HUPPOMEDROL

Methylprednisolone is a prednisolone derivative glucocorticoid with higher potency than prednisone.

It was first described in the literature in the late 1950s. 9, 10 Methylprednisolone was granted FDA approval on 24 October 1957.

In the outbreak of

COVID-19, low dose methylprednisolone-based therapy was successful in treating COVID-19-associated pneumonia in one patient with long-term immunosuppression.

The efficacy of methylprednisolone in novel coronavirus pneumonia is being investigated further in clinical trials.

Oral and intramuscular methylprednisolone are indicated for a number of endocrine, rheumatic, collagen, dermatologic, allergic, ophthalmic, respiratory, hematologic, neoplastic, edematous, gastrointestinal, nervous system, and other disorders. 12, 13 Intra-articular and soft tissue injections are indicated for short term treatment of acute gouty arthritis, acute and subactute bursitis, acute nonspecific tenosynovitis, epicondylitis, rheumatoid arthritis, and synovitis of osteoarthritis.

Intralesional injections are indicated for alopecia areata, discoid lupus erythematosus, keloids, lichen planus, lichen simplex chronicus and psoriatic plaques, necrobiosis lipoidica diabeticorum, and localized hypertrophic infiltrated inflammatory lesions of granuloma annulare.

Corticosteroids bind to the glucocorticoid receptor, inhibiting pro-inflammatory signals, and promoting anti-inflammatory signals.

Corticosteroids have a wide therapeutic window as patients may require doses that are multiples of what the body naturally produces.

Patients taking corticosteroids should be counselled regarding the risk of hypothalamic-pituitary-adrenal axis suppression and increased susceptibility to infections.

Oral methylprednisolone has 89.9% the bioavailability of oral methylprednisolone acetate, while rectal methylprednisolone has 14.2% the bioavailability.

Intravitreal methylprednisolone has a

T max of 2.5h.

Approximately 1/10 of an oral or Intravenous dose of methylprednisolone will reach the vitreous humor.

Further data regarding the absorption of methylprednisolone are not readily available. 12, 13.

The average volume of distribution of methylprednisolone is 1.38 L/kg.

The metabolism of methylprednisolone is thought to be mostly mediated by 11beta-hydroxysteroid dehydrogenases and 20-ketosteroid reductases.

Hover over products below to view reaction partners Methylprednisolone Methylprednisolone M13 Metabolite Methylprednisolone M15 Metabolite Methylprednisolone M14 Metabolite Methylprednisolone M7 Metabolite Methylprednisolone M10 Metabolite + Methylprednisolone M9 Metabolite Methylprednisolone M4 Metabolite Methylprednisolone M5 Metabolite + Methylprednisolone M6 Metabolite Methylprednisolone M2 Metabolite + Methylprednisolone M3 Metabolite Methylprednisolone M1 Metabolite Methylprednisolone M11 Metabolite + Methylprednisolone M12 Metabolite Methylprednisolone M8 Metabolite.

Methylprednisolone and its metabolites have been collected in urine in humans.

A study in dogs showed 25-31% elimination in urine and 44-52% elimination in feces.

Methylprednisolone has a half life of 2.3h. 1, 6.

The average plasma clearance of methylprednisolone is 336 mL/h/kg.

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The oral

LD in rats is >4 g/kg.

The intraperitoneal

LD in mice is 2292 mg/kg and in rats is 100 mg/kg.

Data regarding acute overdoses of glucocorticoids are rare. 12, 13 Chronic high doses of glucocorticoids can lead to the development of cataract, glaucoma, hypertension, water retention, hyperlipidemia, peptic ulcer, pancreatitis, myopathy, osteoporosis, mood changes, psychosis, dermal atrophy, allergy, acne, hypertrichosis, immune suppression, decreased resistance to infection, moon face, hyperglycemia, hypocalcemia, hypophosphatemia, metabolic acidosis, growth suppression, and secondary adrenal insufficiency.

Treat acute overdoses with symptomatic and supportive therapy, while chronic overdoses will require temporarily reduced dosages. 8, 13.

Serious Neurologic Adverse Reactions with Epidural Administration Serious neurologic events, some resulting in death, have been reported with epidural injection of corticosteroids.

Specific events reported include, but are not limited to, spinal cord infarction, paraplegia, quadriplegia, cortical blindness, and stroke.

These serious neurologic events have been reported with and without use of fluoroscopy.

The safety and effectiveness of epidural administration of corticosteroids have not been established, and corticosteroids are not approved for this use.

This product is not suitable for multi-dose use.

Following administration of the desired dose, any remaining suspension should be discarded.

Injection of methylprednisolone acetate may result in dermal and/or subdermal changes forming depressions in the skin at the injection site.

In order to minimize the incidence of dermal and subdermal atrophy, care must be exercised not to exceed recommended doses in injections.

Multiple small injections into the area of the lesion should be made whenever possible.

The technique of intra-articular and intramuscular injection should include precautions against injection or leakage into the dermis.

Injection into the deltoid muscle should be avoided because of a high incidence of subcutaneous atrophy.

It is critical that, during administration of methylprednisolone acetate injectable suspension, appropriate technique be used and care taken to ensure proper placement of drug.

Rare instances of anaphylactoid reactions have occurred in patients receiving corticosteroid therapy See ADVERSE REACTIONS.

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

Results from one multicenter, randomized, placebo-controlled study with methylprednisolone hemisuccinate, an IV corticosteroid, showed an increase in early (at 2 weeks) and late (at 6 months) mortality in patients with cranial trauma who were determined not to have other clear indications for corticosteroid treatment.

High doses of systemic corticosteroids, including methylprednisolone acetate, should not be used for the treatment of traumatic brain injury.

Average and large doses of corticosteroids can cause elevation of blood pressure, salt and water retention, and increased excretion of potassium.

These effects are less likely to occur with synthetic derivatives when used in large doses.

Dietary salt restriction and potassium supplementation may be necessary.

All corticosteroids increase calcium excretion.

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.

Hypothalamic-pituitary adrenal (HPA) axis suppression.

Cushing’s syndrome, and Hyperglycemia: Monitor patients for these conditions with chronic use.

Corticosteroids can produce reversible

HPA axis suppression with the potential for glucocorticosteroid insufficiency after withdrawal of treatment.

Drug induced secondary adrenocortical insufficiency may be minimized by gradual reduction of dosage.

This type of relative insufficiency may persist for months after discontinuation of therapy; therefore, in any situation of stress occurring during that period, hormone therapy should be reinstituted.

Infections General Persons who are on corticosteroids are more susceptible to infections than are healthy individuals.

There may be decreased resistance and inability to localize infection when corticosteroids are used.

Infections with any pathogen (viral, bacterial, fungal, protozoan, or helminthic) in any location of the body, may be associated with the use of corticosteroids alone or in combination with other immunosuppressive agents.

These infections may be mild, but can be severe and at times fatal.

With increasing doses of corticosteroids, the rate of occurrence of infectious complications increases.

Do not use intra-articularly, intrabursally, or for intratendinous administration for local effect in the presence of an acute infection.

Corticosteroids may mask some signs of infection and new infections may appear during their use.

Infections 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 interactions.

There have been cases reported in which concomitant use of amphotericin B and hydrocortisone was followed by cardiac enlargement and congestive heart failure See CONTRAINDICATIONS and PRECAUTIONS: Drug Interactions, Amphotericin B injection and potassium-depleting agents.

Latent disease may be activated or there may be an exacerbation of intercurrent infections due to pathogens, including those caused by Amoeba, Candida, Cryptococcus, Mycobacterium, Nocardia, Pneumocystis, and Toxoplasma.

It is recommended that latent amebiasis 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.

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.

Corticosteroids should not be used in cerebral malaria.

There is currently no evidence of benefit from steroids in this condition.

The use of corticosteroids 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.

Administration of live or live, attenuated vaccines is contraindicated in patients receiving immunosuppressive doses of corticosteroids.

Killed or inactivated vaccines may be administered.

However, the response to such vaccines cannot be predicted.

Immunization procedures may be undertaken in patients who are receiving corticosteroids as replacement therapy (e.g., for Addison’s disease).

Infections Chicken pox and measles can have a more serious or even fatal course in pediatric and adult patients on corticosteroids.

In pediatric and adult patients who have not had these diseases, particular care should be taken to avoid exposure.

The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known.

If exposed to chicken pox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated.

If exposed to measles, prophylaxis with immunoglobulin (IG) may be indicated.

If chicken pox develops, treatment with antiviral agents should be considered.

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 bacteria, fungi, or viruses.

The use of systemic corticosteroids is not recommended in the treatment of optic neuritis and may lead to an increase in the risk of new episodes.

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

Corticosteroids should not be used in active ocular herpes simplex.

Injection/Bupivacaine Hydrochloride and Epinephrine Injection is contraindicated in: obstetrical paracervical block anesthesia.

Its use in this technique has resulted in fetal bradycardia and death. intravenous regional anesthesia (Bier Block) . patients with a known hypersensitivity to bupivacaine or to any local anesthetic agent of the amide-type or to other components of Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection.

Obstetrical paracervical block anesthesia.

Its use in this technique has resulted in fetal bradycardia and death.

Intravenous regional anesthesia (Bier Block).

Known hypersensitivity to bupivacaine or to any local anesthetic agent of the amide-type or to other components of Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection.

Not for intrathecal use.

Avoid use of solutions containing antimicrobial preservatives (i.e., multiple-dose vials) for epidural or caudal anesthesia.

Three mL of Bupivacaine Hydrochloride and Epinephrine Injection without antimicrobial preservative (0.5% bupivacaine with 1:200,000 epinephrine) is recommended for use as a test dose prior to caudal and lumbar epidural blocks when clinical conditions permit.

See full prescribing information for

Recommended concentrations and dosages of Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection according to type of block.

Additional dosage and administration information pertaining to use in epidural anesthesia, test dose for caudal and lumbar epidural blocks, use in dentistry, and use in ophthalmic surgery. 2.1 Important Dosage and Administration Information Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection is not for intrathecal use.

Avoid use of Bupivacaine Hydrochloride

Injection/Bupivacaine Hydrochloride and Epinephrine Injection solutions containing antimicrobial preservatives (i.e., multiple-dose vials) for epidural or caudal anesthesia.

Discard unused portions of solution not containing preservatives, i.e., those supplied in single-dose vials, following initial use.

Visually inspect this product for particulate matter and discoloration prior to administration whenever solution and container permit.

Injection/Bupivacaine Hydrochloride and Epinephrine Injection are clear, colorless solutions.

Do not administer solutions which are discolored or contain particulate matter.

Mixing or the prior or intercurrent use of any other local anesthetic with Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection is not recommended because of insufficient data on the clinical use of such mixtures.

Administration Precautions Bupivacaine Hydrochloride Injection

Injection/Bupivacaine Hydrochloride and Epinephrine Injection are to be administered in carefully adjusted dosages by or under the supervision of experienced clinicians who are well versed in the diagnosis and management of dose-related toxicity and other acute emergencies which might arise from the block to be employed.

Injection/Bupivacaine Hydrochloride and Epinephrine Injection only if the following are immediately available: oxygen, cardiopulmonary resuscitative equipment and drugs, and the personnel resources needed for proper management of toxic reactions and related emergencies.

The toxic effects of local anesthetics are additive.

Monitor for neurologic and cardiovascular effects related to local anesthetic systemic toxicity when additional local anesthetics are administered with Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection.

Aspirate for blood or cerebrospinal fluid (where applicable) prior to injecting Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection, both the initial dose and all subsequent doses, to avoid intravascular or intrathecal injection.

However, a negative aspiration for blood or cerebrospinal fluid does not ensure against an intravascular or intrathecal injection.

Avoid rapid injection of a large volume of Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection and use fractional (incremental) doses when feasible.

During major regional nerve blocks, such as those of the brachial plexus or lower extremity, the patient should have an indwelling intravenous catheter to assure adequate intravenous access.

The lowest dosage of Bupivacaine Hydrochloride

Injection/Bupivacaine Hydrochloride and Epinephrine Injection that results in effective anesthesia should be used to avoid high plasma levels and serious adverse reactions.

Perform careful and constant monitoring of cardiovascular and respiratory (adequacy of oxygenation and ventilation) vital signs and the patient's level of consciousness after each local anesthetic injection.

Injection 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. 2.2 Recommended Concentrations and Dosages of Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection The dosage of Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection 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.

Administer the smallest dosage and concentration required to produce the desired result.

The types of block and recommended Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection concentrations are shown in Table 1.

Table 1.

Types of Block and Recommended Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection Concentrations Type of Block Bupivacaine Hydrochloride Bupivacaine Hydrochloride and Epinephrine 0.25% (2.5 mg/mL) 0.5% (5 mg/mL) 0.75% (7.5 mg/mL) Bupivacaine Hydrochloride Injection 0.75% (7.5 mg/mL) is not recommended for nonobstetrical surgical procedures in pregnant patients. 0.25% (2.5 mg/mL) 0.5% (5 mg/mL) ✓= indicated use.

Local infiltration ✓ ✓ Peripheral nerve block ✓ ✓ ✓ ✓ Retrobulbar block ✓ Sympathetic block ✓ Caudal block Avoid use of multiple-dose vials of Bupivacaine Hydrochloride Injection and Bupivacaine Hydrochloride and Epinephrine Injection for caudal or epidural anesthesia. ✓ ✓ ✓ ✓ Lumbar epidural block ✓ ✓ ✓ (not for obstetrical anesthesia) ✓ ✓ Epidural test dose ✓ Dental block ✓ At recommended dosages, Bupivacaine Hydrochloride/Bupivacaine Hydrochloride and Epinephrine produces complete sensory block, but the effect on motor function differs among the three concentrations.

Table 2 provides information on the expected effect on motor function for the three concentrations.

Table 2.

Injection/Bupivacaine Hydrochloride and Epinephrine Injection Concentration vs. Motor Function Bupivacaine Hydrochloride Injection Concentration Motor Function 0.25% (2.5 mg/mL) These products include Bupivacaine Hydrochloride Injection and Bupivacaine Hydrochloride and Epinephrine Injection [the epinephrine concentration (1:200,000) is not included in the table.

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% (5 mg/mL) or 0.75% (7.5 mg/mL) solutions. 0.5% (5 mg/mL) 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% (7.5 mg/mL) These are only Bupivacaine Hydrochloride Injection products [there is no 0.75% (7.5 mg/mL) concentration for Bupivacaine Hydrochloride and Epinephrine Injection.

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/Bupivacaine Hydrochloride and Epinephrine Injection is such that for most indications, a single-dose is sufficient.

The maximum dosage limit within the recommended dosage range must be individualized in each case after evaluating the size and physical status of the patient, as well as the anticipated rate of systemic absorption from a particular injection site.

The dosages in

Table are recommended as a guide for use in the average adult.

These doses may be repeated once every three hours.

Do not exceed a total daily dosage of 400 mg in 24 hours.

The duration of anesthetic effect may be prolonged by the addition of epinephrine.

Table 3.

Recommended Concentrations and Doses of Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection in Adults Type of Block Concentration of Bupivacaine Hydrochloride Injection Each Dose Motor Block With continuous (intermittent) techniques, repeat doses increase the degree of motor block.

The first repeat dose of 0.5% (5 mg/mL) may produce complete motor block.

Intercostal nerve block with 0.25% (2.5 mg/mL) also may produce complete motor block for intra-thoracic and upper intra-abdominal surgery. mL mg of Bupivacaine Hydrochloride Injection Local infiltration 0.25% (2.5 mg/mL) Solutions with or without epinephrine (i.e., applies to Bupivacaine Hydrochloride Injection and Bupivacaine Hydrochloride and Epinephrine Injection).

Injection products include epinephrine (1:200,000).

Up to 70 (without epinephrine) Up to 175 (without epinephrine) ― Up to 90 (with epinephrine) Up to 225 (with epinephrine) Peripheral nerve block 0.5% (5 mg/mL) 5–35 (without epinephrine) 25–175 (without epinephrine) moderate to complete 5–45 (with epinephrine) 25–225 (with epinephrine) 0.25% (2.5 mg/mL) 5–70 (without epinephrine) 12.5–175 (without epinephrine) moderate to complete 5–90 (with epinephrine) 12.5–225 (with epinephrine) Retrobulbar block 0.75% (7.5 mg/mL) 2–4 15–30 complete Sympathetic block 0.25% (2.5 mg/mL) 20–50 50–125 ― Caudal block 0.5% (5 mg/mL) 15–30 75–150 moderate to complete 0.25% (2.5 mg/mL) 15–30 37.5–75 moderate Lumbar epidural block 0.75% (7.5 mg/mL) For single-dose use; not for intermittent epidural technique.

Not for obstetrical anesthesia. 10–20 75–150 complete 0.5% (5 mg/mL) 10–20 50–100 moderate to complete 0.25% (2.5 mg/mL) 10–20 25–50 partial to moderate Epidural test dose 0.5% (5 mg/mL) with epinephrine 2–3 10–15 (10–15 micrograms epinephrine) ― Dental 0.5% (5 mg/mL) with epinephrine 1.8–3.6 per site 9–18 per site ― 2.3 Use in Epidural Anesthesia During the administration of epidural anesthesia, it is recommended that a test dose of Bupivacaine Hydrochloride and Epinephrine Injection without antimicrobial preservative (0.5% bupivacaine with 1:200,000 epinephrine) 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 initial and all supplemental doses, because a catheter in the epidural space can migrate into a blood vessel or through the dura.

During epidural administration, administer Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection, 0.5% (5 mg/mL) and Bupivacaine Hydrochloride Injection 0.75% (7.5 mg/mL) solutions in incremental doses of 3 mL to 5 mL with sufficient time between doses to detect toxic manifestations of unintentional intravascular or intrathecal injection.

Administer injections slowly, with frequent aspirations before and during the injection to avoid intravascular injection.

Perform syringe aspirations before and during each supplemental injection in continu.

Store at 20 °C to 25 °C (68 °F to 77 °F); excursions permitted between 15 °C to 30 °C (59 °F to 86 °F).

Injection, USP ─ Solutions of bupivacaine hydrochloride that do not contain epinephrine may be autoclaved.

Autoclave at 15-pound pressure, 121 °C (250 °F) for 15 minutes.

This product is clear and colorless.

Do not use the solution if it is discolored or if it contains a precipitate.

NDC 0409-1159-01 Tray of 25 single-dose teartop vials 0.25% 25 mg/10 mL (2.5 mg/mL) NDC 0409-1159-02 Tray of 25 single-dose teartop vials 0.25% 75 mg/30 mL (2.5 mg/mL) NDC 0409-1160-01 Tray of 25 multiple-dose fliptop vials 0.25% 125 mg/50 mL (2.5 mg/mL) NDC 0409-1163-01 Tray of 25 multiple-dose fliptop vials 0.5% 250 mg/50 mL (5 mg/mL) NDC 0409-1162-01 Tray of 25 single-dose teartop vials 0.5% 50 mg/10 mL (5 mg/mL) NDC 0409-1162-02 Tray of 25 single-dose teartop vials 0.5% 150 mg/30 mL (5 mg/mL) NDC 0409-1165-01 Tray of 25 single-dose teartop vials 0.75% 75 mg/10 mL (7.5 mg/mL) NDC 0409-1165-02 Tray of 25 single-dose teartop vials 0.75% 225 mg/30 mL (7.5 mg/mL) For single-dose vials: Discard unused portion.

Store at 20 °C to 25 °C (68 °F to 77 °F); excursions permitted between 15 °C to 30 °C (59 °F to 86 °F).

Injection/Bupivacaine Hydrochloride and Epinephrine Injection is contraindicated for obstetrical paracervical block anesthesia.

Its use in this technique has resulted in fetal bradycardia and death.

There are no available data on use of Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection in pregnant women to inform a drug-associated risk of adverse developmental outcomes.

In animal studies, embryo-fetal lethality was noted when bupivacaine was administered subcutaneously to pregnant rabbits during organogenesis at clinically relevant doses.

Decreased pup survival was observed in a rat pre.

• and post-natal developmental study (dosing from implantation through weaning) at a dose level comparable to the daily maximum recommended human dose (MRHD) on a body surface area (BSA) basis.

Based on animal data, advise pregnant women of the potential risks to a fetus.

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.

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.

If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, inform the patient of the potential hazard to the fetus.

The estimated background risk of major birth defects and miscarriage for the indicated populations are unknown.

In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.

Clinical Considerations Maternal Adverse Reactions

Maternal hypotension has resulted from regional anesthesia.

Local anesthetics produce vasodilation by blocking sympathetic nerves.

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.

Elevating the patient's legs will also 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.

Bupivacaine hydrochloride produced developmental toxicity when administered subcutaneously to pregnant rats and rabbits at clinically relevant doses.

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 MRHD of 400 mg/day on a mg/m 2 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 0.3 times the MRHD on a BSA basis.

In a rat pre-and post-natal developmental 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.

Systemically administered corticosteroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects.

Because of the potential for serious adverse reactions in nursing infants from corticosteroids, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Injection/Bupivacaine Hydrochloride and Epinephrine Injection is approved for use in adults.

Injection/Bupivacaine Hydrochloride and Epinephrine Injection in pediatric patients younger than 12 years is not recommended.

Continuous infusions of bupivacaine in pediatric patients have been reported to result in high systemic levels of bupivacaine and seizures; high plasma levels may also be associated with cardiovascular abnormalities.

Patients 65 years and over, particularly those with hypertension, may be at increased risk for developing hypotension while undergoing anesthesia with Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection.

In clinical studies of bupivacaine, elderly patients reached the maximal spread of analgesia and maximal motor blockade more rapidly than younger adult patients.

Differences in various pharmacokinetic parameters have been observed between elderly and younger adult patients.

This product is known to be substantially excreted by the kidney, and the risk of adverse 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.

Elderly patients may require lower doses of Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection.