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Naropin

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Naropin

SIDE EFFECTS

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 Naropin (ropivacaine hcl) at concentrations up to 1% in clinical trials. Each patient was counted once for each type of adverse event.

Incidence ≥ 5%

For the indications of epidural administration in surgery, cesarean section, post-operative 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%), paraesthesia (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 Naropin (ropivacaine hcl) (concentrations ranged from 0.125% to 1% for Naropin (ropivacaine hcl) and 0.25% to 0.75% for bupivacaine) in the U.S. and other countries involving 3,094 patients. Table 3A and 3B list adverse events (number and percentage) that occurred in at least 1% of Naropin (ropivacaine hcl) -treated patients in these studies. The majority of patients receiving concentrations higher than 5 mg/mL (0.5%) were treated with Naropin (ropivacaine hcl) .

Table 3A: Adverse Events Reported in ≥1% of Adult Patients Receiving Regional or Local Anesthesia (Surgery, Labor, Cesarean Section, Post-Operative Pain Management, Peripheral Nerve Block and Local Infiltration)

Adverse Reaction Naropin
total N=1661
Bupivacaine
total N=1433
N (%) 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 3B: Adverse Events Reported in ≥1% of Fetuses or Neonates of Mothers Who Received Regional Anesthesia (Cesarean Section and Labor Studies)

Adverse Reaction Naropin
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 Naropin (ropivacaine hcl) 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 Naropin (ropivacaine hcl) and bupivacaine. Table 4 is based on data from trials in the U.S. and other countries where Naropin (ropivacaine hcl) was administered as an epidural anesthetic for surgery.

Table 4: Common Events (Epidural Administration)

Adverse Reaction Naropin Bupivacaine
5 mg/mL total
N=256
7.5 total mg/mL
N=297
10 mg/mL total
N=207
5 mg/mL total
N=236
7.5 m total g/mL
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 Naropin (ropivacaine hcl) are broken down by gender.

Table 5: Effects of Age on Hypotension (Epidural Administration) Total N: Naropin (ropivacaine hcl) = 760, bupivacaine = 410

AGE Nar opin Bupi vacaine
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, diminished tolerance or from unintentional intravascular injection of the local anesthetic solution. In addition to systemic dose-related toxicity, unintentional subarachnoid injection of drug during the intended performance of lumbar epidural block or nerve blocks near the vertebral column (especially in the head and neck region) may result in underventilation or apnea ("Total or High Spinal"). Also, hypotension due to loss of sympathetic tone and respiratory paralysis or underventilation due to cephalad extension of the motor level of anesthesia may occur. This may lead to secondary cardiac arrest if untreated. Factors influencing plasma protein binding such as acidosis, systemic diseases that alter protein production or competition with other drugs for protein binding sites, may diminish individual tolerance.

Epidural administration of Naropin (ropivacaine hcl) has, in some cases, as with other local anesthetics, been associated with transient increases in temperature to > 38.5°C. This occurred more frequently at doses of Naropin (ropivacaine hcl) > 16 mg/h.

Neurologic Reactions

These are characterized by excitation and/or depression. Restlessness, anxiety, dizziness, tinnitus, blurred vision or tremors may occur, possibly proceeding to convulsions. However, excitement may be transient or absent, with depression being the first manifestation of an adverse reaction. This may quickly be followed by drowsiness merging into unconsciousness and respiratory arrest. Other central nervous system effects may be nausea, vomiting, chills, and constriction of the pupils.

The incidence of convulsions associated with the use of local anesthetics varies with the route of administration and the total dose administered. In a survey of studies of epidural anesthesia, overt toxicity progressing to convulsions occurred in approximately 0.1% of local anesthetic administrations.

The incidence of adverse neurological reactions associated with the use of local anesthetics may be related to the total dose and concentration of local anesthetic administered and are also dependent upon the particular drug used, the route of administration, and the physical status of the patient. Many of these observations may be related to local anesthetic techniques, with or without a contribution from the drug. During lumbar epidural block, occasional unintentional penetration of the subarachnoid space by the catheter or needle may occur. Subsequent adverse effects may depend partially on the amount of drug administered intrathecally as well as the physiological and physical effects of a dural puncture. These observations may include spinal block of varying magnitude (including high or total spinal block), hypotension secondary to spinal block, urinary retention, loss of bladder and bowel control (fecal and urinary incontinence), and loss of perineal sensation and sexual function. Signs and symptoms of subarachnoid block typically start within 2 to 3 minutes of injection. Doses of 15 and 22.5 mg of Naropin (ropivacaine hcl) resulted in sensory levels as high as T5 and T4, respectively. Analgesia started in the sacral dermatomes in 2 to 3 minutes and extended to the T10 level in 10 to 13 minutes and lasted for approximately 2 hours. Other neurological effects following unintentional subarachnoid administration during epidural anesthesia may include persistent anesthesia, paresthesia, weakness, paralysis of the lower extremities, and loss of sphincter control; all of which may have slow, incomplete or no recovery. Headache, septic meningitis, meningismus, slowing of labor, increased incidence of forceps delivery, or cranial nerve palsies due to traction on nerves from loss of cerebrospinal fluid have been reported (see DOSAGE AND ADMINISTRATION discussion of Lumbar Epidural Block). A high spinal is characterized by paralysis of the arms, loss of consciousness, respiratory paralysis and bradycardia.

Cardiovascular System Reactions

High doses or unintentional intravascular injection may lead to high plasma levels and related depression of the myocardium, decreased cardiac output, heart block, hypotension, bradycardia, ventricular arrhythmias, including ventricular tachycardia and ventricular fibrillation, and possibly cardiac arrest (see WARNINGS, PRECAUTIONS, and OVERDOSAGE).

Allergic Reactions

Allergic type reactions are rare and may occur as a result of sensitivity to the local anesthetic (see WARNINGS). These reactions are characterized by signs such as urticaria, pruritus, erythema, angioneurotic edema (including laryngeal edema), tachycardia, sneezing, nausea, vomiting, dizziness, syncope, excessive sweating, elevated temperature, and possibly, anaphylactoid symptomatology (including severe hypotension). Cross-sensitivity among members of the amide-type local anesthetic group has been reported. The usefulness of screening for sensitivity has not been definitively established.

Read the Naropin (ropivacaine hcl) Side Effects Center for a complete guide to possible side effects

DRUG INTERACTIONS

Specific trials studying the interaction between ropivacaine and class III antiarrhythmic drugs (eg, amiodarone) have not been performed, but caution is advised (see WARNINGS).

Naropin (ropivacaine hcl) 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 Naropin (ropivacaine hcl) , can interact with Naropin (ropivacaine hcl) 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.

Last reviewed on RxList: 3/8/2010
This monograph has been modified to include the generic and brand name in many instances.

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