4.1. Therapeutic indications

EXPAREL liposomal is indicated (see section 5.1):

• in adults as a brachial plexus block or femoral nerve block for treatment of post-operative pain.

• in adults and children aged 6 years or older as a field block for treatment of somatic post-operative pain from small- to medium-sized surgical wounds.

4.2. Posology and method of administration

EXPAREL liposomal should be administered in a setting where trained personnel and appropriate resuscitation equipment are available to promptly treat patients who show evidence of neurological or cardiac toxicity.

Posology

The recommended dose of EXPAREL liposomal in adults and children aged 6 years or older is based on the following factors:

• Size of the surgical site

• Volume required to cover the area

• Individual patient factors

A maximum dosage of 266 mg (20 mL of undiluted medicinal product) must not be exceeded.

Field block (infiltration around small- to medium-sized surgical wounds)

• In patients undergoing bunionectomy, a total of 106 mg (8 mL) of EXPAREL liposomal was administered, with 7 mL infiltrated into the tissues surrounding the osteotomy and 1 mL infiltrated into the subcutaneous tissue.

• In patients undergoing haemorrhoidectomy, a total of 266 mg (20 mL) of EXPAREL liposomal was diluted with 10 mL of normal saline, for a total of 30 mL, divided into six 5 mL aliquots, injected by visualizing the anal sphincter as a clock face and slowly infiltrating one aliquot to each of the even numbers to produce a field block.

• In paediatric patients aged 6 years and older , EXPAREL liposomal should be administered at a dose of 4 mg/kg (maximum not to exceed 266 mg). EXPAREL liposomal may be either administered 'as is' or expanded with normal (0.9%) saline to increase the volume up to a final concentration of 0.89 mg/mL (ie, 1:14 dilution by volume). The total volume of expansion will be dependent on the incision length. Examples are given is section 6.6.

Peripheral nerve block (femoral and brachial plexus)

• In patients undergoing total knee arthroplasty (TKA), a total of 266 mg (20 mL) of EXPAREL liposomal was administered as a femoral nerve block.

• In patients undergoing total shoulder arthroplasty or rotator cuff repair, a total of 133 mg (10 mL) of EXPAREL liposomal was diluted with 10 mL of normal saline, for a total volume of 20 mL, was administered as a brachial plexus nerve block.

Co-administration with other local anaesthetics

The toxic effects of local anaesthetics are additive and their co-administration, taking into account the dose of local anaesthetic and the extended pharmacokinetic profile of EXPAREL liposomal, should be used with caution including monitoring for neurologic and cardiovascular effects related to local anaesthetic systemic toxicity. See section 4.5.

EXPAREL liposomal is a liposomal preparation and should not be used interchangeably with any other formulations of bupivacaine. Bupivacaine hydrochloride (immediate release formulations) and EXPAREL liposomal may be administered simultaneously in the same syringe as long as the ratio of the milligram dose of bupivacaine solution to EXPAREL liposomal does not exceed 1:2. If preparing admixture, the total amount of bupivacaine used (EXPAREL liposomal + bupivacaine HCl) should not exceed 400 mg equivalents of bupivacaine HCl in adults. For more information, see section 4.4.

Special populations

Elderly patients (65 years of age or older)

Care should be taken in dose selection of EXPAREL liposomal in elderly patients because bupivacaine is known to be substantially excreted by the kidney, and the risk of toxic reactions to bupivacaine may be greater in patients with impaired renal function. No dosage adjustment is required; however, greater sensitivity of some older individuals cannot be ruled out (see sections 5.1 and 5.2).

The risk of falls may increase for the elderly patients.

Renal impairment

Bupivacaine or its metabolites are known to be substantially excreted by the kidney, and the risk of toxic reactions may be greater in patients with impaired renal function. Impaired renal function should be considered when performing dose selection of EXPAREL liposomal (see sections 4.4 and 5.2).

Hepatic impairment

Bupivacaine is metabolized by the liver. No dosage adjustment is required in patients with mild hepatic impairment (Child-Pugh score 5-6) or moderate hepatic impairment (Child Pugh score 7-9). There are insufficient data to recommend the use of EXPAREL liposomal in patients with severe (Child-Pugh score ≥10) hepatic impairment (see sections 4.4 and 5.2).

Paediatric population

EXPAREL liposomal may be administered to paediatric patients 6 years of age and older at a dose of 4 mg/kg (maximum not to exceed 266 mg) for use as a single-dose field block for treatment of somatic post-operative pain from small- to medium-sized surgical wounds.

The safety and efficacy of EXPAREL liposomal have not yet been established for administration as a field block in children aged 1 to less than 6 years of age, nor as a nerve block in children aged 1 to less than 18 years of age. No data are available.

EXPAREL liposomal should not be used in children aged less than 1 year of age because neonates and infants have a decreased ability to metabolize anaesthetics due to an immature hepatic system.

Method of administration

EXPAREL liposomal is for administration by infiltration or perineural use only.

EXPAREL liposomal is intended for single-dose administration only.

EXPAREL liposomal should be injected slowly (generally 1 to 2 mL per injection) with frequent aspiration when clinically appropriate, to check for blood and minimize the risk of inadvertent intravascular injection.

EXPAREL liposomal is to be administered with a 25 gauge or larger bore needle to maintain the structural integrity of the liposomal bupivacaine particles.

For instructions on the preparation of the medicinal product before administration, see section 6.6.

4.3. Contraindications

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

• Hypersensitivity to local anaesthetic medicinal products of the amide type.

• Obstetrical paracervical block anaesthesia due to risk of foetal bradycardia or death.

• Intravascular administration.

• Intraarticular administration (see section 4.4).

4.4. Special warnings and precautions for use

Efficacy and safety have not been established in major abdominal, vascular and thoracic surgeries.

Local anaesthetic systemic toxicity (LAST)

As there is a potential risk of severe life-threatening adverse reactions associated with the administration of bupivacaine, any bupivacaine-containing product should be administered in a setting where trained personnel and equipment are available to promptly treat patients who show evidence of neurological or cardiac toxicity.

Careful and constant monitoring of cardiovascular and respiratory (adequacy of ventilation) vital signs and the patient's state of consciousness should be performed after injection of bupivacaine. Restlessness, anxiety, incoherent speech, light headedness, numbness and tingling of the mouth and lips, metallic taste, tinnitus, dizziness, blurred vision, tremors, twitching, depression, or drowsiness may be early warning signs of central nervous system toxicity.

Toxic local anaesthetic blood concentrations depress cardiac conductivity and excitability, which may lead to atrioventricular block, ventricular arrhythmia, and cardiac arrest, which can be fatal. In addition, toxic local anaesthetic blood concentrations depress myocardial contractility and cause peripheral vasodilation, leading to decreased cardiac output and arterial blood pressure.

Acute emergencies due to neurological or cardiovascular toxicity from local anaesthetics are generally related to high plasma concentrations encountered during therapeutic use of local anaesthetics or due to unintended intravascular injection of local anaesthetic solution (see sections 4.3 and 4.9).

Injection of multiple doses of bupivacaine and other amide-containing products may cause significant increases in plasma concentrations with each repeated dose due to slow accumulation of the active substance or its metabolites or due to slow metabolic degradation. Tolerance to elevated blood concentrations varies with the status of the patient.

Potential cases of LAST have been observed in the post-marketing setting. Although the majority with a recorded time to onset were observed within less than 1 hour of EXPAREL liposomal administration, a small number with a time to onset greater than 24 hours was reported. No correlation of cases of potential LAST with surgical procedure or route of administration has been found with EXPAREL liposomal, but redosing of EXPAREL liposomal, overdose, or concomitant use with other local anaesthetics may increase the risk of LAST (see section 4.5).

Neurologic effects

Central nervous system reactions are characterized by excitation and/or depression. Restlessness, anxiety, dizziness, tinnitus, blurred vision, or tremors may occur, possibly proceeding to convulsions. However, excitation 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 include nausea, vomiting, chills, and constriction of the pupils. The incidence of convulsions associated with the use of local anaesthetics varies with the procedure used and the total dose administered.

Neurologic effects following field block may include persistent anaesthesia, paraesthesias, weakness, and paralysis, all of which may have slow, incomplete, or no recovery.

Cardiovascular function impairment

Bupivacaine should also be used with caution in patients with impaired cardiovascular function because they may be less able to compensate for functional changes associated with the prolongation of atrioventricular conduction produced by these medicinal products.

Hepatic impairment

Bupivacaine is metabolised by the liver, so it should be used cautiously in patients with hepatic disease. Patients with severe hepatic disease are at a greater risk of developing toxic plasma concentrations because of their inability to metabolise local anaesthetics normally. Increased monitoring for local anaesthetic systemic toxicity should be considered in subjects with moderate to severe hepatic disease (see sections 4.2 and 5.2).

Renal impairment

Only 6% of bupivacaine is excreted unchanged in the urine. Bupivacaine metabolites are known to be extensively excreted by the kidney. Urinary excretion is affected by urinary perfusion and factors affecting urinary pH. Acidifying the urine hastens the renal elimination of local anaesthetics. Various pharmacokinetic parameters of local anaesthetics can be significantly altered by the presence of renal disease, factors affecting urinary pH, and renal blood flow. Thus, the risk of toxic reactions to this medicinal product may be greater in patients with impaired renal function.

Allergic reactions

Allergic-type reactions may rarely occur as a result of hypersensitivity to the local anaesthetic or to other formulation ingredients. These reactions are characterised by signs such as urticaria, pruritus, erythema, angioneurotic oedema (including laryngeal oedema), tachycardia, sneezing, nausea, vomiting, dizziness, syncope, excessive sweating, elevated temperature, and possibly anaphylactoid-like symptoms (including severe hypotension). Cross-sensitivity among members of the amide-type local anaesthetic group has been reported. Allergic symptoms should be treated symptomatically.

Chondrolysis

Intra-articular infusions of local anaesthetics, including EXPAREL liposomal, following arthroscopic and other surgical procedures are contraindicated (see section 4.3). There have been post-marketing reports of chondrolysis in patients receiving such infusions.

Methaemoglobinaemia

Cases of methaemoglobinaemia have been reported in association with local anaesthetic use. Although all patients are at risk for methaemoglobinaemia, infants under 6 months of age and patients with glucose-6-phosphate dehydrogenase deficiency, congenital or idiopathic methaemoglobinaemia, cardiac or pulmonary compromise, or concurrent exposure to oxidizing agents or their metabolites (see section 4.5) are more susceptible to developing clinical manifestations of the condition. If local anaesthetics must be used in these patients, close monitoring for symptoms and signs of methaemoglobinaemia is recommended.

Signs and symptoms of methaemoglobinaemia may occur immediately or may be delayed some hours after exposure and are characterized by a cyanotic skin discoloration and abnormal coloration of the blood. Methaemoglobin levels may continue to rise; therefore, immediate treatment is required to avert more serious central nervous system and cardiovascular adverse reactions, including seizures, coma, arrhythmias, and death. Bupivacaine should be discontinued as well as any other oxidizing medicinal product. Depending on the severity of the symptoms, patients may respond to supportive care (i.e. oxygen therapy, hydration). More severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.

Warnings and precautions specific to EXPAREL liposomal

Different formulations of bupivacaine are not bioequivalent even if the milligram dosage is the same. Therefore, it is not possible to convert dosing from any other formulations of bupivacaine to EXPAREL liposomal and vice versa. No substitution with other bupivacaine containing products should be made.

Caution is advised when co-administering EXPAREL liposomal and bupivacaine HCl, particularly when administering to highly vascular areas where higher systemic absorption is expected. Admixing of EXPAREL with other local anaesthetics has not been studied in children and is not recommended

Using EXPAREL liposomal followed by other bupivacaine formulations has not been studied in clinical trials. However, based on the clinical situation, bupivacaine hydrochloride may be administered, taking into account the relevant PK profiles and individual patient considerations. As with all local anaesthetics, physicians need to evaluate local anaesthetic systemic toxicity risk based on total dose with respect to time of administration.

EXPAREL liposomal has not been evaluated for the following uses and, therefore, is not recommended for these types of analgesia or routes of administration:

• epidural

• intrathecal

EXPAREL liposomal is not recommended for use as a femoral nerve block if early mobilization and ambulation is part of the patient's recovery plan (see section 4.7). Sensory and/or motor loss may occur with EXPAREL liposomal use, however, this is temporary and degree of loss and duration varies depending on the site of injection and dosage administered. As seen during clinical trials, any temporary sensory and/or motor loss may last for up to 5 days.

Excipients with known effect

Sodium

This medicinal product contains 21 mg sodium per 10 mL vial and 42 mg sodium per 20 mL vial, equivalent to 1.1% and 2.1%, respectively, of the WHO recommended maximum daily intake of 2 g sodium for an adult.

4.5. Interaction with other medicinal products and other forms of interaction

Use of EXPAREL liposomal with other local anaesthetics

The addition of local anaesthetics administered within 96 hours following administration of EXPAREL liposomal should take into account the total bupivacaine exposure.

EXPAREL liposomal should be used with caution in patients receiving other local anaesthetics or active substances structurally related to amide-type local anaesthetics, e.g. certain anti-arrhythmics, such as lidocaine and mexiletine, since the systemic toxic effects are additive.

Other bupivacaine products

The impact on pharmacokinetic and/or physicochemical properties of EXPAREL liposomal when it is co-administered with bupivacaine HCl is concentration dependent. Therefore, bupivacaine HCl can be administered simultaneously in the same syringe as long as the ratio of the milligram dose of bupivacaine HCl solution to EXPAREL liposomal does not exceed 1:2. The total amount of bupivacaine HCl and EXPAREL liposomal being co-administered should not exceed 400 mg equivalents of bupivacaine HCl in adults (see sections 4.4 and 6.6).

Non-bupivacaine local anaesthetics

EXPAREL liposomal should only be admixed with bupivacaine as admixing with either lidocaine, ropivacaine or mepivacaine has been shown to cause an immediate release of bupivacaine from the multivesicular liposomes of the drug delivery system. When EXPAREL liposomal is admixed with lidocaine, lidocaine binds to the liposomes, leading to an immediate displacement and release of bupivacaine. This displacement can be prevented by ensuring that EXPAREL liposomal is administered at least 20 minutes after administering lidocaine. There are no data to support administration of other local anaesthetics prior to administration of EXPAREL liposomal.

Oxidizing medicinal products

Patients that are administered local anaesthetics may be at increased risk of developing methaemoglobinamia when concurrently exposed to the following oxidizing medicinal products:

• Nitrates/Nitrites - nitroglycerin, nitroprusside, nitric oxide, nitrous oxide

• Local anaesthetics - benzocaine, lidocaine, bupivacaine, mepivacaine, tetracaine, prilocaine, procaine, articaine, ropivacaine

• Antineoplastic medicinal products - cyclophosphamide, flutamide, rasburicase, isofamide, hydroxyurea

• Antibiotics - dapsone, sulfonamides, nitrofurantoin, para-aminosalicylic acid

• Antimalarials - chloroquine, primaquine

• Anticonvulsants - phenytoin, sodium valproate, phenobarbital

• Other medicinal products - acetaminophen, metoclopramide, sulfa medicines (e,g., sulfasalazine), quinine

Other medicinal products

When a topical antiseptic, such as povidone iodine, is applied, the site should be allowed to dry before EXPAREL liposomal is administered into the site. EXPAREL liposomal should not be allowed to come into contact with antiseptics such as povidone iodine in solution (see also section 6.2).

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no or limited amount of data from the use of bupivacaine in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). EXPAREL liposomal is not recommended during pregnancy and in women of childbearing potential not using contraception.

Breastfeeding

Bupivacaine and its metabolite, pipecoloxylidide, are present in human milk at low levels. There is no available information on effects of the medicinal product in the breastfed infant or effects of the medicinal product on milk production. Because of the potential for serious adverse reactions in breastfed infants a decision must be made whether to discontinue breast-feeding or to discontinue/abstain from EXPAREL liposomal therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.

Fertility

There are no clinical data on the effects of EXPAREL liposomal on fertility.

4.7. Effects on ability to drive and use machines

Bupivacaine could have a major influence on the ability to drive and use machines. Patients should be informed in advance that bupivacaine liposomal dispersion can cause temporary loss of sensation or motor function. The potential sensory and/or motor loss with EXPAREL liposomal is temporary and varies in degree and duration depending on the site of injection, route of administration (i.e. field block or nerve block) and dosage administered, and may last for up to 5 days as seen in clinical trials.

4.8. Undesirable effects

Summary of the safety profile

The most common adverse reactions (≥ 5%) associated with EXPAREL liposomal in clinical trials were dysgeusia (6.0%) and hypoaesthesia oral (6.5%).

The most important serious adverse reactions associated with EXPAREL liposomal were systemic toxic reactions. Systemic toxic reactions usually present shortly after administration of bupivacaine but may be delayed in some cases. Severe central nervous system toxicity due to EXPAREL liposomal may result in convulsions (< 0.001% from post-marketing data). Severe cardiac toxicity due to EXPAREL liposomal may result in serious dysrhythmia (0.7% in clinical trials), serious hypotension (0.7% in clinical trials), and/or cardiac arrest (< 0.001% from post-marketing data).

Tabulated list of adverse reactions in adults

The adverse reactions associated with EXPAREL liposomal in adults from clinical trials and post-marketing surveillance are presented below in Table 1 according to the MedDRA System Organ Classification and by frequency. Frequencies are defined as very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1 000 to < 1/100), rare (≥ 1/10 000 to < 1/1 000) and very rare (< 1/10 000) and frequency not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 1 Table of adverse drug reactions (ADRs) in adults

System organ class

Frequency

Adverse drug reactions

Immune system disorders

Not known

Hypersensitivity

Psychiatric disorders

Rare

Confusional state, anxiety

Nervous system disorders

Common

Dysgeusia

Uncommon

Motor dysfunction, sensory loss, dizziness, somnolence, hypoaesthesia, burning sensation, headache

Rare

Syncope, monoplegia, presyncope, lethargy

Not known

Seizure, palsy

Eye disorders

Rare

Visual impairment, vision blurred

Ear and labyrinth disorders

Rare

Diplacusis

Cardiac disorders

Uncommon

Bradycardia, tachycardia

Rare

Atrial fibrillation, tachyarrhythmia, sinus tachycardia

Not known

Cardiac arrest

Vascular disorders

Uncommon

Hypotension

Rare

Hypertension, flushing

Respiratory, thoracic, and mediastinal disorders

Rare

Apnoea, hypoxia, atelectasis, dyspnoea, oropharyngeal pain

Gastrointestinal disorders

Common

Vomiting, constipation, hypoaesthesia oral, nausea

Rare

Haematochezia, dysphagia, abdominal distension, abdominal discomfort, abdominal pain upper, diarrhoea, salivary hypersecretion, dry mouth, dyspepsia, oral pruritus, paraesthesia oral

Skin and subcutaneous tissue disorders

Uncommon

Urticaria, pruritus generalised, pruritus, skin irritation

Rare

Drug eruption, hyperhidrosis, erythema, rash, nail discolouration

Musculoskeletal and connective tissue disorders

Uncommon

Mobility decreased, muscular weakness, muscle spasms, muscle twitching, arthralgia

Rare

Joint swelling, groin pain, joint stiffness, musculoskeletal chest pain, pain in extremity

Renal and urinary disorders

Not known

Urinary retention

General disorders and administration site conditions

Uncommon

Pyrexia

Rare

Peripheral swelling, non-cardiac chest pain, chills, feeling hot, injection site pain, pain

Not known

Lack of efficacy

Investigations

Uncommon

Blood creatinine increased, alanine aminotransferase increased, aspartate aminotransferase increased

Rare

Electrocardiogram ST segment elevation, hepatic enzyme increased, white blood cell count increased

Injury, poisoning, and procedural complications

Uncommon

Contusion, post procedural oedema, fall

Rare

Muscle injury, seroma, wound complication, incision site erythema, procedural pain

Not known

Local anaesthetic systemic toxicity (LAST)

Tabulated list of adverse reactions in the paediatric population

Adverse reactions associated with EXPAREL liposomal in paediatrics from clinical trials and post-marketing surveillance are presented below in Table 2 according to the MedDRA System Organ Classification and by frequency. Frequencies are defined as very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1 000 to < 1/100), rare (≥ 1/10 000 to < 1/1 000) and very rare (< 1/10 000) and frequency not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 2 Table of adverse drug reactions (ADRs) in children

System organ class

Frequency

Adverse drug reactions

Blood and lymphatic system disorders

Very common

Anaemia

Immune system disorders

Common

Hypersensitivity

Psychiatric disorders

Common

Anxiety

Nervous system disorders

Common

Hypoaesthesia, paraesthesia, burning sensation, dizziness, dysgeusia and syncope

Not known

Somnolence

Eye disorders

Common

Visual impairment, vision blurred

Ear and labyrinth disorders

Common

Hypoacusis

Cardiac disorders

Very common

Tachycardia

Common

Bradycardia

Vascular disorders

Very common

Hypotension

Common

Hypertension

Respiratory, thoracic, and mediastinal disorders

Common

Dyspnoea, tachypnoea

Gastrointestinal disorders

Very common

Vomiting, constipation, nausea

Common

Abdominal pain, diarrhoea, hypoaesthesia oral, dyspepsia

Skin and subcutaneous tissue disorders

Very common

Pruritus

Common

Rash

Musculoskeletal and connective tissue disorders

Very common

Muscle twitching

Common

Musculoskeletal chest pain, pain in extremity, muscular weakness, muscle spasms

General disorders and administration site conditions

Common

Chest pain, pyrexia

Injury, poisoning, and procedural complications

Common

Delayed recovery from anaesthesia, seroma, fall

Not known

Local anaesthetic systemic toxicity (LAST)

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Clinical presentation

Rare reports of overdose with EXPAREL liposomal alone or in combination with another local anaesthetic have been received. Systemic toxic reactions, primarily involving the central nervous system and the cardiovascular system may occur following high blood concentrations of local anaesthetics. Approximately 30% of overdose reports were associated with adverse reactions.

Signs and symptoms of overdose may include CNS symptoms (perioral paraesthesia, dizziness, dysarthria, confusion, mental obtundation, sensory and visual disturbances, and eventually convulsions) and cardiovascular effects (that range from hypertension and tachycardia to myocardial depression, hypotension, bradycardia, and asystole).

Management of local anaesthetic overdose

At the first sign of local anaesthetic overdose, oxygen should be administered.

The first step in the management of convulsions, as well as hypoventilation or apnoea, consists of immediate attention to the maintenance of a patent airway and assisted or controlled ventilation with oxygen and a delivery system capable of permitting immediate positive airway pressure by mask. Immediately after the institution of these ventilatory measures, the adequacy of the circulation should be evaluated, keeping in mind that medicinal products used to treat convulsions sometimes depress the circulation when administered intravenously. Should convulsions persist despite adequate respiratory support, and if the status of the circulation permits, small increments of an ultra-short acting barbiturate (such as thiopental or thiamylal) or a benzodiazepine (such as diazepam) may be administered intravenously. Supportive treatment of circulatory depression may require administration of intravenous fluids and, when appropriate, a vasopressor dictated by the clinical situation (such as ephedrine to enhance myocardial contractile force).

If not treated immediately, both convulsions and cardiovascular depression can result in hypoxia, acidosis, bradycardia, dysrhythmias, and cardiac arrest. If cardiac arrest should occur, standard cardiopulmonary resuscitative measures should be instituted.

Endotracheal intubation employing medicinal products may be indicated after initial administration of oxygen by mask if difficulty is encountered in the maintenance of a patent airway or if prolonged ventilatory support (assisted or controlled) is indicated.

Lipid emulsion has been used to treat some cases of overdose in the post-marketing setting.