Naropin Side Effects Center

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 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 NAROPIN (concentrations ranged from 0.125% to 1% for NAROPIN 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 NAROPIN-treated patients in these studies. The majority of patients receiving concentrations higher than 5 mg/mL (0.5%) were treated with NAROPIN.

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	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 3 : 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 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 and bupivacaine. Table 4 is based on data from trials in the U.S. and other countries where NAROPIN 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 mg/mL total N=297		10 mg/mL total N=207		5 mg/mL total N=236		7.5 mg/mL 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	5	(2)	8	(2.7)	10	(4.8)	10	(4.2)
retention
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 are broken down by gender.

Table 5 : Effects of Age on Hypotension (Epidural Administration)
Total N: NAROPIN = 760, Bupivacaine = 410

AGE	NAROPIN						Bupivacaine
	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 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 > 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 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]. 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 AND PRECAUTIONS and OVERDOSAGE].

Allergic Reactions

Allergic type reactions are rare and may occur as a result of sensitivity to the local anesthetic [see WARNINGS AND PRECAUTIONS]. 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 amidetype local anesthetic group has been reported. The usefulness of screening for sensitivity has not been definitively established.

DRUG 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]:

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

NAROPIN should be used with caution in patients receiving other local anesthetics or agents structurally related to amidetype 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, can interact with NAROPIN 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].

Read the entire FDA prescribing information for Naropin (Ropivacaine Hcl)