Label: LUDAXINE- dexamethasone sodium phosphate, bupivacaine hydrochloride

  • Category: HUMAN PRESCRIPTION DRUG LABEL

Drug Label Information

Updated July 9, 2018

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  • Dexamethasone Sodium Phosphate Injection USP

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  • DESCRIPTION

    Dexamethasone sodium phosphate injection USP is a sterile, clear, colorless solution, free from visible particles and a water-soluble inorganic ester of dexamethasone which produces a rapid response even when injected intramuscularly.

    Dexamethasone Sodium Phosphate USP, C22H28FNa2O8P, has a molecular weight of 516.41 and chemically is Pregn-4-ene-3, 20-dione, 9-fluoro-11, 17-dihydroxy-16-methyl-21 (phosphonooxy)-, disodium salt, (11β, 16α).

    It occurs as a white to practically white powder, is exceedingly hygroscopic, is soluble in water and its solutions have a pH between 7.0 and 8.5. It has the following structural formula:

    dexstructure-1

    Dexamethasone sodium phosphate injection USP is available in 4 mg/mL concentration.

    Each mL of dexamethasone sodium phosphate injection USP, 4 mg/mL, contains 4.37 mg of dexamethasone sodium phosphate, USP equivalent to 4 mg dexamethasone phosphate; 1 mg sodium sulfite; 10 mg benzyl alcohol (preservative). Made isotonic with sodium citrate. pH adjusted with citric acid or sodium hydroxide.

    ACTIONS — Naturally occurring glucocorticoids (hydrocortisone), which also have salt-retaining properties, are used as replacement therapy in adrenocortical deficiency states. Their synthetic analogs are primarily used for their potent anti-inflammatory effects in disorders of many organ systems.

    Glucocorticoids cause profound and varied metabolic effects. In addition, they modify the body’s immune responses to diverse stimuli.

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  • INDICATIONS AND USAGE

    A. Intravenous or intramuscular administration. When oral therapy is not feasible and the strength, dosage form, and route of administration of the drug reasonably lend the preparation to the treatment of the condition, those products labeled for intravenous or intramuscular use are indicated as follows:

    1. Endocrine disorders. Primary or secondary adrenocortical insufficiency (hydrocortisone or cortisone is the drug of choice; synthetic analogs may be used in conjunction with mineralocorticoids where applicable; in infancy, mineralocorticoid supplementation is of particular importance).

    Acute adrenocortical insufficiency (hydrocortisone or cortisone is the drug of choice; mineralocorticoid supplementation may be necessary, particularly when synthetic analogs are used).

    Preoperatively, and in the event of serious trauma or illness, in patients with known adrenal insufficiency or when adrenocortical reserve is doubtful.

    Shock unresponsive to conventional therapy if adrenocortical insufficiency exists or is suspected.

    Congenital adrenal hyperplasia.

    Nonsuppurative thyroiditis.

    Hypercalcemia associated with cancer.

    2. Rheumatic disorders. As adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in:

    Post-traumatic osteoarthritis.

    Synovitis of osteoarthritis.

    Rheumatoid arthritis, including juvenile rheumatoid arthritis (selected cases may require low-dose maintenance therapy).

    Acute and subacute bursitis.

    Epicondylitis.

    Acute nonspecific tenosynovitis.

    Acute gouty arthritis.

    Psoriatic arthritis.

    Ankylosing spondylitis.

    3. Collagen diseases. During an exacerbation or as maintenance therapy in selected cases of:

    Systemic lupus erythematosus.
    Acute rheumatic carditis.

    4. Dermatologic diseases.

    Pemphigus.

    Severe erythema multiforme (Stevens-Johnson Syndrome).

    Exfoliative dermatitis.

    Bullous dermatitis herpetiformis.

    Severe seborrheic dermatitis.

    Severe psoriasis.

    Mycosis fungoides.

    5. Allergic states. Control of severe or incapacitating allergic conditions intractable to adequate trials of conventional treatment in:

    Bronchial asthma.

    Contact dermatitis.

    Atopic dermatitis.

    Serum sickness.

    Seasonal or perennial allergic rhinitis.

    Drug hypersensitivity reactions.

    Urticarial transfusion reactions.

    Acute noninfectious laryngeal edema (epinephrine is the drug of first choice).

    6. Ophthalmic diseases. Severe acute and chronic allergic and inflammatory processes involving the eye, such as:

    Herpes zoster ophthalmicus.

    Iritis, iridocyclitis.

    Chorioretinitis.

    Diffuse posterior uveitis and choroiditis.

    Optic neuritis.

    Sympathetic ophthalmia.

    Anterior segment inflammation.

    Allergic conjunctivitis.

    Allergic corneal marginal ulcers.
    Keratitis.

    7. Gastrointestinal diseases. To tide the patient over a critical period of the disease in:

    Ulcerative colitis (systemic therapy).

    Regional enteritis (systemic therapy).

    8. Respiratory diseases:

    Symptomatic Sarcoidosis.

    Berylliosis.

    Fulminating or disseminated pulmonary tuberculosis when used concurrently with appropriate anti-tuberculosis chemotherapy.

    Loeffler's syndrome not manageable by other means.

    Aspiration pneumonitis.

    9. Hematologic disorders:

    Acquired (autoimmune) hemolytic anemia.

    Idiopathic thrombocytopenic purpura in adults (I.V. only; I.M. administration is contraindicated).

    Secondary thrombocytopenia in adults.

    Erythroblastopenia (RBC anemia).

    Congenital (erythroid) hypoplastic anemia.

    10. Neoplastic diseases. For palliative management of:

    Leukemias and lymphomas in adults.

    Acute leukemia of childhood.

    11. Edematous states. To induce diuresis or remission of proteinuria in the nephrotic syndrome, without uremia, of the idiopathic type or that due to lupus erythematosus.

    12. Nervous system.

    Acute exacerbations of multiple sclerosis.

    13. Miscellaneous.

    Tuberculous meningitis with subarachnoid block or impending block when used concurrently with appropriate anti-tuberculosis chemotherapy.

    Trichinosis with neurologic or myocardial involvement.

    Diagnostic testing of adrenocortical hyperfunction.

    Cerebral edema of diverse etiologies in conjunction with adequate neurological evaluation and management.

    B. Intra-articular or soft tissue administration. When the strength and dosage form of the drug lend the preparation to the treatment of the condition, those products labeled for intra-articular or soft tissue administration are indicated as adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in:

    Synovitis of osteoarthritis.

    Rheumatoid arthritis.

    Acute and subacute bursitis.

    Acute gouty arthritis.

    Epicondylitis.

    Acute nonspecific tenosynovitis.

    Post-traumatic osteoarthritis.

    C. Intralesional administration. When the strength and dosage form of the drug lend the preparation to the treatment of the condition, those products labeled for intralesional administration are indicated for:

    Keloids.

    Localized hypertrophic, infiltrated, inflammatory lesions of: lichen planus, psoriatic plaques, granuloma annulare, and lichen simplex chronicus (neurodermatitis).

    Discoid lupus erythematosus.

    Necrobiosis lipoidica diabeticorum.

    Alopecia areata.

    They also may be useful in cystic tumors of an aponeurosis tendon (ganglia).

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  • CONTRAINDICATIONS

    Systemic fungal infections.

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  • WARNINGS

    Serious Neurologic Adverse Reactions with Epidural Administration

    Serious neurologic events, some resulting in death, have been reported with epidural injection of corticosteroids. Specific events reported include, but are not limited to, spinal cord infarction, paraplegia, quadriplegia, cortical blindness, and stroke. These serious neurologic events have been reported with and without use of fluoroscopy. The safety and effectiveness of epidural administration of corticosteroids have not been established, and corticosteroids are not approved for this use.

    In patients on corticosteroid therapy subject to any unusual stress, increased dosage of rapidly acting corticosteroids before, during and after the stressful situation is indicated. Corticosteroids may mask some signs of infection, and new infections may appear during their use. There may be decreased resistance and inability to localize infection when corticosteroids are used.

    Prolonged use of corticosteroids may produce posterior subcapsular cataracts, glaucoma with possible damage to the optic nerves, and may enhance the establishment of secondary ocular infections due to fungi or viruses.

    Children who are on immunosuppressant drugs are more susceptible to infections than healthy children. Chickenpox and measles, for example, can have a more serious or even fatal course in children on immunosuppressant corticosteroids. In such children, or in adults who have not had these diseases, particular care should be taken to avoid exposure. If exposed, therapy with varicella zoster immune globulin (VZIG) or pooled intravenous immunoglobulin (IVIG), as appropriate, may be indicated. If chickenpox develops, treatment with antiviral agents may be considered.

    Similarly, corticosteroids should be used with great care in patients with known or suspected Strongyloides (threadworm) infestation. In such patients, corticosteroid-induced immunosuppression may lead to Strongyloides hyperinfection and dissemination with widespread larval migration, often accompanied by severe enterocolitis and potentially fatal gram-negative septicemia.

    Usage in Pregnancy. Since adequate human reproduction studies have not been done with corticosteroids, use of these drugs in pregnancy, nursing mothers or women of childbearing potential requires that the possible benefits of the drug be weighed against the potential hazards to the mother and embryo or fetus. Infants born of mothers who have received substantial doses of corticosteroids during pregnancy should be carefully observed for signs of hypoadrenalism.

    Average and large doses of cortisone or hydrocortisone can cause elevation of blood pressure, salt and water retention, and increased excretion of potassium. These effects are less likely to occur with the synthetic derivatives except when used in large doses. Patients with a stressed myocardium should be observed carefully and the drug administered slowly since premature ventricular contractions may occur with rapid administration. Dietary salt restriction and potassium supplementation may be necessary. All corticosteroids increase calcium excretion.

    While on corticosteroid therapy patients should not be vaccinated against smallpox. Other immunization procedures should not be undertaken in patients who are on corticosteroids, especially in high doses, because of possible hazards of neurological complications and lack of antibody response.

    The use of dexamethasone sodium phosphate injection USP in active tuberculosis should be restricted to those cases of fulminating or disseminated tuberculosis in which the corticosteroid is used for the management of the disease in conjunction with an appropriate anti-tuberculosis regimen.

    If corticosteroids are indicated in patients with latent tuberculosis or tuberculin reactivity, close observation is necessary as reactivation of the disease may occur. During prolonged corticosteroid therapy, these patients should receive chemoprophylaxis.

    Because rare instances of anaphylactoid reactions have occurred in patients receiving parenteral corticosteroid therapy, appropriate precautionary measures should be taken prior to administration, especially when the patient has a history of allergy to any drug.

    Dexamethasone sodium phosphate injection contains sodium sulfite, 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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  • PRECAUTIONS

    Drug-induced secondary adrenocortical insufficiency may be minimized by gradual reduction of dosage. This type of relative insufficiency may persist for months after discontinuation of therapy; therefore, in any situation of stress occurring during that period, hormone therapy should be reinstituted. Since mineralocorticoid secretion may be impaired, salt and/or a mineralocorticoid should be administered concurrently.

    There is an enhanced effect of corticosteroids in patients with hypothyroidism and in those with cirrhosis.

    Corticosteroids should be used cautiously in patients with ocular herpes simplex for fear of corneal perforation.

    The lowest possible dose of corticosteroid should be used to control the condition under treatment, and when reduction in dosage is possible, the reduction must be gradual.

    Psychic derangements may appear when corticosteroids are used ranging from euphoria, insomnia, mood swings, personality changes, and severe depression to frank psychotic manifestations. Also, existing emotional instability or psychotic tendencies may be aggravated by corticosteroids.

    Aspirin should be used cautiously in conjunction with corticosteroids in hypoprothrombinemia.

    Steroids should be used with caution in nonspecific ulcerative colitis, if there is a probability of impending perforation, abscess or other pyogenic infection, also in diverticulitis, fresh intestinal anastomoses, active or latent peptic ulcer, renal insufficiency, hypertension, osteoporosis, and myasthenia gravis.

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

    Patients who are on immunosuppressant doses of corticosteroids should be warned to avoid exposure to chickenpox or measles and, if exposed, to obtain medical advice.

    Intra-articular injection of a corticosteroid may produce systemic as well as local effects.

    Appropriate examination of any joint fluid present is necessary to exclude a septic process.

    A marked increase in pain accompanied by local swelling, further restriction of joint motion, fever, and malaise are suggestive of septic arthritis. If this complication occurs and the diagnosis of sepsis is confirmed, appropriate antimicrobial therapy should be instituted.

    Local injection of a steroid into a previously infected joint is to be avoided. Corticosteroids should not be injected into unstable joints.

    Although controlled clinical trials have shown corticosteroids to be effective in speeding the resolution of acute exacerbations of multiple sclerosis they do not show that they affect the ultimate outcome or natural history of the disease. The studies do show that relatively high doses of corticosteroids are necessary to demonstrate a significant effect. (See Dosage and Administration Section).

    Since complications of treatment with glucocorticoids are dependent on the size of the dose and the duration of treatment a risk/benefit decision must be made in each individual case as to dose and duration of treatment and as to whether daily or intermittent therapy should be used.

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  • ADVERSE REACTIONS

    Fluid and electrolyte disturbances:

       Sodium retention

       Fluid retention

       Congestive heart failure in susceptible patients

       Potassium loss

       Hypokalemic alkalosis

       Hypertension

    Musculoskeletal:

       Muscle weakness

       Steroid myopathy

       Loss of muscle mass

       Osteoporosis

       Vertebral compression fractures

       Aseptic necrosis of femoral and humeral heads

       Pathologic fracture of long bones

    Gastrointestinal:

       Peptic ulcer with possible subsequent perforation and hemorrhage

       Pancreatitis

       Abdominal distention

       Ulcerative esophagitis

    Dermatological:

       Impaired wound healing

       Thin fragile skin

       Facial erythema

       Increased sweating

       May suppress reactions to skin tests

       Petechiae and ecchymoses

    Neurological:

       Convulsions

       Increased intracranial pressure with papilledema (pseudotumor cerebri) usually after treatment

       Vertigo

       Headache

    Ophthalmic:

       Posterior subcapsular cataracts

       Increased intraocular pressure

       Glaucoma

    Endocrine:

       Menstrual irregularities

       Development of cushingoid state

       Suppression of growth in children

       Secondary adrenocortical and pituitary unresponsiveness, particularly in times of stress, as in trauma, surgery, or illness

       Decreased carbohydrate tolerance

       Manifestations of latent diabetes mellitus

       Increased requirements for insulin or oral hypoglycemic agents in diabetics

    Metabolic:

       Negative nitrogen balance due to protein catabolism

    Miscellaneous:

       Hyperpigmentation or hypopigmentation

       Subcutaneous and cutaneous atrophy

       Sterile abscess

       Postinjection flare, following intra-articular use

       Charcot-like arthropathy

       Itching, burning, tingling in the ano-genital region

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  • DOSAGE AND ADMINISTRATION

    A. Intravenous or intramuscular administration. The initial dosage of dexamethasone sodium phosphate injection USP may vary from 0.50 mg/day to 9 mg/day depending on the specific disease entity being treated. In situations of less severity, lower doses will generally suffice while in selected patients higher initial doses may be required. Usually the parenteral dosage ranges are one-third to one-half the oral dose given every 12 hours. However, in certain overwhelming, acute, life-threatening situations, administration of dosages exceeding the usual dosages may be justified and may be in multiples of the oral dosages.

    For the treatment of unresponsive shock high pharmacologic doses of this product are currently recommended. Reported regimens range from 1 to 6 mg/kg of body weight as a single intravenous injection to 40 mg initially followed by repeat intravenous injection every 2 to 6 hours while shock persists.

    For the treatment of cerebral edema in adults an initial intravenous dose of 10 mg is recommended followed by 4 mg intramuscularly every six hours until maximum response has been noted. This regimen may be continued for several days postoperatively in patients requiring brain surgery. Oral dexamethasone, 1 to 3 mg t.i.d., should be given as soon as possible and dosage tapered off over a period of five to seven days. Nonoperative cases may require continuous therapy to remain free of symptoms of increased intracranial pressure. The smallest effective dose should be used in children, preferably orally. This may approximate 0.2 mg/kg/24 hours in divided doses.

    In treatment of acute exacerbations of multiple sclerosis daily doses of 200 mg of prednisolone for a week followed by 80 mg every other day or 4 to 8 mg dexamethasone every other day for 1 month have been shown to be effective.

    The initial dosage should be maintained or adjusted until a satisfactory response is noted. If after a reasonable period of time there is a lack of satisfactory clinical response, dexamethasone sodium phosphate injection USP should be discontinued and the patient transferred to other appropriate therapy. It should be emphasized that dosage requirements are variable and must be individualized on the basis of the disease under treatment and the response of the patient.

    After a favorable response is noted, the proper maintenance dosage should be determined by decreasing the initial drug dosage in small decrements at appropriate time intervals until the lowest dosage which will maintain an adequate clinical response is reached. It should be kept in mind that constant monitoring is needed in regard to drug dosage. Included in the situations which may make dosage adjustments necessary are changes in clinical status secondary to remissions or exacerbations in the disease process, the patient’s individual drug responsiveness and the effect of patient exposure to stressful situations not directly related to the disease entity under treatment. In this later situation it may be necessary to increase the dosage of dexamethasone sodium phosphate injection USP for a period of time consistent with the patient’s condition. If after a long-term therapy the drug is to be stopped, it is recommended that it be withdrawn gradually rather than abruptly.

    B. Intra-articular, soft tissue or intralesional administration. The dose for instrasynovial administration is usually 2 to 4 mg for large joints and 0.8 to 1 mg for small joints. For soft tissue and bursal injections a dose of 2 to 4 mg is recommended. Ganglia require a dose of 1 to 2 mg. A dose of 0.4 to 1 mg is used for injection into tendon sheaths. Injection into intervertebral joints should not be attempted at any time and hip joint injection cannot be recommended as an office procedure.

    Intrasynovial and soft tissue injections should be employed only when affected areas are limited to 1 or 2 sites. It should be remembered that corticoids provide palliation only and that other conventional or curative methods of therapy should be employed when indicated.

    Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

    Frequency of injection usually ranges from once every 3 to 5 days to once every 2 to 3 weeks. Frequent intra-articular injection may cause damage to joint tissue.

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  • HOW SUPPLIED

    Dexamethasone sodium phosphate injection USP is a sterile, clear, colorless solution, free from visible particles and is supplied as follows:

    120 mg per 30 mL (4 mg / mL)

    30 mL Multiple-Dose Vials

    Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]

    Sensitive to heat - Do not autoclave.

    Protect from light.

    The vial stoppers are not made with natural rubber latex.

    Revised: July 2017

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  • Bupivacaine Hydrochloride Injection USP

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  • DESCRIPTION

    Bupivacaine hydrochloride USP is 2-Piperidinecarboxamide, 1-butyl-N-(2,6-dimethylphenyl)-, monohydrochloride, monohydrate, a white, odorless, crystalline powder that is freely soluble in 95 percent ethanol, soluble in water, and slightly soluble in chloroform or acetone. It has the following structural formula:

    Bupistruct-1

    Bupivacaine hydrochloride injection USP is available in sterile isotonic solution for injection via local infiltration, peripheral nerve block, and caudal and lumbar epidural blocks. Solution of bupivacaine hydrochloride injection USP may be autoclaved. Solution is clear and colorless.

    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.

    Bupivacaine hydrochloride injection USP — Sterile isotonic solution containing sodium chloride. In multiple-dose vials, each mL also contains 1 mg methylparaben as antiseptic preservative. The pH of the solution is adjusted to between 4 and 6.5 with sodium hydroxide or hydrochloric acid.

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  • 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 (CNS). At blood concentrations achieved with normal 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 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 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 state.

    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 mcg/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 strong 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 to 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 distribution depends largely upon the ability of binding sites in the circulation to carry it to the liver where it is metabolized.

    After injection of bupivacaine hydrochloride 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 three to six 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. Pipecoloxylidine is the major metabolite of bupivacaine.

    The kidney is the main excretory organ for most local anesthetics and their metabolites. Urinary excretion is affected by urinary perfusion and factors affecting urinary pH. Only 6% of bupivacaine is excreted unchanged in the urine.

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

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  • INDICATIONS AND USAGE

    Bupivacaine hydrochloride injection USP is indicated for the production of local or regional anesthesia or analgesia for surgery, 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 nonobstetrical surgical procedures in pregnant patients is not sufficient to recommend use of 0.75% concentration of bupivacaine hydrochloride injection USP in these patients.

    Bupivacaine hydrochloride injection USP is not recommended for intravenous regional anesthesia (Bier Block). See WARNINGS.

    The routes of administration and indicated bupivacaine hydrochloride injection USP concentrations are:

    • local infiltration                          0.25%
    • peripheral nerve block               0.25% and 0.5%
    • retrobulbar block                       0.75%
    • sympathetic block                     0.25%
    • lumbar epidural                         0.25%, 0.5%, and 0.75% (0.75% not for obstetrical anesthesia)
    • caudal                                        0.25% and 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 bupivacaine hydrochloride injection USP.

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  • CONTRAINDICATIONS

    Bupivacaine hydrochloride injection is contraindicated in obstetrical paracervical block anesthesia. Its use in this technique has resulted in fetal bradycardia and death.

    Bupivacaine hydrochloride injection 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 hydrochloride injection solutions.

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  • WARNINGS

    THE 0.75% CONCENTRATION OF BUPIVACAINE HYDROCHLORIDE IS NOT RECOMMENDED FOR OBSTETRICAL ANESTHESIA. THERE HAVE BEEN REPORTS OF CARDIAC ARREST WITH DIFFICULT RESUSCITATION OR DEATH DURING USE OF BUPIVACAINE HYDROCHLORIDE 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, i.e., 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 intentionally or unintentionally, of such preservatives.

    Intra-articular infusions of local anesthetics following arthroscopic and other surgical procedures is an unapproved use, and there have been post-marketing reports of chondrolysis in patients receiving such infusions. The majority of reported cases of chondrolysis have involved the shoulder joint; cases of gleno-humeral chondrolysis have been described in pediatric and adult patients following intra-articular infusions of local anesthetics with and without epinephrine for periods of 48 to 72 hours. There is insufficient information to determine whether shorter infusion periods are not associated with these findings. The time of onset of symptoms, such as joint pain, stiffness and loss of motion can be variable, but may begin as early as the 2nd month after surgery. Currently, there is no effective treatment for chondrolysis; patients who experienced chondrolysis have required additional diagnostic and therapeutic procedures and some required arthroplasty or shoulder replacement.

    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.

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

    Mixing or the prior or intercurrent use of any other local anesthetic with bupivacaine hydrochloride 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 hydrochloride for intravenous regional anesthesia (Bier Block). Information on safe dosages and techniques of administration of bupivacaine hydrochloride in this procedure is lacking. Therefore, bupivacaine hydrochloride is not recommended for use in this technique.

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  • 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 IV 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 bupivacaine hydrochloride, 0.5% and 0.75% solutions should be administered in incremental doses of 3 mL to 5 mL with sufficient time between doses to detect toxic manifestations of unintentional intravascular or intrathecal injection. Injections should be made slowly, with frequent aspirations before and during the injection to avoid intravascular 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 mcg to 15 mcg has been suggested) to serve as a warning 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/or 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 a transient rise in systolic blood pressure. The test dose should also contain 10 mg to 15 mg of bupivacaine hydrochloride or an equivalent amount of another local anesthetic to detect an unintended intrathecal administration. This will be evidenced 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). The Test Dose formulation of bupivacaine hydrochloride contains 15 mg of bupivacaine and 15 mcg of epinephrine in a volume of 3 mL. 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 status of the patient. Debilitated, elderly patients and acutely ill patients should be given reduced doses commensurate with their age and physical status. Local anesthetics should also be used with caution in patients with hypotension or heartblock.

    Careful and constant monitoring of cardiovascular and respiratory (adequacy of ventilation) vital signs 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, 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 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, or penis. Patients with hypertensive vascular disease may exhibit exaggerated vasoconstrictor response. Ischemic injury or necrosis may result.

    Because amide-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 AV conduction produced by these drugs.

    Serious dose-related cardiac arrhythmias may occur if preparations containing a vasoconstrictor such as epinephrine are employed in patients 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 institution of treatment, including oxygen therapy, indicated supportive measures and dantrolene. (Consult dantrolene sodium intravenous package insert before using.)

    Use in Head and Neck Area

    Small doses of local anesthetics injected into the head and neck area, including retrobulbar, and stellate ganglion blocks, 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. They may also be due to puncture of the dural sheath of the optic nerve during retrobulbar block with diffusion of any local anesthetic along the subdural space to the midbrain. 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. (See DOSAGE AND ADMINISTRATION.)

    Use in Ophthalmic Surgery

    Clinicians who perform retrobulbar blocks should be aware that there have been reports of respiratory arrest following local anesthetic injection. Prior to retrobulbar block, as with all other regional procedures, the immediate availability of equipment, drugs, and personnel to manage respiratory arrest or depression, convulsions, and cardiac stimulation or depression should be assured (see also WARNINGS and Use in Head and Neck Area, above). As with other anesthetic procedures, patients should be constantly monitored following ophthalmic blocks for signs of these adverse reactions, which may occur following relatively low total doses.

    A concentration of 0.75% bupivacaine is indicated for retrobulbar block; however, this concentration is not indicated for any other peripheral nerve block, including the facial nerve, and not indicated for local infiltration, including the conjunctiva (see INDICATIONS AND USAGE and PRECAUTIONS, General). Mixing bupivacaine hydrochloride with other local anesthetics is not recommended because of insufficient data on the clinical use of such mixtures.

    When bupivacaine hydrochloride 0.75% is used for retrobulbar block, complete corneal anesthesia usually precedes onset of clinically acceptable external ocular muscle akinesia. Therefore, presence of akinesia rather than anesthesia alone should determine readiness of the patient for surgery.

    Information for Patients

    When appropriate, patients should be informed in advance that they may experience temporary loss of sensation and motor activity, usually in the lower half of the body, following proper administration of caudal or epidural anesthesia. Also, when appropriate, the physician should discuss other information including adverse reactions in the package insert of bupivacaine hydrochloride.

    Clinically Significant Drug Interactions

    The administration of local anesthetic solutions containing epinephrine or norepinephrine to patients receiving monoamine oxidase inhibitors or tricyclic antidepressants may produce severe, prolonged hypertension. Concurrent use of these agents should generally be avoided. In situations when concurrent therapy is necessary, careful patient monitoring is essential.

    Concurrent administration of vasopressor drugs and of ergot-type oxytocic drugs may cause severe, persistent hypertension or cerebrovascular accidents.

    Phenothiazines and butyrophenones may reduce or reverse the pressor effect of epinephrine.

    Carcinogenesis, Mutagenesis, Impairment of Fertility

    Long-term studies in animals to evaluate the carcinogenic potential of bupivacaine hydrochloride have not been conducted. The mutagenic potential and the effect on fertility of bupivacaine hydrochloride have not been determined.

    Pregnancy Category C

    There are no adequate and well-controlled studies in pregnant women. Bupivacaine hydrochloride should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Bupivacaine hydrochloride produced developmental toxicity when administered subcutaneously to pregnant rats and rabbits at clinically relevant doses. This does not exclude the use of bupivacaine hydrochloride at term for obstetrical anesthesia or analgesia. (See Labor and Delivery.)

    Bupivacaine hydrochloride was administered subcutaneously to rats at doses of 4.4, 13.3, & 40 mg/kg and to rabbits at doses of 1.3, 5.8, & 22.2 mg/kg during the period of organogenesis (implantation to closure of the hard palate). The high doses are comparable to the daily maximum recommended human dose (MRHD) of 400 mg/day on a mg/m2 body surface area (BSA) basis. No embryo-fetal effects were observed in rats at the high dose which caused increased maternal lethality. An increase in embryo-fetal deaths was observed in rabbits at the high dose in the absence of maternal toxicity with the fetal No Observed Adverse Effect Level representing approximately 1/5th the MRHD on a BSA basis.

    In a rat pre- and post-natal development study (dosing from implantation through weaning) conducted at subcutaneous doses of 4.4, 13.3, & 40 mg/kg mg/kg/day, decreased pup survival was observed at the high dose. The high dose is comparable to the daily MRHD of 400 mg/day on a BSA basis.

    Labor and Delivery

    SEE BOXED WARNING REGARDING OBSTETRlCAL USE OF 0.75% BUPIVACAINE HYDROCHLORIDE.

    Bupivacaine hydrochloride is contraindicated for obstetrical paracervical block anesthesia.

    Local anesthetics rapidly cross the placenta, and when used for epidural, caudal, or pudendal block anesthesia, can cause varying degrees of maternal, fetal, and neonatal toxicity. (See CLINICAL PHARMACOLOGY, Pharmacokinetics.) 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 has resulted from regional anesthesia. Local anesthetics produce vasodilation by blocking sympathetic nerves. 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.

    Epidural, caudal, or pudendal anesthesia may alter the forces of parturition through changes in uterine contractility or maternal expulsive efforts. Epidural anesthesia has been reported to prolong the second stage of labor by removing the parturient’s reflex urge to bear down or by interfering with motor function. The use of obstetrical anesthesia may increase the need for forceps assistance.

    The use of some local anesthetic drug products during labor and delivery may be followed by diminished muscle strength and tone for the first day or two of life. This has not been reported with bupivacaine.

    It is extremely important to avoid aortocaval compression by the gravid uterus during administration of regional block to parturients. To do this, the patient must be maintained in the left lateral decubitus position or a blanket roll or sandbag may be placed beneath the right hip and gravid uterus displaced to the left.

    Nursing Mothers

    Bupivacaine has been reported to be excreted in human milk suggesting that the nursing infant could be theoretically exposed to a dose of the drug. Because of the potential for serious adverse reactions in nursing infants from bupivacaine, a decision should be made whether to discontinue nursing or not administer bupivacaine, taking into account the importance of the drug to the mother.

    Pediatric Use

    Until further experience is gained in pediatric patients younger than 12 years, administration of bupivacaine hydrochloride in this age group is not recommended. Continuous infusions of bupivacaine in children have been reported to result in high systemic levels of bupivacaine and seizures; high plasma levels may also be associated with cardiovascular abnormalities. (See WARNINGS, PRECAUTIONS, and OVERDOSAGE.)

    Geriatric Use

    Patients over 65 years, particularly those with hypertension, may be at increased risk for developing hypotension while undergoing anesthesia with bupivacaine hydrochloride. (See ADVERSE REACTIONS.)

    Elderly patients may require lower doses of bupivacaine hydrochloride. (See PRECAUTIONS, Epidural Anesthesiaand DOSAGE AND ADMINISTRATION.)

    In clinical studies, differences in various pharmacokinetic parameters have been observed between elderly and younger patients. (See CLINICAL PHARMACOLOGY.)

    This product is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. (See CLINICAL PHARMACOLOGY.)

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  • ADVERSE REACTIONS

    Reactions to bupivacaine hydrochloride are characteristic of those associated with other amide-type local anesthetics. A major cause of adverse reactions to this group of drugs is excessive plasma levels, which may be due to overdosage, unintentional intravascular injection, or slow metabolic degradation.

    The most commonly encountered acute adverse experiences which demand immediate counter-measures are related to the central nervous system and the cardiovascular system. These adverse experiences are generally dose related and due to high plasma levels which may result from overdosage, rapid absorption from the injection site, diminished tolerance, or from unintentional intravascular injection of the local anesthetic solution. In addition to systemic dose-related toxicity, unintentional subarachnoid injection of drug during the intended performance of caudal or lumbar epidural block or nerve blocks near the vertebral column (especially in the head and neck region) may result in underventilation or apnea (“Total or High Spinal”). Also, hypotension due to loss of sympathetic tone and respiratory paralysis or underventilation due to cephalad extension of the motor level of anesthesia may occur. This may lead to secondary cardiac arrest if untreated. Patients over 65 years, particularly those with hypertension, may be at increased risk for experiencing the hypotensive effects of bupivacaine hydrochloride. Factors influencing plasma protein binding, such as acidosis, systemic diseases which alter protein production, or competition of other drugs for protein binding sites, may diminish individual tolerance.

    Central Nervous System Reactions

    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 central nervous system 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. In a survey of studies of epidural anesthesia, overt toxicity progressing to convulsions occurred in approximately 0.1% of local anesthetic administrations.

    Cardiovascular System Reactions

    High doses or unintentional intravascular injection may lead to high plasma levels and related depression of the myocardium, decreased cardiac output, heartblock, hypotension, bradycardia, ventricular arrhythmias, including ventricular tachycardia and ventricular fibrillation, and cardiac arrest. (See WARNINGS, PRECAUTIONS, and OVERDOSAGE.)

    Allergic

    Allergic-type reactions are rare and may occur as a result of sensitivity to the local anesthetic or to other formulation ingredients, such as the antimicrobial preservative methylparaben contained in multiple-dose vials. 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 has been reported. The usefulness of screening for sensitivity has not been definitely established.

    Neurologic

    The incidences of adverse neurologic reactions associated with the use of local anesthetics may be related to the total dose of local 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 a contribution from the drug.

    In the practice of caudal or lumbar epidural block, occasional unintentional penetration of the subarachnoid space by the catheter or needle may occur. Subsequent adverse effects may depend partially on the amount of drug administered intrathecally and the physiological and physical effects of a dural puncture. A high spinal is characterized by paralysis of the legs, loss of consciousness, respiratory paralysis, and bradycardia.

    Neurologic effects following epidural or caudal anesthesia may include spinal block of varying magnitude (including high or total 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; and cranial nerve palsies due to traction on nerves from loss of cerebrospinal fluid.

    Neurologic effects following other procedures or routes of administration may include persistent anesthesia, paresthesia, weakness, paralysis, all of which may have slow, incomplete, or no recovery.

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  • OVERDOSAGE

    Acute emergencies from local anesthetics are generally related to high plasma levels encountered during therapeutic use of local anesthetics or to unintended subarachnoid injection of local anesthetic solution. (See ADVERSE REACTIONS, WARNINGS, and PRECAUTIONS.)

    Management of Local Anesthetic Emergencies

    The first consideration is prevention, best accomplished by careful and constant monitoring of cardiovascular and respiratory vital signs and the patient’s state of consciousness after each local anesthetic injection. At the first sign of change, oxygen should be administered.

    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 effective assisted or controlled ventilation with 100% oxygen with 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. A 50 mg to 100 mg bolus IV injection of succinylcholine will paralyze the patient without depressing the central nervous or cardiovascular systems and facilitate ventilation. A bolus IV dose of 5 mg to 10 mg of diazepam or 50 mg to 100 mg of thiopental will permit ventilation and counteract central nervous system stimulation, but these drugs also depress central nervous system, respiratory, and cardiac function, add to postictal depression and may result in apnea. Intravenous barbiturates, anticonvulsant agents, or muscle relaxants should only be administered by those familiar with their use. Immediately after the institution of these ventilatory measures, the adequacy of the circulation should be evaluated. Supportive treatment of circulatory depression may require administration of intravenous fluids, and when appropriate, a vasopressor dictated by the clinical situation (such as ephedrine or epinephrine to enhance myocardial contractile force).

    Endotracheal intubation, employing drugs and techniques familiar to the clinician, may be indicated after initial administration of oxygen by mask if difficulty is encountered in the maintenance of a patent airway, or if prolonged ventilatory support (assisted or controlled) is indicated.

    Recent clinical data from patients experiencing local anesthetic-induced convulsions demonstrated rapid development of hypoxia, hypercarbia, and acidosis with bupivacaine 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.

    If not treated immediately, convulsions with simultaneous hypoxia, hypercarbia, and acidosis plus myocardial depression from the direct effects of the local anesthetic may result in cardiac arrhythmias, bradycardia, asystole, ventricular fibrillation, or cardiac arrest. Respiratory abnormalities, including apnea, may occur. Underventilation or apnea due to unintentional subarachnoid injection of local anesthetic solution may produce these same signs and also lead to cardiac arrest if ventilatory support is not instituted. If cardiac arrest should occur, successful outcome may require prolonged resuscitative efforts.

    The supine position is dangerous in pregnant women at term because of aortocaval 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 be accomplished.

    The mean seizure dosage of bupivacaine in rhesus monkeys was found to be 4.4 mg/kg with mean arterial plasma concentration of 4.5 mcg/mL. The intravenous and subcutaneous LD50 in mice is 6 mg/kg to 8 mg/kg and 38 mg/kg to 54 mg/kg respectively.

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  • DOSAGE AND ADMINISTRATION

    NOTE: The products accompanying this insert do not contain epinephrine.

    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. The smallest dose and concentration required to produce the desired result should be administered. Dosages of bupivacaine hydrochloride injection should be reduced for elderly and/or debilitated patients and patients with cardiac and/or liver disease. The rapid injection of a large volume of local anesthetic solution should be avoided and fractional (incremental) doses should be used when feasible.

    For specific techniques and procedures, refer to standard textbooks.

    There have been adverse event reports of chondrolysis in patients receiving intra-articular infusions of local anesthetics following arthroscopic and other surgical procedures. Bupivacaine hydrochloride injection is not approved for this use (see WARNINGS and DOSAGE AND ADMINISTRATION).

    In recommended doses, bupivacaine hydrochloride produces complete sensory block, but the effect on motor function differs among the three concentrations.

    0.25% — when used for caudal, epidural, or peripheral nerve block, produces incomplete motor block. Should be used for operations in which muscle relaxation is not important, or when another means of providing muscle relaxation is used concurrently. Onset of action may be slower than with the 0.5% or 0.75% solutions.

    0.5% — provides motor blockade for caudal, epidural, or nerve block, but muscle relaxation may be inadequate for operations in which complete muscle relaxation is essential.

    0.75% — produces complete motor block. Most useful for epidural block in abdominal operations requiring complete muscle relaxation, and for retrobulbar anesthesia. Not for obstetrical anesthesia.

    The duration of anesthesia with bupivacaine hydrochloride injection is such that for most indications, a single dose is sufficient.

    Maximum dosage limit must be individualized in each case after evaluating the size and physical status of the patient, as well as the usual rate of systemic absorption from a particular injection site. Most experience to date is with single doses of bupivacaine hydrochloride injection up to 225 mg with epinephrine 1:200,000 and 175 mg without epinephrine; more or less drug may be used depending on individualization of each case.

    These doses may be repeated up to once every three hours. In clinical studies to date, total daily doses have been up to 400 mg. Until further experience is gained, this dose should not be exceeded in 24 hours. The duration of anesthetic effect may be prolonged by the addition of epinephrine.

    The dosages in Table 1 have generally proved satisfactory and are recommended as a guide for use in the average adult. These dosages should be reduced for elderly or debilitated patients. Until further experience is gained, bupivacaine hydrochloride injection is not recommended for pediatric patients younger than 12 years. Bupivacaine hydrochloride injection is contraindicated for obstetrical paracervical blocks, and is not recommended for intravenous regional anesthesia (Bier Block). 

    Use in Epidural Anesthesia

    During epidural administration of bupivacaine hydrochloride injection, 0.5% and 0.75% solutions should be administered in incremental doses of 3 mL to 5 mL with sufficient time between doses to detect toxic manifestations of unintentional intravascular or intrathecal injection. In obstetrics, only the 0.5% and 0.25% concentrations should be used; incremental doses of 3 mL to 5 mL of the 0.5% solution not exceeding 50 mg to 100 mg at any dosing interval are recommended. Repeat doses should be preceded by a test dose containing epinephrine if not contraindicated. Use only the single-dose ampuls 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.

    Test Dose for Caudal and Lumbar Epidural Blocks


    See PRECAUTIONS

    This product 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.

    Table 1. Recommended Concentrations and Doses of Bupivacaine Hydrochloride Injection
    Type of
    Block
    Conc. Each Dose Motor
    Block1
    (mL) (mg)
    1With continuous (intermittent) techniques, repeat doses increase the degree of motor block. The first repeat dose of 0.5% may produce complete motor block. Intercostal nerve block with 0.25% may also produce complete motor block for intra-abdominal surgery.
    2 For single-dose use, not for intermittent epidural technique. Not for obstetrical anesthesia.
    3 See PRECAUTIONS.
    4 Solutions with or without epinephrine.
    Local
    infiltration
    0.25%4 up to
    max.
    up to
    max.
    ––
    Epidural 0.75%2,4 10 to 20 75 to 150 complete
    0.5%4 10 to 20 50 to 100 moderate to complete
    0.25%4 10 to 20 25 to 50 partial to moderate
    Caudal 0.5%4 15 to 30 75 to 150 moderate to complete
    0.25%4 15 to 30 37.5 to 75 moderate
    Peripheral
    nerves
    0.5%4 5 to max. 25 to max. moderate to complete
    0.25%4 5 to max. 12.5 to max. moderate to complete
    Retrobulbar3 0.75%4 2 to 4 15 to 30 complete
    Sympathetic 0.25% 20 to 50 50 to 125
    Epidural3
    Test Dose
               0.5%
               w/epi
    2 to 3                                                  10 to 15
                                           (10 to 15 micrograms epinephrine)
                                    ––

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  • HOW SUPPLIED

    These solutions are not for spinal anesthesia.
    Bupivacaine Hydrochloride Injection USP — Solution of Bupivacaine hydrochloride injection USP may be autoclaved. Autoclave at 15-pound pressure, 121°C (250°F) for 15 minutes.

    Bupivacaine Hydrochloride Injection USP is a clear, colorless, sterile isotonic solution and is available as follows:

    Bupivacaine Hydrochloride Injection USP 0.5% (5 mg/mL)             50 mL Multiple Dose Vial

    Store at
    20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]

    The vial stoppers are not made with natural rubber latex.

    Sterile, Nonpyrogenic
    Revised: June 2017

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  • SPL UNCLASSIFIED SECTION

    Contents:

    1 - 30mL Dexamethasone Sodium Phosphate (4mg/mL)

    1 - 50mL Bupivacaine HCL 0.5%

    1 - 3cc Syringe w/ 18-22 Gauge 1-1 1/2 in Needle (Draw)

    1 - 5cc Syringe w/ 18-22 Gauge 1-1 1/2 in Needle (Draw)

    1 - 22-27 Gauge 1/2 - 1 1/2 in Needle (Administer)

    1 - 3x3 Gauze Sponge Sterile Square

    1 - Bandage 1x3 in

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  • SPL UNCLASSIFIED SECTION

    Assembled and Distributed by IT3 Medical, LLC 190 E Stacy Road; STE 306-298 Allen, TX 75002-8734

    For questions or comments: info@IT3-Medical.com, www.IT3-Medical.com

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  • PACKAGING-KIT LABEL
  • PACKAGING-KIT COMPONENTS LABELING
  • INGREDIENTS AND APPEARANCE
    LUDAXINE 
    dexamethasone sodium phosphate, bupivacaine hydrochloride kit
    Product Information
    Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:70529-053
    Packaging
    # Item Code Package Description Marketing Start Date Marketing End Date
    1 NDC:70529-053-01 1 in 1 PACKAGE; Type 9: Other Type of Part 3 Combination Product (e.g., Drug/Device/Biological Product) 11/01/2018
    Quantity of Parts
    Part # Package Quantity Total Product Quantity
    Part 1 1 VIAL, MULTI-DOSE 30 mL
    Part 2 1 VIAL, MULTI-DOSE 50 mL
    Part 1 of 2
    DEXAMETHASONE SODIUM PHOSPHATE 
    dexamethasone sodium phosphate injection, solution
    Product Information
    Item Code (Source) NDC:55150-239
    Route of Administration INTRAVENOUS, INTRAMUSCULAR, INTRA-ARTICULAR, INTRALESIONAL, SOFT TISSUE
    Active Ingredient/Active Moiety
    Ingredient Name Basis of Strength Strength
    DEXAMETHASONE SODIUM PHOSPHATE (UNII: AI9376Y64P) (DEXAMETHASONE - UNII:7S5I7G3JQL) DEXAMETHASONE PHOSPHATE 4 mg  in 1 mL
    Inactive Ingredients
    Ingredient Name Strength
    BENZYL ALCOHOL (UNII: LKG8494WBH) 10 mg  in 1 mL
    SODIUM SULFITE (UNII: VTK01UQK3G) 1 mg  in 1 mL
    ANHYDROUS TRISODIUM CITRATE (UNII: RS7A450LGA)  
    ANHYDROUS CITRIC ACID (UNII: XF417D3PSL)  
    SODIUM HYDROXIDE (UNII: 55X04QC32I)  
    WATER (UNII: 059QF0KO0R)  
    Packaging
    # Item Code Package Description Marketing Start Date Marketing End Date
    1 30 mL in 1 VIAL, MULTI-DOSE; Type 0: Not a Combination Product
    Marketing Information
    Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
    ANDA ANDA206781 12/01/2015
    Part 2 of 2
    BUPIVACAINE HYDROCHLORIDE 
    bupivacaine hydrochloride injection, solution
    Product Information
    Item Code (Source) NDC:55150-250
    Route of Administration PERINEURAL
    Active Ingredient/Active Moiety
    Ingredient Name Basis of Strength Strength
    BUPIVACAINE HYDROCHLORIDE (UNII: 7TQO7W3VT8) (BUPIVACAINE - UNII:Y8335394RO) BUPIVACAINE HYDROCHLORIDE ANHYDROUS 5 mg  in 1 mL
    Inactive Ingredients
    Ingredient Name Strength
    METHYLPARABEN (UNII: A2I8C7HI9T)  
    SODIUM CHLORIDE (UNII: 451W47IQ8X)  
    SODIUM HYDROXIDE (UNII: 55X04QC32I)  
    HYDROCHLORIC ACID (UNII: QTT17582CB)  
    WATER (UNII: 059QF0KO0R)  
    Packaging
    # Item Code Package Description Marketing Start Date Marketing End Date
    1 50 mL in 1 VIAL, MULTI-DOSE; Type 0: Not a Combination Product
    Marketing Information
    Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
    ANDA ANDA207183 05/13/2016
    Marketing Information
    Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
    ANDA ANDA206781 11/01/2018
    Labeler - IT3 Medical LLC (079971231)
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