Bupivacaine

N01B - Anesthetics, local ATC N01BB01 Small molecule approved 1972 Parenteral Natural product Black-box warning

🧬 Cross-allergy: Amide local anesthetics

JFDA label: Bucaine 0.25% Vial

⚠ Black-Box Warning

Obstetrical anesthesia:

Mechanism of Action

Blocker of Sodium channel protein type 4 subunit alpha — Sodium channel protein type IV alpha subunit blocker

Target	Action	Gene / class
Sodium channel protein type 4 subunit alpha efficacy	BLOCKER	SCN4A

Indications

Approved

0.25%
0.5%
0.75% (not for obstetrical anesthesia)

Contraindications

Source: Lexicomp

Additional contraindications (not in US labeling): Obstetric paracervical block anesthesia Absolute
Hypersensitivity to bupivacaine hydrochloride, amide-type local anesthetics, or any component of the formulation Absolute
obstetrical paracervical block anesthesia Note: Use as intravenous regional anesthesia (Bier block) is considered contraindicated per accepted clinical practice due to reports of cardiac arrest and death Absolute
severe shock and in heart block where there is inflammation and/or sepsis near the proposed injection site Absolute

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Cardiac disorders (6)

Not Known Bradycardia · cardiac arrest · heart block · hypotension · palpitations · ventricular arrhythmia

Nervous system disorders (3)

Not Known Anxiety · dizziness · restlessness

Immune system disorders (2)

Not Known Anaphylactoid reaction · hypersensitivity reaction (urticaria, pruritus, angioedema)

Gastrointestinal disorders (2)

Not Known Nausea · vomiting

Musculoskeletal and connective tissue disorders (2)

Not Known Chondrolysis (continuous intra-articular administration) · weakness

Eye disorders (2)

Not Known Blurred vision · miosis

Ear and labyrinth disorders (1)

Not Known Tinnitus

Other (4)

Not Known and are often due to accelerated absorption from the injection site · Incidence of adverse reactions is difficult to define. Most effects are dose related · or slow metabolic degradation. The development of any central nervous system symptoms may be an early indication of more significant toxicity (seizure) · unintentional intravascular injection

Respiratory, thoracic and mediastinal disorders (2)

Not Known Apnea · hypoventilation (usually associated with unintentional subarachnoid injection during high spinal anesthesia)

Dosing

Source: Lexicomp

Note: Dose varies with procedure, depth of anesthesia, vascularity of tissues, duration of anesthesia, and condition of patient. Do not use solutions containing preservatives for caudal or epidural block. Local anesthesia: Infiltration: 0.25% infiltrated locally; maximum: 175 mg. Note: Aspiration should be performed prior to each injection; however, absence of blood in the syringe does not guarantee that intravascular injection has been avoided (Mulroy 2010). Caudal block (preservative free): 15 to 30 mL of 0.25% or 0.5% Epidural block (other than caudal block; preservative free): Administer in 3 to 5 mL increments, allowing sufficient time to detect toxic manifestations of inadvertent IV or intrathecal administration: 10 to 20 mL of 0.25% or 0.5% Surgical procedures requiring a high degree of muscle relaxation and prolonged effects only: 10 to 20 mL of 0.75% (Note: Not to be used in obstetrical cases) Peripheral nerve block: 5 mL of 0.25% or 0.5%; maximum: 400 mg/day Sympathetic nerve block: 20 to 50 mL of 0.25% Retrobulbar anesthesia: 2 to 4 mL of 0.75% Spinal anesthesia: Preservative free solution of 0.75% bupivacaine in 8.25% dextrose: Lower extremity and perineal procedures: 1 mL Lower abdominal procedures: 1.6 mL Normal vaginal delivery: 0.8 mL (higher doses may be required in some patients) Cesarean delivery: 1 to 1.4 mL Combined spinal-epidural (CSE) technique for labor analgesia (off-label dosing [spinal component]): 1.75 to 2.5 mg combined with fentanyl 15 mcg (Eltzschig 2003; Ngan Kee 2014; Whitty 2007). Combined spinal-epidural (CSE) technique for anesthesia for Cesarean delivery (off-label dosing [spinal component]): 9 to 12 mg combined with fentanyl 15 mcg; in addition to fentanyl, may also include a longer-acting opioid (ie, morphine 100 to 150 mcg) for postoperative analgesia (Santos 2015).

(For additional information see "Bupivacaine: Pediatric drug information") Note: Dose varies with procedure, depth of anesthesia, vascularity of tissues, duration of anesthesia, and condition of patient. Do not use solutions containing preservatives for caudal or epidural block. Caudal block, epidural block, local anesthesia: Adolescents: Refer to adult dosing. Peripheral or sympathetic nerve block: Adolescents: Refer to adult dosing. Retrobulbar anesthesia: Adolescents: Refer to adult dosing.

Refer to adult dosing.

There are no dosage adjustments provided in the manufacturer’s labeling; use with caution.

Warnings & Precautions

Source: Lexicomp

Cardiovascular effects

Bupivacaine-containing products have been associated with rare occurrences of arrhythmias, cardiac arrest, and death.

Intra-articular infusion related chondrolysis

Continuous intra-articular infusion of local anesthetics after arthroscopic or other surgical procedures is not an approved use; chondrolysis (primarily shoulder joint) has occurred following infusion, with some patients requiring arthroplasty or shoulder replacement.

Respiratory arrest

Local anesthetics have been associated with rare occurrences of sudden respiratory arrest, especially when administered near the head or neck.

Seizures

Convulsions due to systemic toxicity leading to cardiac arrest have also been reported, presumably following unintentional intravascular injection or administration near the head or neck. Disease-related concerns:

Cardiovascular disease

Use with caution in patients with cardiovascular disease including patients with hypotension or heart block.

Hepatic impairment

Use with caution in patients with hepatic impairment. Special populations:

Acutely ill patients

Use with caution in acutely ill patients; dose reduction may be required.

Debilitated patients

Use with caution in debilitated patients; dose reduction may be required.

Elderly

Use with caution in the elderly; dose reduction may be required. Dosage form specific issues:

Obstetrical anesthesia

The 0.75% concentration is not recommended for obstetrical anesthesia; cardiac arrest with difficult resuscitation or death has occurred.

Preservative-containing solutions

Do not use solutions containing preservatives for caudal or epidural block.

Sodium metabisulfite

May contain sodium metabisulfite; use caution in patients with asthma or a sulfite allergy. Other warnings/precautions:

Administration

Intravascular injections should be avoided; aspiration should be performed prior to administration; the needle must be repositioned until no return of blood can be elicited by aspiration; however, absence of blood in the syringe does not guarantee that intravascular injection has been avoided. Intravenous regional anesthesia (Bier block) is not recommended; cardiac arrest and death have occurred with this method of administration.

Test dose

A test dose is recommended prior to epidural administration (prior to initial dose) and all reinforcing doses with continuous catheter technique.

Trained personnel

Clinicians using local anesthetic agents should be well trained in diagnosis and management of emergencies that may arise from the use of these agents. Resuscitative equipment, oxygen, and other resuscitative drugs should be available for immediate use.

Pregnancy & Lactation

Pregnancy

FDA category C

Adverse events were observed in animal reproduction studies. Bupivacaine crosses the placenta. Bupivacaine is approved for use at term in obstetrical anesthesia or analgesia. [U.S. Boxed Warning]: The 0.75% is not recommended for obstetrical anesthesia. Bupivacaine 0.75% solutions have been associated with cardiac arrest following epidural anesthesia in obstetrical patients and use of this concentration is not recommended for this purpose. Use in obstetrical paracervical block anesthesia is contraindicated.

Lactation

Bupivacaine is excreted in breast milk. Due to the potential for serious adverse reactions in the nursing infant, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of treatment to the mother.

Monitoring

Clinical pearl	Vital signs, state of consciousness; signs of CNS toxicity

Chemistry & Properties

Formula	C18H28N2O
Molecular weight	288.44 g/mol
IUPAC name	1-butyl-N-(2,6-dimethylphenyl)piperidine-2-carboxamide
CAS	2180-92-9
PubChem CID	2474
InChIKey	`LEBVLXFERQHONN-UHFFFAOYSA-N`
logP	3.9 (XLogP 3.4)
Polar surface area	32.34 Å²
H-bond acceptors / donors	2 / 1
Drug-likeness (QED)	0.89
Lipinski violations	0

SMILES

CCCCN1CCCCC1C(=O)Nc1c(C)cccc1C

Biology & Pharmacokinetics

Pharmacokinetics

BBB penetrant	No

Enzyme interactions

Enzyme	Role	Detail
CYP1A2	Substrate	—
CYP2B6	Inhibitor	—
CYP2C19	Substrate	—
CYP2D6	Inhibitor	—
CYP2D6	Substrate	—
CYP3A4	Substrate	—

Receptor binding (top 2)

Target	Action	Affinity
Nav1.5 (SCN5A)	Channel blocker	pIC50 5.7
Kv1.5 (KCNA5)	Channel blocker	pKd 5.4

Transporters

BCRP (Inhibitor)BCRP (Inhibitor)BSEP (Inhibitor)BSEP (Inhibitor)MRP1 (Inhibitor)MRP2 (Inhibitor)MRP3 (Inhibitor)MRP4 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)OATP1B3 (Inhibitor)P-gp (Inhibitor)OCT1 (Substrate)P-gp (Substrate)

Drug–drug interactions (17, DDInter)

Interacting drug	Severity	Management
Aprepitant	moderate
Benzocaine (topical)	moderate
Cinchocaine (topical)	moderate
Cocaine (nasal)	moderate
Cocaine (topical)	moderate
Fostamatinib	moderate
Lidocaine (ophthalmic)	moderate
Lidocaine (topical)	moderate
Lorlatinib	moderate
Morphine (liposomal)	moderate
Oxybuprocaine (ophthalmic)	moderate
Sirolimus	moderate
Tacrolimus	moderate
Temsirolimus	moderate
Tetracaine (ophthalmic)	moderate
Tetracaine (topical)	moderate
Hyaluronidase	minor

Registered Products (11)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
Betolina 2.5 mg/1ml Solution for inj	Injection 2.5 mg/1 ml	1 vial pack varies	MS PHARMA/JORDAN	—
Betolina 2.5 mg/1ml Solution for inj	Injection 2.5 mg/1 ml	5 vial pack varies	MS PHARMA/JORDAN	—
Betolina 5mg/1ml Solution For Inj	Injection 5 mg/1 ml	1 vial pack varies	MS PHARMA/JORDAN	—
Betolina 5mg/1ml Solution For Inj	Injection 5 mg/1 ml	5 vial pack varies	MS PHARMA/JORDAN	—
Betolina Spinal Heavy 20mg/4ml solution for injection	Injection 20 mg/4 ml	5 vial	MS PHARMA/JORDAN	—
Bucaine	Vial 2.5 mg/ml	1 vial	Hikma Pharmaceuticals Co.Ltd/Jordan	—
Bucaine 0.5% Vials(20ml)	Vial 5 mg/ml	1 vial	Hikma Pharmaceuticals Co.Ltd/Jordan	—
Bucaine Heavy	Ampoule 5 mg/ml	5 amp	HIKMA PHARMACEUTICALS - JORDAN	—
MARCAINE SPINAL HEAVY (hyperbaric)	Injection 5 mg/ml	4 ml	Shawi & Rushedat Drug Store	—
Marcaine	Powder for Injection 0.5 %	20 ml	Shawi & Rushedat Drug Store	—
Surgicaine	Injection 0.5 %, 0.0091 mg/ml	50 Catrridges	Ajyal Al Ghad Al Jadeed Drug Store	—