Ropidex

WARNINGS Because rare instances of anaphylactoid reactions have occurred in patients receiving parenteral corticosteroid therapy, appropriate precautionary measures should be taken prior to administration, especially when the patient has a history of allergy to any drug. Anaphylactoid and hypersensitivity reactions have been reported for dexamethasone sodium phosphate injection (see ADVERSE REACTIONS ). Corticosteroids may exacerbate systemic fungal infections and, therefore, should not be used in the presence of such infections unless they are needed to control drug reactions due to amphotericin B. Moreover, there have been cases reported in which concomitant use of amphotericin B and hydrocortisone was followed by cardiac enlargement and congestive failure. In patients on corticosteroid therapy subjected to any unusual stress, increased dosage of rapidly acting corticosteroids before, during, and after the stressful situation is indicated. Drug-induced secondary adrenocortical insufficiency may result from too rapid withdrawal of corticosteroids and may be minimized by gradual reduction of dosage. This type of relative insufficiency may persist for months after discontinuation of therapy; therefore, in any situation of stress occurring during that period, hormone therapy should be reinstituted. If the patient is receiving steroids already, dosage may have to be increased. Since mineralocorticoid secretion may be impaired, salt and/or a mineralocorticoid should be administered concurrently. Corticosteroids may mask some signs of infection, and new infections may appear during their use. There may be decreased resistance and inability to localize infection when corticosteroids are used. Moreover, corticosteroids may affect the nitroblue-tetrazolium test for bacterial infection and produce false negative results. In cerebral malaria, a double-blind trial has shown that the use of corticosteroids is associated with prolongation of coma and a higher incidence of pneumonia and gastrointestinal bleeding. Corticosteroids may activate latent amebiasis. Therefore, it is recommended that latent or active amebiasis be ruled out before initiating corticosteroid therapy in any patient who has spent time in the tropics or in any patient with unexplained diarrhea. Prolonged use of corticosteroids may produce posterior subcapsular cataracts, glaucoma with possible damage to the optic nerves, and may enhance the establishment of secondary ocular infections due to fungi or viruses. Average and large doses of cortisone or hydrocortisone can cause elevation of blood pressure, salt and water retention, and increased excretion of potassium. These effects are less likely to occur with the synthetic derivatives except when used in large doses. Dietary salt restriction and potassium supplementation may be necessary. All corticosteroids increase calcium excretion. Administration of live virus vaccines, including smallpox, is contraindicated in individuals receiving immunosuppressive doses of corticosteroids. If inactivated viral or bacterial vaccines are administered to individuals receiving immunosuppressive doses of corticosteroids, the expected serum antibody response may not be obtained. However, immunization procedures may be undertaken in patients who are receiving corticosteroids as replacement therapy, e.g., for Addison’s disease. Patients who are on drugs which suppress the immune system are more susceptible to infections than healthy individuals. Chickenpox and measles, for example, can have a more serious or even fatal course in non-immune children or adults on corticosteroids. In such children or adults who have not had these diseases, particular care should be taken to avoid exposure. The risk of developing a disseminated infection varies among individuals and can be related to the dose, route and duration of corticosteroid administration as well as to the underlying disease. If exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If chickenpox develops, treatment with antiviral agents may be considered. If exposed to measles, prophylaxis with immune globulin (IG) may be indicated. (See the respective package inserts for VZIG and IG for complete prescribing information). The use of dexamethasone sodium phosphate injection in active tuberculosis should be restricted to those cases of fulminating or disseminated tuberculosis in which the corticosteroid is used for the management of the disease in conjunction with an appropriate antituberculous regimen. If corticosteroids are indicated in patients with latent tuberculosis or tuberculin reactivity, close observation is necessary as reactivation of the disease may occur. During prolonged corticosteroid therapy, these patients should receive chemoprophylaxis. Literature reports suggest an apparent association between use of corticosteroids and left ventricular free wall rupture after a recent myocardial infarction; therefore, therapy with corticosteroids should be used with great caution in these patients. Serious Neurologic Adverse Reactions with Epidural Administration Serious neurologic events, some resulting in death, have been reported with epidural injection of corticosteroids. Specific events reported include, but are not limited to, spinal cord infarction, paraplegia, quadriplegia, cortical blindness, and stroke. These serious neurologic events have been reported with and without use of fluoroscopy. The safety and effectiveness of epidural administration of corticosteroids has not been established, and corticosteroids are not approved for this use. Usage in Pregnancy Since adequate human reproduction studies have not been done with corticosteroids, use of these drugs in pregnancy or in women of childbearing potential requires that the anticipated benefits be weighed against the possible hazards to the mother and embryo or fetus. Infants born of mothers who have received substantial doses of corticosteroids during pregnancy should be carefully observed for signs of hypoadrenalism. Corticosteroids appear in breast milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other unwanted effects. Mothers taking pharmacologic doses of corticosteroids should be advised not to nurse.

Serious Neurologic Adverse Reactions with Epidural Administration Serious neurologic events, some resulting in death, have been reported with epidural injection of corticosteroids. Specific events reported include, but are not limited to, spinal cord infarction, paraplegia, quadriplegia, cortical blindness, and stroke. These serious neurologic events have been reported with and without use of fluoroscopy. The safety and effectiveness of epidural administration of corticosteroids has not been established, and corticosteroids are not approved for this use.

Usage in Pregnancy Since adequate human reproduction studies have not been done with corticosteroids, use of these drugs in pregnancy or in women of childbearing potential requires that the anticipated benefits be weighed against the possible hazards to the mother and embryo or fetus. Infants born of mothers who have received substantial doses of corticosteroids during pregnancy should be carefully observed for signs of hypoadrenalism. Corticosteroids appear in breast milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other unwanted effects. Mothers taking pharmacologic doses of corticosteroids should be advised not to nurse.

WARNINGS 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. 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 also ADVERSE REACTIONS , PRECAUTIONS and MANAGEMENT OF LOCAL ANESTHETIC EMERGENCIES ). 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. 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. 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 2 nd 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. 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. A well-known risk of epidural anesthesia may be an unintentional subarachnoid injection of local anesthetic. Two clinical studies have been performed to verify the safety of ropivacaine hydrochloride at a volume of 3 mL injected into the subarachnoid space since this dose represents an incremental epidural volume that could be unintentionally injected. The 15 and 22.5 mg doses injected resulted in sensory levels as high as T5 and T4, respectively. Anesthesia to pinprick started in the sacral dermatomes in 2 to 3 minutes, extended to the T10 level in 10 to 13 minutes and lasted for approximately 2 hours. The results of these two clinical studies showed that a 3 mL dose did not produce any serious adverse events when spinal anesthesia blockade was achieved. Ropivacaine hydrochloride 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. Patients treated with class III antiarrhythmic drugs (e.g., amiodarone) should be under close surveillance and ECG monitoring considered, since cardiac effects may be additive. 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.

ADVERSE REACTIONS Fluid and electrolyte disturbances: Sodium retention Fluid retention Congestive heart failure in susceptible patients Potassium loss Hypokalemic alkalosis Hypertension Musculoskeletal: Muscle weakness Steroid myopathy Loss of muscle mass Osteoporosis Vertebral compression fractures Aseptic necrosis of femoral and humeral heads Tendon rupture Pathologic fracture of long bones Gastrointestinal: Peptic ulcer with possible subsequent perforation and hemorrhage Perforation of the small and large bowel; particularly in patients with inflammatory bowel disease Pancreatitis Abdominal distention Ulcerative esophagitis Dermatologic: Impaired wound healing Thin fragile skin Petechiae and ecchymoses Erythema Increased sweating May suppress reactions to skin tests Burning or tingling, especially in the perineal area (after IV injection) Other cutaneous reactions, such as allergic dermatitis, urticaria, angioneurotic edema Neurologic: Convulsions Increased intracranial pressure with papilledema (pseudotumor cerebri) usually after treatment Vertigo Headache Psychic disturbances Endocrine: Menstrual irregularities Development of cushingoid state Suppression of growth in pediatric patients Secondary adrenocortical and pituitary unresponsiveness, particularly in times of stress, as in trauma, surgery, or illness Decreased carbohydrate tolerance Manifestations of latent diabetes mellitus Increased requirements for insulin or oral hypoglycemic agents in diabetics Hirsutism Ophthalmic: Posterior subcapsular cataracts Increased intraocular pressure Glaucoma Exophthalmos Retinopathy of prematurity Metabolic: Negative nitrogen balance due to protein catabolism Cardiovascular: Myocardial rupture following recent myocardial infarction (see WARNINGS ) Hypertrophic cardiomyopathy in low birth weight infants Other: Anaphylactoid or hypersensitivity reactions Thromboembolism Weight gain Increased appetite Nausea Malaise Hiccups The following additional adverse reactions are related to parenteral corticosteroid therapy: Hyperpigmentation or hypopigmentation Subcutaneous and cutaneous atrophy Sterile abscess Charcot-like arthropathy

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 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, 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 (concentrations ranged from 0.125% to 1% for ropivacaine hydrochloride 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 ropivacaine hydrochloride-treated patients in these studies. The majority of patients receiving concentrations higher than 5 mg/mL (0.5%) were treated with ropivacaine hydrochloride. Table 3A 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 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 Ropivacaine Hydrochloride 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 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 and bupivacaine. Table 4 is based on data from trials in the U.S. and other countries where ropivacaine hydrochloride was administered as an epidural anesthetic for surgery. Table 4 Common Events (Epidural Administration) Adverse Reaction Ropivacaine Hydrochloride 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 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 are broken down by gender. Table 5 Effects of Age on Hypotension (Epidural Administration) Total N: Ropivacaine Hydrochloride = 760, Bupivacaine = 410 AGE Ropivacaine Hydrochloride 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 ropivacaine hydrochloride 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 ropivacaine hydrochloride >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 ropivacaine hydrochloride 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.

<table cellspacing="0" cellpadding="0" border="0" width="98%"><caption>Adverse Events Reported in &#x2265;1% of Adult Patients Receiving Regional or Local Anesthesia (Surgery, Labor, Cesarean Section, Postoperative Pain Management, Peripheral Nerve Block and Local Infiltration) </caption><col width="37.08%"/><col width="13.92%"/><col width="22.1%"/><col width="12.62%"/><col width="14.28%"/><tbody><tr styleCode="Botrule"><td rowspan="2" styleCode="Lrule Rrule" valign="top"><content styleCode="bold"> Adverse Reaction </content> </td><td colspan="2" align="center" styleCode="Rrule" valign="top"><content styleCode="bold">Ropivacaine Hydrochloride</content> <content styleCode="bold">total N=1661 </content> </td><td colspan="2" align="center" styleCode="Rrule" valign="top"><content styleCode="bold">Bupivacaine </content> <content styleCode="bold">total N=1433 </content> </td></tr><tr styleCode="Botrule"><td align="center" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">N</content><content styleCode="bold"/> </td><td align="center" styleCode="Rrule" valign="top"><content styleCode="bold">(%)</content><content styleCode="bold"/> </td><td align="center" styleCode="Rrule" valign="top"><content styleCode="bold">N</content> </td><td align="center" styleCode="Rrule" valign="top"><content styleCode="bold">(%)</content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Hypotension </td><td align="center" styleCode="Rrule" valign="top">536 </td><td align="center" styleCode="Rrule" valign="top">(32.3) </td><td align="center" styleCode="Rrule" valign="top">408 </td><td align="center" styleCode="Rrule" valign="top">(28.5) </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"> Nausea </td><td align="center" styleCode="Rrule" valign="middle">283 </td><td align="center" styleCode="Rrule" valign="middle">(17) </td><td align="center" styleCode="Rrule" valign="middle">207 </td><td align="center" styleCode="Rrule" valign="middle">(14.4) </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"> Vomiting </td><td align="center" styleCode="Rrule" valign="middle">117 </td><td align="center" styleCode="Rrule" valign="middle">(7) </td><td align="center" styleCode="Rrule" valign="middle">88 </td><td align="center" styleCode="Rrule" valign="middle">(6.1) </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"> Bradycardia </td><td align="center" styleCode="Rrule" valign="middle">96 </td><td align="center" styleCode="Rrule" valign="middle">(5.8) </td><td align="center" styleCode="Rrule" valign="middle">73 </td><td align="center" styleCode="Rrule" valign="middle">(5.1) </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"> Headache </td><td align="center" styleCode="Rrule" valign="middle">84 </td><td align="center" styleCode="Rrule" valign="middle">(5.1) </td><td align="center" styleCode="Rrule" valign="middle">68 </td><td align="center" styleCode="Rrule" valign="middle">(4.7) </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"> Paresthesia </td><td align="center" styleCode="Rrule" valign="middle">82 </td><td align="center" styleCode="Rrule" valign="middle">(4.9) </td><td align="center" styleCode="Rrule" valign="middle">57 </td><td align="center" styleCode="Rrule" valign="middle">(4) </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"> Back pain </td><td align="center" styleCode="Rrule" valign="middle">73 </td><td align="center" styleCode="Rrule" valign="middle">(4.4) </td><td align="center" styleCode="Rrule" valign="middle">75 </td><td align="center" styleCode="Rrule" valign="middle">(5.2) </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"> Pain </td><td align="center" styleCode="Rrule" valign="middle">71 </td><td align="center" styleCode="Rrule" valign="middle">(4.3) </td><td align="center" styleCode="Rrule" valign="middle">71 </td><td align="center" styleCode="Rrule" valign="middle">(5) </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"> Pruritus </td><td align="center" styleCode="Rrule" valign="middle">63 </td><td align="center" styleCode="Rrule" valign="middle">(3.8) </td><td align="center" styleCode="Rrule" valign="middle">40 </td><td align="center" styleCode="Rrule" valign="middle">(2.8) </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"> Fever </td><td align="center" styleCode="Rrule" valign="middle">61 </td><td align="center" styleCode="Rrule" valign="middle">(3.7) </td><td align="center" styleCode="Rrule" valign="middle">37 </td><td align="center" styleCode="Rrule" valign="middle">(2.6) </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"> Dizziness </td><td align="center" styleCode="Rrule" valign="middle">42 </td><td align="center" styleCode="Rrule" valign="middle">(2.5) </td><td align="center" styleCode="Rrule" valign="middle">23 </td><td align="center" styleCode="Rrule" valign="middle">(1.6) </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"> Rigors (Chills) </td><td align="center" styleCode="Rrule" valign="middle">42 </td><td align="center" styleCode="Rrule" valign="middle">(2.5) </td><td align="center" styleCode="Rrule" valign="middle">24 </td><td align="center" styleCode="Rrule" valign="middle">(1.7) </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"> Postoperative complications </td><td align="center" styleCode="Rrule" valign="middle">41 </td><td align="center" styleCode="Rrule" valign="middle">(2.5) </td><td align="center" styleCode="Rrule" valign="middle">44 </td><td align="center" styleCode="Rrule" valign="middle">(3.1) </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"> Hypoesthesia </td><td align="center" styleCode="Rrule" valign="middle">27 </td><td align="center" styleCode="Rrule" valign="middle">(1.6) </td><td align="center" styleCode="Rrule" valign="middle">24 </td><td align="center" styleCode="Rrule" valign="middle">(1.7) </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"> Urinary retention </td><td align="center" styleCode="Rrule" valign="middle">23 </td><td align="center" styleCode="Rrule" valign="middle">(1.4) </td><td align="center" styleCode="Rrule" valign="middle">20 </td><td align="center" styleCode="Rrule" valign="middle">(1.4) </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"> Progression of labor poor/failed </td><td align="center" styleCode="Rrule" valign="middle">23 </td><td align="center" styleCode="Rrule" valign="middle">(1.4) </td><td align="center" styleCode="Rrule" valign="middle">22 </td><td align="center" styleCode="Rrule" valign="middle">(1.5) </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"> Anxiety </td><td align="center" styleCode="Rrule" valign="middle">21 </td><td align="center" styleCode="Rrule" valign="middle">(1.3) </td><td align="center" styleCode="Rrule" valign="middle">11 </td><td align="center" styleCode="Rrule" valign="middle">(0.8) </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"> Breast disorder, breast-feeding </td><td align="center" styleCode="Rrule" valign="middle">21 </td><td align="center" styleCode="Rrule" valign="middle">(1.3) </td><td align="center" styleCode="Rrule" valign="middle">12 </td><td align="center" styleCode="Rrule" valign="middle">(0.8) </td></tr><tr><td styleCode="Lrule Rrule" valign="middle"> Rhinitis </td><td align="center" styleCode="Rrule" valign="middle">18 </td><td align="center" styleCode="Rrule" valign="middle">(1.1) </td><td align="center" styleCode="Rrule" valign="middle">13 </td><td align="center" styleCode="Rrule" valign="middle">(0.9) </td></tr></tbody></table>

<table cellspacing="0" cellpadding="0" border="0" width="100%"><caption>Adverse Events Reported in &#x2265;1% of Fetuses or Neonates of Mothers Who Received Regional Anesthesia (Cesarean Section and Labor Studies) </caption><col width="34.02%"/><col width="14.4%"/><col width="21.54%"/><col width="15.2%"/><col width="14.84%"/><tbody><tr styleCode="Botrule"><td rowspan="2" styleCode="Lrule Rrule" valign="top"><content styleCode="bold"> Adverse Reaction </content> </td><td colspan="2" align="center" styleCode="Rrule" valign="top"><content styleCode="bold">Ropivacaine Hydrochloride </content> <content styleCode="bold">total N=639 </content> </td><td colspan="2" align="center" styleCode="Rrule" valign="top"><content styleCode="bold"> Bupivacaine </content> <content styleCode="bold"> total N=573 </content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"><content styleCode="bold"> N</content><content styleCode="bold"/> </td><td styleCode="Rrule" valign="top"><content styleCode="bold"> (%)</content><content styleCode="bold"/> </td><td align="center" styleCode="Rrule" valign="top"><content styleCode="bold"> N</content> </td><td align="center" styleCode="Rrule" valign="top"><content styleCode="bold">(%)</content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Fetal bradycardia </td><td styleCode="Rrule" valign="top"> 77 </td><td styleCode="Rrule" valign="top"> (12.1) </td><td styleCode="Rrule" valign="top"> 68 </td><td styleCode="Rrule" valign="top"> (11.9) </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"> Neonatal jaundice </td><td styleCode="Rrule" valign="middle"> 49 </td><td styleCode="Rrule" valign="middle"> (7.7) </td><td styleCode="Rrule" valign="middle"> 47 </td><td styleCode="Rrule" valign="middle"> (8.2) </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"> Neonatal complication-NOS </td><td styleCode="Rrule" valign="middle"> 42 </td><td styleCode="Rrule" valign="middle"> (6.6) </td><td styleCode="Rrule" valign="middle"> 38 </td><td styleCode="Rrule" valign="middle"> (6.6) </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"> Apgar score low </td><td styleCode="Rrule" valign="middle"> 18 </td><td styleCode="Rrule" valign="middle"> (2.8) </td><td styleCode="Rrule" valign="middle"> 14 </td><td styleCode="Rrule" valign="middle"> (2.4) </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"> Neonatal respiratory disorder </td><td styleCode="Rrule" valign="middle"> 17 </td><td styleCode="Rrule" valign="middle"> (2.7) </td><td styleCode="Rrule" valign="middle"> 18 </td><td styleCode="Rrule" valign="middle"> (3.1) </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"> Neonatal tachypnea </td><td styleCode="Rrule" valign="middle"> 14 </td><td styleCode="Rrule" valign="middle"> (2.2) </td><td styleCode="Rrule" valign="middle"> 15 </td><td styleCode="Rrule" valign="middle"> (2.6) </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"> Neonatal fever </td><td styleCode="Rrule" valign="middle"> 13 </td><td styleCode="Rrule" valign="middle"> (2) </td><td styleCode="Rrule" valign="middle"> 14 </td><td styleCode="Rrule" valign="middle"> (2.4) </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"> Fetal tachycardia </td><td styleCode="Rrule" valign="middle"> 13 </td><td styleCode="Rrule" valign="middle"> (2) </td><td styleCode="Rrule" valign="middle"> 12 </td><td styleCode="Rrule" valign="middle"> (2.1) </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"> Fetal distress </td><td styleCode="Rrule" valign="middle"> 11 </td><td styleCode="Rrule" valign="middle"> (1.7) </td><td styleCode="Rrule" valign="middle"> 10 </td><td styleCode="Rrule" valign="middle"> (1.7) </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"> Neonatal infection </td><td styleCode="Rrule" valign="middle"> 10 </td><td styleCode="Rrule" valign="middle"> (1.6) </td><td styleCode="Rrule" valign="middle"> 8 </td><td styleCode="Rrule" valign="middle"> (1.4) </td></tr><tr><td styleCode="Lrule Rrule" valign="middle"> Neonatal hypoglycemia </td><td styleCode="Rrule" valign="middle"> 8 </td><td styleCode="Rrule" valign="middle"> (1.3) </td><td styleCode="Rrule" valign="middle"> 16 </td><td styleCode="Rrule" valign="middle"> (2.8) </td></tr></tbody></table>