Label: MARDEX 25 KIT- dexamethasone sodium phosphate, bupivacaine hydrochloride, povidine iodine kit

  • NDC Code(s): 55150-167-10, 63323-506-01, 67777-419-02, 76420-810-01
  • Packager: Asclemed USA, Inc.
  • Category: HUMAN PRESCRIPTION DRUG LABEL
  • DEA Schedule: None
  • Marketing Status: unapproved drug other

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Drug Label Information

Updated September 14, 2020

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  • SPL UNCLASSIFIED SECTION

    Dexamethasone Sodium Phosphate Injection, USP

    For Intravenous or Intramuscular Use Only

    Rx only

  • DESCRIPTION

    Dexamethasone Sodium Phosphate Injection, USP, is a water-soluble inorganic ester of dexamethasone which produces a rapid response even when injected intramuscularly.

    Dexamethasone Sodium Phosphate, USP chemically is Pregna-1,4-diene-3,20-dione, 9-fluoro- 11,17-dihydroxy-16-methyl-21-(phosphonooxy)-, disodium salt, (11ß, 16α).

    It occurs as a white to creamy 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:

    image description

    Each mL of Dexamethasone Sodium Phosphate Injection, USP (Preservative Free) contains dexamethasone sodium phosphate, USP equivalent to 10 mg dexamethasone phosphate; 24.75 mg sodium citrate, dihydrate; and Water for Injection, q.s. pH adjusted with citric acid or sodium hydroxide, if necessary. pH: 7.0 to 8.5.

  • CLINICAL PHARMACOLOGY

    Dexamethasone sodium phosphate injection has a rapid onset but short duration of action when compared with less soluble preparations. Because of this, it is suitable for the treatment of acute disorders responsive to adrenocortical steroid therapy.

    Naturally occurring glucocorticoids (hydrocortisone and cortisone), which also have salt-retaining properties, are used as replacement therapy in adrenocortical deficiency states. Their synthetic analogs, including dexamethasone, 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.

    At equipotent anti-inflammatory doses, dexamethasone almost completely lacks the sodium-retaining property of hydrocortisone and closely related derivatives of hydrocortisone.

  • INDICATIONS AND USAGE

    By intravenous or intramuscular injection when oral therapy is not feasible:

    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

    Keratitis

    Allergic corneal marginal ulcers

    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 antituberculous chemotherapy.

    Loeffler’s syndrome not manageable by other means.

    Aspiration pneumonitis

    9. Hematologic Disorders

    Acquired (autoimmune) hemolytic anemia.

    Idiopathic thrombocytopenic purpura in adults

    (IV only; IM 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. Miscellaneous

    Tuberculous meningitis with subarachnoid block or impending block when used concurrently with appropriate antituberculous chemotherapy.

    Trichinosis with neurologic or myocardial involvement.

    13. Diagnostic testing of adrenocortical hyperfunction.

    14. Cerebral Edema associated with primary or metastatic brain tumor, craniotomy, or head injury. Use in cerebral edema is not a substitute for careful neurosurgical evaluation

    and definitive management such as neurosurgery or other specific therapy.

  • CONTRAINDICATIONS

    Systemic fungal infections (see WARNINGSregarding amphotericin B).

    Hypersensitivity to any component of this product (see WARNINGS) .

  • WARNINGS

    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. Anaphylactoid and hypersensitivity reactions have been reported for dexamethasone sodium phosphate injection (see ADVERSE REACTIONS).

    Corticosteroids may exacerbate systemic fungal infections and, therefore, should not be used in the presence of such infections unless they are needed to control drug reactions due to amphotericin B. Moreover, there have been cases reported in which concomitant use of amphotericin B and hydrocortisone was followed by cardiac enlargement and congestive failure.

    In patients on corticosteroid therapy subjected to any unusual stress, increased dosage of rapidly acting corticosteroids before, during, and after the stressful situation is indicated.

    Drug-induced secondary adrenocortical insufficiency may result from too rapid withdrawal of corticosteroids and 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. If the patient is receiving steroids already, dosage may have to be increased. Since mineralocorticoid secretion may be impaired, salt and/or a mineralocorticoid should be administered concurrently.

    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. Moreover, corticosteroids may affect the nitroblue-tetrazolium test for bacterial infection and produce false negative results.

    In cerebral malaria, a double-blind trial has shown that the use of corticosteroids is associated with prolongation of coma and a higher incidence of pneumonia and gastrointestinal bleeding.

    Corticosteroids may activate latent amebiasis. Therefore, it is recommended that latent or active amebiasis be ruled out before initiating corticosteroid therapy in any patient who has spent time in the tropics or in any patient with unexplained diarrhea.

    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.

    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. Dietary salt restriction and potassium supplementation may be necessary. All corticosteroids increase calcium excretion.

    Administration of live virus vaccines, including smallpox, is contraindicated in individuals receiving immunosuppressive doses of corticosteroids. If inactivated viral or bacterial vaccines are administered to individuals receiving immunosuppressive doses of corticosteroids, the expected serum antibody response may not be obtained. However, immunization procedures may be undertaken in patients who are receiving corticosteroids as replacement therapy, e.g., for Addison’s disease.

    Patients who are on drugs which suppress the immune system are more susceptible to infections than healthy individuals. Chickenpox and measles, for example, can have a more serious or even fatal course in non-immune children or adults on corticosteroids. In such children or adults who have not had these diseases, particular care should be taken to avoid exposure. The risk of developing a disseminated infection varies among individuals and can be related to the dose, route and duration of corticosteroid administration as well as to the underlying disease. If exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If chickenpox develops, treatment with antiviral agents may be considered. If exposed to measles, prophylaxis with immune globulin (IG) may be indicated. (See the respective package inserts for VZIG and IG for complete prescribing information).

    The use of dexamethasone sodium phosphate injection 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 antituberculous 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.

    Literature reports suggest an apparent association between use of corticosteroids and left ventricular free wall rupture after a recent myocardial infarction; therefore, therapy with corticosteroids should be used with great caution in these patients.

    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 has not been established, and corticosteroids are not approved for this use.

    Usage in Pregnancy

    Since adequate human reproduction studies have not been done with corticosteroids, use of these drugs in pregnancy or in women of childbearing potential requires that the anticipated benefits be weighed against the possible 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.

    Corticosteroids appear in breast milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other unwanted effects. Mothers taking pharmacologic doses of corticosteroids should be advised not to nurse.

  • PRECAUTIONS

    This product, like many other steroid formulations, is sensitive to heat. Therefore, it should not be autoclaved when it is desirable to sterilize the exterior of the vial.

    Following prolonged therapy, withdrawal of corticosteroids may result in symptoms of the corticosteroid withdrawal syndrome including fever, myalgia, arthralgia, and malaise. This may occur in patients even without evidence of adrenal insufficiency.

    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 within caution 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. Signs of peritoneal irritation following gastrointestinal perforation in patients receiving large doses of corticosteroids may be minimal or absent. Fat embolism has been reported as a possible complication of hypercortisonism.

    When large doses are given, some authorities advise that antacids be administered between meals to help prevent peptic ulcer.

    Steroids may increase or decrease motility and number of spermatozoa in some patients.

    Phenytoin, phenobarbital, ephedrine, and rifampin may enhance the metabolic clearance of corticosteroids resulting in decreased blood levels and lessened physiologic activity, thus requiring adjustment in corticosteroid dosage. These interactions may interfere with dexamethasone suppression tests which should be interpreted with caution during administration of these drugs.

    False negative results in the dexamethasone suppression test (DST) in patients being treated with indomethacin have been reported. Thus, results of the DST should be interpreted with caution in these patients.

    The prothrombin time should be checked frequently in patients who are receiving corticosteroids and coumarin anticoagulants at the same time because of reports that corticosteroids have altered the response to these anticoagulants. Studies have shown that the usual effect produced by adding corticosteroids is inhibition of response to coumarins, although there have been some conflicting reports of potentiation not substantiated by studies.

    When corticosteroids are administered concomitantly with potassium-depleting diuretics, patients should be observed closely for development of hypokalemia.

    The slower rate of absorption by intramuscular administration should be recognized.

    Information for Patients

    Susceptible patients who are on immunosuppressant doses of corticosteroids should be warned to avoid exposure to chickenpox or measles. Patients should also be advised that if they are exposed, medical advice should be sought without delay.

    Pediatric Use

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

  • 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

    Tendon rupture

    Pathologic fracture of long bones

    Gastrointestinal:

    Peptic ulcer with possible subsequent perforation and hemorrhage

    Perforation of the small and large bowel; particularly in patients with inflammatory

    bowel disease

    Pancreatitis

    Abdominal distention

    Ulcerative esophagitis

    Dermatologic:

    Impaired wound healing

    Thin fragile skin

    Petechiae and ecchymoses

    Erythema

    Increased sweating

    May suppress reactions to skin tests

    Burning or tingling, especially in the perineal area (after IV injection)

    Other cutaneous reactions, such as allergic dermatitis, urticaria, angioneurotic edema

    Neurologic:

    Convulsions

    Increased intracranial pressure with papilledema (pseudotumor cerebri) usually after

    treatment

    Vertigo

    Headache

    Psychic disturbances

    Endocrine:

    Menstrual irregularities

    Development of cushingoid state

    Suppression of growth in pediatric patients

    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

    Hirsutism

    Ophthalmic:

    Posterior subcapsular cataracts

    Increased intraocular pressure

    Glaucoma

    Exophthalmos

    Retinopathy of prematurity

    Metabolic:

    Negative nitrogen balance due to protein catabolism

    Cardiovascular:

    Myocardial rupture following recent myocardial infarction (see WARNINGS)

    Hypertrophic cardiomyopathy in low birth weight infants

    Other:

    Anaphylactoid or hypersensitivity reactions

    Thromboembolism

    Weight gain

    Increased appetite

    Nausea

    Malaise

    Hiccups

    The following additional adverse reactions are related to parenteral corticosteroid therapy:

    Hyperpigmentation or hypopigmentation

    Subcutaneous and cutaneous atrophy

    Sterile abscess

    Charcot-like arthropathy

  • OVERDOSAGE

    Reports of acute toxicity and/or death following overdosage of glucocorticoids are rare. In the event of overdosage, no specific antidote is available; treatment is supportive and symptomatic.

    The oral LD 50 of dexamethasone in female mice was 6.5 g/kg. The intravenous LD 50 of dexamethasone sodium phosphate in female mice was 794 mg/kg.

  • DOSAGE AND ADMINISTRATION

    Dexamethasone sodium phosphate injection, 10 mg/mL– For intravenous and intramuscular injection only.

    Dexamethasone sodium phosphate injection can be given directly from the vial, or it can be added to Sodium Chloride Injection or Dextrose Injection and administered by intravenous drip.

    Solutions used for intravenous administration or further dilution of this product should be preservative free when used in the neonate, especially the premature infant.

    When it is mixed with an infusion solution, sterile precautions should be observed. Since infusion solutions generally do not contain preservatives, mixtures should be used within 24 hours.

    DOSAGE REQUIREMENTS ARE VARIABLE AND MUST BE INDIVIDUALIZED ON THE BASIS OF THE DISEASE AND THE RESPONSE OF THE PATIENT.

    Intravenous and Intramuscular Injection

    The initial dosage of dexamethasone sodium phosphate injection varies from 0.5 to 9 mg a day depending on the disease being treated. In less severe diseases doses lower than 0.5 mg may suffice, while in severe diseases doses higher than 9 mg may be required.

    The initial dosage should be maintained or adjusted until the patient’s response is satisfactory. If a satisfactory clinical response does not occur after a reasonable period of time, discontinue dexamethasone sodium phosphate injection and transfer the patient to other therapy.

    After a favorable initial response, the proper maintenance dosage should be determined by decreasing the initial dosage in small amounts to the lowest dosage that maintains an adequate clinical response.

    Patients should be observed closely for signs that might require dosage adjustment, including changes in clinical status resulting from remissions or exacerbations of the disease, individual drug responsiveness, and the effect of stress (e.g., surgery, infection, trauma). During stress it may be necessary to increase dosage temporarily.

    If the drug is to be stopped after more than a few days of treatment, it usually should be withdrawn gradually.

    When the intravenous route of administration is used, dosage usually should be the same as the oral dosage. In certain overwhelming, acute, life-threatening situations, however, administration in dosages exceeding the usual dosages may be justified and may be in multiples of the oral dosages. The slower rate of absorption by intramuscular administration should be recognized.

    Shock

    There is a tendency in current medical practice to use high (pharmacologic) doses of corticosteroids for the treatment of unresponsive shock. The following dosages of dexamethasone sodium phosphate injection have been suggested by various authors:

    Author

    Dosage

    Cavanagh 1

    3 mg/kg of body weight per 24 hours by constant intravenous infusion after an initial intravenous injection of 20 mg


    Dietzman 2

    2 to 6 mg/kg of body weight as a single intravenous injection


    Frank 3

    40 mg initially followed by repeat intravenous injection every 4 to 6 hours while shock persists


    Oaks 4

    40 mg initially followed by repeat intravenous injection every 2 to 6 hours while shock persists


    Schumer 5

    1 mg/kg of body weight as a single intravenous injection

    Administration of high dose corticosteroid therapy should be continued only until the patient’s condition has stabilized and usually not longer than 48 to 72 hours.

    Although adverse reactions associated with high dose, short-term corticosteroid therapy are uncommon, peptic ulceration may occur.

    Cerebral Edema

    Dexamethasone sodium phosphate injection is generally administered initially in a dosage of 10 mg intravenously followed by four mg every six hours intramuscularly until the symptoms of cerebral edema subside. Response is usually noted within 12 to 24 hours and dosage may be reduced after two to four days and gradually discontinued over a period of five to seven days. For palliative management of patients with recurrent or inoperable brain tumors, maintenance therapy with 2 mg two or three times a day may be effective.

    Acute Allergic Disorders

    In acute, self-limited allergic disorders or acute exacerbations of chronic allergic disorders, the following dosage schedule combining parenteral and oral therapy is suggested:

    Dexamethasone sodium phosphate injection, first day, 4 or 8 mg intramuscularly.

    Dexamethasone tablets, 0.75 mg: second and third days, 4 tablets in two divided doses each day; fourth day, 2 tablets in two divided doses; fifth and sixth days, 1 tablet each day; seventh day, no treatment; eighth day, follow-up visit.

    This schedule is designed to ensure adequate therapy during acute episodes, while minimizing the risk of overdosage in chronic cases.

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

  • HOW SUPPLIED

    Dexamethasone Sodium Phosphate Injection, USP (Preservative Free) equivalent to 10 mg dexamethasone phosphate, is supplied in a single dose vial as follows:

    Product

    No.

    NDC

    No.

    Strength

    Vial Size

    500601

    63323-506-01

    10 mg per mL

    1 mL vial, packaged in twenty-fives.

    This container closure is not made with natural rubber latex.

    Storage

    Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Sensitive to heat. Do not autoclave.

    Protect from freezing.

    Protect from light.

    Single dose vials–Store in container until time of use. Discard unused portion.

    Multiple dose vials–Store in container until contents are used.

  • REFERENCES

    1. Cavanagh, D.; Singh, K.B.: Endotoxin shock in pregnancy and abortion, in: “Corticosteroids in the Treatment of Shock”, Schumer, W.; Nyhus, L.M., Editors, Urbana, University of Illinois Press, 1970, pp. 86-96.
    2. Dietzman, R.H.; Ersek, R.A.; Bloch, J.M.; Lilleheir, R.C.: High-output, low-resistance gram-negative septic shock in man, Angiology 20: 691-700, Dec. 1969.
    3. Frank, E.: Clinical observations in shock and management (in: Shields, T.F., ed.: Symposium on current concepts and management of shock), J. Maine Med. Ass. 59: 195-200, Oct. 1968.
    4. Oaks, W. W.; Cohen, H.E.: Endotoxin shock in the geriatric patient, Geriat. 22: 120-130, Mar. 1967.
    5. Schumer, W.; Nyhus, L.M.: Corticosteroid effect on biochemical parameters of human oligemic shock, Arch. Surg. 100: 405-408, Apr. 1970.
  • SPL UNCLASSIFIED SECTION

    image description

    45955E

    Revised: May 2014

  • SPL UNCLASSIFIED SECTION

    Bupivacaine Hydrochloride Injection, USP

    Rx only

  • 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:

    image description

    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. The pH of the solution is adjusted to between 4 and 6.5 with sodium hydroxide or hydrochloric acid.

  • CLINICAL PHARMACOLOGY

    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 CNS 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.

  • INDICATIONS AND USAGE


    Bupivacaine hydrochloride injection, USP is indicated for the production of local or regional anesthesia or analgesia for surgery, oral surgery procedures, 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.

  • 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.

  • 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.

    Methemoglobinemia

    Cases of methemoglobinemia have been reported in association with local anesthetic use. Although all patients are at risk for methemoglobinemia, patients with glucose-6-phosphate dehydrogenase deficiency, congenital or idiopathic methemoglobinemia, cardiac or pulmonary compromise, infants under 6 months of age, and concurrent exposure to oxidizing agents or their metabolites are more susceptible to developing clinical manifestations of the condition. If local anesthetics must be used in these patients, close monitoring for symptoms and signs of methemoglobinemia is recommended.

    Signs of methemoglobinemia may occur immediately or may be delayed some hours after exposure, and are characterized by a cyanotic skin discoloration and/or abnormal coloration of the blood. Methemoglobin levels may continue to rise; therefore, immediate treatment is required to avert more serious CNS and cardiovascular adverse effects, including seizures, coma, arrhythmias, and death. Discontinue bupivacaine hydrochloride and any other oxidizing agents. Depending on the severity of the signs and symptoms, patients may respond to supportive care, i.e., oxygen therapy, hydration. A more severe clinical presentation may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.

    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.

  • PRECAUTIONS

    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 intravenous 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 CNS 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.

    Inform patients that use of local anesthetics may cause methemoglobinemia, a serious condition that must be treated promptly. Advise patients or caregivers to seek immediate medical attention if they or someone in their care experience the following signs or symptoms: pale, gray, or blue colored skin (cyanosis); headache; rapid heart rate; shortness of breath; lightheadedness; or fatigue.

    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.

    Patients who are administered local anesthetics are at increased risk of developing methemoglobinemia when concurrently exposed to following drugs, which could include other local anesthetics:

    Examples of Drugs Associated with Methemoglobinemia:

    Class

    Examples

    Nitrates/Nitrites

    nitric oxide, nitroglycerin, nitroprusside, nitrous oxide

    Local anesthetics

    articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, tetracaine

    Antineoplastic agents

    cyclophosphamide, flutamide, hydroxyurea, isofamide, rasburicase

    Antibiotics

    dapsone, nitrofurantoin, para-aminosalicylic acid, sulfonamides

    Antimalarials

    chloroquine, primaquine

    Anticonvulsants

    phenobarbital, phenytoin, sodium valproate

    Other drugs

    acetaminophen, metoclopramide, quinine, sulfasalazine

    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

    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, 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 OBSTETRICAL 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 CNS, 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 Anesthesia and 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).

  • ADVERSE REACTIONS

    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 CNS 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.

    CNS 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 CNS effects may be nausea, vomiting, chills, and constriction of the pupils.

    The incidence of convulsions associated with the use of local anesthetics varies with the procedure used and the total dose administered. 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. 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.

  • OVERDOSAGE

    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).

    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.

    Management of Local Anesthetic Emergencies

    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 intravenous injection of succinylcholine will paralyze the patient without depressing the CNS or cardiovascular system and facilitate ventilation. A bolus intravenous dose of 5 mg to 10 mg of diazepam or 50 mg to 100 mg of thiopental will permit ventilation and counteract CNS stimulation, but these drugs also depress CNS, 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 LD 50 in mice is 6 mg/kg to 8 mg/kg and 38 mg/kg to 54 mg/kg respectively.

  • DOSAGE & ADMINISTRATION

    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.

    Test Dose for Caudal and Lumbar Epidural Blocks


    See PRECAUTIONS.

    Unused portions of solution should be discarded following initial use.

    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 DoseMotor
    Block 1
    (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% 4up to
    max.
    up to
    max.
    ––
    Epidural0.75% 2,410 to 2075 to 150complete
    0.5% 410 to 2050 to 100moderate to complete
    0.25% 410 to 2025 to 50partial to moderate
    Caudal0.5% 415 to 3075 to 150moderate to complete
    0.25% 4 15 to 3037.5 to 75moderate
    Peripheral
    nerves
    0.5% 45 to max.25 to max.moderate to complete
    0.25% 45 to max.12.5 to max.moderate to complete
    Retrobulbar 30.75% 42 to 415 to 30complete
    Sympathetic0.25%20 to 5050 to 125
    Epidural 3
    Test Dose
    0.5%
    w/epi
    2 to 3 10 to 15
    (10 to 15 micrograms
    epinephrine)
    ––

  • 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 0.25% (2.5 mg/mL)

    10 mL Single Dose Vials in a Carton of 25 NDC 55150-167-10

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

    Discard unused portion.

    This container closure is not made with natural rubber latex.

    Sterile, Nonpyrogenic

    Distributed by:
    AuroMedics Pharma LLC

    279 Princeton-Hightstown Rd.
    E. Windsor, NJ 08520

    Manufactured by:
    Aurobindo Pharma Limited
    Hyderabad - 500038
    India

    Revised: March 2019

  • Povidone-Iodine Swabsticks

  • ACTIVE INGREDIENT

    Active Ingredient                                                  Purpose

    Povidone Iodine 10% w/v (9.85% w/w)                Antiseptic

  • Purpose:


    Purpose:

    • First aid antiseptic to help prevent skin infection in minor cuts, scrapes and burns.
    • For preparation of the skin prior to surgery.
    • Helps reduce bacteria that can potentially cause skin infections.
  • Warnings:

    • FOR EXTERNAL USE ONLY
  • Do not use:


    • As a first aid antiseptic for more than 1 week.
    • In the eyes.
    • Over large areas of the body.
  • Ask a doctor before use if you have:


    • Deep puncture wounds
    • Animal bites
    • Serious burns
  • Stop Use:


    • If irritation and redness develop
    • If condition persists for more than 72 hours, consult a physician.
  • Keep Out Of Reach Of Children

    Keep out of reach of children.If swallowed, get medical help or contact a Poison Control Center.


  • Directions Povidone iodine:

    Tear at notch, remove applicator, use only once.

    As a first aid antiseptic

    • clean affected area
    • apply 1 to 3 times daily
    • may be covered with a sterile bandage, if bandaged let dry.

    For preoperative patient skin preparation

    • clean area
    • apply to operative site prior to surgery using the applicator


  • Other information:

    Store at room temperature.

    Avoid excessive heat

  • INDICATIONS & USAGE

    For use as an

    • first aid antiseptic
    • pre-operative skin preperation
  • Inactive Ingredients

    Inactive ingredients: Citric acid, glycerin, polysorbate 80, sodium citrate USP, sodium phosphate dibasic, water

  • Isopropyl Alcohol 70% Prep Pads

  • Active ingredient

    Isopropyl Alcohol 70% v/v

  • Purpose

    Antiseptic

  • Uses

    For first aid to decrease germs in

    • minor cuts
    • scrapes
    • burns

    For preparation of the skin prior to injection

  • Warnings

    For external use only

    Flammable - keep away from fire or flame

    Do not use

    with electrocautery procedures

    When using this product do not

    • get into eyes
    • apply over large areas of the body
    • in case of deep or puncture wounds, animal bites or serious burns consult a doctor

    Stop use and ask a doctor if

    • condition persists or gets worse or lasts for more than 72 hours
    • do not use longer than 1 week unless directed by a doctor

    Keep out of reach of children.

    If swallowed, get medical help or contact a Poison Control Center right away.

  • Directions

    • apply to skin as needed
    • discard after single use
  • Other information

    Protect from freezing and avoid excessive heat

  • Inactive ingredient

    Water

  • PRINCIPAL DISPLAY PANEL

    PRINCIPAL DISPLAY PANEL

    NDC: 76420-810-01

    Rx Only

    Mardex-25™

    Kit Contains

    1 Bupivacaine HCl 0.25% Single Dose Vial (10mL)

    1 Dexamethasone Sodium Phosphate Inj., USP 10mg/mL (1mL)

    1 Povidone-Iodine Swabsticks (3 Swabs)

    3 Isopropyl Alcohol 70% Prep Pads

    1 Pair Nitrile Powder Free Sterile Gloves (M)

    1 Drape

    1 Adhesive Bandage

    5 Non Sterile 4x4 Gauze

    Needles and Syringes Not Included

    1 Dose

    Single Use Only

    Distributed by:

    Enovachem™

    PHARMACEUTICALS

    Torrance, CA 90501

    Principal Display Panel
  • INGREDIENTS AND APPEARANCE
    MARDEX 25 KIT 
    dexamethasone sodium phosphate, bupivacaine hydrochloride, povidine iodine kit
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC:76420-810
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC:76420-810-011 in 1 CARTON; Type 1: Convenience Kit of Co-Package08/21/2014
    Quantity of Parts
    Part #Package QuantityTotal Product Quantity
    Part 11 VIAL 1 mL
    Part 21 VIAL, SINGLE-DOSE 10 mL
    Part 31 PACKET 0.9 mL
    Part 43 POUCH 15 mL
    Part 1 of 4
    DEXAMETHASONE SODIUM PHOSPHATE 
    dexamethasone sodium phosphate injection, solution
    Product Information
    Item Code (Source)NDC:63323-506
    Route of AdministrationINTRAMUSCULAR, INTRAVENOUS
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    DEXAMETHASONE SODIUM PHOSPHATE (UNII: AI9376Y64P) (DEXAMETHASONE - UNII:7S5I7G3JQL) DEXAMETHASONE PHOSPHATE10 mg  in 1 mL
    Inactive Ingredients
    Ingredient NameStrength
    SODIUM CITRATE (UNII: 1Q73Q2JULR)  
    CITRIC ACID MONOHYDRATE (UNII: 2968PHW8QP)  
    SODIUM HYDROXIDE (UNII: 55X04QC32I)  
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC:63323-506-0125 in 1 TRAY
    11 mL in 1 VIAL; Type 0: Not a Combination Product
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    ANDAANDA04049105/29/2003
    Part 2 of 4
    BUPIVACAINE HYDROCHLORIDE 
    bupivacaine hydrochloride injection, solution
    Product Information
    Item Code (Source)NDC:55150-167
    Route of AdministrationEPIDURAL, INFILTRATION
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    BUPIVACAINE HYDROCHLORIDE (UNII: 7TQO7W3VT8) (BUPIVACAINE - UNII:Y8335394RO) BUPIVACAINE HYDROCHLORIDE ANHYDROUS2.5 mg  in 1 mL
    Inactive Ingredients
    Ingredient NameStrength
    SODIUM CHLORIDE (UNII: 451W47IQ8X)  
    SODIUM HYDROXIDE (UNII: 55X04QC32I)  
    HYDROCHLORIC ACID (UNII: QTT17582CB)  
    WATER (UNII: 059QF0KO0R)  
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC:55150-167-1025 in 1 CARTON
    110 mL in 1 VIAL, SINGLE-DOSE; Type 0: Not a Combination Product
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    ANDAANDA20389511/05/2013
    Part 3 of 4
    POVIDINE IODINE 
    povidine iodine swab
    Product Information
    Item Code (Source)NDC:67777-419
    Route of AdministrationTOPICAL
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    POVIDONE-IODINE (UNII: 85H0HZU99M) (IODINE - UNII:9679TC07X4) IODINE10 mg  in 1 mL
    Inactive Ingredients
    Ingredient NameStrength
    GLYCERIN (UNII: PDC6A3C0OX)  
    POLYSORBATE 80 (UNII: 6OZP39ZG8H)  
    SODIUM CITRATE (UNII: 1Q73Q2JULR)  
    SODIUM PHOSPHATE, DIBASIC, ANHYDROUS (UNII: 22ADO53M6F)  
    CITRIC ACID ACETATE (UNII: DSO12WL7AU)  
    WATER (UNII: 059QF0KO0R)  
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC:67777-419-020.9 mL in 1 PACKET; Type 0: Not a Combination Product
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    OTC monograph finalpart333C09/13/2016
    Part 4 of 4
    ISOPROPYL ALCOHOL 
    isopropyl alcohol swab
    Product Information
    Route of AdministrationTOPICAL
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    ISOPROPYL ALCOHOL (UNII: ND2M416302) (ISOPROPYL ALCOHOL - UNII:ND2M416302) ISOPROPYL ALCOHOL70 mL  in 100 mL
    Inactive Ingredients
    Ingredient NameStrength
    WATER (UNII: 059QF0KO0R)  
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    15 mL in 1 POUCH; Type 0: Not a Combination Product
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    OTC monograph not finalpart333A01/01/2007
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    unapproved drug other08/21/2014
    Labeler - Asclemed USA, Inc. (059888437)