bupivacaine (Rx)

>10%

Posimir

• Visible bruising (91.1%)
• Postprocedural contusion (14-71.2%)
• Nausea (20-55.8%)
• Surgical site bleeding (8.7-48.9%)
• Dizziness (15-40.3%)
• Somnolence (8.3-40%)
• Constipation (30.4%)
• Vomiting (4.4-29%)
• Bradycardia (22.9%)
• Headache (11.1-27.2%)
• Pruritus generalized (2.2-21.6%)
• Paresthesia (7.5-18.4%)
• Dysgeusia (13-17.6%)
• Hypoesthesia (17.3%)
• Anemia (4.5-16.7%)
• Tinnitus (13.2%)
• C-reactive protein increased (11.7%)
• Pyrexia (6-11.7%)
• Procedural pain (<11.4%)
• Dysuria (10.1%)

1-10%

Posimir

• Diarrhea (9.8%)
• Abdominal distension (8.2%)
• Incision site erythema (4.1-8.1%)
• Postprocedural discharge (7.5%)
• Insomnia (3.9-7.1%)
• Blood potassium decreased (6.7%)
• Hypertension (6.7%)
• Hypokalemia (5.9%)
• Headache (5.7%)
• Contusion (5.7%)
• Dyspepsia (3.8-5.7%)
• Incision site hematoma (5-5.2%)
• Oropharyngeal pain (3.5-4.6%)
• Tachycardia (4.6%)
• Flatulence (4.6%)
• Hypertension (2.8-4.6%)
• Incision site infection (4.5%)
• Drainage from surgical incision (4.4%)
• Abdominal pain (4.4%)
• Musculoskeletal pain (4.2%)
• Viral infection (4.1%)
• Back pain (4.1%)
• Electrocardiogram (ECG) T wave inversion (3.8%)
• Hypoesthesia (3.8%)
• Dyspnea (3.8%)
• Muscle twitching (3.8%)
• Wound dehiscence (3.6%)
• Cough (3.6%)
• Peripheral swelling (3.9%)
• ECG change (3.3%)
• Procedural hemorrhage (3.3%)
• Vaginal hematoma (3.3%)
• Dry throat (3.2%)
• Testicular swelling (3.2%)
• Hyperhidrosis (3%)
• Local swelling (3%)
• Upper respiratory tract infection (3%)
• Chest pain (2.9%)
• Ileus (2.7%)
• Urinary retention (2.7-2.8%)
• Dysmenorrhea (2.7%)
• Incision site pruritus (2.7%)
• Abdominal pain upper (2.5%)
• Nasal congestion (2.5%)
• Pruritus generalized (2.5%)
• Contusion (2.5%)
• Body temperature increased (2.4%)
• Dry mouth (2.2%)
• Rash (2.1%)
• Pain in extremity (2.1%)
• Nasopharyngitis (2.1%)
• Angina pectoris (<2%)
• Blepharospasm (<2%)
• ECG T-wave amplitude decreased (<2%)
• Fatigue (<2%)
• Osteoarthritis (<2%)
• Procedural nausea (<2%)
• Pulmonary arterial hypertension (<2%)

Frequency Not Defined

Respiratory: Respiratory paralysis, underventilation

Cardiovascular: Myocardium depression, decreased cardiac output, bradycardia, heart block, ventricular arrhythmias, possible cardiac arrest

Neurologic: Excitement and/or depression, restlessness, anxiety, dizziness, tinnitus, blurred vision, tremors, convulsions, loss of perineal sensation and sexual function, persistent anesthesia, paresthesia, weakness and paralysis of the lower extremities, loss of sphincter control, high or total spinal block, urinary retention, septic meningitis, meningismus, arachnoiditis, shivering, cranial nerve palsies, fecal and urinary incontinence

Labor and delivery: Slowing of labor, increased incidence of forceps delivery. Allergic:

Immune system disorders: Urticaria, pruritus, erythema, angioneurotic edema (including laryngeal edema), tachycardia, sneezing, nausea, vomiting, dizziness, syncope, excessive sweating, elevated temperature, anaphylactoid-like symptomatology (including severe hypotension)

Other: Nausea, vomiting

Contraindications

Hypersensitivity to any amide local anesthetics, or other product components

Marcaine

• Undergoing obstetrical paracervical block anesthesia
• IV regional anesthesia (Bier Block)

Bupivacaine spinal

• Severe hemorrhage, severe hypotension or shock and arrhythmias (eg, complete heart block)
• Local infection at the site of proposed lumbar puncture
• Septicemia
• Intravenous regional anesthesia (Bier Block)
• Obstetrical paracervical block anesthesia; its use in this technique has resulted in fetal bradycardia and death

Posimir

• Undergoing obstetrical paracervical block anesthesia; use of bupivacaine HCl with this technique has resulted in fetal bradycardia and death

Cautions

Safety and effectiveness of local anesthetics depend on proper dosage, correct technique, adequate precautions, and readiness for emergencies; resuscitative equipment, oxygen, and other resuscitative drugs should be available for immediate use

Caution with impaired cardiovascular function (eg, hypotension, heart block), as patients may be unable to compensate for functional changes associated with prolongation of AV conduction produced by bupivacaine; consider reduced dosing; closely monitor for blood pressure, heart rate, and ECG changes

Many drugs used during anesthesia may trigger malignant familial hyperthermia; potential for amide-type local anesthetics to also trigger such a response is unknown; consider a standard protocol for therapeutic management to be available

Avoid solutions containing antimicrobial preservatives, (ie, multiple-dose vials), for epidural or caudal anesthesia; safety not established for use

Infants and neonates are at greater risk for bupivacaine toxicity owing to a lower amount of serum alpha-1-acid-glycoprotein concentration compared with older children; this protein is the major binding site for bupivacaine, therefore, infants and neonates may have an increase of free fraction of local anesthetics

Bupivacaine is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with renal impairment; this should be considered when selecting the dosage

Because of long duration of anesthesia, when used for dental injections, warn patients about possibility of inadvertent trauma to tongue, lips, and buccal mucosa and advise them not to chew solid foods until sensation returns

Risk of adverse reactions with use in head and neck area

• Small doses of local anesthetics injected into head and neck area, including retrobulbar, dental, and stellate ganglion blocks, may produce adverse reactions similar to systemic toxicity seen with unintentional intravascular injections of larger doses
• The injection procedures require the utmost care; confusion, convulsions, respiratory depression, and/or respiratory arrest, and cardiovascular stimulation or depression reported; these reactions may be due to intra-arterial injection of local anesthetic with retrograde flow to cerebral circulation
• They may also be due to puncture of dural sheath of optic nerve during retrobulbar block with diffusion of any local anesthetic along subdural space to the midbrain
• Monitor circulation and respiration and constantly observe patients receiving nerve blocks; resuscitative equipment and drugs, and personnel for treating adverse reactions should be immediately available; dosage recommendations should not be exceeded

Risk of respiratory arrest with use in ophthalmic surgery

• Clinicians who perform retrobulbar blocks should be aware that there have been reports of respiratory arrestfollowing local anesthetic injection
• Prior to retrobulbar block, as with all other regional procedures, resuscitative equipment and drugs, and personnel to manage respiratory arrest or depression, convulsions, and cardiac stimulation or depression should be immediately available
• As with other anestheticprocedures, patients should be constantly monitored following ophthalmic blocks for signs of these adverse reactions, which may occur following relatively low total doses
• A concentration of 0.75% bupivacaine is indicated for retrobulbar block; however, this concentration is notindicated for any other peripheral nerve block, including the facial nerve, and not indicated for local infiltration,including the conjunctiva

Dose-related toxicity

• Possible early warning signs of central nervous system (CNS) toxicity are restlessness, anxiety, incoherentspeech, lightheadedness, numbness and tingling of the mouth and lips, metallic taste, tinnitus, dizziness, blurred vision, tremors, twitching, CNS depression, or drowsiness
• 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
• During major regional nerve blocks, such as those of the brachial plexus or lower extremity, the patient shouldhave an indwelling intravenous catheter to assure adequate intravenous access;
• Use the lowest dosage that results in effective anesthesia to avoid highplasma levels and serious adverse effects
• Avoid rapid injection of a large volume solution and administer fractional (incremental) doses when feasible

Methemoglobinemia

• Use of local anesthetics may cause methemoglobinemia
• Patients with glucose-6-phosphate dehydrogenase deficiency, congenital or idiopathic methemoglobinemia, cardiac or pulmonary compromise, infants ≤6 months, and concurrent exposure to oxidizing agents or their metabolites are more susceptible to developing clinical manifestations of the condition
• Advise patient to seek immediate medical attention if they experience the following signs or symptoms: pale, gray, or blue colored skin (cyanosis); headache; rapid heart rate; shortness of breath; lightheadedness; or fatigue
• Discontinue any other oxidizing agents
• Depending on severity of signs and symptoms, patients may respond to supportive care, including oxygen therapy and hydration
• More severe clinical presentations may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen

Chondrolysis

• Chondrolysis associated with intra-articular infusions following arthroscopic and other surgical procedure; majority of reported cases involved the shoulder joint
• Information on determining whether shorter infusion periods are not associated with these findings is insufficient
• Time of onset of symptoms (eg, joint pain, stiffness, loss of motion) varies; may begin as early as 2nd month postsurgery
• Currently, there is no effective treatment; may require additional diagnostic and therapeutic procedures (eg, arthroplasty or shoulder replacement)
• Use of bupivacaine for spinal anesthesia and Posimir are not recommend in patients <18 years

Risk of system toxicity

• Unintended intravascular injection may be associated with systemic toxicities, including CNS or cardiorespiratory depression and coma, progressing ultimately to respiratory arrest
• Safety and effectiveness of bupivacaine depend on proper dosage, correct technique, adequate precautions, and readiness for emergencies
• Closely monitor cardiovascular and respiratory (adequacy of ventilation) vital signs and mental status after injection
• Avoid additional use of local anesthetics within 168 hr following administration
• Repeated doses may cause significant increases in plasma levels owing slow accumulation of drug or metabolites, or because of slow metabolic degradation
• Consider increased monitoring for systemic toxicity in debilitated, elderly, or acutely ill patients
• Unintended intravascular or intrathecal injection may be associated with systemic toxicities, including CNS or cardiorespiratory depression and coma, progressing ultimately to respiratory arrest
• Unintentional intrathecal injection during the intended performance of caudal or lumbar epidural block or nerve blocks near the vertebral column has resulted in under ventilationor apnea (“Total or High Spinal”)
• A high spinal has been characterized by paralysis of the legs, loss of consciousness, respiratory paralysis, and bradycardia
• Aspirate for blood or cerebrospinal fluid (where applicable) before injecting 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

Spinal anesthetics

• Use with caution in patient with severe disturbances of cardiac rhythm, shock, or heart block
• Sympathetic blockade occurring during spinal anesthesia may result in peripheral vasodilation and hypotension, depending on number of dermatomes blocked
• Patients >65 years, especially with hypertension, may be at an increased risk of hypotensive effects
• Carefully monitor blood pressure and level of anesthesia

• Conditions preventing use of spinal anesthesia

  • Depending upon clinician’s evaluation and ability to manage potential complications, conditions may include:
  • Preexisting CNS disease (eg, disease associated with pernicious anemia, poliomyelitis, syphilis, tumor)
  • Hematological disorders predisposing to coagulopathies or concurrent anticoagulant therapy
  • Chronic backache and preoperative headache
  • Hypotension or hypertension
  • Technical problems (persistent paresthesias, persistent bloody tap)
  • Arthritis or spinal deformity; extremes of age
  • Psychosis or other causes of poor patient cooperation

Posimir only

• Inadvertent intravascular injection may deposit droplets into pulmonary and other capillary beds
• Confirm proper needle placement with direct arthroscopic visualization; administer into subacromial space at end of arthroscopic shoulder surgery
• In a study, use in dogs following intra-articular administration demonstrated joint cartilage necrosis; not approved for use via intra-articular injection
• Safety and effectiveness in surgical procedures other than subacromial decompression not established

Drug interaction overview

• Drugs associated with methemoglobinemia

  • Use of drugs associated with methemoglobinemia (eg, nitrates, local anesthetics) with bupivacaine may exacerbate the risk of methemoglobinemia

Pregnancy

Contraindicated for obstetrical paracervical block anesthesia; use has resulted in fetal bradycardia and death

Data are unavailable on use in pregnant women to inform a drug-associated risks of adverse developmental outcomes

Local anesthetics rapidly cross placenta, and when used for epidural, caudal, or pudendal block anesthesia, can cause varying degrees of maternal, fetal, and neonatal toxicity

Incidence and degree of toxicity depend upon procedure performed, type, and amount of drug used, and technique of drug administration

Adverse reactions in parturient, fetus, and neonate involve alterations of CNS, peripheral vascular tone, and cardiac function

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

Maternal hypotension

• 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 gravid uterus; therefore, during treatment of systemic toxicity, maternal hypotension orfetal 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

Animal data

• Embryofetal lethality was noted when administered SC to pregnant rabbits during organogenesis at clinically relevant doses
• Decreased pup survival was observed in rat pre-and postnatal developmental study at a dose level comparable to daily maximum recommended human dose on body surface area basis
• Advise pregnant women of potential risks to fetus

Labor or delivery

• Epidural, caudal, or pudendal anesthesia may alter 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

Lactation

Not studied in nursing mothers

Bupivacaine can persist in plasma for up to 168 hr and benzyl alcohol, a Posimir excipient, for up to 12 hr after administration

Bupivacaine and benzyl alcohol (in Posimir only) reported to be excreted in human milk

Consider developmental and health benefits of breastfeeding along with mother’s clinical need for bupivacaine and any potential adverse effects on breastfed child from drug or underlying maternal condition

Bupivacaine has been reported to be excreted in human milk suggesting that the nursing infant could be theoretically exposed to a dose of the drug; administer to lactating women only if clearly indicated

Studies assessing the effects of the drug in breastfed children have not been performed; studies to assess the effect on milk production or excretion have not been performed

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Blocks initiation and conduction of nerve impulses by decreasing permeability of neuronal membrane to sodium ions, resulting in inhibition of depolarization with resultant blockade of conduction

Absorption

Onset of action

• Marcaine Spinal: Very rapid (within 1 minute); achieves maximum motor blockade and dermatome level within 15 minutes in most cases

• Marcaine Spinal

  • Time of complete sensation returns in operative site or regression of two dermatomes: ~2 hr (12-mg dose) averages
  • Time to complete motor ability returns: ~3.5 hr (12-mg dose)

Mean peak plasma concentration

• Posimir: 593-1,006 ng/mL

Peak plasma time

• Posimir: 5.9-8 hr
• Marcaine, Sensorcaine, generic: 30-45 min (caudal, epidural, or peripheral nerve block)

AUC

• Posimir: 19,395-47,015 ng⋅h/mL

Distribution

Depending upon route of administration, distribution to some extent to all body tissues, with high concentrations found in highly perfused organs such as the liver, lungs, heart, and brain

Protein bound: 95%

Crosses the placenta via passive diffusion

Fetal/maternal ratio: 0.2-0.4

Metabolism

Primarily metabolized in the liver via conjugation with glucuronic acid

Major metabolite: Pipecoloxylidine

Elimination

Excretion: Urine (6% as unchanged)

Half-life

• Posimir: 16.4-26.1 hr
• Marcaine, Sensorcaine, generic: 2.7 hr (adults); 8.1 hr (neonates)

Compatibilities

Posimir

• Commonly implantable materials, such as polypropylene and polyester
• Silk, nylon, gut, polypropylene, polydioxanone, and polyglycolic acid sutures

Precautions

Administer in carefully adjusted dosages by or under supervision of clinicians experienced in diagnosis and management dose-related toxicity and other acute emergencies

Toxic effects of local anesthetics are additive; monitor for neurologic and cardiovascular effects related to local anesthetic systemic toxicity when administering additional local anesthetics

Marcaine, Sensorcaine, or generic injection

• Aspirate for blood or cerebrospinal fluid (when applicable before administration) before administration, both initial and all subsequent doses, to avoid intravascular or intrathecal use

• Use 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

Administration

Marcaine, Sensorcaine, generic

• Not for intrathecal use
• Epidural or caudal anesthesia: Avoid use of solutions containing antimicrobial preservatives (ie, multiple-dose vials)
• Avoid rapid injection of large volumes; use incremental doses when possible
• For major regional nerve blocks (eg, brachial plexus, lower extremity), an indwelling IV catheter should be placed to assure adequate IV access
• Closely monitor cardiovascular and respiratory (adequacy of oxygenation and ventilation) vital signs and level of consciousness after each local anesthetic injection
• Carefully restrict quantities in areas of body supplied by end arteries or having otherwise compromised blood supply (eg, digits, nose, external ear, penis)

Posimir

• Subacromial space administration
• Single-dose administration only
• Do NOT dilute or mix with local anesthetics, other drugs, or diluents
• Avoid additional use of local anesthetics within 168 hr following administration
• Administer in a setting where trained personnel and equipment are available to promptly treat any evidence of neurological or cardiac toxicity

• Not indicated for following administrations

  • Epidural
  • Intrathecal
  • Intravascular; avoid administration owing to convulsions and cardiac arrests reported with accidental intravascular injection
  • Intra-articular use
  • Regional nerve blocks
  • Pre-incisional or pre-procedural locoregional anesthetic techniques requiring deep and complete sensory block in area of administration

• Administration and dosing instructions

  • Ready-to-use; no dilution or mixing required
  • Draw up dose into a 5-mL syringe using a large bore needle (16 gauge or larger); discard needle after 5 mL is drawn
  • At the end of surgery, administer entire 5-mL (660-mg) dose into subacromial space using an 18-gauge or larger bore-needle
  • May insert needle through an existing arthroscopic port or through intact skin to reach subacromial space
  • Use direct arthroscopic visualization to confirm correct placement of needle tip within subacromial space
  • Do not administer into glenohumeral intra-articular space

Storage

Protect from light

Product is clear and colorless; do not use solution if discolored or contains a precipitate

Vials

• Store at 20-25ºC (68-77ºF); excursions permitted to 15-30ºC (59-86ºF)
• May be autoclaved once at 15 pound pressure, 121ºC (250ºF) for 15 min
• Discard any unused portion

Single-dose ampules

• Store at 20-25ºC (68-77ºF); excursions permitted to 15-30ºC (59-86ºF)
• May be autoclaved once at 15 pound pressure, 121ºC (250ºF) for 15 min
• Discard any unused portion

Posimir

• Store at a controlled room temperature (20-25ºC [68-77ºF]), excursions permitted to 15-30ºC (59-86ºF)
• Keep in carton until time of use