Naropin (Ropivacaine HCl)

NAROPIN®

Astra

Ropivacaine HCl

Local Anesthetic

Action And Clinical Pharmacology: Mechanism of Action: Ropivacaine, a local anesthetic of the amino amide class, is supplied as the pure S-(-)-enantiomer. Ropivacaine, like other local anesthetics, causes reversible blockade of impulse propagation along nerve fibres by preventing the inward movement of sodium ions through the cell membrane of the nerve fibres.

Ropivacaine has both anesthetic and analgesic effects. At high doses, surgical anesthesia is achieved. At lower doses, ropivacaine produces sensory block (analgesia) with limited and nonprogressive motor block.

After epidural infusion of ropivacaine, the spread of sensory block and the degree of motor block, as well as their subsequent regression, are dose-dependent.

The duration of action of local anesthetics depends on the injection site, the route of administration, and the concentration and volume of the drug. The duration and intensity of ropivacaine block are not improved by the addition of epinephrine.

Pharmacodynamics: In 2 clinical pharmacology studies (total N=24) ropivacaine and bupivacaine were infused (10 mg/min) in human volunteers until the appearance of CNS symptoms, e.g., visual or hearing disturbances, perioral numbness, tingling and others. Similar symptoms were seen with both drugs. In one study, the mean±SD maximum tolerated i.v. dose of ropivacaine infused (124±38 mg) was significantly higher than that of bupivacaine (99±30 mg), while in the other study the doses were not different (115±29 mg of ropivacaine and 103±30 mg of bupivacaine). In the latter study, the number of subjects reporting each symptom was similar for both drugs with the exception of muscle twitching, which was reported by more subjects with bupivacaine than ropivacaine at comparable i.v. doses. At the end of the infusion, ropivacaine in both studies caused significantly less depression of cardiac conductivity (less QRS widening) than bupivacaine. Ropivacaine and bupivacaine caused evidence of depression of cardiac contractility, but there were no changes in cardiac output.

Hemodynamics: Ropivacaine, like other local anesthetics, can also have effects on the central nervous and cardiovascular systems. If excessive amounts of drug reach the systemic circulation rapidly, symptoms and signs of CNS toxicity and cardiotoxicity may appear.

Signs and symptoms of CNS toxicity (see Overdose: Symptoms and Treatment) generally occur at lower plasma concentrations than do those of cardiotoxicity. Following systemic absorption, local anesthetics can produce CNS stimulation, depression or both. Apparent central stimulation is usually manifested as restlessness, tremors, and shivering, progressing to convulsions, followed by depression and coma, leading ultimately to respiratory arrest. However, the local anesthetics have a primary depressant effect on the medulla and on higher centres. The depressed stage may occur without a prior excited stage. High blood concentrations of local anesthetics resulting from systemic absorption or intravascular injection can depress cardiac conduction and excitability. At toxic levels, atrioventricular block, ventricular arrhythmias, cardiac arrest, and death are possibilities.

Indirect cardiovascular effects (hypotension, bradycardia) may occur after epidural administration, depending on the extent of the concomitant sympathetic block.

Pharmacokinetics: Absorption: The systemic concentration of local anesthetics is dependent upon the total dose and the concentration administered, the route of administration, the patient’s hemodynamic/circulatory condition and the vascularity of the injection site. Ropivacaine follows linear pharmacokinetics and the maximum plasma concentration is proportional to the dose.

Ropivacaine shows complete and biphasic absorption from the epidural space. The mean half-lives of the 2 phases are in the order of 14 min and 4 h. The slow absorption is the rate-limiting factor in the elimination of ropivacaine, which explains why the apparent elimination half-life is longer after epidural than after i.v. administration. Ropivacaine shows dose proportionality at epidural doses up to 250 mg and i.v. doses up to 80 mg.

Distribution: Following i.v. administration, the volume of distribution of ropivacaine is approximately 40 L. Ropivacaine is extensively bound to alpha1-acid glycoprotein in plasma with an unbound, i.e., pharmacologically active, fraction of about 6%. An increase in total plasma concentration during continuous epidural infusion has been observed in postoperative patients and is related to the postoperative increase of alpha1-acid glycoprotein. Variations in unbound concentration have been much less than in total plasma concentration.

Ropivacaine readily crosses the placenta and equilibrium, in regard to unbound concentration, is rapidly reached. The degree of plasma protein binding in the fetus is less than in the mother, which results in lower total plasma concentrations in the fetus than in the mother. The ratios of umbilical vein to maternal vein total and free concentrations are 0.31 and 0.74, respectively.

Metabolism: Ropivacaine is extensively metabolized in the liver predominantly to 3-OH-ropivacaine by an aromatic hydroxylation process mediated by cytochrome P4501A. Conjugated and unconjugated 3-hydroxy-ropivacaine represent the major urinary metabolites. Urinary excretion of the 4-hydroxy and both the 3-hydroxy and 4-hydroxy N-dealkylated metabolites accounts for less than 3% of the dose. An additional metabolite, 2-hydroxy-methyl-ropivacaine has been identified, but not quantified in urine. 3-Hydroxy- and 4-hydroxy-ropivacaine have local anesthetic activity in animal models although less than that of ropivacaine.

There is no evidence of in vivo racemization of ropivacaine.

Elimination: After intravascular administration, 86% of the total dose of ropivacaine is excreted in the urine of which approximately 1% is the parent compound and 36% is 3-OH ropivacaine. Ropivacaine has a total plasma clearance in the order of 300 to 400 mL/min, an unbound plasma clearance of 8 L/min, and a renal clearance of 1 mL/min. Ropivacaine has an intermediate hepatic extraction ratio of about 0.4. The terminal elimination half-life is 1.6 to 1.8 hours after i.v. administration, 4.1 to 6.5 hours after epidural administration, and 5.7 to 8.0 hours after brachial plexus block. The total and unbound clearance of epidural ropivacaine at term in pregnancy (223 to 256 mL/min and 2.8 to 3.3 L/min, respectively), are lower than that observed in nonpregnant patients.

Clinical Trials: Epidural Administration in Surgery: The use of ropivacaine for epidural anesthesia in general surgery was investigated in 25 clinical studies performed in 942 patients. Ropivacaine was administered in doses ranging from 75 to 250 mg. The intensity and duration of sensory and motor block were dose-dependent. At doses ranging from 100 to 200 mg, the median time to achieve a T10 sensory block was 10 (5 to 13) minutes, while the median duration of anesthesia at this dermatome was 4 (3 to 5) hours. For 20 mL volumes of 5, 7.5 and 10 mg/mL solutions, the median duration of motor block was 3, 4 and 5 hours, respectively.

Epidural Administration in Cesarean Section: Seven studies of epidural anesthesia with ropivacaine have been performed in a total of 194 women undergoing Cesarean section. In these studies, ropivacaine 5 mg/mL was administered at mean total doses ranging from 110 to 150 mg. The median onset of sensory block at T6 ranged from 11 to 26 minutes, while the median duration of sensory block at this dermatome ranged from 1.7 to 3.2 hours. The duration of motor block ranged from 1.4 to 2.9 hours. The quality of analgesia was considered to be satisfactory in 73 to 100% of patients, while the quality of muscle relaxation was rated as satisfactory in 100% of patients.

Major Nerve Block: Eight studies have been performed to investigate the efficacy of ropivacaine in a single instance of major nerve block, brachial plexus block. In studies in which the 5 mg/mL solution (total doses of 175 to 190 mg) was administered by the supraclavicular approach, anesthesia at dermatomes T1 to C5 was achieved in 83 to 100% of patients. Following median onset times ranging from 10 to 25 minutes, the median duration of anesthesia at these dermatomes ranged from 8 to 12 hours. The quality of brachial plexus block was rated as satisfactory in 91 to 100% of these patients.

Success rates were lower with axillary blocks than with supraclavicular blocks. In patients receiving 175 to 275 mg of ropivacaine 5 mg/mL by the axillary approach, satisfactory analgesia was achieved in 62 to 72% of patients. The frequency of anesthesia at the nerves studied ranged from 52 to 90%. The mean onset time ranged from 10 to 45 min with a duration of anesthesia in the range of 3.7 to 8.7 hours.

Epidural Administration in Labor and Delivery: Nine studies have been performed to investigate the use of epidural ropivacaine for pain relief during labor in pregnant females with full term singleton fetuses in the vertex presentation. Loading doses of approximately 25 mg were administered as fractionated doses. In 4 clinical trials in which continuous infusions were administered, the total infusion dose ranged from 3 to 30 mg/h with median values of 22 to 25 mg/h. Infusion times up to 13 hours have been studied. In the remaining studies, supplementary analgesia was provided by up to 8 top up doses of ropivacaine at median doses ranging from 14 to 18 mg/h. In these studies, the median values for the onset of pain relief after the main dose ranged from 9 to 18 min. Median upper spread of sensory block ranged from T5 to T10.

Epidural Administration in Postoperative Pain Management: Eight clinical trials have been performed to investigate the epidural use of ropivacaine in postoperative pain management following orthopedic or upper or lower abdominal surgery. All patients had received epidural anesthesia with ropivacaine intraoperatively prior to the initiation of postoperative epidural infusion. A total of 421 patients received ropivacaine in these studies. Of these, 382 were eligible for efficacy analyses. The infusion of ropivacaine at doses ranging from 10 to 30 mg/h was associated with decreases in pain scores and morphine requirement. The frequency and intensity of motor block tended to decrease during the 21 hour period. Motor block was dose-dependent. In 2 dose-controlled studies, infusion rates of 12 to 20 mg/h provided satisfactory analgesia (85 to 100% rated good or excellent) with relatively slight motor block. At the end of the infusion, 14 to 24% of patients exhibited motor block at 20 mg/h as compared with 41% at 24 mg/h and 50 to 67% at 28 mg/h. Infusion times up to 21 hours have been studied.

Infiltration: Pre- and postoperative wound infiltration with ropivacaine for postoperative pain relief have been studied in 6 clinical trials. An additional study examined local infiltration with ropivacaine for operation upon benign nevi. Of the 308 patients studied, 297 were evaluable for efficacy. In the wound infiltration studies, ropivacaine at doses of 100 to 200 mg resulted in lower pain scores and/or a decreased analgesia requirement in the immediate postoperative period in 3 of 4 studies which contained inactive control groups. In the study of nevus excision, doses of 5 to 20 mg were considered to provide adequate analgesia in the 30 patients studied.

Indications And Clinical Uses: Analgesia: Acute pain management in connection with: continuous epidural infusion or intermittent bolus administration e.g., postoperative or labor pain; field block e.g., infiltration.

Anesthesia: Surgical anesthesia in connection with: epidural block for surgery, including Cesarean section; major nerve block e.g., brachial plexus block; field block e.g., infiltration.

Contra-Indications: In patients with a known hypersensitivity to ropivacaine or any other local anesthetic agent of the amide type.

The use of ropivacaine is contraindicated for i.v. regional anesthesia (Bier block).

Ropivacaine should not be used in obstetric paracervical block anesthesia. Use of other local anesthetics in this technique has resulted in fetal bradycardia and death.

Manufacturers’ Warnings In Clinical States: Local anesthetics should only be employed 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. For management of toxic reactions and related emergencies, cardiopulmonary resuscitative equipment, oxygen, resuscitative drugs, and personnel resources should be immediately available when any local anesthetic is used. 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 (see Adverse Effects and Overdose).

For Cesarean section, the 5 mg/mL ropivacaine solution in doses up to 150 mg is recommended. The 7.5 and 10 mg/mL solutions should not be used for this indication. As with all local anesthetics, ropivacaine should be administered in incremental doses. Since ropivacaine should not be injected rapidly in large 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 bupivacaine was inadvertently administered by rapid i.v. injection.

Solutions of ropivacaine should not be used for the production of retrobulbar block or spinal anesthesia (subarachnoid block) due to insufficient data to support such use.

It is essential that aspiration for blood and cerebrospinal fluid be done prior to injecting any local anesthetic, both for 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 is unintentional subarachnoid injection of the local anesthetic. Two clinical studies have been performed to verify the safety of ropivacaine injected into the subarachnoid space at a volume of 3 mL, selected to be representative of an incremental epidural volume that could be unintentionally injected. The 15 and 22.5 mg doses injected resulted in sensory block levels as high as T5 and T4, respectively. Sensory block 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 2 clinical studies showed that a 3 mL dose did not produce any serious adverse events when spinal anesthesia was achieved.

Epidural anesthesia or analgesia may lead to hypotension and bradycardia. This risk can be reduced either by preloading the circulation or by injecting a vasopressor such as ephedrine 20 to 40 mg i.m. Hypotension should be treated promptly with e.g., ephedrine 5 to 10 mg i.v. and repeated as necessary.

Ropivacaine should be used with caution in patients receiving other local anesthetics or agents structurally related to amide-type local anesthetics, since the toxic effects are additive.

Precautions: The safe and effective use of local anesthetics depends on proper dosage, correct technique, adequate precautions and readiness for emergencies. Resuscitative equipment, oxygen and resuscitative drugs should be available for immediate use (see Adverse Effects and Overdose). During major regional nerve blocks, the patients should have i.v. fluids running via an indwelling catheter to assure a functioning i.v. pathway. The lowest dosage of local anesthetic that results in effective anesthesia should be used. 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 be performed before and during each supplemental injection.

Epidural Anesthesia and Analgesia: During epidural administration, it is recommended that a test dose of a local anesthetic with a fast onset of action be administered initially. The patient should be monitored for CNS and cardiovascular toxicity, as well as for signs of unintended intrathecal administration, before proceeding. When clinical conditions permit, test doses of local anesthetic solutions which contain epinephrine should be considered because circulatory changes compatible with epinephrine may also serve as a warning sign of unintended intravascular injection. If injected into a blood vessel, this amount of epinephrine is likely to produce a transient “epinephrine response” within 45 seconds, consisting of an increase in heart rate and systolic blood pressure, circumoral pallor, palpitations and nervousness in the unsedated patient. The sedated patient may exhibit only a pulse rate increase of 20 or more beats/minute for 15 or more seconds. Therefore, following the test dose, the heart rate should be continuously monitored. Patients on beta-blockers may not manifest changes in heart rate, but blood pressure monitoring can detect a rise in systolic blood pressure. A test dose of a short-acting amide anesthetic such as lidocaine (30 to 40 mg) is recommended to detect an unintentional intrathecal administration. This will be manifested within a few minutes by signs of spinal block (e.g., decreased sensation of the buttocks, paresis of the legs, or, in the sedated patient, absent knee jerk). An intravascular or subarachnoid injection is still possible even if results of the test dose are negative. The test dose itself may produce a systemic toxic reaction, high spinal or epinephrine-induced cardiovascular effects.

During epidural administration, ropivacaine should be administered in incremental doses of 3 to 5 mL with sufficient time between doses to detect toxic manifestations of unintentional intravascular or subarachnoid injection. Frequent aspirations for blood or cerebrospinal fluid (where applicable, i.e., when using a “continuous” intermittent catheter technique) should be performed before and during each supplemental injection because plastic tubing in the epidural space can migrate into a blood vessel or through the dura. A negative aspiration, however, does not ensure against an intravascular or intrathecal injection.

If blood is aspirated, relocate the needle. Inadvertent intravascular injection may cause serious consequences. Absorption is more rapid when injections are made into highly vascular tissues. Administration of higher than recommended doses of ropivacaine to achieve greater motor blockade or increased duration of sensory blockade may pose a particular risk in the event that an inadvertent intravascular injection occurs. In epidural administration, the procedure should be discontinued and re-initiated if the subarachnoid space has been entered, as shown by aspiration of spinal fluid.

Careful and constant monitoring of cardiovascular and respiratory vital signs (adequacy of ventilation) and the patient’s state of consciousness should be performed during the anesthetic procedure. It should be kept in mind at such times that restlessness, anxiety, incoherent speech, lightheadedness, 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 CNS toxicity.

High Risk Populations: Local anesthetics should be used with caution in patients in poor general condition due to advanced age, debilitation, or other compromising factors such as partial or complete heart conduction block, advanced liver disease, or severe renal dysfunction. To reduce the risk of potentially serious adverse reactions, attempts should be made to optimize the patient’s condition before major blocks are performed. Dosage should be adjusted accordingly.

Hepatic or Renal Impairment: 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 an increased risk of developing toxic plasma concentrations.

Normally there is no need to modify the dose of ropivacaine when used for single dose or short-term treatment in patients with impaired renal function. Acidosis and reduced plasma protein concentration, frequently seen in patients with chronic renal failure, may increase the risk of systemic toxicity.

Inflammation: Local anesthetic procedures should be performed with care in inflamed regions. Injections should not be performed through inflamed tissue nor when there is sepsis at or near the injection site.

Psychomotor Effects: Local anesthetics may have a dose-dependent effect on mental function and coordination, causing temporary impairment of locomotion and alertness, even in the absence of overt CNS toxicity.

Head and Neck Area: Small doses of local anesthetics injected into the head and neck area, including dental and stellate ganglion blocks, may produce adverse reactions as a result of inadvertent intra-arterial injection and subsequent retrograde flow to the cerebral circulation. These adverse reactions may be similar to systemic toxicity seen with unintentional intravascular injections of larger doses. Confusion, convulsions, respiratory depression, and/or respiratory arrest, and cardiovascular stimulation or depression have been reported. Patients receiving these blocks should have their circulation and respiration monitored and be constantly observed. Resuscitative equipment and personnel for treating adverse reactions should be immediately available. Dosage recommendations should not be exceeded.

Geriatrics: The risk of hypotension and bradycardia in patients receiving epidural anesthesia with ropivacaine increases in an age-dependent manner (see Adverse Effects).

Cardiovascular Disease: Local anesthetics should also be used with caution in patients with impaired cardiovascular function who may be less able to compensate for functional changes associated with prolongation of AV conduction produced by these drugs. Hypotension, hypovolemia, or heart block represent risk factors.

Ophthalmic Surgery: The use of ropivacaine in retrobulbar blocks for ophthalmic surgery has not been studied. Until appropriate experience is gained, the use of ropivacaine for such surgery is not recommended.

Pregnancy : Reproduction studies have been performed in rats and rabbits.

No effects on fertility and general reproductive performance were seen in rats over 2 generations. At the highest dose level, increased pup loss was seen during the first 3 days post partum, which was considered to be secondary to impaired maternal care of the newborn, due to maternal toxicity.

Teratogenicity studies in rats and rabbits did not show evidence of any adverse effects of ropivacaine on organogenesis or early fetal development. There were no treatment-related effects on late fetal development, parturition, lactation, neonatal viability or growth of the offspring in a perinatal and postnatal study in rats using the maximum tolerated dose.

An additional perinatal and postnatal study in rats, in which ropivacaine was compared with bupivacaine, showed that maternal toxicity was observed at much lower dose levels and at lower unbound plasma concentrations of bupivacaine than of ropivacaine.

There are no clinical studies in preterm pregnant women on the effects of ropivacaine on the developing fetus. Ropivacaine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. The use of ropivacaine at term for obstetric anesthesia or analgesia is well documented.

Labor and Delivery: Local anesthetics, including ropivacaine, rapidly cross the placenta, and when used for an epidural block, can cause varying degrees of maternal, fetal and neonatal toxicity. The incidence and degree of toxicity depend upon the procedure performed, the type and amount of drug used, and the technique of drug administration. Adverse reactions in the parturient, fetus and neonate involve alterations of the CNS, peripheral vascular tone and cardiac function. Maternal hypotension has resulted from epidural analgesia with ropivacaine for obstetrical pain relief. Elevating the patient’s legs and positioning her on her left side will help prevent decreases in blood pressure. The fetal heart rate also should be monitored continuously, and electronic fetal monitoring is highly advisable.

It is extremely important to avoid aorto-caval compression by the gravid uterus during administration of regional block to parturients. The patient should be maintained in the left lateral decubitus position if possible, or manual displacement of the uterus off the great vessels should be accomplished.

Lactation : 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. Caution should be exercised when ropivacaine is administered to a nursing woman. Assuming that the milk/plasma concentration ratio in humans is of the same order, the total ropivacaine dose to which the baby is exposed by breast-feeding is far lower than by exposure in utero in pregnant women at term.

Children: As the safety and efficacy of ropivacaine have not been investigated in children under 18 years of age, no dosage recommendations can be provided.

Drug Interactions: Ropivacaine should be used with caution in patients receiving other local anesthetics or agents structurally related to amide-type local anesthetics, since the toxic effects are additive.

If sedatives are employed to reduce patient apprehension, they should be used in reduced doses, since local anesthetic agents, like sedatives, are CNS depressants which in combination may have an additive effect.

In vitro studies indicate that cytochrome P4501A is involved in the formation of 3-hydroxy ropivacaine, the major metabolite. Thus, agents administered concomitantly with ropivacaine which are also metabolized by this isozyme family may potentially interact with ropivacaine. Such interactions might occur with drugs known to be metabolized by P4501A2 such as theophylline or imipramine or with potent inhibitors such as fluvoxamine and verapamil.

Adverse Reactions: Reactions to ropivacaine are characteristic of those associated with other long-acting local anesthetics of the amide type.

Most Common Adverse Events: In clinical trials, the great majority of adverse events reported with ropivacaine were related to the expected effects of the block and to the clinical situation, rather than reactions to the drug. When all clinical studies were pooled (Total n=2 250), hypotension and nausea were registered in 39% (n=872) and 25% (n=556) of the patients, respectively. Similar incidences were reported for bupivacaine in the double-blind comparisons.

Adverse reactions to local anesthetics are very rare in the absence of overdose or inadvertent intravascular injection. The effects of systemic overdose and unintentional intravascular injections can be serious, but should be distinguished from the physiological effects of the nerve block itself e.g., a decrease in blood pressure and bradycardia during epidural anesthesia.

Acute systemic toxicity from local anesthetics is generally dose-related and due to high plasma levels which may result from overdosage, rapid absorption from the injection site, diminished tolerance, or from inadvertent intravascular injection. Most commonly, the acute adverse experiences originate from the central nervous and cardiovascular systems.

CNS: 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 CNS 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 procedure used and the total dose administered. One case of convulsions has been observed after an unintended intravascular injection occurred while attempting a brachial plexus block with 200 mg ropivacaine. The patient was treated with a standard regimen of drugs and recovered completely.

Cardiovascular System: 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 cardiac arrest. Reactions due to systemic absorption may be either slow or rapid in onset. Cardiovascular collapse and cardiac arrest can occur rapidly (see Overdose: Symptoms and Treatment).

Allergic: Allergic type reactions are rare and may occur as a result of sensitivity to local anesthetics of the amide-type. 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 in the most severe instances, anaphylactic shock.

Neurologic: The incidence of adverse neurologic reactions may be related to the total dose of local anesthetic administered but is also dependent upon the particular drug used, the route of administration and the physical status of the patient. Neuropathy and spinal cord dysfunction (e.g., anterior spinal artery syndrome, arachnoiditis, cauda equina syndrome), have been associated with regional anesthesia. Neurological effects may be related to local anesthetic techniques, with or without a contribution from the drug.

In the practice of lumbar epidural block, occasional unintentional penetration of the subarachnoid space by the catheter or needle may occur. For example, a high spinal is characterized by paralysis of the legs, loss of consciousness, respiratory paralysis and bradycardia.

Neurologic effects following unintentional subarachnoid administration during epidural anesthesia may include spinal block of varying magnitude (including total or high spinal block), hypotension secondary to spinal block, urinary retention, fecal and urinary incontinence, loss of perineal sensation and sexual function, 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, backache, 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.

Elevation of Body Temperature: Epidural infusion of ropivacaine has, in some cases, been associated with transient elevations in body temperature to >38.5°C. This has occurred more frequently at doses greater than 16 mg/hour.

Symptoms And Treatment Of Overdose: In clinical trials, 1 patient experienced a life-threatening generalized aclonic convulsion, and another, grand mal convulsions, following the inadvertent intravascular injection of 200 and 225 mg ropivacaine, respectively. These patients recovered completely following treatment.

Acute systemic toxicity from local anesthetics is generally related to high plasma levels encountered during therapeutic use or to unintended intravascular or subarachnoid injection (see Adverse Effects, Warnings and Precautions).Symptoms: Accidental intravascular injections may cause immediate toxic effects. In the event of overdose, peak plasma concentrations may not be reached for 1 to 2 hours, depending on the site of injection, with signs of toxicity thus being delayed.

CNS toxicity is a graded response with symptoms and signs of escalating severity. Initially symptoms such as visual or hearing disturbances, perioral numbness, dizziness, lightheadedness, tingling and paresthesia are seen. Dysarthria, muscular rigidity and muscular twitching are more serious and may precede the onset of generalized convulsions. These signs must not be mistaken for a neurotic behavior. Unconsciousness and grand mal convulsions may follow which may last from a few seconds to several minutes. Hypoxia and hypercarbia occur rapidly following convulsions due to the increased muscular activity, together with the interference with normal respiration and loss of the airway. In severe cases apnea may occur. The respiratory and metabolic acidosis increases the toxic effects of local anesthetics.

Recovery is due to redistribution and metabolism of the local anesthetic drug. Recovery may be rapid unless large amounts of the drug have been administered.

Cardiovascular toxicity indicates a more severe situation. Hypotension, bradycardia, arrhythmia and cardiac arrest may occur as a result of high systemic concentrations of local anesthetic. In volunteers, the i.v. infusion of ropivacaine resulted in signs of depression of conductivity and contractility.

Cardiovascular toxic effects are generally preceded by signs of toxicity in the CNS, unless the patient is receiving a general anesthetic or is heavily sedated with drugs such as a benzodiazepine or barbiturate.

Treatment: The first consideration is prevention, best accomplished by incremental injection of ropivacaine, careful and constant monitoring of cardiovascular and respiratory vital signs and the patient’s state of consciousness after each local anesthetic injection and during continuous infusion. At the first sign of change, oxygen should be administered. If signs of acute systemic toxicity appear, injection of the local anesthetic should be immediately stopped.

The first step in the management of systemic toxic reactions, as well as underventilation or apnea due to unintentional subarachnoid injection of drug solution, consists of immediate attention to the establishment and maintenance of a patent airway and assisted or controlled ventilation with oxygen and a delivery system capable of permitting immediate positive airway pressure by mask. This may prevent convulsions if they have not already occurred.

If necessary, use drugs to control the convulsions. An anticonvulsant should be given i.v. if the convulsions do not stop spontaneously in 15 to 20 seconds. Thiopental 100 to 150 mg i.v. will abort the convulsions rapidly. Alternatively diazepam 5 to 10 mg i.v. may be used, although its action is slower. Both these drugs, however, depress the CNS, respiratory and cardiac function, add to postictal depression, and may result in apnea. Succinylcholine will stop the muscle convulsions rapidly, but will require tracheal intubation and controlled ventilation.

If cardiovascular depression is evident (hypotension, bradycardia) administration of i.v. fluids or a vasopressor such as ephedrine or epinephrine may be required.

Should circulatory arrest occur, immediate cardiopulmonary resuscitation should be instituted. Optimal oxygenation and ventilation and circulatory support as well as treatment of acidosis are of vital importance.

Clinical data from patients experiencing local anesthetic-induced convulsions demonstrated rapid development of hypoxia, hypercarbia, and acidosis within a minute of the onset of convulsions. These observations suggest that oxygen consumption and carbon dioxide production are greatly increased during local anesthetic convulsions and emphasize the importance of immediate and effective ventilation with oxygen which may avoid cardiac arrest.

The supine position is dangerous in pregnant women at term because of aorto-caval compression by the gravid uterus. Therefore, during treatment of systemic toxicity, maternal hypotension or fetal bradycardia following regional block, the parturient should be maintained in the left lateral decubitus position if possible, or manual displacement of the uterus off the great vessels should be accomplished. Resuscitation of obstetrical patients may take longer than resuscitation of nonpregnant patients and closed-chest cardiac compression may be ineffective. Rapid delivery of the fetus may improve the response to resuscitative efforts.

In human volunteers given i.v. ropivacaine, the mean maximum tolerated total and free arterial plasma concentrations were 4.3 and 0.6 g/mL respectively, at which time moderate CNS symptoms (muscle twitching) were noted.

Dosage And Administration: Ropivacaine should only be used by or under the supervision of clinicians experienced in regional anesthesia.

It is recommended that hospitals using local anesthetic infusions have a treatment protocol in place for nursing to follow in order to safely monitor the level of the block and for the proper management of complications and/or toxic reactions. If toxic reactions occur, the infusion should be stopped immediately.

Adults: The dosages in Table VI are recommended as a guide for use in the average adult for the more commonly used blocks. The clinician’s experience and knowledge of the patient’s physical status are of importance in calculating the required dose.

Ropivacaine should be administered at the smallest dose and the lowest concentration which are consistent with the necessary degree of anesthesia or analgesia. The rapid injection of a large volume of local anesthetic solution should be avoided and fractional doses should always be used. In general, surgical anesthesia, e.g., epidural administration, requires the use of higher concentrations and doses. For analgesia, e.g., epidural administration for acute pain management, lower concentrations and doses are recommended.

The dose of any local anesthetic administered varies with the anesthetic procedure, the area to be anesthetized, the vascularity of the tissues, the number of neuronal segments to be blocked, the depth of anesthesia and degree of muscle relaxation required, the duration of anesthesia desired, individual tolerance, and the physical condition of the patient. Patients in poor general condition due to advanced age or other compromising factors such as partial or complete heart conduction block, advanced liver disease or severe renal dysfunction require special attention although regional anesthesia is frequently indicated in these patients. To reduce the risk of potentially serious adverse reactions, attempts should be made to optimize the patient’s condition before major blocks are performed, and the dosage should be adjusted accordingly.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Solutions which are discolored or which contain particulate matter should not be administered. For specific techniques and procedures, refer to standard contemporary textbooks.

Careful aspiration before and during injection is recommended to prevent intravascular injection. When employing an epidural block, a test dose of 3 to 5 mL lidocaine 1.5% with epinephrine is recommended. An inadvertent intravascular injection may be recognized by a temporary increase in heart rate and an accidental subarachnoid injection by signs of a spinal block. Aspiration should be repeated prior to and during administration of the main dose, which should be injected slowly or in incremental doses, at a rate of 25 to 50 mg/min, while closely observing the patient’s vital functions and maintaining verbal contact. If toxic symptoms occur, the injection should be stopped immediately. The test dose should be repeated if the patient is moved in such a fashion as to have displaced the epidural catheter.

In epidural block for surgery, single doses of up to 250 mg ropivacaine have been used and are well tolerated.

When prolonged blocks are used, either through continuous infusion or through repeated bolus administration, the risks of reaching a toxic plasma concentration or inducing local neural injury must be considered. Experience to date indicates that a cumulative dose of up to 770 mg ropivacaine administered over 24 hours is well tolerated in adults when used for postoperative pain management.

For treatment of postoperative pain, the following technique is recommended: Unless preoperatively instituted, an epidural block with ropivacaine 5 to 7.5 mg/mL is induced via an epidural catheter. Analgesia is maintained with ropivacaine 2 mg/mL infusion. Clinical studies have demonstrated that infusion rates of 6 to 10 mL (12 to 20 mg)/h provide adequate analgesia with only slight and nonprogressive motor block in most cases of moderate to severe postoperative pain. With this technique, a significant reduction in the need for opioids has been observed. Clinical studies also show, however, that some patients require higher doses. Infusion rates of 12 to 14 mL (24 to 28 mg)/h have been well tolerated. Clinical experience supports the use of ropivacaine epidural infusions for up to 21 hours.

As the safety and efficacy of ropivacaine have not been investigated in children under 18 years of age, no dosage recommendations can be provided.

The duration and intensity of ropivacaine block are not improved by the addition of epinephrine.

Alkalinization may lead to precipitation since ropivacaine is poorly soluble above pH 6.0.

Ropivacaine solutions are sterile, without preservative and are for single use only. Discard unused portion.

Parenteral products should be visually inspected for precipitation, haziness, particulate matter and leakage prior to use.

Availability And Storage: 2 mg/mL: Each mL of sterile isotonic solution contains: ropivacaine HCl 2 mg. Nonmedicinal ingredients: sodium chloride, sodium hydroxide and/or hydrochloric acid to adjust pH to 4.0 to 6.0 and water for injection. Polybag (plastic infusion bags) of 100 and 200 mL packed in a sterile pack. Polyamp Duofit (plastic ampuls suitable for Luer lock and Luer fit syringes) of 10 and 20 mL packed in sterile blister packs.

5 mg/mL: Each mL of sterile isotonic solution contains: ropivacaine HCl 5 mg. Nonmedicinal ingredients: sodium chloride, sodium hydroxide and/or hydrochloric acid to adjust pH to 4.0 to 6.0 and water for injection. Polyamp Duofit (plastic ampuls suitable for Luer lock and Luer fit syringes) of 10 and 20 mL packed in sterile blister packs.

7.5 mg/mL: Each mL of sterile isotonic solution contains: ropivacaine HCl 7.5 mg. Nonmedicinal ingredients: sodium chloride, sodium hydroxide and/or hydrochloric acid to adjust pH to 4.0 to 6.0 and water for injection. Polyamp Duofit (plastic ampuls suitable for Luer lock and Luer fit syringes) of 10 and 20 mL packed in sterile blister packs.

10 mg/mL: Each mL of sterile isotonic solution contains: ropivacaine HCl 10 mg. Nonmedicinal ingredients: sodium chloride, sodium hydroxide and/or hydrochloric acid to adjust pH to 4.0 to 6.0 and water for injection. Polyamp Duofit (plastic ampuls suitable for Luer lock and Luer fit syringes) of 10 and 20 mL packed in sterile blister packs.

Store solutions at 15 to 30°C. Do not autoclave.

NAROPIN® Astra Ropivacaine HCl Local Anesthetic

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