SENSORCAINE MPF: Package Insert and Label Information

SENSORCAINE MPF- bupivacaine hydrochloride injection
SENSORCAINE MPF WITH EPINEPHRINE- bupivacaine hydrochloride and epinephrine injection
SENSORCAINE- bupivacaine hydrochloride injection
AstraZeneca LP

DESCRIPTION

Sensorcaine® (bupivacaine HCl) injections are sterile isotonic solutions that contain a local anesthetic agent with and without epinephrine (as bitartrate) 1:200,000 and are administered parenterally by injection. See INDICATIONS AND USAGE for specific uses. Solutions of bupivacaine HCl may be autoclaved if they do not contain epinephrine.

Sensorcaine injections contain bupivacaine HCl which is chemically designated as 2-piperidinecarboxamide, 1-butyl-N-(2,6-dimethylphenyl)-, monohydrochloride, monohydrate and has the following structure:

Epinephrine is (-)-3,4-Dihydroxy-α [(methylamino)methyl] benzyl alcohol. It has the following structural formula:

The pK_a of bupivacaine (8.1) is similar to that of lidocaine (7.86). However, bupivacaine possesses a greater degree of lipid solubility and is protein bound to a greater extent than lidocaine.

Bupivacaine is related chemically and pharmacologically to the aminoacyl local anesthetics. It is a homologue of mepivacaine and is chemically related to lidocaine. All three of these anesthetics contain an amide linkage between the aromatic nucleus and the amino or piperidine group. They differ in this respect from the procaine-type local anesthetics, which have an ester linkage.

Dosage forms listed as Sensorcaine-MPF indicates single dose solutions that are M ethyl P araben F ree (MPF).

Sensorcaine-MPF is a sterile isotonic solution containing sodium chloride. Sensorcaine in multiple dose vials, each mL also contains 1 mg methylparaben as antiseptic preservative. The pH of these solutions is adjusted to between 4.0 and 6.5 with sodium hydroxide and/or hydrochloric acid.

Sensorcaine-MPF with Epinephrine 1:200,000 (as bitartrate) is a sterile isotonic solution containing sodium chloride. Each mL contains bupivacaine hydrochloride and 0.005 mg epinephrine, with 0.5 mg sodium metabisulfite as an antioxidant and 0.2 mg citric acid (anhydrous) as stabilizer. Sensorcaine with Epinephrine 1:200,000 (as bitartrate) in multiple dose vials, each mL also contains 1 mg methylparaben as antiseptic preservative. The pH of these solutions is adjusted to between 3.3 to 5.5 with sodium hydroxide and/or hydrochloric acid. Filled under nitrogen.

Note: The user should have an appreciation and awareness of the formulations and their intended uses. (See DOSAGE AND ADMINISTRATION.)

CLINICAL PHARMACOLOGY

Local anesthetics block the generation and the conduction of nerve impulses, presumably by increasing the threshold for electrical excitation in the nerve, by slowing the propagation of the nerve impulse, and by reducing the rate of rise of the action potential. In general, the progression of anesthesia is related to the diameter, myelination and conduction velocity of affected nerve fibers. Clinically, the order of loss of nerve function is as follows: (1) pain, (2) temperature, (3) touch, (4) proprioception, and (5) skeletal muscle tone.

Systemic absorption of local anesthetics produces effects on the cardiovascular and central nervous systems. At blood concentrations achieved with therapeutic doses, changes in cardiac conduction, excitability, refractoriness, contractility, and peripheral vascular resistance are minimal. However, toxic blood concentrations depress cardiac conduction and excitability, which may lead to atrioventricular block, ventricular arrhythmias and to cardiac arrest, sometimes resulting in fatalities. In addition, myocardial contractility is depressed and peripheral vasodilation occurs, leading to decreased cardiac output and arterial blood pressure. Recent clinical reports and animal research suggest that these cardiovascular changes are more likely to occur after unintended intravascular injection of bupivacaine. Therefore, incremental dosing is necessary.

Following systemic absorption, local anesthetics can produce central nervous system stimulation, depression or both. Apparent central stimulation is usually manifested as restlessness, tremors and shivering, progressing to convulsions, followed by depression and coma, progressing ultimately to respiratory arrest. However, the local anesthetics have a primary depressant effect on the medulla and on higher centers. The depressed stage may occur without a prior excited stage.

Pharmacokinetics:

The rate of systemic absorption of local anesthetics is dependent upon the total dose and concentration of drug administered, the route of administration, the vascularity of the administration site, and the presence or absence of epinephrine in the anesthetic solution. A dilute concentration of epinephrine (1:200,000 or 5 μg/mL) usually reduces the rate of absorption and peak plasma concentration of bupivacaine, permitting the use of moderately larger total doses and sometimes prolonging the duration of action.

The onset of action with bupivacaine is rapid and anesthesia is long-lasting. The duration of anesthesia is significantly longer with bupivacaine than with any other commonly used local anesthetic. It has also been noted that there is a period of analgesia that persists after the return of sensation, during which time the need for potent analgesics is reduced.

Local anesthetics are bound to plasma proteins in varying degrees. Generally, the lower the plasma concentration of drug, the higher the percentage of drug bound to plasma proteins.

Local anesthetics appear to cross the placenta by passive diffusion. The rate and degree of diffusion is governed by: (1) the degree of plasma protein binding, (2) the degree of ionization, and (3) the degree of lipid solubility. Fetal/maternal ratios of local anesthetics appear to be inversely related to the degree of plasma protein binding, because only the free, unbound drug is available for placental transfer. Bupivacaine, with a high protein binding capacity (95%), has a low fetal/maternal ratio (0.2−0.4). The extent of placental transfer is also determined by the degree of ionization and lipid solubility of the drug. Lipid soluble, nonionized drugs readily enter the fetal blood from the maternal circulation.

Depending upon the route of administration, local anesthetics are distributed to some extent to all body tissues, with high concentrations found in highly perfused organs such as the liver, lungs, heart, and brain.

Pharmacokinetic studies on the plasma profile of bupivacaine after direct intravenous injection suggest a three-compartment open model. The first compartment is represented by the rapid intravascular distribution of the drug. The second compartment represents the equilibration of the drug throughout the highly perfused organs such as the brain, myocardium, lungs, kidneys, and liver. The third compartment represents an equilibration of the drug with poorly perfused tissues, such as muscle and fat. The elimination of drug from tissue depends largely upon the ability of binding sites in the circulation to carry it to the liver where it is metabolized.

After injection of Sensorcaine (bupivacaine HCl) for caudal, epidural or peripheral nerve block in man, peak levels of bupivacaine in the blood are reached in 30 to 45 minutes, followed by a decline to insignificant levels during the next 3 to 6 hours.

Various pharmacokinetic parameters of the local anesthetics can be significantly altered by the presence of hepatic or renal disease, addition of epinephrine, factors affecting urinary pH, renal blood flow, the route of drug administration, and the age of the patient. The half-life of bupivacaine in adults is 2.7 hours and in neonates 8.1 hours.

In clinical studies, elderly patients reached the maximal spread of analgesia and maximal motor blockade more rapidly than younger patients. Elderly patients also exhibited higher peak plasma concentrations following administration of this product. The total plasma clearance was decreased in these patients.

Amide-type local anesthetics such as bupivacaine are metabolized primarily in the liver via conjugation with glucuronic acid. Patients with hepatic disease, especially those with severe hepatic disease, may be more susceptible to the potential toxicities of the amide-type local anesthetics. The major metabolite of bupivacaine is 2,6-pipecoloxylidine.

The kidney is the main excretory organ for most local anesthetics and their metabolites. Urinary excretion is affected by renal perfusion and factors affecting urinary pH. Only 5% of bupivacaine is excreted unchanged in the urine.

When administered in recommended doses and concentrations, Sensorcaine (bupivacaine HCl) does not ordinarily produce irritation or tissue damage and does not cause methemoglobinemia.

INDICATIONS AND USAGE

Sensorcaine (bupivacaine HCl) is indicated for the production of local or regional anesthesia or analgesia for surgery, for oral surgery procedures, for diagnostic and therapeutic procedures, and for obstetrical procedures. Only the 0.25% and 0.5% concentrations are indicated for obstetrical anesthesia. (See WARNINGS.)

Experience with non-obstetrical surgical procedures in pregnant patients is not sufficient to recommend use of the 0.75% concentration in these patients. Sensorcaine is not recommended for intravenous regional anesthesia (Bier Block). (See WARNINGS.)

The routes of administration and indicated Sensorcaine concentrations are:

local infiltration 0.25%

peripheral nerve block 0.25%, 0.5%

retrobulbar block 0.75%

sympathetic block 0.25%

lumbar epidural 0.25%, 0.5% and 0.75%

(non-obstetrical)

caudal 0.25%, 0.5%

epidural test dose (see PRECAUTIONS)

(See DOSAGE AND ADMINISTRATION for additional information.) Standard textbooks should be consulted to determine the accepted procedures and techniques for the administration of Sensorcaine.

Use only the single dose ampules and single dose vials for caudal or epidural anesthesia; the multiple dose vials contain a preservative and, therefore, should not be used for these procedures.

CONTRAINDICATIONS

Sensorcaine (bupivacaine HCl) is contraindicated in obstetrical paracervical block anesthesia. Its use by this technique has resulted in fetal bradycardia and death.

Sensorcaine is contraindicated in patients with a known hypersensitivity to it or to any local anesthetic agent of the amide type or to other components of bupivacaine solutions.

WARNINGS

THE 0.75% CONCENTRATION OF SENSORCAINE INJECTION IS NOT RECOMMENDED FOR OBSTETRICAL ANESTHESIA. THERE HAVE BEEN REPORTS OF CARDIAC ARREST WITH DIFFICULT RESUSCITATION OR DEATH DURING USE OF BUPIVACAINE FOR EPIDURAL ANESTHESIA IN OBSTETRICAL PATIENTS. IN MOST CASES, THIS HAS FOLLOWED USE OF THE 0.75% CONCENTRATION. RESUSCITATION HAS BEEN DIFFICULT OR IMPOSSIBLE DESPITE APPARENTLY ADEQUATE PREPARATION AND APPROPRIATE MANAGEMENT. CARDIAC ARREST HAS OCCURRED AFTER CONVULSIONS RESULTING FROM SYSTEMIC TOXICITY, PRESUMABLY FOLLOWING UNINTENTIONAL INTRAVASCULAR INJECTION. THE 0.75% CONCENTRATION SHOULD BE RESERVED FOR SURGICAL PROCEDURES WHERE A HIGH DEGREE OF MUSCLE RELAXATION AND PROLONGED EFFECT ARE NECESSARY.

LOCAL ANESTHETICS SHOULD ONLY BE EMPLOYED BY CLINICIANS WHO ARE WELL VERSED IN DIAGNOSIS AND MANAGEMENT OF DOSE-RELATED TOXICITY AND OTHER ACUTE EMERGENCIES WHICH MIGHT ARISE FROM THE BLOCK TO BE EMPLOYED, AND THEN ONLY AFTER INSURING THE IMMEDIATE AVAILABILITY OF OXYGEN, OTHER RESUSCITATIVE DRUGS, CARDIOPULMONARY RESUSCITATIVE EQUIPMENT, AND THE PERSONNEL RESOURCES NEEDED FOR PROPER MANAGEMENT OF TOXIC REACTIONS AND RELATED EMERGENCIES. (See also ADVERSE REACTIONS, PRECAUTIONS, and OVERDOSAGE.) 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.

Local anesthetic solutions containing antimicrobial preservatives, ie, those supplied in multiple dose vials should not be used for epidural or caudal anesthesia because safety has not been established with regard to intrathecal injection, either intentional or unintentional, of such preservatives.

It is essential that aspiration for blood or cerebrospinal fluid (where applicable) be done prior to injecting any local anesthetic, both the original dose and all subsequent doses, to avoid intravascular or subarachnoid injection. However, a negative aspiration does not ensure against an intravascular or subarachnoid injection.

Bupivacaine and Epinephrine Injection or other vasopressors should not be used concomitantly with ergot-type oxytocic drugs, because a severe persistent hypertension may occur. Likewise, solutions of bupivacaine containing a vasoconstrictor, such as epinephrine, should be used with extreme caution in patients receiving monoamine oxidase (MAO) inhibitors or antidepressants of the triptyline or imipramine types, because severe prolonged hypertension may result.

Until further experience is gained in children younger than 12 years, administration of bupivacaine in this age group is not recommended.

Mixing of the prior or intercurrent use of any local anesthetic with bupivacaine cannot be recommended because of insufficient data on the clinical use of such mixtures.

There have been reports of cardiac arrest and death during the use of bupivacaine for intravenous regional anesthesia (Bier Block). Information on safe dosages and techniques of administration of bupivacaine in this procedure is lacking. Therefore, bupivacaine is not recommended for use in this technique.

Sensorcaine with epinephrine solutions contain sodium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people.

PRECAUTIONS

General:

The safety and effectiveness of local anesthetics depend 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, ADVERSE REACTIONS, and OVERDOSAGE.) During major regional nerve blocks, the patient should have I.V. fluids running via an indwelling catheter to assure a functioning intravenous pathway. The lowest dosage of local anesthetic that results in effective anesthesia should be used to avoid high plasma levels and serious adverse effects. The rapid injection of a large volume of local anesthetic solution should be avoided and fractional (incremental) doses should be used when feasible.

Epidural Anesthesia:

During epidural administration of Sensorcaine (bupivacaine HCl), concentrated solutions (0.5−0.75%) 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. An intravascular injection is still possible even if aspirations for blood are negative.

During the administration of epidural anesthesia, it is recommended that a test dose be administered initially and the effects monitored before the full dose is given. When using a “continuous” catheter technique, test doses should be given prior to both the original and all reinforcing doses, because plastic tubing in the epidural space can migrate into a blood vessel or through the dura. When clinical conditions permit, the test dose should contain epinephrine (10 to 15 μg have been suggested) to serve as a warning of unintentional 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 per minute for 15 or more seconds. Therefore, following the test dose, the heart rate should be monitored for a heart rate increase. Patients on beta-blockers may not manifest changes in heart rate, but blood pressure monitoring can detect an evanescent rise in systolic blood pressure. The test dose should also contain 10 to 15 mg of Sensorcaine or an equivalent dose of a short-acting amide anesthetic such as 30 to 40 mg of lidocaine, to detect an unintentional intrathecal administration. This will be manifested within a few minutes by signs of spinal block (eg, 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.

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. Debilitated, elderly patients, acutely ill patients and children should be given reduced doses commensurate with their age and physical condition. Local anesthetics should also be used with caution in patients with hypotension 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.

Local anesthetic solutions containing a vasoconstrictor should be used cautiously and in carefully restricted quantities in areas of the body supplied by end arteries or having otherwise compromised blood supply such as digits, nose, external ear, penis, etc. Patients with hypertensive vascular disease may exhibit exaggerated vasoconstrictor response. Ischemic injury or necrosis may result.

Because amide-type local anesthetics such as bupivacaine 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.

Serious dose-related cardiac arrhythmias may occur if preparations containing a vasoconstrictor such as epinephrine are employed in patient’s during or following the administration of potent inhalation anesthetics. In deciding whether to use these products concurrently in the same patient, the combined action of both agents upon the myocardium, the concentration and volume of vasoconstrictor used, and the time since injection, when applicable, should be taken into account.

Many drugs used during the conduct of anesthesia are considered potential triggering agents for familial malignant hyperthermia. Because it is not known whether amide-type local anesthetics may trigger this reaction and because the need for supplemental general anesthesia cannot be predicted in advance, it is suggested that a standard protocol for management should be available. Early unexplained signs of tachycardia, tachypnea, labile blood pressure and metabolic acidosis may precede temperature elevation. Successful outcome is dependent on early diagnosis, prompt discontinuance of the suspect triggering agent(s) and prompt treatment, including oxygen therapy, dantrolene (consult dantrolene sodium intravenous package insert before using) and other supportive measures.