adrenocortical insufficiency exists or is suspected. congenital adrenal hyperplasia. nonsuppurative thyroiditis. hypercalcemia associated with cancer. 2. rheumatic disorders. as adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in: post-traumatic osteoarthritis. synovitis of osteoarthritis. rheumatoid arthritis, including juvenile rheumatoid arthritis (selected cases may require low-dose maintenance therapy). acute and subacute bursitis. epicondylitis. acute nonspecific tenosynovitis. acute gouty arthritis. psoriatic arthritis. ankylosing spondylitis. 3. collagen diseases. during an exacerbation or as maintenance therapy in selected cases of: systemic lupus erythematosus. acute rheumatic carditis. 4. dermatologic diseases. pemphigus. severe erythema multiforme (stevens-johnson syndrome). exfoliative dermatitis. bullous dermatitis herpetiformis. severe seborrheic dermatitis. severe psoriasis. mycosis fungoides. 5. allergic states. control of severe or incapacitating allergic conditions intractable to adequate trials of conventional treatment in: bronchial asthma. contact dermatitis. atopic dermatitis. serum sickness. seasonal or perennial allergic rhinitis. drug hypersensitivity reactions. urticarial transfusion reactions. acute noninfectious laryngeal edema (epinephrine is the drug of first choice). 6. ophthalmic diseases. severe acute and chronic allergic and inflammatory processes involving the eye, such as: herpes zoster ophthalmicus. iritis, iridocyclitis. chorioretinitis. diffuse posterior uveitis and choroiditis. optic neuritis. sympathetic ophthalmia. anterior segment inflammation. allergic conjunctivitis. allergic corneal marginal ulcers. keratitis. 7. gastrointestinal diseases. to tide the patient over a critical period of the disease in: ulcerative colitis (systemic therapy). regional enteritis (systemic therapy). 8. respiratory diseases: symptomatic sarcoidosis. berylliosis. fulminating or disseminated pulmonary tuberculosis when used concurrently with appropriate anti-tuberculosis chemotherapy. loeffler's syndrome not manageable by other means. aspiration pneumonitis. 9. hematologic disorders: acquired (autoimmune) hemolytic anemia. idiopathic thrombocytopenic purpura in adults (i.v. only; i.m. administration is contraindicated). secondary thrombocytopenia in adults. erythroblastopenia (rbc anemia). congenital (erythroid) hypoplastic anemia. 10. neoplastic diseases. for palliative management of: leukemias and lymphomas in adults. acute leukemia of childhood. 11. edematous states. to induce diuresis or remission of proteinuria in the nephrotic syndrome, without uremia, of the idiopathic type or that due to lupus erythematosus. 12. nervous system. acute exacerbations of multiple sclerosis. 13. miscellaneous. tuberculous meningitis with subarachnoid block or impending block when used concurrently with appropriate anti-tuberculosis chemotherapy. trichinosis with neurologic or myocardial involvement. diagnostic testing of adrenocortical hyperfunction. cerebral edema of diverse etiologies in conjunction with adequate neurological evaluation and management. b. intra-articular or soft tissue administration. when the strength and dosage form of the drug lend the preparation to the treatment of the condition, those products labeled for intra-articular or soft tissue administration are indicated as adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in: synovitis of osteoarthritis. rheumatoid arthritis. acute and subacute bursitis. acute gouty arthritis. epicondylitis. acute nonspecific tenosynovitis. post-traumatic osteoarthritis. c. intralesional administration. when the strength and dosage form of the drug lend the preparation to the treatment of the condition, those products labeled for intralesional administration are indicated for: keloids. localized hypertrophic, infiltrated, inflammatory lesions of: lichen planus, psoriatic plaques, granuloma annulare, and lichen simplex chronicus (neurodermatitis). discoid lupus erythematosus. necrobiosis lipoidica diabeticorum. alopecia areata. they also may be useful in cystic tumors of an aponeurosis tendon (ganglia).

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.

sterior subcapsular cataracts, glaucoma with possible damage to the optic nerves, and may enhance the establishment of secondary ocular infections due to fungi or viruses. children who are on immunosuppressant drugs are more susceptible to infections than healthy children. chickenpox and measles, for example, can have a more serious or even fatal course in children on immunosuppressant corticosteroids. in such children, or in adults who have not had these diseases, particular care should be taken to avoid exposure. if exposed, therapy with varicella zoster immune globulin (vzig) or pooled intravenous immunoglobulin (ivig), as appropriate, may be indicated. if chickenpox develops, treatment with antiviral agents may be considered. similarly, corticosteroids should be used with great care in patients with known or suspected strongyloides (threadworm) infestation. in such patients, corticosteroid-induced immunosuppression may lead to strongyloides hyperinfection and dissemination with widespread larval migration, often accompanied by severe enterocolitis and potentially fatal gram-negative septicemia. usage in pregnancy. since adequate human reproduction studies have not been done with corticosteroids, use of these drugs in pregnancy, nursing mothers or women of childbearing potential requires that the possible benefits of the drug be weighed against the potential hazards to the mother and embryo or fetus. infants born of mothers who have received substantial doses of corticosteroids during pregnancy should be carefully observed for signs of hypoadrenalism. average and large doses of cortisone or hydrocortisone can cause elevation of blood pressure, salt and water retention, and increased excretion of potassium. these effects are less likely to occur with the synthetic derivatives except when used in large doses. patients with a stressed myocardium should be observed carefully and the drug administered slowly since premature ventricular contractions may occur with rapid administration. dietary salt restriction and potassium supplementation may be necessary. all corticosteroids increase calcium excretion. while on corticosteroid therapy patients should not be vaccinated against smallpox. other immunization procedures should not be undertaken in patients who are on corticosteroids, especially in high doses, because of possible hazards of neurological complications and lack of antibody response. the use of dexamethasone sodium phosphate injection usp in active tuberculosis should be restricted to those cases of fulminating or disseminated tuberculosis in which the corticosteroid is used for the management of the disease in conjunction with an appropriate anti-tuberculosis regimen. if corticosteroids are indicated in patients with latent tuberculosis or tuberculin reactivity, close observation is necessary as reactivation of the disease may occur. during prolonged corticosteroid therapy, these patients should receive chemoprophylaxis. because rare instances of anaphylactoid reactions have occurred in patients receiving parenteral corticosteroid therapy, appropriate precautionary measures should be taken prior to administration, especially when the patient has a history of allergy to any drug. dexamethasone sodium phosphate injection contains sodium sulfite, a sulfite that may cause allergic type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. the overall prevalence of sulfite sensitivity in the general population is unknown and probably low. sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people.

ity of oxygen, other resuscitative drugs, cardiopulmonary resuscitative equipment, and the personnel resources needed for proper management of toxic reactions and related emergencies. (see also adverse reactions , precautions , and overdosage . ) delay in proper management of dose­-related toxicity, underventilation from any cause, and/or altered sensitivity may lead to the development of acidosis, cardiac arrest and, possibly, death. local anesthetic solutions containing antimicrobial preservatives, i.e., those supplied in multiple-dose vials, should not be used for epidural or caudal anesthesia because safety has not been established with regard to intrathecal injection, either intentionally or unintentionally, of such preservatives. intra-articular infusions of local anesthetics following arthroscopic and other surgical procedures is an unapproved use, and there have been post-marketing reports of chondrolysis in patients receiving such infusions. the majority of reported cases of chondrolysis have involved the shoulder joint; cases of gleno-humeral chondrolysis have been described in pediatric and adult patients following intra-articular infusions of local anesthetics with and without epinephrine for periods of 48 to 72 hours. there is insufficient information to determine whether shorter infusion periods are not associated with these findings. the time of onset of symptoms, such as joint pain, stiffness and loss of motion can be variable, but may begin as early as the 2nd month after surgery. currently, there is no effective treatment for chondrolysis; patients who experienced chondrolysis have required additional diagnostic and therapeutic procedures and some required arthroplasty or shoulder replacement. it is essential that aspiration for blood or cerebrospinal fluid (where applicable) be done prior to injecting any local anesthetic, both the original dose and all subsequent doses, to avoid intravascular or subarachnoid injection. however, a negative aspiration does not ensure against an intravascular or subarachnoid injection. until further experience is gained in pediatric patients younger than 12 years, administration of bupivacaine hydrochloride in this age group is not recommended. mixing or the prior or intercurrent use of any other local anesthetic with bupivacaine hydrochloride cannot be recommended because of insufficient data on the clinical use of such mixtures. there have been reports of cardiac arrest and death during the use of bupivacaine hydrochloride for intravenous regional anesthesia (bier block). information on safe dosages and techniques of administration of bupivacaine hydrochloride in this procedure is lacking. therefore, bupivacaine hydrochloride is not recommended for use in this technique.

initial intravenous dose of 10 mg is recommended followed by 4 mg intramuscularly every six hours until maximum response has been noted. this regimen may be continued for several days postoperatively in patients requiring brain surgery. oral dexamethasone, 1 to 3 mg t.i.d., should be given as soon as possible and dosage tapered off over a period of five to seven days. nonoperative cases may require continuous therapy to remain free of symptoms of increased intracranial pressure. the smallest effective dose should be used in children, preferably orally. this may approximate 0.2 mg/kg/24 hours in divided doses. in treatment of acute exacerbations of multiple sclerosis daily doses of 200 mg of prednisolone for a week followed by 80 mg every other day or 4 to 8 mg dexamethasone every other day for 1 month have been shown to be effective. the initial dosage should be maintained or adjusted until a satisfactory response is noted. if after a reasonable period of time there is a lack of satisfactory clinical response, dexamethasone sodium phosphate injection usp should be discontinued and the patient transferred to other appropriate therapy. it should be emphasized that dosage requirements are variable and must be individualized on the basis of the disease under treatment and the response of the patient. after a favorable response is noted, the proper maintenance dosage should be determined by decreasing the initial drug dosage in small decrements at appropriate time intervals until the lowest dosage which will maintain an adequate clinical response is reached. it should be kept in mind that constant monitoring is needed in regard to drug dosage. included in the situations which may make dosage adjustments necessary are changes in clinical status secondary to remissions or exacerbations in the disease process, the patient’s individual drug responsiveness and the effect of patient exposure to stressful situations not directly related to the disease entity under treatment. in this later situation it may be necessary to increase the dosage of dexamethasone sodium phosphate injection usp for a period of time consistent with the patient’s condition. if after a long-term therapy the drug is to be stopped, it is recommended that it be withdrawn gradually rather than abruptly. b. intra-articular, soft tissue or intralesional administration. the dose for instrasynovial administration is usually 2 to 4 mg for large joints and 0.8 to 1 mg for small joints. for soft tissue and bursal injections a dose of 2 to 4 mg is recommended. ganglia require a dose of 1 to 2 mg. a dose of 0.4 to 1 mg is used for injection into tendon sheaths. injection into intervertebral joints should not be attempted at any time and hip joint injection cannot be recommended as an office procedure. intrasynovial and soft tissue injections should be employed only when affected areas are limited to 1 or 2 sites. it should be remembered that corticoids provide palliation only and that other conventional or curative methods of therapy should be employed when indicated. parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. frequency of injection usually ranges from once every 3 to 5 days to once every 2 to 3 weeks. frequent intra-articular injection may cause damage to joint tissue.

ing intra-articular infusions of local anesthetics following arthroscopic and other surgical procedures. bupivacaine hydrochloride injection is not approved for this use (see warnings and dosage and administration ). in recommended doses, bupivacaine hydrochloride produces complete sensory block, but the effect on motor function differs among the three concentrations. 0.25% — when used for caudal, epidural, or peripheral nerve block, produces incomplete motor block. should be used for operations in which muscle relaxation is not important, or when another means of providing muscle relaxation is used concurrently. onset of action may be slower than with the 0.5% or 0.75% solutions. 0.5% — provides motor blockade for caudal, epidural, or nerve block, but muscle relaxation may be inadequate for operations in which complete muscle relaxation is essential. 0.75% — produces complete motor block. most useful for epidural block in abdominal operations requiring complete muscle relaxation, and for retrobulbar anesthesia. not for obstetrical anesthesia. the duration of anesthesia with bupivacaine hydrochloride injection is such that for most indications, a single dose is sufficient. maximum dosage limit must be individualized in each case after evaluating the size and physical status of the patient, as well as the usual rate of systemic absorption from a particular injection site. most experience to date is with single doses of bupivacaine hydrochloride injection up to 225 mg with epinephrine 1:200,000 and 175 mg without epinephrine; more or less drug may be used depending on individualization of each case. these doses may be repeated up to once every three hours. in clinical studies to date, total daily doses have been up to 400 mg. until further experience is gained, this dose should not be exceeded in 24 hours. the duration of anesthetic effect may be prolonged by the addition of epinephrine. the dosages in table 1 have generally proved satisfactory and are recommended as a guide for use in the average adult. these dosages should be reduced for elderly or debilitated patients. until further experience is gained, bupivacaine hydrochloride injection is not recommended for pediatric patients younger than 12 years. bupivacaine hydrochloride injection is contraindicated for obstetrical paracervical blocks, and is not recommended for intravenous regional anesthesia (bier block). use in epidural anesthesia during epidural administration of bupivacaine hydrochloride injection, 0.5% and 0.75% solutions should be administered in incremental doses of 3 ml to 5 ml with sufficient time between doses to detect toxic manifestations of unintentional intravascular or intrathecal injection. in obstetrics, only the 0.5% and 0.25% concentrations should be used; incremental doses of 3 ml to 5 ml of the 0.5% solution not exceeding 50 mg to 100 mg at any dosing interval are recommended. repeat doses should be preceded by a test dose containing epinephrine if not contraindicated. use only the single-dose ampuls and single-dose vials for caudal or epidural anesthesia; the multiple-dose vials contain a preservative and therefore should not be used for these procedures. test dose for caudal and lumbar epidural blocks see precautions this product should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. solutions which are discolored or which contain particulate matter should not be administered. table 1. recommended concentrations and doses of bupivacaine hydrochloride injection type of block conc. each dose motor block 1 (ml) (mg) 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. local infiltration 0.25% 4 up to max. up to max. –– epidural 0.75% 2,4 10 to 20 75 to 150 complete 0.5% 4 10 to 20 50 to 100 moderate to complete 0.25% 4 10 to 20 25 to 50 partial to moderate caudal 0.5% 4 15 to 30 75 to 150 moderate to complete 0.25% 4 15 to 30 37.5 to 75 moderate peripheral nerves 0.5% 4 5 to max. 25 to max. moderate to complete 0.25% 4 5 to max. 12.5 to max. moderate to complete retrobulbar 3 0.75% 4 2 to 4 15 to 30 complete sympathetic 0.25% 20 to 50 50 to 125 — epidural 3 test dose 0.5% w/epi 2 to 3 10 to 15 (10 to 15 micrograms epinephrine) ––

econdary adrenocortical and pituitary unresponsiveness, particularly in times of stress, as in trauma, surgery, or illness decreased carbohydrate tolerance manifestations of latent diabetes mellitus increased requirements for insulin or oral hypoglycemic agents in diabetics metabolic: negative nitrogen balance due to protein catabolism miscellaneous: hyperpigmentation or hypopigmentation subcutaneous and cutaneous atrophy sterile abscess postinjection flare, following intra-articular use charcot-like arthropathy itching, burning, tingling in the ano-genital region

result in underventilation or apnea (“total or high spinal”). also, hypotension due to loss of sympathetic tone and respiratory paralysis or underventilation due to cephalad extension of the motor level of anesthesia may occur. this may lead to secondary cardiac arrest if untreated. patients over 65 years, particularly those with hypertension, may be at increased risk for experiencing the hypotensive effects of bupivacaine hydrochloride. factors influencing plasma protein binding, such as acidosis, systemic diseases which alter protein production, or competition of other drugs for protein binding sites, may diminish individual tolerance. central nervous system reactions these are characterized by excitation and/or depression. restlessness, anxiety, dizziness, tinnitus, blurred vision, or tremors may occur, possibly proceeding to convulsions. however, excitement may be transient or absent, with depression being the first manifestation of an adverse reaction. this may quickly be followed by drowsiness merging into unconsciousness and respiratory arrest. other central nervous system effects may be nausea, vomiting, chills, and constriction of the pupils. the incidence of convulsions associated with the use of local anesthetics varies with the procedure used and the total dose administered. in a survey of studies of epidural anesthesia, overt toxicity progressing to convulsions occurred in approximately 0.1% of local anesthetic administrations. cardiovascular system reactions high doses or unintentional intravascular injection may lead to high plasma levels and related depression of the myocardium, decreased cardiac output, heartblock, hypotension, bradycardia, ventricular arrhythmias, including ventricular tachycardia and ventricular fibrillation, and cardiac arrest. (see warnings , precautions , and overdosage . ) allergic allergic-type reactions are rare and may occur as a result of sensitivity to the local anesthetic or to other formulation ingredients, such as the antimicrobial preservative methylparaben contained in multiple-dose vials. these reactions are characterized by signs such as urticaria, pruritus, erythema, angioneurotic edema (including laryngeal edema), tachycardia, sneezing, nausea, vomiting, dizziness, syncope, excessive sweating, elevated temperature, and possibly, anaphylactoid-like symptomatology (including severe hypotension). cross sensitivity among members of the amide-type local anesthetic group has been reported. the usefulness of screening for sensitivity has not been definitely established. neurologic the incidences of adverse neurologic reactions associated with the use of local anesthetics may be related to the total dose of local anesthetic administered and are also dependent upon the particular drug used, the route of administration, and the physical status of the patient. many of these effects may be related to local anesthetic techniques, with or without a contribution from the drug. in the practice of caudal or lumbar epidural block, occasional unintentional penetration of the subarachnoid space by the catheter or needle may occur. subsequent adverse effects may depend partially on the amount of drug administered intrathecally and the physiological and physical effects of a dural puncture. a high spinal is characterized by paralysis of the legs, loss of consciousness, respiratory paralysis, and bradycardia. neurologic effects following epidural or caudal anesthesia may include spinal block of varying magnitude (including high or total spinal block); hypotension secondary to spinal block; urinary retention; fecal and urinary incontinence; loss of perineal sensation and sexual function; persistent anesthesia, paresthesia, weakness, paralysis of the lower extremities and loss of sphincter control all of which may have slow, incomplete, or no recovery; headache; backache; septic meningitis; meningismus; slowing of labor; increased incidence of forceps delivery; and cranial nerve palsies due to traction on nerves from loss of cerebrospinal fluid. neurologic effects following other procedures or routes of administration may include persistent anesthesia, paresthesia, weakness, paralysis, all of which may have slow, incomplete, or no recovery.

yo-fetal deaths was observed in rabbits at the high dose in the absence of maternal toxicity with the fetal no observed adverse effect level representing approximately 1/5th the mrhd on a bsa basis. in a rat pre- and post-natal development study (dosing from implantation through weaning) conducted at subcutaneous doses of 4.4, 13.3, & 40 mg/kg mg/kg/day, decreased pup survival was observed at the high dose. the high dose is comparable to the daily mrhd of 400 mg/day on a bsa basis.

icular arrhythmias, and cardiac arrest, sometimes resulting in fatalities. in addition, myocardial contractility is depressed and peripheral vasodilation occurs, leading to decreased cardiac output and arterial blood pressure. recent clinical reports and animal research suggest that these cardiovascular changes are more likely to occur after unintended intravascular injection of bupivacaine. therefore, incremental dosing is necessary. following systemic absorption, local anesthetics can produce central nervous system stimulation, depression, or both. apparent central stimulation is manifested as restlessness, tremors and shivering progressing to convulsions, followed by depression and coma progressing ultimately to respiratory arrest. however, the local anesthetics have a primary depressant effect on the medulla and on higher centers. the depressed stage may occur without a prior excited state. pharmacokinetics the rate of systemic absorption of local anesthetics is dependent upon the total dose and concentration of drug administered, the route of administration, the vascularity of the administration site, and the presence or absence of epinephrine in the anesthetic solution. a dilute concentration of epinephrine (1:200,000 or 5 mcg/ml) usually reduces the rate of absorption and peak plasma concentration of bupivacaine, permitting the use of moderately larger total doses and sometimes prolonging the duration of action. the onset of action with bupivacaine is rapid and anesthesia is long lasting. the duration of anesthesia is significantly longer with bupivacaine than with any other commonly used local anesthetic. it has also been noted that there is a period of analgesia that persists after the return of sensation, during which time the need for strong analgesics is reduced. local anesthetics are bound to plasma proteins in varying degrees. generally, the lower the plasma concentration of drug the higher the percentage of drug bound to plasma proteins. local anesthetics appear to cross the placenta by passive diffusion. the rate and degree of diffusion is governed by (1) the degree of plasma protein binding, (2) the degree of ionization, and (3) the degree of lipid solubility. fetal/maternal ratios of local anesthetics appear to be inversely related to the degree of plasma protein binding, because only the free, unbound drug is available for placental transfer. bupivacaine with a high protein binding capacity (95%) has a low fetal/maternal ratio (0.2 to 0.4). the extent of placental transfer is also determined by the degree of ionization and lipid solubility of the drug. lipid soluble, nonionized drugs readily enter the fetal blood from the maternal circulation. depending upon the route of administration, local anesthetics are distributed to some extent to all body tissues, with high concentrations found in highly perfused organs such as the liver, lungs, heart, and brain. pharmacokinetic studies on the plasma profile of bupivacaine after direct intravenous injection suggest a three-compartment open model. the first compartment is represented by the rapid intravascular distribution of the drug. the second compartment represents the equilibration of the drug throughout the highly perfused organs such as the brain, myocardium, lungs, kidneys, and liver. the third compartment represents an equilibration of the drug with poorly perfused tissues, such as muscle and fat. the elimination of drug from tissue distribution depends largely upon the ability of binding sites in the circulation to carry it to the liver where it is metabolized. after injection of bupivacaine hydrochloride for caudal, epidural, or peripheral nerve block in man, peak levels of bupivacaine in the blood are reached in 30 to 45 minutes, followed by a decline to insignificant levels during the next three to six hours. various pharmacokinetic parameters of the local anesthetics can be significantly altered by the presence of hepatic or renal disease, addition of epinephrine, factors affecting urinary ph, renal blood flow, the route of drug administration, and the age of the patient. the half-life of bupivacaine in adults is 2.7 hours and in neonates 8.1 hours. in clinical studies, elderly patients reached the maximal spread of analgesia and maximal motor blockade more rapidly than younger patients. elderly patients also exhibited higher peak plasma concentrations following administration of this product. the total plasma clearance was decreased in these patients. amide-type local anesthetics such as bupivacaine are metabolized primarily in the liver via conjugation with glucuronic acid. patients with hepatic disease, especially those with severe hepatic disease, may be more susceptible to the potential toxicities of the amide-type local anesthetics. pipecoloxylidine is the major metabolite of bupivacaine. the kidney is the main excretory organ for most local anesthetics and their metabolites. urinary excretion is affected by urinary perfusion and factors affecting urinary ph. only 6% of bupivacaine is excreted unchanged in the urine. when administered in recommended doses and concentrations, bupivacaine hydrochloride does not ordinarily produce irritation or tissue damage and does not cause methemoglobinemia.