 5% in all clinical studies (N=3988): hypotension (37%), nausea (24.8%), vomiting (11.6%), bradycardia (9.3%), fever (9.2%), pain (8%), postoperative complications (7.1%), anemia (6.1%), paresthesia (5.6%), headache (5.1%), pruritus (5.1%), and back pain (5%).

Incidence 1 to 5% Urinary retention, dizziness, rigors, hypertension, tachycardia, anxiety, oliguria, hypoesthesia, chest pain, hypokalemia, dyspnea, cramps, and urinary tract infection. Incidence in Controlled Clinical Trials The reported adverse events are derived from controlled clinical studies with ropivacaine hydrochloride injection (concentrations ranged from 0.125% to 1% for ropivacaine hydrochloride injection and 0.25% to 0.75% for bupivacaine) in the U.S. and other countries involving 3,094 patients.

Table 2 and Table 3 list adverse events (number and percentage) that occurred in at least 1% of ropivacaine hydrochloride injection-treated patients in these studies. The majority of patients receiving concentrations higher than 5 mg/mL (0.5%) were treated with ropivacaine hydrochloride injection. Table 2 Adverse Events Reported in ≥1% of Adult Patients Receiving Regional or Local Anesthesia (Surgery, Labor, Cesarean Section, Postoperative Pain Management, Peripheral Nerve Block and Local Infiltration) Adverse Reaction Ropivacaine Hydrochloride Injection total N=1661 N % Bupivacaine total N=1433 N % Hypotension 536 (32.3) 408 (28.5) Nausea 283 (17) 207 (14.4) Vomiting 117 (7) 88 (6.1) Bradycardia 96 (5.8) 73 (5.1) Headache 84 (5.1) 68 (4.7) Paresthesia 82 (4.9) 57 (4) Back pain 73 (4.4) 75 (5.2) Pain 71 (4.3) 71 (5) Pruritus 63 (3.8) 40 (2.8) Fever 61 (3.7) 37 (2.6) Dizziness 42 (2.5) 23 (1.6) Rigors (Chills) 42 (2.5) 24 (1.7) Postoperative complications 41 (2.5) 44 (3.1) Hypoesthesia 27 (1.6) 24 (1.7) Urinary retention 23 (1.4) 20 (1.4) Progression of labor poor/failed 23 (1.4) 22 (1.5) Anxiety 21 (1.3) 11 (0.8) Breast disorder, breast-feeding 21 (1.3) 12 (0.8) Rhinitis 18 (1.1) 13 (0.9) Table 3 Adverse Events Reported in ≥1% of Fetuses or Neonates of Mothers Who Received Regional Anesthesia (Cesarean Section and Labor Studies) Adverse Reaction Ropivacaine Hydrochloride Injection total N = 639 Bupivacaine total N = 573 N % N % Fetal bradycardia 77 (12.1) 68 (11.9) Neonatal jaundice 49 (7.7) 47 (8.2) Neonatal complication-NOS 42 (6.6) 38 (6.6) Apgar score low 18 (2.8) 14 (2.4) Neonatal respiratory disorder 17 (2.7) 18 (3.1) Neonatal tachypnea 14 (2.2) 15 (2.6) Neonatal fever 13 (2) 14 (2.4) Fetal tachycardia 13 (2) 12 (2.1) Fetal distress 11 (1.7) 10 (1.7) Neonatal infection 10 (1.6) 8 (1.4) Neonatal hypoglycemia 8 (1.3) 16 (2.8) Incidence <1% The following adverse events were reported during the ropivacaine hydrochloride injection clinical program in more than one patient (N=3988), occurred at an overall incidence of <1%, and were considered relevant: Application Site Reactions - injection site pain Cardiovascular System - vasovagal reaction, syncope, postural hypotension, non-specific ECG abnormalities Female Reproductive - poor progression of labor, uterine atony Gastrointestinal System - fecal incontinence, tenesmus, neonatal vomiting General and Other Disorders - hypothermia, malaise, asthenia, accident and/or injury Hearing and Vestibular - tinnitus, hearing abnormalities Heart Rate and Rhythm - extrasystoles, non-specific arrhythmias, atrial fibrillation Liver and Biliary System - jaundice Metabolic Disorders - hypomagnesemia Musculoskeletal System – myalgia Myo/Endo/Pericardium - ST segment changes, myocardial infarction Nervous System - tremor, Horner's syndrome, paresis, dyskinesia, neuropathy, vertigo, coma, convulsion, hypokinesia, hypotonia, ptosis, stupor Psychiatric Disorders - agitation, confusion, somnolence, nervousness, amnesia, hallucination, emotional lability, insomnia, nightmares Respiratory System - bronchospasm, coughing Skin Disorders - rash, urticaria Urinary System Disorders - urinary incontinence, micturition disorder Vascular - deep vein thrombosis, phlebitis, pulmonary embolism Vision - vision abnormalities For the indication epidural anesthesia for surgery, the 15 most common adverse events were compared between different concentrations of ropivacaine hydrochloride injection and bupivacaine.

Table 4 is based on data from trials in the U.S. and other countries where ropivacaine hydrochloride injection was administered as an epidural anesthetic for surgery. Table 4 Common Events (Epidural Administration) Adverse Reaction Ropivacaine Hydrochloride Injection Bupivacaine 5 mg/mL 7.5 mg/mL 10 mg/mL 5 mg/mL 7.5 mg/mL total N=256 total N=297 total N=207 total N=236 total N=174 N (%) N (%) N (%) N (%) N (%) hypotension 99 (38.7) 146 (49.2) 113 (54.6) 91 (38.6) 89 (51.1) nausea 34 (13.3) 68 (22.9) 41 (17.4) 36 (20.7) bradycardia 29 (11.3) 58 (19.5) 40 (19.3) 32 (13.6) 25 (14.4) back pain 18 (7) 23 (7.7) 34 (16.4) 21 (8.9) 23 (13.2) vomiting 18 (7) 33 (11.1) 23 (11.1) 19 (8.1) 14 (8) headache 12 (4.7) 20 (6.7) 16 (7.7) 13 (5.5) 9 (5.2) fever 8 (3.1) 5 (1.7) 18 (8.7) 11 (4.7) chills 6 (2.3) 7 (2.4) 6 (2.9) 4 (1.7) 3 (1.7) urinary retention 5 (2) 8 (2.7) 10 (4.8) 10 (4.2) paresthesia 5 (2) 10 (3.4) 5 (2.4) 7 (3) pruritus 14 (4.7) 3 (1.4) 7 (4) Using data from the same studies, the number (%) of patients experiencing hypotension is displayed by patient age, drug and concentration in Table 5.

In Table 6, the adverse events for ropivacaine hydrochloride injection are broken down by gender. Table 5 Effects of Age on Hypotension (Epidural Administration) Total N: Ropivacaine Hydrochloride Injection = 760, Bupivacaine = 410 Ropivacaine Hydrochloride Injection Bupivacaine AGE 5 mg/mL 7.5 mg/mL 10 mg/mL 5 mg/mL 7.5 mg/mL N (%) N (%) N (%) N (%) N (%) < 65 68 (32.2) 99 (43.2) 87 (51.5) 64 (33.5) 73 (48.3) ≥ 65 31 (68.9) 47 (69.1) 26 (68.4) 27 (60) 16 (69.6) Table 6 Most Common Adverse Events by Gender (Epidural Administration) Total N: Females = 405, Males = 355 Adverse Reaction Female Male N (%) N (%) hypotension 220 (54.3) 138 (38.9) nausea 119 (29.4) 23 (6.5) bradycardia 65 (16) 56 (15.8) vomiting 59 (14.6) 8 (2.3) back pain 41 (10.1) 23 (6.5) headache 33 (8.1) 17 (4.8) chills 18 (4.4) 5 (1.4) fever 16 (4) 3 (0.8) pruritus 16 (4) 1 (0.3) pain 12 (3) 4 (1.1) urinary retention 11 (2.7) 7 (2) dizziness 9 (2.2) 4 (1.1) hypoesthesia 8 (2) 2 (0.6) paresthesia 8 (2) 10 (2.8) Systemic Reactions The most commonly encountered acute adverse experiences that demand immediate countermeasures are related to the central nervous system and the cardiovascular system.

These adverse experiences are generally dose-related and due to high plasma levels that may result from overdosage, rapid absorption from the injection site, diminish

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Ropivacaine Hydrochloride

Indications

Contraindications

Warnings and precautions

5.1General Warnings and Precautions Prior

Two medicines in one question?

Ropivacaine Hydrochloride

Indications

Contraindications

Warnings and precautions

5.1General Warnings and Precautions Prior

Two medicines in one question?

5.2Unintended Intravenous Injection

5.3Intra-Articular Infusions and Risk of Chondrolysis

5.4Risk of Methemoglobinemia Cases

5.5Central Nervous System Toxicity Careful

Interactions

Pregnancy and breastfeeding

8.1Pregnancy Risk Summary

Adverse reactions

Composition

Strengths and forms

Official product information

At a glance