Prescription Drug Information: SENSORCAINE MPF

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:

Image from Drug Label Content

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

Image from Drug Label Content

The pKa 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.

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