Levovacain® Injection 0.5%, each ml contains : Levobupivacaine HCl monohydrate equivalent to Levobupivacaine 5 mg.
Levobupivacaine HCl monohydrate solution for injection is indicated in adults for :
- Surgical anesthesia
- Major : Epidural (for obstetric procedures, including caesarean section, concentrations higher than 0.5% are not recommended, see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS,PREGNANCY and LACTATION), intrathecal, and peripheral nerve block.
- Minor : Local infiltration, peribulbar block in ophthalmic surgery.
- Pain management
- Continous epidural infusion, single or multiple bolus administration for postoperative, labor or chronic pain.
- For continuous epidural analgesia, Levobupivacaine HCl monohydrate may be administered in combination with epidural Fentanyl, Morphine or Clonidine.
Levobupivacaine HCl monohydrate is indicated in children for infiltration analgesia (ilioingunal/iliohypogastric blocks).
DOSAGE AND ADMINISTRATIONS :
The rapid injection of a large volume of local anesthetic solution should be avoided and fractional (incremental) doses should always be used. The smallest dose and concentration required to produce the desired result should be administered. The dose of any local anesthetic differs with the anesthetic procedure, the area to be anesthetized, the vascularity of the tissues, the number of neuronal segments to be blocked, theintensity of the block, the degree of muscle relaxation required, the duration of the anesthesia desired, individual tolerance and the physical condition of the patient. Patients in poor general condition due to aging or other compromising factors, such as impaired cardiovascular function, advanced liver disease or several renal dysfunction, require special attention.
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. Use an adequate test dose (3 to 5 ml) of a short-acting local anesthetic solution containing Epinephrine prior to induction of complete nerve block. This test dose should be repeated if the patient is moved in such a fashion as to have displaced the epidural catheter. It is recommended that adequate time be allowed for the onset of anesthesia following administration of each test dose.
The use of Levobupivacaine HCl monohydrate is not recommended for more than 24 hours. Disinfecting agents containing heavy metals, which cause release of ions (mercury, zinc, copper, etc) should not be used for skin or mucous membrane disinfection since they have been related to incidents of swelling and edema.
When chemical disinfection of the container surface is desired, either isopropyl alcohol (91%) or ethyl alcohol (70%) is recommended. It is recommended that chemical disinfection be accomplished by wiping the ampoule thoroughly with cotton or gauze that has been moistened with the recommended alcohol prior to use.
These products are intended for single use and do not contain preservatives; any solution remaining from an open container should be discarded.
For specific techniques and procedures, refer to standard contemporary textbooks.
Levobupivacaine HCl monohydrate compatibility
Levobupivacaine HCl monohydrate is compatible with 0.9% sodium chloride injection.
After dilution in 0.9% sodium chloride solution, Levobupivacaine HCl monohydrate is physically and chemically stable at temperature 30°C for 7 days.
This solution for injection should be prepared for single patient use only. Aseptic technique should be used to prepare the diluted products.
The unused portion of diluted Levobupivacaine HCl monohydrate should be discarded after each use.
This product should be used immediately.
If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user.
Note : Parenteral products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Solutions that are not clear and colorless should not be used.
|Concentration (%)||Dose (ml)||Dose (mg)||Motor block|
|Epidural for surgery||0.5 – 0.75||10 – 20||50 – 150||Moderate to complete|
|Epidural for caesarean section||0.5||15 – 30||75 – 150||Moderate to complete|
|Peripheral nerve||0.25 – 0.5||1 – 40||Maximum 150||Moderate to complete|
|Intrathecal||0.5||3||15||Moderate to complete|
|Ophtalmic||0.75||5 – 15||37.5 – 112.5||Moderate to complete|
|Local infiltration-Adults||0.25||1 – 60||Maximum 150||Not applicable|
|Local infiltration-Children <12 years old||0.25||0.50 ml/kg/side||1.25 mg/kg/side||Not applicable|
|0.5||0.25 ml/kg/side||1.25 mg/kg/side||Not applicable|
|Labor analgesia (epidural bolus)||0.25||10 – 20||25 – 50||Moderate to complete|
|Labor analgesia (epidural infusion)||0.125c||4 – 10 ml/hour||5 – 12.5 mg/hour||Moderate to complete|
|Postoperative pain (epidural infusion)||0.125c||10 – 15 ml/hour||12.5 – 18.75 mg/hour||Moderate to complete|
|0.25||5 – 7.5 ml/hour||12.5 – 18.75 mg/hour||Moderate to complete|
|aIn pain management, Levobupivacaine HCl monohydrate can be used epidurally with Fentanyl, Morphine or Clonidine|
|bIn cases where Levobupivacaine HCl monohydrate is combined with other agents, e.g., Opioids in pain management, the Levobupivacaine HCl monohydrate dose should be reduced as use of a lower concentration (e.g., 1.25 mg/ml) is preferable.|
|cDilutions of Levobupivacaine HCl monohydrate standard solutions should be made with preservative free 0.9% saline according to standard hospital procedures for sterility|
|The doses in the table are those considered to be necessary to produce a successful block and should be regarded as guidelines for use Individual variations in onset and duration occur.|
Epidural doses up to 375 mg have been administered incrementally to patients during a surgical procedur.
The maximum dose in 24 hours for intraoperative block and postoperative asin management was 695 mg.
The maximum dose administered as a postoperative epidural infusion over 24 hours was 570 mg.
The maximum dose administered to patients as a single fractionated injection was 300 mg for brachial plexus block.
For caesarean section, the maximum recommended doses is 150 mg.
In children, the maximum recommended dose for infiltration analgesia (ilioinguinal-iliohypogastric block) is 1.25 mg/kg/side.
Acute emergencies from local anesthetics are generally related to high plasma levels or high dermatomal levels (“high spinal”) encountered during therapeutic use of local anesthetics or to unintended intrathecal or intravascular injection of local anesthetic solution (see ADVERSE REACTIONS and WARNINGS AND PRECAUTIONS).
Management of local anesthetic emergencies
The first consideration is prevention, best accomplished by incremental injection of Levobupivacaine HCl monohydrate, 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 and further measures as warranted.
General contraindications related to regional anesthesia should be taken into account with the use of any regional anesthetic agent, including Levobupivacaine HCl monohydrate. Levobupivacaine HCl monohydrate solution for injection is contraindicated in those with a known sensitivity to local anesthetic amide agents.
Levobupivacaine HCl monohydrate is contraindicated in patients with severe hypotension such as cardiogenic or hypovolemic shock.
Levobupivacaine HCl monohydrate also should not be used for intravenous regional anesthesia (e.g., Bier block). Additionally, Levobupivacaine HCl monohydrate 7.5 mg/ml solution should not be employed for obstetric procedures, nor should it be used in paracervical blocks in obstetrics. Contraindications for use in Bier block, paracervical block and 0.75% Levobupivacaine HCl monohydrate use in obstetric procedures are based upon documented experiences with Bupivacaine.
WARNINGS AND PRECAUTIONS :
In performing Levobupivacaine HCl monohydrate blocks, unintended intravenous injection is possible and may result in cardiac arrest (some cases fatal). Despite rapid detection and appropriate treatment, prolonged resuscitation may be required. The resuscitability relative to Bupivacaine is unknown at this point in time as it has not been studied. As with all local anesthetics of the amide type, Levobupivacaine HCl monohydrate should be administered in incremental doses. Cases of severe bradycardia, hypotension and respiratory compromise with cardiac arrest (some of them fatal), have been reported in conjunction with local anesthetics, including Levobupivacaine HCl monohydrate. Since Levobupivacaine HCl monohydrate 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 arrhytmias, cardiac/circulatory arrest and death when Bupivacaine was inadvertently rapidly injected intravenously. For caesarean section, the 5 mg/ml (0.5%) Levobupivacaine HCl monohydrate solution in doses up to 150 mg is recommended.
Local anesthetics should only be administered by clinicians who are well versed in the diagnosis and management of drug-related toxicity and other acute emergencies which might arise from the block being administered. The immediate availability of oxygen, other resuscitative drugs, cardiopulmonary resuscitative equipment, and the personnel resources needed for proper management of toxic reactions and related emergencies must be ensured (see ADVERSE REACTIONS). Delay in proper management of drug-related toxicity, underventilation from any cause, and/or altered sensitivity may lead to the development of acidosis, cardiac arrest, and possibly death.
When contemplating a peripheral nerve block, where large volumes of local anesthetic are needed, caution should be exercised when using the higher mg/ml concentrations of Levobupivacaine HCl monohydrate.
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 REACTIONS). The lowest dosage that results in effective anesthesia should be used to avoid high plasma or dermatomal levels and serious adverse effects. 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 that 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.
Systemic adverse reactions following overdose for accidental intravascular injection reported with long acting local anesthetic agents involve both CNS and cardiovascular effects.
Levobupivacaine HCl monohydrate should be used with caution in conditions associated with impaired cardiovascular functions (see CONTRAINDICATIONS).
Injection of repeated doses of local anesthetics may cause significant increases in plasma levels with each repeated dose due to slow accumulation of the drug or its metabolites or to slow metabolic degradation. Tolerance to elevated blood levels varies with the physical condition of the patient. Local anesthetics should also be used with caution in patients with hypotension, hypovolemia or impaired cardiovascular function, especially 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. The clinician must be aware that restlessness, andety, 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 signs of central nervous system toxicity.
Amide-type local anesthetics, such as Levobupivacaine HCl monohydrate, are metabolized by the liver, therefore, 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 greater risk for developing toxic plasma concentrations. Local anesthetics should also be used with caution in patients with impaired cardiovascular function as they may be less able to compensate for functional changes associated with prolonged A-V conduction caused by these drugs.
Many drugs used during the conduct of anesthesia are considered potential triggering agents for malignant hyperthermia. Amide-type local anesthetics are not known to trigger this reaction.
During epidural anesthesia, Levobupivacaine HCl monohydrate should be administered in incremental volumes of three to five milliliters (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 catheter techniques. An intravascular injection is still possible even if aspirations are negative. During the administration of epidural anesthesia, it is s recommended that a test dose is administered initially and the effects monitored before the full dose is given. A test dose of a short-acting amide anesthetic, such as three milliliters (3 ml) of Lidocaine, is recommended to detect unintentional intrathecal administration. This will be manifested within a few minutes by signs of subarachnoid block (e.g., decreased sensation of the buttocks, paresis of the legs or, in the sedated patient, absent knee jerk). Unintentional intrathecal injection of local anesthetics can lead to very high spinal anesthesia, possibly apnea, severe hypotension and loss of consciousness. An intravascular or intrathecal injection is still possible, even if the results of the test dose are negative. The test dose itself may produce a systemic toxic reaction, extensive subarachnoid block or cardiovascular effects.
There have been reports of cauda equina syndrome and events indicative of neurotoxicity (see ADVERSE REACTIONS) temporally associated with the use of Levobupivacaine HCl monohydrate for greater than or equal to 24 hours for epidural analgesia. These events were more severe and in some cases led to permanent sequelae when Levobupivacaine HCl monohydrate was administered for greater than 24 hours. Therefore, the use of Levobupivacaine HCl monohydrate is not recommended for more than 24 hours.
It is essential that aspiration for blood or cerebrospinal fluid (where applicable) be done prior to injecting any local anesthetic, both before the original dose and all subsequent doses, to avoid intravascular or intrathecal injection. However, a negative aspiration does not ensure against intravascular or intrathecal injection. Levobupivacaine HCl monohydrate 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.
Use in head and neck area
Small doses of local anesthetics injected into the head and neck area may produce adverse reactions similar to systemic toxicity seen with unintentional intravascular injections of larger doses. The injection procedures require the utmost care. Confusion, convulsions, respiratory depression, and/or respiratory arrest and cardiovascular stimulation or depression have been reported. These reactions may be due to intra-arterial injection of the local anesthetic with retrograde flow to the cerebral circulation. Patients receiving these blocks should have their respirations and circulation monitored and be constantly observed. Resuscitative equipment and personnel for treating adverse reactions should be immediately available. Dosage recommendations should not be exceeded (see DOSAGE AND ADMINISTRATIONS).
There were no adequate and well-controlled studies in pregnant women of the effects of Levobupivacaine HCl monohydrate on the developing fetus. Levobupivacaine HCl monohydrate should only be used during pregnancy if the benefits outweigh the risks.
Labor and Delivery
Local anesthetics, including Levobupivacaine HCl monohydrate, rapidly cross the placenta and when used for 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 central nervous system, peripheral vascular tone, and cardiac function. Maternal hypotension, fetal bradycardia and fetal decelerations have resulted from regional anesthesia with Levobupivacaine HCl monohydrate for obstetrical pain relief. Local anesthetics produce vasodilation by blocking sympathetic nerves. Administration of intravenous fluids, elevation of the patient’s legs and left uterine displacement will help prevent decreases in blood pressure. The fetal heart rate should also be monitored continuously and electronic fetal monitoring is highly advisable.
The 7.5 mg/ml solution is not recommended for obstetric use due to an enhanced risk for cardiotoxic events based on experienced with Bupivacaine. There is no experience of Levobupivacaine 7.5 mg/ml in obstetric surgery.
Some local anesthetic drugs are excreted in breast milk and caution should be exercised when Levobupivacaine HCl monohydrate is administered to a nursing woman. The excretion of Levobupivacaine or its metabolites in human milk has not been studied.
No overall differences in safety and effectiveness between geriatric patients and younger patients. Greater sensitivity of some older individuals cannot be rulled out.
Information for the patient
When appropriate, patients should be informed in advance that they may experience temporary loss of sensation and motor activity in the anesthetized part of the body following correct administration of the regional anesthesia. Also, when appropriate, the physician should discuss other information including adverse reactions in the Levobupivacaine HCl monohydrate package insert.
DRUG INTERACTIONS :
Levobupivacaine HCl monohydrate 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 could be additive. CYP3A4 isoform and CYP1A2 isoform mediate the metabolism of Levobupivacaine to desbutyl Levobupivacaine and 3-hydroxy Levobupivacaine, respectively. Thus, agents likely to be concomitantly administered with Levobupivacaine that are metabolized by this isoenzyme family may potentially interact with Levobupivacaine. It is likely that the metabolism of Levobupivacaine may be affected by the known CYP3A4 inducers (such as Phenytoin, Phenobarbital, Rifampin); CYP3A4 inhibitors (azole antimycotics, e.g., Ketoconazole; certain protease inhibitors, e.g., Ritonavir; macrolide antibiotics, e.g., Erythromycin; and calcium channel antagonists, e.g., Verapamil), CYP1A2 inducers (Omeprazole) and CYP1A2 inhibitors (Furafylline and Clarithromycin). Dosage adjustments may be warranted when Levobupivacaine HCl monohydrate is concurrently administered with CYP3A4 inhibitors and CYP1A2 inhibitors, as systemic Levobupivacaine levels may rise resulting in toxicity.
Levobupivacaine HCl monohydrate should be used with caution in patients receiving antiarrythmic agents with local anesthetic activity, e.g., Mexiletine or class III antiarrythmic agents since their use may be additive.
ADVERSE REACTIONS :
Reactions to Levobupivacaine are characteristic of those associated with other amide-type anesthetics. A major cause of the adverse reactions to this group of drugs is associated with excessive plasma levels or high dermatomal levels, which may be due to overdose, unintentional intravascular injection or slow metabolic degradation. Systems involved may include the central nervous system, the cardiovascular system and the respiratory system (see WARNINGS AND PRECAUTIONS).
Adverse reactions that occurred in Levobupivacaine-treated patients are :
Hypotension, nausea, postoperative pain, fever, vomiting, anemia, pruritus, pain, headache, constipation, dizziness, fetal distress, backpain, delayed delivery, abnormal ECG. enlarged abdomen, albuminemia, rigors, diplopia, hypoesthesia, flatulence, abdominal pain, hypothermia, bradycardia, dyspepsia, hematuria, hemorrhage in pregnancy, paresthesia, tachycardia, abnormal urine, purpura, increased wound drainage, coughing, leukocytosis, somnolence, urinary incontinence, local anesthesia, anxiety, breast pain (female), hypertension, decreased urine flow, urinary tract infection, diarrhea.
The following adverse reactions were also reported and were considered clinically relevant :
|Body as a whole||Asthenia, edema|
|Cardiovascular disorders, general||Postural hypotension|
|Central and peripheral nervous system disorders||Hypokinesia, involuntary muscle contraction, spasm (generalized), tremor, syncope|
|Heart rate and rhythm disorders||Arrhythmia, extrasystoles, fibrillation (atrial), cardiac arrest|
|Gastrointestinal system disorders||Ileus|
|Liver and biliary system disorders||Elevated bilirubin|
|Psychiatric system disorders||Confusion|
|Respiratory system disorders||Apnea, bronchospasm, dyspnea, pulmonary edema, respiratory insufficiency|
|Skin and appendage disorders||Increased sweating, skin discoloration|
The incidence of adverse neurological reactions associated with the use of local anesthetics may be related to the total dose of 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 effects may be related to local anesthetic techniques, with or without contribution from the drug.
Allergic-type reactions are rare and may occur as a result of sensitivity to the local anesthetic. 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-like symptomatology (including severe hypotension). Cross sensitivity among members of the amide-type local anesthetic group have been reported. Anaphylaxis has been reported. Very rare reports of convulsions have occurred following accidental intravenous administration. There have been reports of prolonged weakness or sensory disturbance, some of which may have been permanent, in association with Levobupivacaine therapy. It is difficult to determine whether the long-term effects were the result of medication toxicity or unrecognized trauma during surgery or other mechanical factors, such as catheter insertion and manipulation.
Reports have been received of cauda equina syndrome or signs and symptoms of potential injury to the base of the spinal cord or spinal nerve roots (including lower extremity paresthesias, weakness or paralysis, loss of bowel control and/or bladder control and priapism) associated with Levobupivacaine administration. These events were more severe and in some cases did not resolve when Levobupivacaine was administered for greater than 24 hours (see WARNINGS AND PRECAUTIONS). However, it cannot be determined whether these events are due to an effect of Levobupivacaine, mechanical trauma to the spinal cord or spinal nerve roots, or blood collection at the base of spine.
There have also been reports of transient Horner’s syndrome (ptosis, miosis, enophthalmus, unilateral sweating and/or flushing) in association with use of regional anesthetics, including Levobupivacaine. This event resolves with discontinuation of therapy.
Levovacain® Injection 0.5% Box, 1 blister @ 5 ampoules @ 10 ml
STORE BELOW 30°C, PROTECT FROM LIGHT
ON MEDICAL PRESCRIPTION ONLY
Manufactured by :
Sidoarjo – Indonesia
Date : November 24th, 2021
Levovacain® is a trademark of PT. BERNOFARM
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