Rx only

Dexamethasone sodium phosphate is a water-soluble inorganic ester of dexamethasone. It occurs as a white or slightly yellow crystalline powder, is odorless or has a slight odor of alcohol, is exceedingly hygroscopic and is freely soluble in water.

Dexamethasone sodium phosphate is an adrenocortical steroid anti-inflammatory drug.

Chemically, dexamethasone sodium phosphate is 9-Fluoro-11ß,17,21-trihydroxy-16α-methylpregna-1, 4-diene-3,20-dione 21-(dihydrogen phosphate) disodium salt and has the following structural formula:

Dexamethasone Sodium Phosphate Injection, USP is a sterile solution of dexamethasone sodium phosphate in water for injection for intravenous (IV), intramuscular (IM), intra-articular, soft-tissue or intralesional use.

Each mL contains dexamethasone sodium phosphate equivalent to dexamethasone phosphate 4 mg or dexamethasone 3.33 mg; benzyl alcohol 10 mg added as preservative; sodium citrate dihydrate 11 mg; sodium sulfite 1 mg as an antioxidant; Water for Injection q.s. Citric acid and/or sodium hydroxide may have been added for pH adjustment (7.0 to 8.5). Air in the container is displaced by nitrogen.

Dexamethasone sodium phosphate 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.

Intravenous or Intramuscular Injection

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:

• 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

• 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

• Collagen Diseases

   During an exacerbation or as maintenance therapy in selected cases of:

   Systemic lupus erythematosus

   Acute rheumatic carditis

• Dermatologic Diseases

   Pemphigus

   Severe erythema multiforme (Stevens-Johnson syndrome)

   Exfoliative dermatitis

   Bullous dermatitis herpetiformis

   Severe seborrheic dermatitis

   Severe psoriasis

   Mycosis fungoides

• 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)

• 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

• Gastrointestinal Diseases

   To tide the patient over a critical period of the disease in:

   Ulcerative colitis (Systemic therapy)

   Regional enteritis (Systemic therapy)

• 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

• 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

• Neoplastic Diseases

   For palliative management of:

   Leukemias and lymphomas in adults

   Acute leukemia of childhood

• 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

• Miscellaneous

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

   Trichinosis with neurologic or myocardial involvement

• Diagnostic testing of adrenocortical hyperfunction

• 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.

Systemic fungal infections (see WARNINGS regarding amphotericin B). Hypersensitivity to any component of this product, including sulfites (see 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 (see ADVERSE REACTIONS).

Dexamethasone sodium phosphate injection contains sodium bisulfite, 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 non-asthmatic people.

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 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.

Persons 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. How the dose, route and duration of corticosteroid administration affects the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. (See the respective package inserts for complete VZIG and IG prescribing information). If chickenpox develops, treatment with antiviral agents may be considered.

The use of dexamethasone sodium phosphate 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.

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 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. 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 to prevent peptic ulcer.

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

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.

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 is suggestive of septic arthritis. If this complication occurs and the diagnosis of sepsis is confirmed, appropriate antimicrobial therapy should be instituted.

Injection of a steroid into an infected site is to be avoided.

Corticosteroids should not be injected into unstable joints.

Patients should be impressed strongly with the importance of not overusing joints in which symptomatic benefit has been obtained as long as the inflammatory process remains active.

Frequent intra-articular injection may result in damage to joint tissues.

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

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

   Pathologic fracture of long bones

   Vertebral compression fractures

   Aseptic necrosis of femoral and humeral heads

   Tendon rupture

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 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

   Hirsutism

Ophthalmic:

   Posterior subcapsular cataracts

   Increased intraocular pressure

   Glaucoma

   Exophthalmos

Metabolic:

   Negative nitrogen balance due to protein catabolism

   Cardiovascular:

   Myocardial rupture following recent myocardial infarction (see WARNINGS)

Other:

   Anaphylactoid or hypersensitivity reactions

   Thromboembolism

   Weight gain

   Increased appetite

   Nausea

   Malaise

   Hiccups

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

   Rare instances of blindness associated with intralesional therapy around the face and head

   Hyperpigmentation or hypopigmentation

   Subcutaneous and cutaneous atrophy

   Sterile abscess

   Post-injection flare (following intra-articular use)

   Charcot-like arthropathy

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 LD50 of dexamethasone in female mice was 6.5 g/kg. The intravenous LD50 of dexamethasone sodium phosphate in female mice was 794 mg/kg.

Dexamethasone sodium phosphate injection, 4 mg per mL– For intravenous, intramuscular, intra-articular, intralesional, and soft tissue injection.

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.

STORE AT:20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Protect from freezing. Sensitive to heat. Do not autoclave.

Protect from light. Store container in carton until contents have been used.

Do not use if precipitate is present.

www.fresenius-kabi.us

45799H

Revised: March 2017

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.; Lillehei, 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.

MarcaineTM

Bupivacaine Hydrochloride Injection, USP 

Rx only

Bupivacaine hydrochloride is 2-Piperidinecarboxamide, 1-butyl-N-(2,6-dimethylphenyl)-, monohydrochloride, monohydrate, a white 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:

MARCAINE is available in sterile isotonic solutions with and without epinephrine (as bitartrate) 1:200,000 for injection via local infiltration, peripheral nerve block, and caudal and lumbar epidural blocks. Solutions of MARCAINE may be autoclaved if they do not contain epinephrine. Solutions are 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.

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

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.

The onset of action with MARCAINE is rapid and anesthesia is long lasting. The duration of anesthesia is significantly longer with MARCAINE 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.

The onset of action following dental injections is usually 2 to 10 minutes and anesthesia may last two or three times longer than lidocaine and mepivacaine for dental use, in many patients up to 7 hours.

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. MARCAINE 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 MARCAINE 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 MARCAINE 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, factors affecting urinary pH, renal blood flow, the route of drug administration, and the age of the patient. The half-life of MARCAINE 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 MARCAINE 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 MARCAINE.

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, MARCAINE does not ordinarily produce irritation or tissue damage and does not cause methemoglobinemia.

MARCAINE is indicated for the production of local or regional anesthesia or analgesia for surgery, dental and 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 MARCAINE in these patients.

MARCAINE is not recommended for intravenous regional anesthesia (Bier Block). See WARNINGS.

The routes of administration and indicated MARCAINE 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%

(See DOSAGE AND ADMINISTRATION for additional information).

Standard textbooks should be consulted to determine the accepted procedures and techniques for the administration of MARCAINE.

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

MARCAINE 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 MARCAINE solutions.

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 MARCAINE in this age group is not recommended.

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

Single-dose ampuls and single-dose vials of MARCAINE without epinephrine do not contain sodium metabisulfite.

Reactions to MARCAINE 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 MARCAINE. 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.

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 intravenous injection of succinylcholine will paralyze the patient without depressing the central nervous or cardiovascular systems 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 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.

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.

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 MARCAINE 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. MARCAINE is not approved for this use (see WARNINGS and DOSAGE AND ADMINISTRATION).

In recommended doses, MARCAINE 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 MARCAINE 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 MARCAINE up to 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 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, MARCAINE is not recommended for pediatric patients younger than 12 years. MARCAINE is contraindicated for obstetrical paracervical blocks, and is not recommended for intravenous regional anesthesia (Bier Block).

Use in Epidural Anesthesia: During epidural administration of MARCAINE, 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.Use only the single-dose ampuls and single-dose vials for caudal or epidural anesthesia.

Unused portions of solution not containing preservatives, i.e., those supplied in single-dose ampuls and single-dose vials, 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.

1 With 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.

These solutions are not for spinal anesthesia.

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

MARCAINE―Solutions of MARCAINE that do not contain epinephrine may be autoclaved. Autoclave at 15-pound pressure, 121°C (250°F) for 15 minutes.

Hospira, Inc., Lake Forest, IL 60045 USA

LAB-1178-1.0

Revised: 11/2017

Drug Facts

Isopropyl Alcohol 70% v/v

First Aid Antiseptic

For preparation of the skin prior to an injection

• For external use only
• Flammable, keep away from fire or flame

• Do not use with electrocautery procedures
• Do not use in the eyes
• Do not apply to irritated skin

• Open packet
• Remove pad
• Apply topically as needed to cleanse intended area. Discard after single use.

• Store at room temperature 59-86°F (15-30°C)
• Contents sterile in unopened, undamaged package

purified water

Contents:

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

1-10 mL Marcaine 0.5%

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

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

1-3x3 Gauze Sponge Sterile Square

1- Bandage 1 x 3in

4- Alcohol Prep Pads