Dexamethasone Sodium Phosphate, Ropivacaine Hydrochloride, Povidine Iodine

Purpose: First aid antiseptic to help prevent skin infection in minor cuts, scrapes and burns. For preparation of the skin prior to surgery. Helps reduce bacteria that can potentially cause skin infections.

By intravenous or intramuscular injection when oral therapy is not feasible: 1. Endocrine Disorders Primary or secondary adrenocortical insufficiency (hydrocortisone or cortisone is the drug of choice; synthetic analogs may be used in conjunction with mineralocorticoids where applicable; in infancy, mineralocorticoid supplementation is of particular importance). Acute adrenocortical insufficiency (hydrocortisone or cortisone is the drug of choice; mineralocorticoid supplementation may be necessary, particularly when synthetic analogs are used). Preoperatively, and in the event of serious trauma or illness, in patients with known adrenal insufficiency or when adrenocortical reserve is doubtful. Shock unresponsive to conventional therapy if adrenocortical insufficiency exists or is suspected. Congenital adrenal hyperplasia Nonsuppurative thyroiditis Hypercalcemia associated with cancer 2. Rheumatic Disorders As adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in: Post-traumatic osteoarthritis Synovitis of osteoarthritis Rheumatoid arthritis, including juvenile rheumatoid arthritis (selected cases may require low-dose maintenance therapy). Acute and subacute bursitis Epicondylitis Acute nonspecific tenosynovitis Acute gouty arthritis Psoriatic arthritis Ankylosing spondylitis 3. Collagen Diseases During an exacerbation or as maintenance therapy in selected cases of: Systemic lupus erythematosus Acute rheumatic carditis 4. Dermatologic Diseases Pemphigus Severe erythema multiforme (Stevens-Johnson syndrome) Exfoliative dermatitis Bullous dermatitis herpetiformis Severe seborrheic dermatitis Severe psoriasis Mycosis fungoides 5. Allergic States Control of severe or incapacitating allergic conditions intractable to adequate trials of conventional treatment in: Bronchial asthma Contact dermatitis Atopic dermatitis Serum sickness Seasonal or perennial allergic rhinitis Drug hypersensitivity reactions Urticarial transfusion reactions Acute noninfectious laryngeal edema (epinephrine is the drug of first choice). 6. Ophthalmic Diseases Severe acute and chronic allergic and inflammatory processes involving the eye, such as: Herpes zoster ophthalmicus Iritis, iridocyclitis Chorioretinitis Diffuse posterior uveitis and choroiditis Optic neuritis Sympathetic ophthalmia Anterior segment inflammation Allergic conjunctivitis Keratitis Allergic corneal marginal ulcers 7. Gastrointestinal Diseases To tide the patient over a critical period of the disease in: Ulcerative colitis (systemic therapy) Regional enteritis (systemic therapy) 8. Respiratory Diseases Symptomatic sarcoidosis Berylliosis Fulminating or disseminated pulmonary tuberculosis when used concurrently with appropriate antituberculous chemotherapy. Loeffler’s syndrome not manageable by other means. Aspiration pneumonitis 9. Hematologic Disorders Acquired (autoimmune) hemolytic anemia. Idiopathic thrombocytopenic purpura in adults (IV only; IM administration is contraindicated). Secondary thrombocytopenia in adults Erythroblastopenia (RBC anemia) Congenital (erythroid) hypoplastic anemia 10. Neoplastic Diseases For palliative management of: Leukemias and lymphomas in adults Acute leukemia of childhood 11. Edematous States To induce diuresis or remission of proteinuria in the nephrotic syndrome, without uremia, of the idiopathic type or that due to lupus erythematosus. 12. Miscellaneous Tuberculous meningitis with subarachnoid block or impending block when used concurrently with appropriate antituberculous chemotherapy. Trichinosis with neurologic or myocardial involvement. 13. Diagnostic testing of adrenocortical hyperfunction. 14. Cerebral Edema associated with primary or metastatic brain tumor, craniotomy, or head injury. Use in cerebral edema is not a substitute for careful neurosurgical evaluation and definitive management such as neurosurgery or other specific therapy.

INDICATIONS AND USAGE Ropivacaine hydrochloride injection, USP 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

For use as an first aid antiseptic pre-operative skin preperation

Purpose Povidone Iodine 10% w/v (9.85% w/w/) Antiseptic

Systemic fungal infections (see WARNINGS regarding amphotericin B). Hypersensitivity to any component of this product (see WARNINGS ) .

CONTRAINDICATIONS Ropivacaine hydrochloride injection is contraindicated in patients with a known hypersensitivity to ropivacaine or to any local anesthetic agent of the amide type.

As a first aid antiseptic for more than 1 week. In the eyes. Over large areas of the body.

Deep puncture wounds Animal bites Serious burns

Stop Use: If irritation and redness develop If condition persists for more than 72 hours, consult a physician.

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. […]

This product, like many other steroid formulations, is sensitive to heat. Therefore, it should not be autoclaved when it is desirable to sterilize the exterior of the vial. Following prolonged therapy, withdrawal of corticosteroids may result in symptoms of the corticosteroid withdrawal syndrome including fever, myalgia, arthralgia, and malaise. This may occur in patients even without evidence of adrenal insufficiency. There is an enhanced effect of corticosteroids in patients with hypothyroidism and in those with cirrhosis. Corticosteroids should be used cautiously in patients with ocular herpes simplex for fear of corneal perforation. The lowest possible dose of corticosteroid should be used to control the condition under treatment, and when reduction in dosage is possible, the reduction must be gradual. Psychic derangements may appear when corticosteroids are used, ranging from euphoria, insomnia, mood swings, personality changes, and severe depression to frank psychotic manifestations. Also, existing emotional instability or psychotic tendencies may be aggravated by corticosteroids. Aspirin should be used within caution in conjunction with corticosteroids in hypoprothrombinemia. Steroids should be used with caution in nonspecific ulcerative colitis, if there is a probability of impending perforation, abscess, or other pyogenic infection, also in diverticulitis, fresh intestinal anastomoses, active or latent peptic ulcer, renal insufficiency, hypertension, osteoporosis, and myasthenia gravis. Signs of peritoneal irritation following gastrointestinal perforation in patients receiving large doses of corticosteroids may be minimal or absent. Fat embolism has been reported as a possible complication of hypercortisonism. When large doses are given, some authorities advise that antacids be administered between meals to help prevent peptic ulcer. Steroids may increase or decrease motility and number of spermatozoa in some patients. Phenytoin, phenobarbital, ephedrine, and rifampin may enhance the metabolic clearance of corticosteroids resulting in decreased blood levels and lessened physiologic activity, thus requiring adjustment in corticosteroid dosage. These interactions may interfere with dexamethasone suppression tests which should be interpreted with caution during administration of these drugs. False negative results in the dexamethasone suppression test (DST) in patients being treated with indomethacin have been reported. Thus, results of the DST should be interpreted with caution in these patients. The prothrombin time should be checked frequently in patients who are receiving corticosteroids and coumarin anticoagulants at the same time because of reports that corticosteroids have altered the response to these anticoagulants. Studies have shown that the usual effect produced by adding corticosteroids is inhibition of response to coumarins, although there have been some conflicting reports of potentiation not substantiated by studies. When corticosteroids are administered concomitantly with potassium-depleting diuretics, patients should be observed closely for development of hypokalemia. The slower rate of absorption by intramuscular administration should be recognized. Information for Patients Susceptible patients who are on immunosuppressant doses of corticosteroids should be warned to avoid exposure to chickenpox or measles. Patients should also be advised that if they are exposed, medical advice should be sought without delay. Pediatric Use Growth and development of infants and children patients on prolonged corticosteroid therapy should be carefully followed.

Information for Patients Susceptible patients who are on immunosuppressant doses of corticosteroids should be warned to avoid exposure to chickenpox or measles. Patients should also be advised that if they are exposed, medical advice should be sought without delay.

Pediatric Use Growth and development of infants and children patients on prolonged corticosteroid therapy should be carefully followed.

PRECAUTIONS General 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 WARNINGS and ADVERSE REACTIONS ). 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. Careful and constant monitoring of cardiovascular and respiratory vital signs (adequacy of ventilation) and the patient’s state of consciousness should be performed after each local anesthetic injection. It should be kept in mind at such times that restlessness, anxiety, incoherent speech, light-headedness, numbness and tingling of the mouth and lips, metallic taste, tinnitus, dizziness, blurred vision, tremors, twitching, depression, or drowsiness may be early warning signs of central nervous system toxicity. Because amide-type local anesthetics such as ropivacaine are metabolized by the liver, these drugs, especially repeat doses, should be used cautiously in patients with hepatic disease. Patients with severe hepatic disease, because of their inability to metabolize local anesthetics normally, are at a greater risk of developing toxic plasma concentrations. Local anesthetics should also be used with caution in patients with impaired cardiovascular function because they may be less able to compensate for functional changes associated with the prolongation of A-V conduction produced by these drugs. Many drugs used during the conduct of anesthesia are considered potential triggering agents for malignant hyperthermia (MH). Amide-type local anesthetics are not known to trigger this reaction. However, since the need for supplemental general anesthesia cannot be predicted in advance, it is suggested that a standard protocol for MH management should be available. Epidural Anesthesia During epidural administration, ropivacaine hydrochloride should be administered in incremental doses of 3 to 5 mL with sufficient time between doses to detect toxic manifestations of unintentional intravascular or intrathecal injection. Syringe aspirations should also be performed before and during each supplemental injection in continuous (intermittent) catheter techniques. […]

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. […]

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 ). 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. 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, can interact with ropivacaine hydrochloride 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. 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: 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

Category B Reproduction toxicity studies have been performed in pregnant New Zealand white rabbits and Sprague-Dawley rats. During gestation days 6 to 18, rabbits received 1.3, 4.2, or 13 mg/kg/day subcutaneously. In rats, subcutaneous doses of 5.3, 11 and 26 mg/kg/day were administered during gestation days 6 to 15. No teratogenic effects were observed in rats and rabbits at the highest doses tested. The highest doses of 13 mg/kg/day (rabbits) and 26 mg/kg/day (rats) are approximately 1/3 of the maximum recommended human dose (epidural, 770 mg/24 hours) based on a mg/m 2 basis. In 2 prenatal and postnatal studies, the female rats were dosed daily from day 15 of gestation to day 20 postpartum. The doses were 5.3, 11 and 26 mg/kg/day subcutaneously. There were no treatment-related effects on late fetal development, parturition, lactation, neonatal viability, or growth of the offspring. In another study with rats, the males were dosed daily for 9 weeks before mating and during mating. The females were dosed daily for 2 weeks before mating and then during the mating, pregnancy, and lactation, up to day 42 post coitus. At 23 mg/kg/day, an increased loss of pups was observed during the first 3 days postpartum. The effect was considered secondary to impaired maternal care due to maternal toxicity. There are no adequate or well-controlled studies in pregnant women of the effects of ropivacaine hydrochloride on the developing fetus. Ropivacaine hydrochloride should only be used during pregnancy if the benefits outweigh the risk. Teratogenicity studies in rats and rabbits did not show evidence of any adverse effects on organogenesis or early fetal development in rats (26 mg/kg sc) or rabbits (13 mg/kg). The doses used were approximately equal to total daily dose based on body surface area. There were no treatment-related effects on late fetal development, parturition, lactation, neonatal viability, or growth of the offspring in 2 perinatal and postnatal studies in rats, at dose levels equivalent to the maximum recommended human dose based on body surface area. In another study at 23 mg/kg, an increased pup loss was seen during the first 3 days postpartum, which was considered secondary to impaired maternal care due to maternal toxicity.

Some local anesthetic drugs are excreted in human milk and caution should be exercised when they are administered to a nursing woman. The excretion of ropivacaine or its metabolites in human milk has not been studied. Based on the milk/plasma concentration ratio in rats, the estimated daily dose to a pup will be about 4% of the dose given to the mother. Assuming that the milk/plasma concentration in humans is of the same order, the total ropivacaine hydrochloride dose to which the baby is exposed by breast-feeding is far lower than by exposure in utero in pregnant women at term (see PRECAUTIONS ).

The safety and efficacy of ropivacaine hydrochloride in pediatric patients have not been established.

Of the 2,978 subjects that were administered ropivacaine hydrochloride injection in 71 controlled and uncontrolled clinical studies, 803 patients (27%) were 65 years of age or older which includes 127 patients (4%) 75 years of age and over. Ropivacaine hydrochloride injection was found to be safe and effective in the patients in these studies. 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. This drug and its metabolites are known to be excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Elderly patients are more likely to have decreased hepatic, renal, or cardiac function, as well as concomitant disease. Therefore, care should be taken in dose selection, starting at the low end of the dosage range, and it may be useful to monitor renal function (see PHARMACOKINETICS, Elimination ).

Keep out of reach of children. If swallowed, get medical help or contact a Poison Control Center.