interscalene exparel pacira
 

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Exparel



Dosage Form: injection, suspension, liposomal
FULL PRESCRIBING INFORMATION 1. INDICATIONS AND USAGE

Exparel is a liposome injection of bupivacaine, an amide-type local anesthetic, indicated for administration into the surgical site to produce postsurgical analgesia.

Exparel has not been studied for use in patients younger than 18 years of age.

2. DOSAGE AND ADMINISTRATION

Exparel is intended for single-dose administration only. The recommended dose of Exparel is based on the surgical site and the volume required to cover the area.

1Infiltrate 7 mL of Exparel into the tissues surrounding the osteotomy and 1 mL into the subcutaneous tissue. 2Dilute 20 mL of Exparel with 10 mL of saline, for a total of 30 mL, and divide the mixture into six 5 mL aliquots. Perform the anal block by visualizing the anal sphincter as a clock face and slowly infiltrating one aliquot to each of the even numbers. Surgery Dose of Exparel Volume of Exparel Bunionectomy1 106 mg 8 mL Hemorrhoidectomy2 266 mg 20 mL Injection Instructions

Exparel should be injected slowly into soft tissues of the surgical site with frequent aspiration to check for blood and minimize the risk of intravascular injection.

Exparel is intended for single-dose infiltration only. Exparel should be administered with a 25 gauge or larger bore needle. The maximum dosage of Exparel should not exceed 266 mg (20 mL, 1.3% of undiluted drug). Do not administer Exparel if the product is discolored. Do not administer Exparel if it is suspected that the vial has been frozen as reflected by the temperature indicator or exposed to high temperature (greater than 40°C or 104°F) for an extended period. Exparel can be administered undiluted or diluted up to 0.89 mg/mL (i.e. 1:14 dilution by volume) with preservative-free normal (0.9%) sterile saline for injection. Vials of Exparel should be inverted multiple times to re-suspend the particles immediately prior to withdrawal from the vial. Diluted suspensions of Exparel should be used within 4 hours of preparation in a syringe. Administration Precautions

Some physicochemical incompatibilities exist between Exparel and certain other drugs. Direct contact of Exparel with these drugs results in a rapid increase in free (unencapsulated) bupivacaine, altering Exparel characteristics and potentially affecting the safety and efficacy of Exparel. Therefore, admixing Exparel with other drugs prior to administration is not recommended [See Drug Interactions (7)].

Non-bupivacaine based local anesthetics, including lidocaine, may cause an immediate release of bupivacaine from Exparel if administered together locally. The administration of Exparel may follow the administration of lidocaine after a delay of 20 minutes or more. Bupivacaine HCl, when injected immediately before Exparel, may impact the pharmacokinetic and/or physicochemical properties of the drugs when the milligram dose of bupivacaine HCl solution exceeds 50% of the Exparel dose. Exparel contains bupivacaine; therefore, coadministration of both drugs will increase the overall exposure to bupivacaine. When a topical antiseptic such as povidone iodine (e.g., Betadine®) is applied, the site should be allowed to dry before Exparel is administered into the surgical site. Exparel should not be allowed to come into contact with antiseptics such as povidone iodine in solution.

Studies conducted with Exparel demonstrated that the most common implantable materials (polypropylene, PTFE, silicone, stainless steel, and titanium) are not affected by the presence of Exparel any more than they are by saline. None of the materials studied had an adverse effect on Exparel.

When administered in recommended doses and concentrations, bupivacaine HCl does not ordinarily produce irritation or tissue damage and does not cause methemoglobinemia.

Non-Interchangeability with Other Formulations of Bupivacaine

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 and vice versa.

Liposomal encapsulation or incorporation in a lipid complex can substantially affect a drug's functional properties relative to those of the unencapsulated or nonlipid-associated drug. In addition, different liposomal or lipid-complexed products with a common active ingredient may vary from one another in the chemical composition and physical form of the lipid component. Such differences may affect functional properties of these drug products. Do not substitute.

Dosing in Special Populations

Exparel has not been studied in patients younger than 18 years of age, pregnant patients or patients who are nursing.

3. DOSAGE FORMS AND STRENGTHS

Exparel (bupivacaine liposome injectable suspension)

10 mL single use vial, 1.3% (13.3 mg/mL) 20 mL single use vial, 1.3% (13.3 mg/mL) 4. CONTRAINDICATIONS

Exparel is contraindicated in obstetrical paracervical block anesthesia. While Exparel has not been tested with this technique, the use of bupivacaine HCl with this technique has resulted in fetal bradycardia and death.

5. WARNINGS AND PRECAUTIONS Warnings and Precautions for Bupivacaine containing Products

The safety and effectiveness of bupivacaine and other amide-containing products depend on proper dosage, correct technique, adequate precautions, and readiness for emergencies. As there is a potential risk of severe life-threatening adverse effects 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 [See Overdosage (10)].

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 and other amide-containing products. Restlessness, anxiety, incoherent speech, lightheadedness, 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.

Bupivacaine and other amide-containing products 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 AV conduction produced by these drugs.

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 drug or its metabolites, or to slow metabolic degradation. Tolerance to elevated blood concentrations varies with the status of the patient.

Because amide-type local anesthetics, such as bupivacaine, are metabolized by the liver, these drugs should be used cautiously in patients with hepatic disease. Patients with severe hepatic disease, because of their inability to metabolize local anesthetics normally, are at a greater risk of developing toxic plasma concentrations.

Central Nervous System Reactions

The incidences of adverse neurologic reactions associated with the use of local anesthetics may be related to the total dose of local anesthetic administered and are also dependent upon the particular drug used, the route of administration, and the physical status of the patient. Many of these effects may be related to local anesthetic techniques, with or without a contribution from the drug. Neurologic effects following infiltration of soft tissue may include persistent anesthesia, paresthesias, weakness, and paralysis, all of which may have slow, incomplete, or no recovery.

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, excitement may be transient or absent, with depression being the first manifestation of an adverse reaction. This may quickly be followed by drowsiness merging into unconsciousness and respiratory arrest. Other central nervous system effects may be nausea, vomiting, chills, and constriction of the pupils. The incidence of convulsions associated with the use of local anesthetics varies with the procedure used and the total dose administered.

Cardiovascular System Reactions

Toxic blood concentrations depress cardiac conductivity and excitability, which may lead to atrioventricular block, ventricular arrhythmias, and cardiac arrest, sometimes resulting in fatalities. In addition, myocardial contractility is depressed and peripheral vasodilation occurs, leading to decreased cardiac output and arterial blood pressure [See Warnings and Precautions (5.1) and Overdosage (10)].

Allergic Reactions

Allergic-type reactions are rare and may occur as a result of hypersensitivity to the local anesthetic or to other formulation ingredients. These reactions are characterized by signs such as urticaria, pruritus, erythema, angioneurotic edema (including laryngeal edema), tachycardia, sneezing, nausea, vomiting, dizziness, syncope, excessive sweating, elevated temperature, and possibly anaphylactoid-like symptoms (including severe hypotension). Cross-sensitivity among members of the amide-type local anesthetic group has been reported. The usefulness of screening for sensitivity has not been definitively established.

Chondrolysis

Intra-articular infusions of local anesthetics following arthroscopic and other surgical procedures is an unapproved use, and there have been postmarketing reports of chondrolysis in patients receiving such infusions. The majority of reported cases of chondrolysis have involved the shoulder joint; cases of gleno-humerol chondrolysis have been described in pediatric patients and adult patients following intra-articular infusions of local anesthetics with and without epinephrine for periods of 48 to 72 hours. There is insufficient information to determine whether shorter infusion periods are not associated with these findings. The time of onset of symptoms, such as joint pain, stiffness, and loss of motion can be variable, but may begin as early as the second month after surgery. Currently, there is no effective treatment for chondrolysis; patients who have experienced chondrolysis have required additional diagnostic and therapeutic procedures and some required arthroplasty or shoulder replacement.

Warnings and Precautions Specific for Exparel

As there is a potential risk of severe life-threatening adverse effects associated with the administration of bupivacaine, Exparel 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 [See Overdosage (10)].

Caution should be taken to avoid accidental intravascular injection of Exparel. Convulsions and cardiac arrest have occurred following accidental intravascular injection of bupivacaine and other amide-containing products.

Using Exparel followed by other bupivacaine formulations has not been studied in clinical trials. Other formulations of bupivacaine should not be administered within 96 hours following administration of Exparel [See Clinical Pharmacology (12.3)].

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

epidural intrathecal regional nerve blocks intravascular or intra-articular use

Exparel has not been evaluated for use in the following patient population and, therefore, it is not recommended for administration to these groups.

patients younger than 18 years old pregnant patients nursing patients

The ability of Exparel to achieve effective anesthesia has not been studied. Therefore, Exparel is not indicated for pre-incisional or pre-procedural loco-regional anesthetic techniques that require deep and complete sensory block in the area of administration.

6. ADVERSE REACTIONS General

The most commonly encountered acute adverse experiences to bupivacaine and all amide-type local anesthetics that demand immediate counter-measures are related to the central nervous and cardiovascular systems.

High plasma concentrations of bupivacaine can occur from overdosage, unintended intravascular injection, or accumulation of bupivacaine in plasma secondary to decreased hepatic metabolic degradation of the drug or diminished plasma protein binding capacity due to acidosis, pathologically lowered plasma protein production, or competition with other drugs for protein binding sites. Although rare, some individuals have a lower tolerance to and are supersensitive to bupivacaine and other amide-type local anesthetics and may rapidly develop signs of toxicity at low doses [See Overdosage (10)].

Adverse Reactions Reported in All Wound Infiltration Clinical Studies

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

The safety of Exparel was evaluated in 10 randomized, double-blind, local administration into the surgical site clinical studies involving 823 patients undergoing various surgical procedures. Patients were administered a dose ranging from 66 to 532 mg of Exparel. In these studies, the most common adverse reactions (incidence greater than or equal to 10%) following Exparel administration were nausea, constipation, and vomiting.

The common adverse reactions (incidence greater than or equal to 2% to less than 10%) following Exparel administration were pyrexia, dizziness, edema peripheral, anemia, hypotension, pruritus, tachycardia, headache, insomnia, anemia postoperative, muscle spasms, hemorrhagic anemia, back pain, somnolence, and procedural pain.

The less common/rare adverse reactions (incidence less than 2%) following Exparel administration were chills, erythema, bradycardia, anxiety, urinary retention, pain, edema, tremor, dizziness postural, paresthesia, syncope, incision site edema, procedural hypertension, procedural hypotension, procedural nausea, muscular weakness, neck pain, pruritus generalized, rash pruritic, hyperhidrosis, cold sweat, urticaria, bradycardia, palpitations, sinus bradycardia, supraventricular extrasystoles, ventricular extrasystoles, ventricular tachycardia, hypertension, pallor, anxiety, confusional state, depression, agitation, restlessness, hypoxia, laryngospasm, apnea, respiratory depression, respiratory failure, body temperature increased, blood pressure increased, blood pressure decreased, oxygen saturation decreased, urinary retention, urinary incontinence, vision blurred, tinnitus, drug hypersensitivity, and hypersensitivity.

Neurological and Cardiac Adverse Reactions Reported in All Wound Infiltration Clinical Studies

In the Exparel wound infiltration studies, adverse reactions with an incidence greater than or equal to 1% in the Nervous System Disorders system organ class following Exparel administration were dizziness (6.2%), headache (3.8%), somnolence (2.1%), hypoesthesia (1.5%), and lethargy (1.3%). The adverse reactions with an incidence greater than or equal to 1% in the Cardiac Disorders system organ class following Exparel administration were tachycardia (3.9%) and bradycardia (1.6%).

Adverse Reactions Reported in Placebo-Controlled Wound Infiltration Clinical Studies

Adverse reactions with an incidence greater than or equal to 2% reported by patients in clinical studies comparing 8 mL Exparel 1.3% (106 mg) to placebo and 20 mL Exparel 1.3% (266 mg) to placebo are shown in Table 1.

Table 1: Treatment-Emergent Adverse Reactions (TEAE) with an Incidence Greater than or Equal to 2%: Placebo Controlled Studies a Study 1: Bunionectomy b Study 2: Hemorrhoidectomy At each level of summation (overall, system organ class, preferred term), patients are only counted once.
Preferred terms are included where at least 2% of patients reported the event in any treatment group.
TEAE = treatment-emergent adverse event. STUDY 1a STUDY 2b Exparel Placebo Exparel Placebo System Organ Class
     Preferred Term 8 mL/1.3% (106 mg)
(N=97)
n (%) (N=96)
n (%) 20 mL/1.3% (266 mg)
(N=95)
n (%) (N=94)
n (%)   Any TEAE 53 (54.6) 59 (61.5) 10 (10.5) 17 (18.1)   Gastrointestinal Disorders 41 (42.3) 38 (39.6) 7 (7.4) 13 (13.8)      Nausea 39 (40.2) 36 (37.5) 2 (2.1) 1 (1.1)      Vomiting 27 (27.8) 17 (17.7) 2 (2.1) 4 (4.3)      Constipation 2 (2.1) 1 (1.0) 2 (2.1) 2 (2.1)      Anal Hemorrhage 0 (0.0) 0 (0.0) 3 (3.2) 4 (4.3)      Painful Defecation 0 (0.0) 0 (0.0) 2 (2.1) 5 (5.3)      Rectal Discharge 0 (0.0) 0 (0.0) 1 (1.1) 3 (3.2)   Nervous System Disorders 20 (20.6) 30 (31.3) 0 (0.0) 0 (0.0)      Dizziness 11 (11.3) 25 (26.0) 0 (0.0) 0 (0.0)      Headache 5 (5.2) 8 (8.3) 0 (0.0) 0 (0.0)      Somnolence 5 (5.2) 1 (1.0) 0 (0.0) 0 (0.0)      Syncope 2 (2.1) 0 (0.0) 0 (0.0) 0 (0.0)   Skin And Subcutaneous Tissue Disorders 8 (8.2) 7 (7.3) 0 (0.0) 0 (0.0)      Pruritus Generalized 5 (5.2) 6 (6.3) 0 (0.0) 0 (0.0)      Pruritus 3 (3.1) 1 (1.0) 0 (0.0) 0 (0.0)   Investigations 5 (5.2) 3 (3.1) 4 (4.2) 3 (3.2)      Alanine Aminotransferase Increased 3 (3.1) 3 (3.1) 1 (1.1) 0 (0.0)      Aspartate Aminotransferase Increased 3 (3.1) 2 (2.1) 0 (0.0) 0 (0.0)      Blood Creatinine Increased 2 (2.1) 0 (0.0) 0 (0.0) 0 (0.0)      Body Temperature Increased 0 (0.0) 0 (0.0) 3 (3.2) 3 (3.2)   General Disorders And Administration Site Conditions 4 (4.1) 0 (0.0) 1 (1.1) 1 (1.1)      Feeling Hot 2 (2.1) 0 (0.0) 0 (0.0) 0 (0.0)      Pyrexia 2 (2.1) 0 (0.0) 1 (1.1) 1 (1.1)   Infections And Infestations 2 (2.1) 1 (1.0) 0 (0.0) 0 (0.0)      Fungal Infection 2 (2.1) 1 (1.0) 0 (0.0) 0 (0.0)   Injury, Poisoning And Procedural Complications 2 (2.1) 0 (0.0) 0 (0.0) 0 (0.0)      Post Procedural Swelling 2 (2.1) 0 (0.0) 0 (0.0) 0 (0.0)   Metabolism And Nutrition Disorders 2 (2.1) 2 (2.1) 0 (0.0) 0 (0.0)      Decreased Appetite 2 (2.1) 2 (2.1) 0 (0.0) 0 (0.0) Drug Interactions

Exparel can be administered undiluted or diluted up to 0.89 mg/mL (i.e., 1:14 dilution by volume) with preservative-free normal (0.9%) sterile saline for injection. Exparel must not be diluted with water or other hypotonic agents as it will result in disruption of the liposomal particles.

Exparel should not be admixed with lidocaine or other non-bupivacaine-based local anesthetics.

Exparel may be locally administered after at least 20 minutes following local administration of lidocaine.

Exparel should not be admixed with other drugs prior to administration.

8. USE IN SPECIFIC POPULATIONS Pregnancy

Pregnancy Category C: There are no adequate and well-controlled studies in pregnant women of the effect of bupivacaine on the developing fetus. Exparel should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Bupivacaine hydrochloride (HCl) produced developmental toxicity when administered subcutaneously to pregnant rats and rabbits at clinically relevant doses. This does not exclude the use of Exparel at term for analgesia [See Labor and Delivery (8.2)].

Bupivacaine HCl was administered subcutaneously to rats and rabbits during the period of fetal organogenesis. 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.

Administration of bupivacaine HCl to rats during pregnancy and lactation resulted in decreased offspring survival.

Labor and Delivery

Bupivacaine hydrochloride is contraindicated for obstetrical paracervical block anesthesia.

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 [See Clinical Pharmacology (12.3)]. 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 central nervous system, peripheral vascular tone, and cardiac function.

Nursing mothers

Bupivacaine has been reported to be excreted to some extent in human milk, suggesting that the nursing infant could be theoretically exposed to a dose of the drug. Because of the potential for serious adverse reactions in nursing infants from bupivacaine, a decision should be made whether to discontinue nursing or not administer Exparel, taking into account the importance of the drug to the mother.

Pediatric use

Safety and effectiveness in pediatric patients below the age of 18 have not been established.

Geriatric use

Of the total number of patients in the Exparel wound infiltration clinical studies (N=823), 171 patients were greater than or equal to 65 years of age and 47 patients were greater than or equal to 75 years of age. No overall differences in safety or effectiveness were observed between these patients and younger patients. Clinical experience with Exparel has not identified differences in efficacy or safety between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

In clinical studies, differences in various pharmacokinetic parameters have been observed between elderly and younger patients. 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. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection of Exparel.

Hepatic Impairment

Because amide-type local anesthetics, such as bupivacaine, are metabolized by the liver, these drugs should be used cautiously in patients with hepatic disease. Patients with severe hepatic disease, because of their inability to metabolize local anesthetics normally, are at a greater risk of developing toxic plasma concentrations.

Renal Impairment

Bupivacaine is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Care should be taken in dose selection of Exparel.

10. OVERDOSAGE

Acute emergencies from local anesthetics are generally related to high plasma concentrations encountered during therapeutic use of local anesthetics or to unintended intravascular injection of local anesthetic solution [See Warnings and Precautions (5) and Adverse Reactions (6)].

In the clinical study program, maximum plasma concentration (Cmax) values of approximately 34,000 ng/mL were reported and likely reflected inadvertent intravascular administration of Exparel or systemic absorption of Exparel at the surgical site. The plasma bupivacaine measurements did not discern between free and liposomal-bound bupivacaine making the clinical relevance of the reported values uncertain; however, no discernable adverse events or clinical sequelae were observed in these patients.

11. DESCRIPTION

Exparel is a sterile, non-pyrogenic white to off-white preservative-free aqueous suspension of multivesicular liposomes (DepoFoam® drug delivery system) containing bupivacaine. Bupivacaine is present at a concentration of 13.3 mg/mL. After injection of Exparel into soft tissue, bupivacaine is released from the multivesicular liposomes over a period of time.

Active Ingredient

Bupivacaine is related chemically and pharmacologically to the amide-type local anesthetics. It is a homologue of mepivacaine and is related chemically to lidocaine. All three of these anesthetics contain an amide linkage between the aromatic nucleus and the amino, or piperidine group. They differ in this respect from the procaine-type local anesthetics, which have an ester linkage. Chemically, bupivacaine is 1-butyl-N-(2,6-dimethylphenyl)-2-piperidinecarboxamide with a molecular weight of 288.4. Bupivacaine has the following structural formula:

Bupivacaine is present in Exparel at a concentration of 13.3 mg/mL.

Lipid Formulation

The median diameter of the liposome particles ranges from 24 to 31 µm. The liposomes are suspended in a 0.9% sodium chloride solution. Each vial contains bupivacaine at a nominal concentration of 13.3 mg/mL. Inactive ingredients and their nominal concentrations are: cholesterol, 4.7 mg/mL; 1, 2-dipalmitoyl-sn-glycero-3 phospho-rac-(1-glycerol) (DPPG), 0.9 mg/mL; tricaprylin, 2.0 mg/mL; and 1, 2-dierucoylphosphatidylcholine (DEPC), 8.2 mg/mL. The pH of Exparel is in the range of 5.8 to 7.4.

Liposomal encapsulation or incorporation in a lipid complex can substantially affect a drug's functional properties relative to those of the unencapsulated or nonlipid-associated drug. In addition, different liposomal or lipid-complexed products with a common active ingredient may vary from one another in the chemical composition and physical form of the lipid component. Such differences may affect functional properties of these drug products. Do not substitute.

12. CLINICAL PHARMACOLOGY Mechanism of action

Local anesthetics block the generation and the conduction of nerve impulses presumably by increasing the threshold for electrical excitation in the nerve, by slowing the propagation of the nerve impulse, and by reducing the rate of rise of the action potential. In general, the progression of anesthesia is related to the diameter, myelination, and conduction velocity of affected nerve fibers. Clinically, the order of loss of nerve function is as follows: (1) pain, (2) temperature, (3) touch, (4) proprioception, and (5) skeletal muscle tone.

Pharmacodynamics

Systemic absorption of local anesthetics produces effects on the cardiovascular and central nervous systems. At blood concentrations achieved with normal therapeutic doses, changes in cardiac conduction, excitability, refractoriness, contractility, and peripheral vascular resistance are minimal. However, toxic blood concentrations depress cardiac conductivity and excitability, which may lead to atrioventricular block, ventricular arrhythmias, and cardiac arrest, sometimes resulting in fatalities. In addition, myocardial contractility is depressed and peripheral vasodilation occurs, leading to decreased cardiac output and arterial blood pressure. Clinical reports and animal research suggest that these cardiovascular changes are more likely to occur after accidental intravascular injection of bupivacaine.

Following systemic absorption, local anesthetics can produce central nervous system stimulation, depression, or both. Apparent central stimulation is manifested as restlessness, tremors, and shivering progressing to convulsions, followed by depression and coma progressing ultimately to respiratory arrest. However, the local anesthetics have a primary depressant effect on the medulla and on higher centers. The depressed stage may occur without a prior excited state.

Pharmacokinetics

Local infiltration of Exparel results in significant systemic plasma levels of bupivacaine which can persist for 96 hours [See Warnings and Precautions (5.2)]. Systemic plasma levels of bupivacaine following administration of Exparel are not correlated with local efficacy.

Absorption

The rate of systemic absorption of bupivacaine is dependent upon the total dose of drug administered, the route of administration, and the vascularity of the administration site.

Pharmacokinetic parameters of Exparel after local administration were evaluated following surgical procedures. Descriptive statistics of pharmacokinetic parameters of representative Exparel doses in each study are provided in Table 2.

Table 2: Summary of Pharmacokinetic Parameters for Bupivacaine after Administration of Single Doses of Exparel Note: Arithmetic mean (standard deviation) except Tmax (median). Exparel Bunionectomy
106 mg (8 mL) Hemorrhoidectomy
266 mg (20 mL)   (N=26) (N=25)   Cmax (ng/mL) 166 (92.7) 867 (353) Tmax (h) 2 0.5 AUC(0-t) (h?ng/mL) 5864 (2038) 16,867 (7868) AUC(inf) (h?ng/mL) 7105 (2283) 18,289 (7569) t? (h) 34.1 (17.0) 23.8 (39.4)

Distribution

After bupivacaine has been released from Exparel and is absorbed systemically, bupivacaine distribution is expected to be the same as for any bupivacaine HCl solution formulation.

Local anesthetics including bupivacaine are distributed to some extent to all body tissues, with high concentrations found in highly perfused organs such as the liver, lungs, heart, and brain.

Local anesthetics including bupivacaine appear to cross the placenta by passive diffusion. The rate and degree of diffusion is governed by (1) the degree of plasma protein binding, (2) the degree of ionization, and (3) the degree of lipid solubility. Fetal/maternal ratios of local anesthetics appear to be inversely related to the degree of plasma protein binding, because only the free, unbound drug is available for placental transfer. Bupivacaine with a high protein binding capacity (95%) has a low fetal/maternal ratio (0.2 to 0.4). The extent of placental transfer is also determined by the degree of ionization and lipid solubility of the drug. Lipid soluble, non-ionized drugs such as bupivacaine readily enter the fetal blood from the maternal circulation.

Metabolism

Amide-type local anesthetics, such as bupivacaine, are metabolized primarily in the liver via conjugation with glucuronic acid. Pipecolylxylidine (PPX) is the major metabolite of bupivacaine; approximately 5% of bupivacaine is converted to PPX. Elimination of drug depends largely upon the availability of plasma protein binding sites in the circulation to carry it to the liver where it is metabolized.

Various pharmacokinetic parameters of the local anesthetics can be significantly altered by the presence of hepatic disease. Patients with hepatic disease, especially those with severe hepatic disease, may be more susceptible to the potential toxicities of the amide-type local anesthetics.

Excretion

After bupivacaine has been released from Exparel and is absorbed systemically, bupivacaine excretion is expected to be the same as for other bupivacaine formulations.

The kidney is the main excretory organ for most local anesthetics and their metabolites. Only 6% of bupivacaine is excreted unchanged in the urine.

Urinary excretion is affected by urinary perfusion and factors affecting urinary pH. Acidifying the urine hastens the renal elimination of local anesthetics. Various pharmacokinetic parameters of the local anesthetics can be significantly altered by the presence of renal disease, factors affecting urinary pH, and renal blood flow.

Specific Populations

Hepatic Impairment

The effects of decreased hepatic function on bupivacaine pharmacokinetics following administration of Exparel were studied in patients with moderate hepatic impairment. Consistent with the hepatic clearance of bupivacaine, mean plasma concentrations were higher in patients with moderate hepatic impairment than in the healthy control volunteers with approximately 1.5- and 1.6-fold increases in the mean values for Cmax and the area under the curve (AUC), respectively.

Because amide-type local anesthetics, such as bupivacaine, are metabolized by the liver, these drugs should be used cautiously in patients with hepatic disease. Patients with severe hepatic disease, because of their inability to metabolize local anesthetics normally, are at a greater risk of developing toxic plasma concentrations [See Warnings and Precautions (5.1) and Use in Specific Populations (8.6)].

Renal Impairment

Bupivacaine is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Care should be taken in dose selection of Exparel [See Use in Specific Populations (8.7)].

Age

Various pharmacokinetic parameters of the local anesthetics such as bupivacaine can be significantly altered by the age of the patient.

In clinical studies, differences in various pharmacokinetic parameters have been observed between elderly and younger patients.

Bupivacaine is known to be substantially excreted by the kidney, and the risk of toxic 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 of Exparel [See Use in Specific Populations (8.5)].

13. NONCLINICAL TOXICOLOGY Carcinogenesis, mutagenesis, impairment of fertility

Long-term studies in animals of most local anesthetics, including bupivacaine, to evaluate the carcinogenic potential have not been conducted. Mutagenic potential and the effect on fertility have not been determined. There is no evidence from human data that bupivacaine may be carcinogenic or mutagenic or that it impairs fertility.

14. CLINICAL STUDIES

The efficacy of Exparel was compared to placebo in two multicenter, randomized, double-blinded clinical trials. One trial evaluated the treatments in patients undergoing bunionectomy; the other trial evaluated the treatments in patients undergoing hemorrhoidectomy. Exparel has not been demonstrated to be safe and effective in other procedures.

Bunionectomy

A multicenter, randomized, double-blind, placebo-controlled, parallel-group study evaluated the safety and efficacy of 106 mg Exparel in 193 patients undergoing bunionectomy. The mean age was 43 years (range 18 to 72). Study medication was administered directly into the wound at the conclusion of the surgery, prior to wound closure. Pain intensity was rated by the patients on a 0 to 10 numeric rating scale (NRS) out to 72 hours. Postoperatively, patients were allowed rescue medication (5 mg oxycodone/325 mg acetaminophen orally every 4 to 6 hours as needed) or, if that was insufficient within the first 24 hours, ketorolac (15 to 30 mg IV). The primary outcome measure was the area under the curve (AUC) of the NRS pain intensity scores (cumulative pain scores) collected over the first 24 hour period. There was a significant treatment effect for Exparel compared to placebo.

In this clinical study, Exparel demonstrated a significant reduction in pain intensity compared to placebo for up to 24 hours. The difference in mean pain intensity between treatment groups occurred only during the first 24 hours following study drug administration. Between 24 and 72 hours after study drug administration, there was minimal to no difference between Exparel and placebo treatments on mean pain intensity.

Hemorrhoidectomy

A multicenter, random


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Naropin 10 mg / ml solution for injection


1. Name Of The Medicinal Product

Naropin®10 mg/ml solution for injection

2. Qualitative And Quantitative Composition

Naropin® 10 mg/ml:

1 ml solution for injection contains ropivacaine hydrochloride monohydrate equivalent to 10 mg ropivacaine hydrochloride.

1 ampoule of 10 ml or 20 ml solution for injection contains ropivacaine hydrochloride monohydrate equivalent to 100 mg and 200 mg ropivacaine hydrochloride respectively.

For excipients, see section 6.1.

3. Pharmaceutical Form

Solution for injection for perineural and epidural administration (10–20 ml).

Clear, colourless solution.

4. Clinical Particulars 4.1 Therapeutic Indications

Naropin is indicated for:

1. Surgical anaesthesia

2. Acute pain management

4.2 Posology And Method Of Administration

Naropin should only be used by, or under the supervision of, clinicians experienced in regional anaesthesia.

Posology

Adults and children above 12 years of age:

The following table is a guide to dosage for the more commonly used blocks. The smallest dose required to produce an effective block should be used. The clinician's experience and knowledge of the patient's physical status are of importance when deciding the dose.

 

 

Conc.

Volume

Dose

Onset

Duration

 

 

mg/ml

ml

mg

minutes

hours

Surgical anaesthesia

         

Lumbar Epidural Administration

 

 

 

 

 

 

 

 

 

 

Surgery

7.5

15–25

113–188

10–20

3–5

 

 

10

15–20

150–200

10–20

4–6

Caesarean section

7.5

15–20

113–150(1)

10–20

3–5

Thoracic Epidural Administration

 

 

 

 

 

 

 

 

 

 

To establish block for postoperative pain relief

7.5

5–15 (depending on the level of injection)

38–113

10–20

n/a(2)

Major Nerve Block *

 

 

 

 

 

 

 

 

 

 

Brachial plexus block

7.5

30–40

225–300(3)

10–25

6–10

Field Block

7.5

1–30

7.5–225

1–15

2–6

(e.g. minor nerve blocks and infiltration)

 

 

 

 

 

 

 

 

 

 

Acute pain management

         

Lumbar Epidural Administration

 

 

 

 

 

 

 

 

 

 

Bolus

2

10–20

20–40

10–15

0.5–1.5

Intermittent injections (top up)

(e.g. labour pain management)

2

10–15

(minimum interval 30 minutes)

20–30

 

 

 

 

Continuous infusion e.g. labour pain

2

6–10 ml/h

12–20 mg/h

n/a(2)

n/a(2)

Postoperative pain management

2

6–14 ml/h

12–28 mg/h

n/a(2)

n/a(2)

Thoracic Epidural Administration

 

 

 

 

 

 

 

 

 

 

Continuous infusion (postoperative pain management)

2

6–14 ml/h

12–28 mg/h

n/a(2)

n/a(2)

Field Block

 

 

 

 

 

 

 

 

 

 

(e.g. minor nerve blocks and infiltration)

2

1–100

2–200

1–5

2–6

Peripheral nerve block

(Femoral or interscalene block)

 

 

 

 

 

 

 

 

 

 

Continuous infusion or intermittent injections

(e.g. postoperative pain management)

2

5–10 ml/h

10–20 mg/h

n/a

n/a

The doses in the table are those considered to be necessary to produce a successful block and should be regarded as guidelines for use in adults. Individual variations in onset and duration occur. The figures in the column 'Dose' reflect the expected average dose range needed. Standard textbooks should be consulted for both factors affecting specific block techniques and individual patient requirements.

         

* With regard to major nerve block, only for brachial plexus block a dose recommendation can be given. For other major nerve blocks lower doses may be required. However, there is presently no experience of specific dose recommendations for other blocks.

         

(1) Incremental dosing should be applied, the starting dose of about 100 mg (97.5 mg = 13 ml; 105 mg = 14 ml) to be given over 3–5 minutes. Two extra doses, in total an additional 50mg, may be administered as needed.

(2) n/a = not applicable

(3) The dose for a major nerve block must be adjusted according to site of administration and patient status. Interscalene and supraclavicular brachial plexus blocks may be associated with a higher frequency of serious adverse reactions, regardless of the local anaesthetic used, (see section 4.4. Special warnings and special precautions for use).

         

In general, surgical anaesthesia (e.g. epidural administration) requires the use of the higher concentrations and doses. The Naropin 10 mg/ml formulation is recommended for epidural anaesthesia in which a complete motor block is essential for surgery. For analgesia (e.g. epidural administration for acute pain management) the lower concentrations and doses are recommended.

Method of administration

Careful aspiration before and during injection is recommended to prevent intravascular injection. When a large dose is to be injected, a test dose of 3–5 ml lidocaine (lignocaine) with adrenaline (epinephrine) (Xylocaine® 2% with Adrenaline (epinephrine) 1:200,000) is recommended. An inadvertent intravascular injection may be recognised by a temporary increase in heart rate and an accidental intrathecal injection by signs of a spinal block.

Aspiration should be performed prior to and during administration of the main dose, which should be injected slowly or in incremental doses, at a rate of 25–50 mg/min, while closely observing the patient's vital functions and maintaining verbal contact. If toxic symptoms occur, the injection should be stopped immediately.

In epidural block for surgery, single doses of up to 250 mg ropivacaine have been used and well tolerated.

In brachial plexus block a single dose of 300 mg has been used in a limited number of patients and was well tolerated.

When prolonged blocks are used, either through continuous infusion or through repeated bolus administration, the risks of reaching a toxic plasma concentration or inducing local neural injury must be considered. Cumulative doses up to 675 mg ropivacaine for surgery and postoperative analgesia administered over 24 hours were well tolerated in adults, as were postoperative continuous epidural infusions at rates up to 28 mg/hour for 72 hours. In a limited number of patients, higher doses of up to 800 mg/day have been administered with relatively few adverse reactions.

For treatment of postoperative pain, the following technique can be recommended: Unless preoperatively instituted, an epidural block with Naropin 7.5 mg/ml is induced via an epidural catheter. Analgesia is maintained with Naropin 2 mg/ml infusion. Infusion rates of 6–14 ml (12–28 mg) per hour provide adequate analgesia with only slight and non-progressive motor block in most cases of moderate to severe postoperative pain. The maximum duration of epidural block is 3 days. However, close monitoring of analgesic effect should be performed in order to remove the catheter as soon as the pain condition allows it. With this technique a significant reduction in the need for opioids has been observed.

In clinical studies an epidural infusion of Naropin 2 mg/ml alone or mixed with fentanyl 1-4 ?g/ml has been given for postoperative pain management for up to 72 hours. The combination of Naropin and fentanyl provided improved pain relief but caused opioid side effects. The combination of Naropin and fentanyl has been investigated only for Naropin 2 mg/ml.

When prolonged peripheral nerve blocks are applied, either through continuous infusion or through repeated injections, the risks of reaching a toxic plasma concentration or inducing local neural injury must be considered. In clinical studies, femoral nerve block was established with 300 mg Naropin 7.5 mg/ml and interscalene block with 225 mg Naropin 7.5 mg/ml, respectively, before surgery. Analgesia was then maintained with Naropin 2 mg/ml. Infusion rates or intermittent injections of 10–20 mg per hour for 48 hours provided adequate analgesia and were well tolerated.

Concentrations above 7.5 mg/ml Naropin have not been documented for Caesarean section.

4.3 Contraindications

Hypersensitivity to ropivacaine or to other local anaesthetics of the amide type.

General contraindications related to epidural anaesthesia, regardless of the local anaesthetic used, should be taken into account.

Intravenous regional anaesthesia.

Obstetric paracervical anaesthesia.

Hypovolaemia.

4.4 Special Warnings And Precautions For Use

Regional anaesthetic procedures should always be performed in a properly equipped and staffed area. Equipment and drugs necessary for monitoring and emergency resuscitation should be immediately available. Patients receiving major blocks should be in an optimal condition and have an intravenous line inserted before the blocking procedure. The clinician responsible should take the necessary precautions to avoid intravascular injection (see section 4.2 Posology and method of administration) and be appropriately trained and familiar with diagnosis and treatment of side effects, systemic toxicity and other complications (see section 4.8 Undesirable effects and 4.9 Overdose) such as inadvertent subarachnoid injection, which may produce a high spinal block with apnoea and hypotension. Convulsions have occurred most often after brachial plexus block and epidural block. This is likely to be the result of either accidental intravascular injection or rapid absorption from the injection site.

Caution is required to prevent injections in inflamed areas.

Cardiovascular

Patients treated with anti-arrhythmic drugs class III (eg, amiodarone) should be under close surveillance and ECG monitoring considered, since cardiac effects may be additive.

There have been rare reports of cardiac arrest during the use of Naropin for epidural anaesthesia or peripheral nerve blockade, especially after unintentional accidental intravascular administration in elderly patients and in patients with concomitant heart disease. In some instances, resuscitation has been difficult. Should cardiac arrest occur, prolonged resuscitative efforts may be required to improve the possibility of a successful outcome.

Head and neck blocks

Certain local anaesthetic procedures, such as injections in the head and neck regions, may be associated with a higher frequency of serious adverse reactions, regardless of the local anaesthetic used.

Major peripheral nerve blocks

Major peripheral nerve blocks may imply the administration of a large volume of local anaesthetic in highly vascularized areas, often close to large vessels where there is an increased risk of intravascular injection and/or rapid systemic absorption, which can lead to high plasma concentrations.

Hypersensitivity

A possible cross–hypersensitivity with other amide–type local anaesthetics should be taken into account.

Hypovolaemia

Patients with hypovolaemia due to any cause can develop sudden and severe hypotension during epidural anaesthesia, regardless of the local anaesthetic used.

Patients in poor general health

Patients in poor general condition due to ageing or other compromising factors such as partial or complete heart conduction block, advanced liver disease or severe renal dysfunction require special attention, although regional anaesthesia is frequently indicated in these patients.

Patients with hepatic and renal impairment

Ropivacaine is metabolised in the liver and should therefore be used with caution in patients with severe liver disease; repeated doses may need to be reduced due to delayed elimination. Normally there is no need to modify the dose in patients with impaired renal function when used for single dose or short-term treatment. Acidosis and reduced plasma protein concentration, frequently seen in patients with chronic renal failure, may increase the risk of systemic toxicity.

Acute porphyria

Naropin® solution for injection and infusion is possibly porphyrinogenic and should only be prescribed to patients with acute porphyria when no safer alternative is available. Appropriate precautions should be taken in the case of vulnerable patients, according to standard textbooks and/or in consultation with disease area experts.

Excipients with recognised action/effect

This medicinal product contains maximum 3.7 mg sodium per ml. To be taken into consideration by patients on a controlled sodium diet.

Prolonged administration

Prolonged administration of ropivacaine should be avoided in patients concomitantly treated with strong CYP1A2 inhibitors, such as fluvoxamine and enoxacin, see section 4.5.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Naropin should be used with caution in patients receiving other local anaesthetics or agents structurally related to amide-type local anaesthetics, e.g. certain antiarrhythmics, such as lidocaine and mexiletine, since the systemic toxic effects are additive. Simultaneous use of Naropin with general anaesthetics or opioids may potentiate each others (adverse) effects. Specific interaction studies with ropivacaine and anti-arrhythmic drugs class III (e.g. amiodarone) have not been performed, but caution is advised (see also section 4.4 Special warnings and precautions for use).

Cytochrome P450 (CYP) 1A2 is involved in the formation of 3-hydroxy-ropivacaine, the major metabolite. In vivo, the plasma clearance of ropivacaine was reduced by up to 77% during co

In vivo, the plasma clearance of ropivacaine was reduced by 15% during co

In vitro, ropivacaine is a competitive inhibitor of CYP2D6 but does not seem to inhibit this isozyme at clinically attained plasma concentrations.

4.6 Pregnancy And Lactation

Pregnancy

Apart from epidural administration for obstetrical use, there are no adequate data on the use of ropivacaine in human pregnancy. Experimental animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/f?tal development, parturition or postnatal development (see section 5.3 Preclinical safety data).

Lactation

There are no data available concerning the excretion of ropivacaine into human milk.

4.7 Effects On Ability To Drive And Use Machines

No data are available. Depending on the dose, local anaesthetics may have a minor influence on mental function and co-ordination even in the absence of overt CNS toxicity and may temporarily impair locomotion and alertness.

4.8 Undesirable Effects

General

The adverse reaction profile for Naropin is similar to those for other long acting local anaesthetics of the amide type. Adverse drug reactions should be distinguished from the physiological effects of the nerve block itself e.g. a decrease in blood pressure and bradycardia during spinal/epidural block.

Table of adverse drug reactions

Within each system organ class, the ADRs have been ranked under the headings of frequency, most frequent reactions first.

Very common (>1/10)

Vascular Disorders

Hypotension

 

 

Gastrointestinal Disorders

Nausea

Common (>1/100)

Nervous System Disorders

Headache, paraesthesia, dizziness

 

 

Cardiac Disorders

Bradycardia, tachycardia

 

Vascular Disorders

Hypertension

 

Gastrointestinal Disorders

Vomiting

 

Renal and Urinary Disorders

Urinary retention

 

General Disorder and Administration Site Conditions

Temperature elevation, rigor, back pain

Uncommon (>1/1,000)

Psychiatric Disorders

Anxiety

 

Nervous System Disorders

Symptoms of CNS toxicity (convulsions, grand mal convulsions, seizures, light headedness, circumoral paraesthesia, numbness of the tongue, hyperacusis, tinnitus, visual disturbances, dysarthria, muscular twitching, tremor)* , Hypoaesthesia.

 

 

Vascular Disorders

Syncope

 

 

Respiratory, Thoracic and Mediastinal Disorders

Dyspnoea

 

 

General Disorders and Administration Site Conditions

Hypothermia

Rare (>1/10,000)

Cardiac Disorders

Cardiac arrest, cardiac arrhythmias

 

 

General Disorder and Administration Site Conditions

Allergic reactions (anaphylactic reactions, angioneurotic oedema and urticaria)

* These symptoms usually occur because of inadvertent intravascular injection, overdose or rapid absorption, see section 4.9

Class-related adverse drug reactions:

Neurological complications

Neuropathy and spinal cord dysfunction (e.g. anterior spinal artery syndrome, arachnoiditis, cauda equina), which may result in rare cases of permanent sequelae, have been associated with regional anaesthesia, regardless of the local anaesthetic used.

Total spinal block

Total spinal block may occur if an epidural dose is inadvertently administered intrathecally.

Acute systemic toxicity

Systemic toxic reactions primarily involve the central nervous system (CNS) and the cardiovascular system (CVS). Such reactions are caused by high blood concentration of a local anaesthetic, which may appear due to (accidental) intravascular injection, overdose or exceptionally rapid absorption from highly vascularized areas, see also section 4.4. CNS reactions are similar for all amide local anaesthetics, while cardiac reactions are more dependent on the drug, both quantitatively and qualitatively.

Central nervous system toxicity

Central nervous system toxicity is a graded response with symptoms and signs of escalating severity. Initially symptoms such as visual or hearing disturbances, perioral numbness, dizziness, light-headedness, tingling and paraesthesia are seen. Dysarthria, muscular rigidity and muscular twitching are more serious and may precede the onset of generalised convulsions. These signs must not be mistaken for neurotic behaviour. Unconsciousness and grand mal convulsions may follow, which may last from a few seconds to several minutes. Hypoxia and hypercarbia occur rapidly during convulsions due to the increased muscular activity, together with the interference with respiration. In severe cases even apnoea may occur. The respiratory and metabolic acidosis increases and extends the toxic effects of local anaesthetics.

Recovery follows the redistribution of the local anaesthetic drug from the central nervous system and subsequent metabolism and excretion. Recovery may be rapid unless large amounts of the drug have been injected.

Cardiovascular system toxicity

Cardiovascular toxicity indicates a more severe situation. Hypotension, bradycardia, arrhythmia and even cardiac arrest may occur as a result of high systemic concentrations of local anaesthetics. In volunteers the intravenous infusion of ropivacaine resulted in signs of depression of conductivity and contractility.

Cardiovascular toxic effects are generally preceded by signs of toxicity in the central nervous system, unless the patient is receiving a general anaesthetic or is heavily sedated with drugs such as benzodiazepines or barbiturates.

In children, early signs of local anaesthetic toxicity may be difficult to detect since they may not be able to verbally express them. See also section 4.4.

Treatment of acute systemic toxicity

See section 4.9 Overdose.

4.9 Overdose

Symptoms:

Accidental intravascular injections of local anaesthetics may cause immediate (within seconds to a few minutes) systemic toxic reactions. In the event of overdose, peak plasma concentrations may not be reached for one to two hours, depending on the site of the injection, and signs of toxicity may thus be delayed. (See section 4.8 Acute systemic toxicity, Central nervous system toxicity and Cardiovascular system toxicity).

Treatment

If signs of acute systemic toxicity appear, injection of the local anaesthetic should be stopped immediately and CNS symptoms (convulsions, CNS depression) must promptly be treated with appropriate airway/respiratory support and the administration of anticonvulsant drugs.

If circulatory arrest should occur, immediate cardiopulmonary resuscitation should be instituted. Optimal oxygenation and ventilation and circulatory support as well as treatment of acidosis are of vital importance.

If cardiovascular depression occurs (hypotension, bradycardia), appropriate treatment with intravenous fluids, vasopressor, and or inotropic agents should be considered. Children should be given doses commensurate with age and weight.

Should cardiac arrest occur, a successful outcome may require prolonged resuscitative efforts.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Anaesthetics, local, Amides

ATC code: N01B B09

Ropivacaine is a long-acting, amide-type local anaesthetic with both anaesthetic and analgesic effects. At high doses Naropin produces surgical anaesthesia, while at lower doses it produces sensory block with limited and non-progressive motor block.

The mechanism is a reversible reduction of the membrane permeability of the nerve fibre to sodium ions. Consequently the depolarisation velocity is decreased and the excitable threshold increased, resulting in a local blockade of nerve impulses.

The most characteristic property of ropivacaine is the long duration of action. Onset and duration of the local anaesthetic efficacy are dependent upon the administration site and dose, but are not influenced by the presence of a vasoconstrictor (e.g. adrenaline (epinephrine)). For details concerning the onset and duration of action of Naropin, see table under posology and method of administration.

Healthy volunteers exposed to intravenous infusions tolerated ropivacaine well at low doses and with expected CNS symptoms at the maximum tolerated dose. The clinical experience with this drug indicates a good margin of safety when adequately used in recommended doses.

5.2 Pharmacokinetic Properties

Ropivacaine has a chiral center and is available as the pure S-(-)-enantiomer. It is highly lipid-soluble. All metabolites have a local anaesthetic effect but of considerably lower potency and shorter duration than that of ropivacaine.

The plasma concentration of ropivacaine depends upon the dose , the route of administration and the vascularity of the injection site. Ropivacaine follows linear pharmacokinetics and the Cmax is proportional to the dose.

Ropivacaine shows complete and biphasic absorption from the epidural space with half-lives of the two phases of the order of 14 min and 4 h in adults. The slow absorption is the rate-limiting factor in the elimination of ropivacaine, which explains why the apparent elimination half-life is longer after epidural than after intravenous administration.

Ropivacaine has a mean total plasma clearance in the order of 440 ml/min, a renal clearance of 1 ml/min, a volume of distribution at steady state of 47 litres and a terminal half-life of 1.8 h after iv administration. Ropivacaine has an intermediate hepatic extraction ratio of about 0.4. It is mainly bound to ?1- acid glycoprotein in plasma with an unbound fraction of about 6%.

An increase in total plasma concentrations during continuous epidural infusion has been observed, related to a postoperative increase of ?1- acid glycoprotein.

Variations in unbound, i.e. pharmacologically active, concentration have been much less than in total plasma concentration.

Ropivacaine readily crosses the placenta and equilibrium in regard to unbound concentration will be rapidly reached. The degree of plasma protein binding in the foetus is less than in the mother, which results in lower total plasma concentrations in the foetus than in the mother.

Ropivacaine is extensively metabolised, predominantly by aromatic hydroxylation. In total, 86% of the dose is excreted in the urine after intravenous administration, of which only about 1% relates to unchanged drug. The major metabolite is 3-hydroxy-ropivacaine, about 37% of which is excreted in the urine, mainly conjugated. Urinary excretion of 4-hydroxy-ropivacaine, the N-dealkylated metabolite and the 4-hydroxy-dealkylated accounts for 1–3%. Conjugated and unconjugated 3-hydroxy-ropivacaine shows only detectable concentrations in plasma.

There is no evidence of in vivo racemisation of ropivacaine.

5.3 Preclinical Safety Data

Based on conventional studies of safety pharmacology, single and repeated dose toxicity, reproduction toxicity, mutagenic potential and local toxicity, no hazards for humans were identified other than those which can be expected on the basis of the pharmacodynamic action of high doses of ropivacaine (e.g. CNS signs, including convulsions, and cardiotoxicity).

6. Pharmaceutical Particulars 6.1 List Of Excipients

Sodium chloride

Hydrochloric acid

Sodium hydroxide

Water for injection

6.2 Incompatibilities

In alkaline solutions precipitation may occur as ropivacaine shows poor solubility at pH > 6

6.3 Shelf Life

3 years.

Shelf life after first opening:

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2–8°C.

6.4 Special Precautions For Storage

Do not store above 30°C. Do not freeze.

For storage after opening, see section 6.3.

6.5 Nature And Contents Of Container

10 ml polypropylene ampoules (Polyamp) in packs of 5 and 10.

10 ml polypropylene ampoules (Polyamp) in sterile blister packs of 5 and 10.

20 ml polypropylene ampoules (Polyamp) in packs of 5 and 10.

20 ml polypropylene ampoules (Polyamp) in sterile blister packs of 5 and 10.

The polypropylene ampoules (Polyamp) are specially designed to fit Luer lock and Luer fit syringes.

6.6 Special Precautions For Disposal And Other Handling

Naropin products are preservative-free and are intended for single use only. Discard any unused solution.

The intact container must not be re-autoclaved. A blistered container should be chosen when a sterile outside is required.

7. Marketing Authorisation Holder

AstraZeneca UK Ltd.,

600 Capability Green,

Luton, LU1 3LU, UK.

8. Marketing Authorisation Number(S)

PL 17901/0150

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of first authorisation: 3rd October 1995

Date of last renewal: 15th September 2005

10. Date Of Revision Of The Text

15th August 2008


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Naropin 7.5 mg / ml solution for injection


1. Name Of The Medicinal Product

Naropin® 7.5 mg/ml solution for injection

2. Qualitative And Quantitative Composition

Naropin® 7.5 mg/ml:

1 ml solution for injection contains ropivacaine hydrochloride monohydrate equivalent to 7.5 mg ropivacaine hydrochloride.

1 ampoule of 10 ml or 20 ml solution for injection contains ropivacaine hydrochloride monohydrate equivalent to 75 mg and 150 mg ropivacaine hydrochloride respectively.

For excipients, see section 6.1.

3. Pharmaceutical Form

Solution for injection for perineural and epidural administration (10–20 ml).

Clear, colourless solution.

4. Clinical Particulars 4.1 Therapeutic Indications

Naropin is indicated for:

1. Surgical anaesthesia

2. Acute pain management

4.2 Posology And Method Of Administration

Naropin should only be used by, or under the supervision of, clinicians experienced in regional anaesthesia.

Posology

Adults and children above 12 years of age:

The following table is a guide to dosage for the more commonly used blocks. The smallest dose required to produce an effective block should be used. The clinician's experience and knowledge of the patient's physical status are of importance when deciding the dose.

 

 

Conc.

Volume

Dose

Onset

Duration

 

 

mg/ml

ml

mg

minutes

hours

Surgical anaesthesia

         

Lumbar Epidural Administration

 

 

 

 

 

 

 

 

 

 

Surgery

7.5

15–25

113–188

10–20

3–5

 

 

10

15–20

150–200

10–20

4–6

Caesarean section

7.5

15–20

113–150(1)

10–20

3–5

Thoracic Epidural Administration

 

 

 

 

 

 

 

 

 

 

To establish block for postoperative pain relief

7.5

5–15 (depending on the level of injection)

38–113

10–20

n/a(2)

Major Nerve Block*

 

 

 

 

 

 

 

 

 

 

Brachial plexus block

7.5

30–40

225–300(3)

10–25

6–10

Field Block

7.5

1–30

7.5–225

1–15

2–6

(e.g. minor nerve blocks and infiltration)

 

 

 

 

 

 

 

 

 

 

Acute pain management

         

Lumbar Epidural Administration

 

 

 

 

 

 

 

 

 

 

Bolus

2

10–20

20–40

10–15

0.5–1.5

Intermittent injections (top up)

(e.g. labour pain management)

2

10–15

(minimum interval 30 minutes)

20–30

 

 

 

 

Continuous infusion e.g. labour pain

2

6–10 ml/h

12–20 mg/h

n/a(2)

n/a(2)

Postoperative pain management

2

6–14 ml/h

12–28 mg/h

n/a(2)

n/a(2)

Thoracic Epidural Administration

 

 

 

 

 

 

 

 

 

 

Continuous infusion (postoperative pain management)

2

6–14 ml/h

12–28 mg/h

n/a(2)

n/a(2)

Field Block

 

 

 

 

 

 

 

 

 

 

(e.g. minor nerve blocks and infiltration)

2

1–100

2–200

1–5

2–6

Peripheral nerve block

(Femoral or interscalene block)

 

 

 

 

 

 

 

 

 

 

Continuous infusion or intermittent injections

(e.g. postoperative pain management)

2

5–10 ml/h

10–20 mg/h

n/a

n/a

The doses in the table are those considered to be necessary to produce a successful block and should be regarded as guidelines for use in adults. Individual variations in onset and duration occur. The figures in the column 'Dose' reflect the expected average dose range needed. Standard textbooks should be consulted for both factors affecting specific block techniques and individual patient requirements.

         

* With regard to major nerve block, only for brachial plexus block a dose recommendation can be given. For other major nerve blocks lower doses may be required. However, there is presently no experience of specific dose recommendations for other blocks.

         

(1) Incremental dosing should be applied, the starting dose of about 100 mg (97.5 mg = 13 ml; 105 mg = 14 ml) to be given over 3–5 minutes. Two extra doses, in total an additional 50mg, may be administered as needed.

(2) n/a = not applicable

(3) The dose for a major nerve block must be adjusted according to site of administration and patient status. Interscalene and supraclavicular brachial plexus blocks may be associated with a higher frequency of serious adverse reactions, regardless of the local anaesthetic used, (see section 4.4. Special warnings and special precautions for use).

         

In general, surgical anaesthesia (e.g. epidural administration) requires the use of the higher concentrations and doses. The Naropin 10 mg/ml formulation is recommended for epidural anaesthesia in which a complete motor block is essential for surgery. For analgesia (e.g. epidural administration for acute pain management) the lower concentrations and doses are recommended.

Method of administration

Careful aspiration before and during injection is recommended to prevent intravascular injection. When a large dose is to be injected, a test dose of 3–5 ml lidocaine (lignocaine) with adrenaline (epinephrine) (Xylocaine® 2% with Adrenaline (epinephrine) 1:200,000) is recommended. An inadvertent intravascular injection may be recognised by a temporary increase in heart rate and an accidental intrathecal injection by signs of a spinal block.

Aspiration should be performed prior to and during administration of the main dose, which should be injected slowly or in incremental doses, at a rate of 25–50 mg/min, while closely observing the patient's vital functions and maintaining verbal contact. If toxic symptoms occur, the injection should be stopped immediately.

In epidural block for surgery, single doses of up to 250 mg ropivacaine have been used and well tolerated.

In brachial plexus block a single dose of 300 mg has been used in a limited number of patients and was well tolerated.

When prolonged blocks are used, either through continuous infusion or through repeated bolus administration, the risks of reaching a toxic plasma concentration or inducing local neural injury must be considered. Cumulative doses up to 675 mg ropivacaine for surgery and postoperative analgesia administered over 24 hours were well tolerated in adults, as were postoperative continuous epidural infusions at rates up to 28 mg/hour for 72 hours. In a limited number of patients, higher doses of up to 800 mg/day have been administered with relatively few adverse reactions.

For treatment of postoperative pain, the following technique can be recommended: Unless preoperatively instituted, an epidural block with Naropin 7.5 mg/ml is induced via an epidural catheter. Analgesia is maintained with Naropin 2 mg/ml infusion. Infusion rates of 6–14 ml (12–28 mg) per hour provide adequate analgesia with only slight and non-progressive motor block in most cases of moderate to severe postoperative pain. The maximum duration of epidural block is 3 days. However, close monitoring of analgesic effect should be performed in order to remove the catheter as soon as the pain condition allows it. With this technique a significant reduction in the need for opioids has been observed.

In clinical studies an epidural infusion of Naropin 2 mg/ml alone or mixed with fentanyl 1-4 ?g/ml has been given for postoperative pain management for up to 72 hours. The combination of Naropin and fentanyl provided improved pain relief but caused opioid side effects. The combination of Naropin and fentanyl has been investigated only for Naropin 2 mg/ml.

When prolonged peripheral nerve blocks are applied, either through continuous infusion or through repeated injections, the risks of reaching a toxic plasma concentration or inducing local neural injury must be considered. In clinical studies, femoral nerve block was established with 300 mg Naropin 7.5 mg/ml and interscalene block with 225 mg Naropin 7.5 mg/ml, respectively, before surgery. Analgesia was then maintained with Naropin 2 mg/ml. Infusion rates or intermittent injections of 10–20 mg per hour for 48 hours provided adequate analgesia and were well tolerated.

Concentrations above 7.5 mg/ml Naropin have not been documented for Caesarean section.

4.3 Contraindications

Hypersensitivity to ropivacaine or to other local anaesthetics of the amide type.

General contraindications related to epidural anaesthesia, regardless of the local anaesthetic used, should be taken into account.

Intravenous regional anaesthesia.

Obstetric paracervical anaesthesia.

Hypovolaemia.

4.4 Special Warnings And Precautions For Use

Regional anaesthetic procedures should always be performed in a properly equipped and staffed area. Equipment and drugs necessary for monitoring and emergency resuscitation should be immediately available. Patients receiving major blocks should be in an optimal condition and have an intravenous line inserted before the blocking procedure. The clinician responsible should take the necessary precautions to avoid intravascular injection (see section 4.2 Posology and method of administration) and be appropriately trained and familiar with diagnosis and treatment of side effects, systemic toxicity and other complications (see section 4.8 Undesirable effects and 4.9 Overdose) such as inadvertent subarachnoid injection, which may produce a high spinal block with apnoea and hypotension. Convulsions have occurred most often after brachial plexus block and epidural block. This is likely to be the result of either accidental intravascular injection or rapid absorption from the injection site.

Caution is required to prevent injections in inflamed areas.

Cardiovascular

Patients treated with anti-arrhythmic drugs class III (eg, amiodarone) should be under close surveillance and ECG monitoring considered, since cardiac effects may be additive.

There have been rare reports of cardiac arrest during the use of Naropin for epidural anaesthesia or peripheral nerve blockade, especially after unintentional accidental intravascular administration in elderly patients and in patients with concomitant heart disease. In some instances, resuscitation has been difficult. Should cardiac arrest occur, prolonged resuscitative efforts may be required to improve the possibility of a successful outcome.

Head and neck blocks

Certain local anaesthetic procedures, such as injections in the head and neck regions, may be associated with a higher frequency of serious adverse reactions, regardless of the local anaesthetic used.

Major peripheral nerve blocks

Major peripheral nerve blocks may imply the administration of a large volume of local anaesthetic in highly vascularized areas, often close to large vessels where there is an increased risk of intravascular injection and/or rapid systemic absorption, which can lead to high plasma concentrations.

Hypersensitivity

A possible cross–hypersensitivity with other amide–type local anaesthetics should be taken into account.

Hypovolaemia

Patients with hypovolaemia due to any cause can develop sudden and severe hypotension during epidural anaesthesia, regardless of the local anaesthetic used.

Patients in poor general health

Patients in poor general condition due to ageing or other compromising factors such as partial or complete heart conduction block, advanced liver disease or severe renal dysfunction require special attention, although regional anaesthesia is frequently indicated in these patients.

Patients with hepatic and renal impairment

Ropivacaine is metabolised in the liver and should therefore be used with caution in patients with severe liver disease; repeated doses may need to be reduced due to delayed elimination. Normally there is no need to modify the dose in patients with impaired renal function when used for single dose or short-term treatment. Acidosis and reduced plasma protein concentration, frequently seen in patients with chronic renal failure, may increase the risk of systemic toxicity.

Acute porphyria

Naropin® solution for injection and infusion is possibly porphyrinogenic and should only be prescribed to patients with acute porphyria when no safer alternative is available. Appropriate precautions should be taken in the case of vulnerable patients, according to standard textbooks and/or in consultation with disease area experts.

Excipients with recognised action/effect

This medicinal product contains maximum 3.7 mg sodium per ml. To be taken into consideration by patients on a controlled sodium diet.

Prolonged administration

Prolonged administration of ropivacaine should be avoided in patients concomitantly treated with strong CYP1A2 inhibitors, such as fluvoxamine and enoxacin, see section 4.5.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Naropin should be used with caution in patients receiving other local anaesthetics or agents structurally related to amide-type local anaesthetics, e.g. certain antiarrhythmics, such as lidocaine and mexiletine, since the systemic toxic effects are additive. Simultaneous use of Naropin with general anaesthetics or opioids may potentiate each others (adverse) effects. Specific interaction studies with ropivacaine and anti-arrhythmic drugs class III (e.g. amiodarone) have not been performed, but caution is advised (see also section 4.4 Special warnings and precautions for use).

Cytochrome P450 (CYP) 1A2 is involved in the formation of 3-hydroxy-ropivacaine, the major metabolite. In vivo, the plasma clearance of ropivacaine was reduced by up to 77% during co

In vivo, the plasma clearance of ropivacaine was reduced by 15% during co

In vitro, ropivacaine is a competitive inhibitor of CYP2D6 but does not seem to inhibit this isozyme at clinically attained plasma concentrations.

4.6 Pregnancy And Lactation

Pregnancy

Apart from epidural administration for obstetrical use, there are no adequate data on the use of ropivacaine in human pregnancy. Experimental animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/f?tal development, parturition or postnatal development (see section 5.3 Preclinical safety data).

Lactation

There are no data available concerning the excretion of ropivacaine into human milk.

4.7 Effects On Ability To Drive And Use Machines

No data are available. Depending on the dose, local anaesthetics may have a minor influence on mental function and co-ordination even in the absence of overt CNS toxicity and may temporarily impair locomotion and alertness.

4.8 Undesirable Effects

General

The adverse reaction profile for Naropin is similar to those for other long acting local anaesthetics of the amide type. Adverse drug reactions should be distinguished from the physiological effects of the nerve block itself e.g. a decrease in blood pressure and bradycardia during spinal/epidural block.

Table of adverse drug reactions

Within each system organ class, the ADRs have been ranked under the headings of frequency, most frequent reactions first.

Very common (>1/10)

Vascular Disorders

Hypotension

 

 

Gastrointestinal Disorders

Nausea

Common (>1/100)

Nervous System Disorders

Headache, paraesthesia, dizziness

 

 

Cardiac Disorders

Bradycardia, tachycardia

 

Vascular Disorders

Hypertension

 

Gastrointestinal Disorders

Vomiting

 

Renal and Urinary Disorders

Urinary retention

 

General Disorder and Administration Site Conditions

Temperature elevation, rigor, back pain

Uncommon (>1/1,000)

Psychiatric Disorders

Anxiety

 

Nervous System Disorders

Symptoms of CNS toxicity (convulsions, grand mal convulsions, seizures, light headedness, circumoral paraesthesia, numbness of the tongue, hyperacusis, tinnitus, visual disturbances, dysarthria, muscular twitching, tremor)* , Hypoaesthesia.

 

 

Vascular Disorders

Syncope

 

 

Respiratory, Thoracic and Mediastinal Disorders

Dyspnoea

 

 

General Disorders and Administration Site Conditions

Hypothermia

Rare (>1/10,000)

Cardiac Disorders

Cardiac arrest, cardiac arrhythmias

 

 

General Disorder and Administration Site Conditions

Allergic reactions (anaphylactic reactions, angioneurotic oedema and urticaria)

* These symptoms usually occur because of inadvertent intravascular injection, overdose or rapid absorption, see section 4.9

Class-related adverse drug reactions:

Neurological complications

Neuropathy and spinal cord dysfunction (e.g. anterior spinal artery syndrome, arachnoiditis, cauda equina), which may result in rare cases of permanent sequelae, have been associated with regional anaesthesia, regardless of the local anaesthetic used.

Total spinal block

Total spinal block may occur if an epidural dose is inadvertently administered intrathecally.

Acute systemic toxicity

Systemic toxic reactions primarily involve the central nervous system (CNS) and the cardiovascular system (CVS). Such reactions are caused by high blood concentration of a local anaesthetic, which may appear due to (accidental) intravascular injection, overdose or exceptionally rapid absorption from highly vascularized areas, see also section 4.4. CNS reactions are similar for all amide local anaesthetics, while cardiac reactions are more dependent on the drug, both quantitatively and qualitatively.

Central nervous system toxicity

Central nervous system toxicity is a graded response with symptoms and signs of escalating severity. Initially symptoms such as visual or hearing disturbances, perioral numbness, dizziness, light-headedness, tingling and paraesthesia are seen. Dysarthria, muscular rigidity and muscular twitching are more serious and may precede the onset of generalised convulsions. These signs must not be mistaken for neurotic behaviour. Unconsciousness and grand mal convulsions may follow, which may last from a few seconds to several minutes. Hypoxia and hypercarbia occur rapidly during convulsions due to the increased muscular activity, together with the interference with respiration. In severe cases even apnoea may occur. The respiratory and metabolic acidosis increases and extends the toxic effects of local anaesthetics.

Recovery follows the redistribution of the local anaesthetic drug from the central nervous system and subsequent metabolism and excretion. Recovery may be rapid unless large amounts of the drug have been injected.

Cardiovascular system toxicity

Cardiovascular toxicity indicates a more severe situation. Hypotension, bradycardia, arrhythmia and even cardiac arrest may occur as a result of high systemic concentrations of local anaesthetics. In volunteers the intravenous infusion of ropivacaine resulted in signs of depression of conductivity and contractility.

Cardiovascular toxic effects are generally preceded by signs of toxicity in the central nervous system, unless the patient is receiving a general anaesthetic or is heavily sedated with drugs such as benzodiazepines or barbiturates.

In children, early signs of local anaesthetic toxicity may be difficult to detect since they may not be able to verbally express them. See also section 4.4.

Treatment of acute systemic toxicity

See section 4.9 Overdose.

4.9 Overdose

Symptoms:

Accidental intravascular injections of local anaesthetics may cause immediate (within seconds to a few minutes) systemic toxic reactions. In the event of overdose, peak plasma concentrations may not be reached for one to two hours, depending on the site of the injection, and signs of toxicity may thus be delayed. (See section 4.8 Acute systemic toxicity, Central nervous system toxicity and Cardiovascular system toxicity).

Treatment

If signs of acute systemic toxicity appear, injection of the local anaesthetic should be stopped immediately and CNS symptoms (convulsions, CNS depression) must promptly be treated with appropriate airway/respiratory support and the administration of anticonvulsant drugs.

If circulatory arrest should occur, immediate cardiopulmonary resuscitation should be instituted. Optimal oxygenation and ventilation and circulatory support as well as treatment of acidosis are of vital importance.

If cardiovascular depression occurs (hypotension, bradycardia), appropriate treatment with intravenous fluids, vasopressor, and or inotropic agents should be considered. Children should be given doses commensurate with age and weight.

Should cardiac arrest occur, a successful outcome may require prolonged resuscitative efforts.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Anaesthetics, local, Amides

ATC code: N01B B09

Ropivacaine is a long-acting, amide-type local anaesthetic with both anaesthetic and analgesic effects. At high doses Naropin produces surgical anaesthesia, while at lower doses it produces sensory block with limited and non-progressive motor block.

The mechanism is a reversible reduction of the membrane permeability of the nerve fibre to sodium ions. Consequently the depolarisation velocity is decreased and the excitable threshold increased, resulting in a local blockade of nerve impulses.

The most characteristic property of ropivacaine is the long duration of action. Onset and duration of the local anaesthetic efficacy are dependent upon the administration site and dose, but are not influenced by the presence of a vasoconstrictor (e.g. adrenaline (epinephrine)). For details concerning the onset and duration of action of Naropin, see table under posology and method of administration.

Healthy volunteers exposed to intravenous infusions tolerated ropivacaine well at low doses and with expected CNS symptoms at the maximum tolerated dose. The clinical experience with this drug indicates a good margin of safety when adequately used in recommended doses.

5.2 Pharmacokinetic Properties

Ropivacaine has a chiral center and is available as the pure S-(-)-enantiomer. It is highly lipid-soluble. All metabolites have a local anaesthetic effect but of considerably lower potency and shorter duration than that of ropivacaine.

The plasma concentration of ropivacaine depends upon the dose , the route of administration and the vascularity of the injection site. Ropivacaine follows linear pharmacokinetics and the Cmax is proportional to the dose.

Ropivacaine shows complete and biphasic absorption from the epidural space with half-lives of the two phases of the order of 14 min and 4 h in adults. The slow absorption is the rate-limiting factor in the elimination of ropivacaine, which explains why the apparent elimination half-life is longer after epidural than after intravenous administration.

Ropivacaine has a mean total plasma clearance in the order of 440 ml/min, a renal clearance of 1 ml/min, a volume of distribution at steady state of 47 litres and a terminal half-life of 1.8 h after iv administration. Ropivacaine has an intermediate hepatic extraction ratio of about 0.4. It is mainly bound to ?1- acid glycoprotein in plasma with an unbound fraction of about 6%.

An increase in total plasma concentrations during continuous epidural infusion has been observed, related to a postoperative increase of ?1- acid glycoprotein.

Variations in unbound, i.e. pharmacologically active, concentration have been much less than in total plasma concentration.

Ropivacaine readily crosses the placenta and equilibrium in regard to unbound concentration will be rapidly reached. The degree of plasma protein binding in the foetus is less than in the mother, which results in lower total plasma concentrations in the foetus than in the mother.

Ropivacaine is extensively metabolised, predominantly by aromatic hydroxylation. In total, 86% of the dose is excreted in the urine after intravenous administration, of which only about 1% relates to unchanged drug. The major metabolite is 3-hydroxy-ropivacaine, about 37% of which is excreted in the urine, mainly conjugated. Urinary excretion of 4-hydroxy-ropivacaine, the N-dealkylated metabolite and the 4-hydroxy-dealkylated accounts for 1–3%. Conjugated and unconjugated 3-hydroxy-ropivacaine shows only detectable concentrations in plasma.

There is no evidence of in vivo racemisation of ropivacaine.

5.3 Preclinical Safety Data

Based on conventional studies of safety pharmacology, single and repeated dose toxicity, reproduction toxicity, mutagenic potential and local toxicity, no hazards for humans were identified other than those which can be expected on the basis of the pharmacodynamic action of high doses of ropivacaine (e.g. CNS signs, including convulsions, and cardiotoxicity).

6. Pharmaceutical Particulars 6.1 List Of Excipients

Sodium chloride

Hydrochloric acid

Sodium hydroxide

Water for injection

6.2 Incompatibilities

In alkaline solutions precipitation may occur as ropivacaine shows poor solubility at pH > 6

6.3 Shelf Life

3 years.

Shelf life after first opening:

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2–8°C.

6.4 Special Precautions For Storage

Do not store above 30°C. Do not freeze.

For storage after opening, see section 6.3.

6.5 Nature And Contents Of Container

10 ml polypropylene ampoules (Polyamp) in packs of 5 and 10.

10 ml polypropylene ampoules (Polyamp) in sterile blister packs of 5 and 10.

20 ml polypropylene ampoules (Polyamp) in packs of 5 and 10.

20 ml polypropylene ampoules (Polyamp) in sterile blister packs of 5 and 10.

The polypropylene ampoules (Polyamp) are specially designed to fit Luer lock and Luer fit syringes.

6.6 Special Precautions For Disposal And Other Handling

Naropin products are preservative-free and are intended for single use only. Discard any unused solution.

The intact container must not be re-autoclaved. A blistered container should be chosen when a sterile outside is required.

7. Marketing Authorisation Holder

AstraZeneca UK Ltd.,

600 Capability Green,

Luton, LU1 3LU, UK.

8. Marketing Authorisation Number(S)

PL 17901/0152

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of first authorisation: 3rd October 1995

Date of last renewal: 15th September 2005

10. Date Of Revision Of The Text

15th August 2008


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Lidocaine Hydrochloride Injection BP 1.0% w / v


1. Name Of The Medicinal Product

Lidocaine Hydrochloride Injection BP 1.0% w/v.

2. Qualitative And Quantitative Composition

Each 1ml of solution contains 1.0% w/v of Lidocaine Hydrochloride BP (Lidocaine Hydrochloride).

3. Pharmaceutical Form

Clear, colourless, sterile solution for injection, intended for parenteral administration to human beings.

4. Clinical Particulars 4.1 Therapeutic Indications

Lidocaine is a local anaesthetic of the amide group. The injectable form has a wide range of applications for nerve blockade. It can be used by percutaneous infiltration; to block a major nerve plexus such as the brachial; for epidural anaesthesia; for intravenous regional analgesia.

4.2 Posology And Method Of Administration

The dosage should be adjusted according to the response of the patient and the site of administration. The lowest concentration and smallest dose producing the required effect should be given. The maximum dose for healthy adults should not exceed 200mg.

Children and elderly or debilitated patients require smaller doses, commensurate with age and physical status.

4.3 Contraindications

Known hypersensitivity to anaesthetics of the amide type.

4.4 Special Warnings And Precautions For Use

Lidocaine should be administered by persons with resuscitative skills and equipment. Extreme care should be observed in patients with hypovolaemia, heart block or other conduction disturbances. It should be used with caution in patients with congestive heart failure, bradycardia or respiratory depression, including where agents are known to interact with Lidocaine either to increase its availability or additive effects e.g. phenytoin or prolong its elimination e.g. hepatic or end renal insufficiency where the metabolites of Lidocaine may accumulate.

Intramuscular Lidocaine may increase creatinine phosphokinase concentrations which can interfere with the diagnosis of acute myocardial infarction. The use of Lidocaine for the treatment of ventricular arrhythmias not associated with a myocardial infarction might be hazardous in patients with hypoxia where there is a depression of the cough reflex. Lidocaine has been shown to be porphyrinogenic in animals and should be avoided in persons suffering from porphyria.

The effect of Lidocaine may be reduced if it is injected into inflamed or infected areas. Care should be observed in patients suffering from epilepsy.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Lidocaine toxicity is enhanced by the co-administration of cimetidine and propranolol. Both drugs decrease hepatic blood flow. Also, cimetidine depresses microsomial activity. Ranitidine produces a small reduction in Lidocaine clearance.

Cardiovascular collapse has been reported following the use of bupivacaine in patients on treatment with verapamil and timolol; Lidocaine is closely related to bupivacaine.

Prenylamine and Lidocaine Infusion may precipitate atrioventricular block and ventricular tachycardia.

Dopamine and 5 hydroxytryptamine reduce the convulsant threshold to Lidocaine.

Narcotics are probably proconvulsants and this would support the evidence that Lidocaine reduces the seizure threshold to fentanyl in man.

Opioid-antiemetic combination sometimes used for sedation in children could reduce the convulsant threshold to Lidocaine and increase the CNS depressant effect.

While adrenaline when used in conjunction with Lidocaine might decrease vascular absorption, it greatly increases the danger of ventricular tachycardia and fibrillation if accidentally injected intravenously.

Hypoxia and acidosis will enhance the cardiovascular and central nervous system toxicity of Lidocaine in animals. In man, such changes commonly accompany convulsions and can be expected to exacerbate cardiac sequelae.

4.6 Pregnancy And Lactation

Lidocaine readily crosses the placental barrier after epidural or intravenous administration to the mother. The ratio of umbilical to maternal venous concentration is 0.5 to 0.6. The foetus appears to be capable of metabolising Lidocaine at term. The elimination half life in the newborn of the drug received in utero is about three hours, compared with 100 minutes in the adult.

Moderate doses of Lidocaine over short periods have been used in mothers receiving antiarrhythmic drugs in late pregnancy. Foetal blood concentrations are about half of the maternal values and by term the foetus is capable of metabolising Lidocaine.

Local anaesthetics are not noted for producing congenital malformations. Foetal bradycardia may occur during extradural analgesia using Lidocaine. This may result from placental drug transfer or it may be secondary to maternal circulatory changes.

Symptoms of overdose will occur in the same order as in the adult. In clinical practice, neonatal effects are generally slight and are largely limited to hypotonia and neonatal depression. Excessive doses can occur following paracervical block probably resulting from direct entry of drug to the placental circulation, or because solution is injected to the head in mistake for the caudal canal or the paracervical region.

Lidocaine is secreted into the breast milk. Although mothers on infusions of Lidocaine could probably continue to breast feed with safety, caution should be exercised. There is a remote possibility of an idiosyncratic or allergic reaction.

4.7 Effects On Ability To Drive And Use Machines

Where major motor nerve block occurs e.g. Brachial plexus, epidural, spinal block. Where there is a loss of sensation resulting from nerve block to areas of muscle co-ordination or balance. Advice is that for general anaesthesia as sedative/hypnotic drugs are often used during nerve blockade.

4.8 Undesirable Effects

Localised nerve damage at the site of injection (very rare).

Prolonged neural blockade following epidural may be due to delayed spread. Permanent neural blockade may be more likely associated with hypotension and cord ischaemia.

Following regional blockade as when Lidocaine is injected intrathecally or extradurally, hypotension, hypoventilation, Horners Syndrome and hypoglycaemia may be seen. The degree of these effects will depend on the dose and the height of the block. Urinary retention may occur following sacral or lumbar epidural block. It should not outlast the duration of the block. Apnoea and coma followed by aphasia and hemiparesis following stellate ganglion block. The probable cause is a direct injection of Lidocaine into the vertebral or carotid arteries.

Profound lethargy and death have been reported following the injection of only 10 - 32mg of Lidocaine for dental blocks.

Diplopia and temporary blindness has been reported following Lidocaine for maxillary block, also respiratory arrest following retrobulbar block.

The major adverse effects on the CNS and CVS are primarily due to the absorption of Lidocaine into the systemic circulation. Lidocaine may also produce methaemoglobinaemia.

The initial CNS toxic effects are demonstrated by a gradual onset of drowsiness or inebriation similar to alcoholic intoxication. Balance is disturbed, circumoral pins and needles, numb tongue, roaring in the ears, visual disturbances, restlessness and twitching may occur. Severe intoxication of rapid onset may immediately lead to convulsions followed by circulatory depression. Major overdosage may depress all systems simultaneously. Psychotic reactions have been reported following infusion for the control of arrhythmia.

Profound hypotension may be associated with B blockade, widespread sympathetic block from spinal or epidural block, intercostal nerve block administration or supine hypotension in pregnancy.

Ventricular fibrillation occurs less frequently than that seen with bupivacaine.

Respiratory Depression

Medullary depression associated with systemic effects, following retrobulbar nerve blockade, high spinal or extradural blocks causing motor block, possible subarachnoid spread following on excessive dose by interscalene brachial plexus block. An increase in extradural pressure may cause transient respiratory depression. Respiratory distress as an allergic response can occur.

Allergic reactions (including anaphylaxis) have been reported rarely.

4.9 Overdose

Systemic toxicity affecting principally the CNS and secondarily the CVS may arise because of acute or cumulative overdosage. Acute toxicity can occur due to excessive doses above that recommended minimum by rapid entry of Lidocaine into the circulation from accidental or deliberate intravenous injection, rapid absorption from a vascular site or transplacental passage. Cumulative toxicity may slow elimination or drug interaction.

Symptoms relating to the central nervous and cardiovascular systems are: gradual onset of drowsiness or inebriation, disturbance in balance, later circumoral pins and needles, numb tongue, roaring in the ears, visual disturbances, restlessness and twitching, progressing to convulsions and coma in severe states. If the overdose is of rapid onset, convulsions may occur closely followed by cardiovascular depression. Major overdosage may depress all symptoms simultaneously.

Psychotic reactions have been reported following I.V. infusions of Lidocaine. Bradycardia and hypotension, the latter being due to sympathetic blockade and vasomotor and cardiac centres depression. In the medulla, cardiac depression, allergic reaction.

Heavy pre-anaesthetic medication should be avoided, which will mask early signs of CNS toxicity, while an anticonvulsant may even suppress seizure activity until circulatory collapse supervenes.

Initially, oxygen should be administered. It may be necessary to give an anticonvulsant. Thiopentone has a more rapid onset of action than diazepam. Both drugs especially thiopentone may seriously exacerbate circulatory and respiratory depression.

Persistent convulsion may require the use of suxamethonium to stop muscle activity and allow for intubation, control of the airway and artificial ventilation. Agents to support the cardiovascular system may also be required. The correction of acidosis is very important.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Lidocaine is used to provide anaesthesia by nerve blockade at various sites in the body and in the control of dysrhythmias. It has a rapid onset of action (about one minute following intravenous injection and fifteen minutes following intramuscular injection) and rapidly spreads through the surrounding tissues. The effect lasts about ten to twenty minutes and about sixty to ninety minutes following intravenous and intramuscular injection respectively.

5.2 Pharmacokinetic Properties

The concentration of Lidocaine in the blood will be determined by its rate of absorption from the site of injection, the rate of tissue distribution and the rate of metabolism and excretion.

The systemic absorption of Lidocaine is determined by the site of injection, the dosage and its pharmacological profile. The maximum blood concentration occurs following intercostal nerve blockade followed in order of decreasing concentration, the lumbar epidural space, brachial plexus site and subcutaneous tissue. The total dose injected regardless of the site is the primary determinant of the absorption rate and blood levels achieved. There is a linear relationship between the amount of Lidocaine injected and the resultant peak anaesthetic blood levels.

The lipid solubility and vasodilator activity will also influence its rate of absorption. This is seen in the epidural space where Lidocaine is absorbed more rapidly than prilocaine.

Lidocaine is distributed throughout the total body water. Its rate of disappearance from the blood can be described by a two or three compartment model. There is a rapid disappearance (alpha) phase which is believed to be related to uptake by rapidly equilibrating tissues (i.e. tissues with a high vascular perfusion). The slower phase is related to distribution, to slowly equilibrating tissues (Betaphase) and to its metabolism and excretion (Gamma phase).

Lidocaine is distributed less rapidly than prilocaine (an amide drug of similar potency and duration of action) but equally as with mepivacaine. Its distribution is throughout all body tissues. In general, the more highly perfused organs will show higher concentrations of Lidocaine. The highest percentage of this drug will be found in skeletal muscle. This is because of the mass of muscle rather than an affinity.

Lidocaine undergoes enzymatic degradation primarily in the liver. Some degradation may take in tissues other than liver. The main pathway involves oxidative de-ethylation to monoethylglycinexylidide followed by a subsequent hydrolysis to xylidine.

The excretion occurs via the kidney with less than 5% in the unchanged form appearing in the urine. The renal clearance is inversely related to its protein binding affinity and the pH of the urine. This suggests by the latter that excretion of Lidocaine occurs by non-ionic diffusion.

5.3 Preclinical Safety Data

No further relevant information other than that which is included in other sections of the Summary of Product Characteristics.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Sodium Chloride

Sodium Hydroxide 10% w/v

Dilute Hydrochloric Acid

Water for Injections

6.2 Incompatibilities

Lidocaine has been found to be incompatible when mixed with amphotericin, methohexitone and glyceryl trinitrate. It is not advisable to mix Lidocaine with other agents.

6.3 Shelf Life

4 years (48 months).

If only part of an ampoule is used, the remainder should be discarded.

6.4 Special Precautions For Storage

Do not store above 25°C.

Keep in outer carton.

6.5 Nature And Contents Of Container

2ml, 5ml, 10ml & 20ml clear glass ampoules, glass type 1 Ph.Eur. presented in cardboard cartons to contain 10 x 2ml ampoules; 10 x 5ml ampoules; 10 x 10ml ampoules and 10 x 20ml ampoules.

6.6 Special Precautions For Disposal And Other Handling

For S.C., I.M. or I.V. injection.

Use as directed by the physician.

Keep out of reach of children.

If only part used, discard the remaining solution.

7. Marketing Authorisation Holder

Antigen International Ltd.

Roscrea

Co. Tipperary

Ireland

8. Marketing Authorisation Number(S)

PL 02848/0002R

9. Date Of First Authorisation/Renewal Of The Authorisation

25 November 1986 / 24 June 1992

10. Date Of Revision Of The Text

April 2008


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