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Marcaine Polyamp

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Indications and Usage (1) (12/2015)
Dosage and Administration (2) (12/2015)
Dosage and Administration, Injection Instructions (2.1) (12/2015)
Dosage and Administration, Compatibility Considerations (2.2) (12/2015)
Warnings and Precautions,

Warnings and Precautions Specific to Marcaine Polyamp (5.2)

 (12/2015)

Marcaine Polyamp is indicated for administration into the surgical site to produce postsurgical analgesia.

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

Marcaine Polyamp is a liposome injection of Marcaine Polyamp, an amide local anesthetic, indicated for single-dose infiltration into the surgical site to produce postsurgical analgesia (1).

2. DOSAGE AND ADMINISTRATION

Marcaine Polyamp is intended for single-dose administration only.

The recommended dose of Marcaine Polyamp is based on the following factors:


As general guidance in selecting the proper dosing for the planned surgical site, two examples of dosing are provided. One example of the recommended dose comes from a study in patients undergoing bunionectomy. A total of 8 mL (106 mg) was administered as 7 mL of Marcaine Polyamp infiltrated into the tissues surrounding the osteotomy, and 1 mL infiltrated into the subcutaneous tissue.

Another example comes from a study of patients undergoing hemorrhoidectomy. A total of 20 mL (266 mg) of Marcaine Polyamp was diluted with 10 mL of saline, for a total of 30 mL, divided into six 5 mL aliquots, injected by visualizing the anal sphincter as a clock face and slowly infiltrating one aliquot to each of the even numbers to produce a field block.

Marcaine Polyamp is intended for single-dose administration only.

The recommended dose of Marcaine Polyamp is based on the following factors:


Inject Marcaine Polyamp slowly into soft tissue via infiltration (2.1).

2.1 Injection Instructions

Marcaine Polyamp 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.

2.2 Compatibility Considerations

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


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

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

2.3 Non-Interchangeability with Other Formulations of Marcaine Polyamp

Different formulations of Marcaine Polyamp are not bioequivalent even if the milligram dosage is the same. Therefore, it is not possible to convert dosing from any other formulations of Marcaine Polyamp to Marcaine Polyamp 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.

3. DOSAGE FORMS AND STRENGTHS

Marcaine Polyamp (bupivacaine liposome injectable suspension)


Marcaine Polyamp (bupivacaine liposome injectable suspension)

20 mL single use vial, 1.3% (13.3 mg/mL) (3)

10 mL single use vial, 1.3% (13.3 mg/mL) (3)

4. CONTRAINDICATIONS

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

Marcaine Polyamp is contraindicated in obstetrical paracervical block anesthesia (4).

5. WARNINGS AND PRECAUTIONS

5.1 Warnings and Precautions for Marcaine Polyamp Containing Products

The safety and effectiveness of Marcaine Polyamp 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 Marcaine Polyamp, 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 Marcaine Polyamp 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.

Marcaine Polyamp 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 Marcaine Polyamp 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 Marcaine Polyamp, 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.

5.2 Warnings and Precautions Specific for Marcaine Polyamp

As there is a potential risk of severe life-threatening adverse effects associated with the administration of Marcaine Polyamp, Marcaine Polyamp 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 Marcaine Polyamp. Convulsions and cardiac arrest have occurred following accidental intravascular injection of Marcaine Polyamp and other amide-containing products.

Using Marcaine Polyamp followed by other Marcaine Polyamp formulations has not been studied in clinical trials. Formulations of Marcaine Polyamp other than Marcaine Polyamp should not be administered within 96 hours following administration of Marcaine Polyamp [See Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].

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


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


The ability of Marcaine Polyamp to achieve effective anesthesia has not been studied. Therefore, Marcaine Polyamp 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

Adverse reactions reported with an incidence greater than or equal to 10% following Marcaine Polyamp administration were nausea, constipation, and vomiting.

To report SUSPECTED ADVERSE REACTIONS, contact Pacira Pharmaceuticals, Inc. at 1-855-RX-EXPAREL (1-855-793-9727) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Bupivacaine Adverse Reactions

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

High plasma concentrations of Marcaine Polyamp can occur from overdosage, unintended intravascular injection, or accumulation of Marcaine Polyamp 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 Marcaine Polyamp and other amide-type local anesthetics and may rapidly develop signs of toxicity at low doses [See Overdosage (10)].

6.2 Clinical Trial Experience

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 Marcaine Polyamp 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 Marcaine Polyamp. In these studies, the most common adverse reactions (incidence greater than or equal to 10%) following Marcaine Polyamp administration were nausea, constipation, and vomiting.

The common adverse reactions (incidence greater than or equal to 2% to less than 10%) following Marcaine Polyamp 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 Marcaine Polyamp 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 incontinence, vision blurred, tinnitus, drug hypersensitivity, and hypersensitivity.

Neurological and Cardiac Adverse Reactions

In the Marcaine Polyamp surgical site infiltration studies, adverse reactions with an incidence greater than or equal to 1% in the Nervous System Disorders system organ class following Marcaine Polyamp 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 Marcaine Polyamp administration were tachycardia (3.9%) and bradycardia (1.6%).

Adverse Reactions Reported in Placebo-Controlled Trials

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

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
Marcaine Polyamp Placebo Marcaine Polyamp 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)

7. DRUG INTERACTIONS

Marcaine Polyamp can be administered in the ready to use suspension or diluted to a concentration of up to 0.89 mg/mL (i.e., 1:14 dilution by volume) with normal (0.9%) saline or lactated Ringer’s solution. Marcaine Polyamp must not be diluted with water or other hypotonic agents as it will result in disruption of the liposomal particles.

Marcaine Polyamp should not be admixed with local anesthetics other than Marcaine Polyamp. Non-bupivacaine based local anesthetics, including lidocaine, may cause an immediate release of Marcaine Polyamp from Marcaine Polyamp if administered together locally. The administration of Marcaine Polyamp may follow the administration of lidocaine after a delay of 20 minutes or more.

Marcaine Polyamp HCl administered together with Marcaine Polyamp may impact the pharmacokinetic and/or physicochemical properties of Marcaine Polyamp, and this effect is concentration dependent. Therefore, Marcaine Polyamp HCl and Marcaine Polyamp may be administered simultaneously in the same syringe, and Marcaine Polyamp HCl may be injected immediately before Marcaine Polyamp as long as the ratio of the milligram dose of Marcaine Polyamp HCl solution to Marcaine Polyamp does not exceed 1:2.

The toxic effects of these drugs are additive and their administration should be used with caution including monitoring for neurologic and cardiovascular effects related to toxicity [See Dosage and Administration (2.2), Warnings and Precautions (5.1) and Overdosage (10)].

Other than Marcaine Polyamp as noted above, Marcaine Polyamp should not be admixed with other drugs prior to administration.

8. USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

There are no studies conducted with Marcaine Polyamp in pregnant women. In animal reproduction studies, embryo-fetal deaths were observed with subcutaneous administration of Marcaine Polyamp to rabbits during organogenesis at a dose equivalent to 1.6 times the maximum recommended human dose (MRHD) of 266 mg. Subcutaneous administration of Marcaine Polyamp to rats from implantation through weaning produced decreased pup survival at a dose equivalent to 1.5 times the MRHD [see Data]. Based on animal data, advise pregnant women of the potential risks to a fetus.

The background risk of major birth defects and miscarriage for the indicated population is unknown. However, the background risk in the U.S. general population of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies.

Clinical Considerations

Labor or Delivery

Marcaine Polyamp is contraindicated for obstetrical paracervical block anesthesia. While Marcaine Polyamp has not been studied with this technique, the use of Marcaine Polyamp for obstetrical paracervical block anesthesia has resulted in fetal bradycardia and death.

Marcaine Polyamp can 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.

Data

Animal Data

Marcaine Polyamp hydrochloride was administered subcutaneously to rats and rabbits during the period of organogenesis (implantation to closure of the hard plate). Rat doses were 4.4, 13.3, and 40 mg/kg/day (equivalent to 0.2, 0.5 and 1.5 times the MRHD, respectively, based on the BSA comparisons and a 60 kg human weight) and rabbit doses were 1.3, 5.8, and 22.2 mg/kg/day (equivalent to 0.1, 0.4 and 1.6 times the MRHD, respectively, based on the BSA comparisons and a 60 kg human weight). No embryo-fetal effects were observed in rats at the doses tested with the high dose causing increased maternal lethality. An increase in embryo-fetal deaths was observed in rabbits at the high dose in the absence of maternal toxicity.

Decreased pup survival was noted at 1.5 times the MRHD in a rat pre- and post-natal development study when pregnant animals were administered subcutaneous doses of 4.4, 13.3, and 40 mg/kg/day buprenorphine hydrochloride (equivalent to 0.2, 0.5 and 1.5 times the MRHD, respectively, based on the BSA comparisons and a 60 kg human weight) from implantation through weaning (during pregnancy and lactation).

8.2 Lactation

Risk Summary

Limited published literature reports that Marcaine Polyamp and its’ metabolite, pipecolylxylidide, are present in human milk at low levels. There is no available information on effects of the drug in the breastfed infant or effects of the drug on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Marcaine Polyamp and any potential adverse effects on the breastfed infant from Marcaine Polyamp or from the underlying maternal condition.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

Of the total number of patients in the Marcaine Polyamp surgical site infiltration clinical studies, 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 Marcaine Polyamp 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. Marcaine Polyamp is known to be substantially excreted by the kidney, and the risk of toxic reactions to Marcaine Polyamp 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 Marcaine Polyamp.

8.6 Hepatic Impairment

Because amide-type local anesthetics, such as Marcaine Polyamp, 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.

8.7 Renal Impairment

Marcaine Polyamp 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 Marcaine Polyamp.

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 Marcaine Polyamp or systemic absorption of Marcaine Polyamp at the surgical site. The plasma Marcaine Polyamp measurements did not discern between free and liposomal-bound Marcaine Polyamp making the clinical relevance of the reported values uncertain; however, no discernible adverse events or clinical sequelae were observed in these patients.

11. DESCRIPTION

Marcaine Polyamp is a sterile, non-pyrogenic white to off-white preservative-free aqueous suspension of multivesicular liposomes containing Marcaine Polyamp. Marcaine Polyamp is present at a concentration of 13.3 mg/mL. After injection of Marcaine Polyamp into soft tissue, Marcaine Polyamp is released from the multivesicular liposomes over a period of time.

11.1 Active Ingredient

Marcaine Polyamp 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, Marcaine Polyamp is 1-butyl-N-(2,6-dimethylphenyl)-2-piperidinecarboxamide with a molecular weight of 288.4. Marcaine Polyamp has the following structural formula:

11.2 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 Marcaine Polyamp 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 Marcaine Polyamp 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

12.1 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: pain, (2) temperature, (3) touch, (4) proprioception, and (5) skeletal muscle tone.

12.2 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 Marcaine Polyamp.

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.

12.3 Pharmacokinetics

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

Absorption

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

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

Note: Arithmetic mean (standard deviation) except Tmax where it is median (range).
Surgical Site Administration
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 (0.5-24) 0.5 (0.25-36)
AUC(0-t) (h×ng/mL) 5864 (2038) 16,867 (7868)
AUC(inf) (h×ng/mL) 7105 (2283) 18,289 (7569)
t½ (h) 34 (17) 24 (39)

Distribution

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

Local anesthetics including Marcaine Polyamp 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 Marcaine Polyamp 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. Marcaine Polyamp 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 Marcaine Polyamp readily enter the fetal blood from the maternal circulation.

Metabolism

Amide-type local anesthetics, such as Marcaine Polyamp, are metabolized primarily in the liver via conjugation with glucuronic acid. Pipecolylxylidine (PPX) is the major metabolite of Marcaine Polyamp; approximately 5% of Marcaine Polyamp 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 Marcaine Polyamp has been released from Marcaine Polyamp and is absorbed systemically, Marcaine Polyamp excretion is expected to be the same as for other Marcaine Polyamp formulations.

The kidney is the main excretory organ for most local anesthetics and their metabolites. Only 6% of Marcaine Polyamp 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 Marcaine Polyamp pharmacokinetics following administration of Marcaine Polyamp were studied in patients with moderate hepatic impairment. Consistent with the hepatic clearance of Marcaine Polyamp, 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 Marcaine Polyamp, 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

Marcaine Polyamp 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 Marcaine Polyamp [See Use in Specific Populations (8.7)].

Age

Various pharmacokinetic parameters of the local anesthetics such as Marcaine Polyamp 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.

Marcaine Polyamp 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 Marcaine Polyamp [See Use in Specific Populations (8.5)].

13. NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis. Long-term studies in animals to evaluate the carcinogenic potential of Marcaine Polyamp have not been conducted.

Mutagenesis. The mutagenic potential of Marcaine Polyamp has not been determined.

Impairment of Fertility. The effect of Marcaine Polyamp on fertility has not been determined.

14. CLINICAL STUDIES

The efficacy of Marcaine Polyamp 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.

14.1 Study 1

A multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trial evaluated the safety and efficacy of 106 mg Marcaine Polyamp in 193 patients undergoing bunionectomy. The mean age was 43 years (range 18 to 72).

Study medication was administered directly into the site at the conclusion of the surgery, prior to closure. There was an infiltration of 7 mL of Marcaine Polyamp into the tissues surrounding the osteotomy and 1 mL into the subcutaneous tissue.

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 Marcaine Polyamp compared to placebo. Marcaine Polyamp demonstrated a significant reduction in pain intensity compared to placebo for up to 24 hours (p<0.001).

14.2 Study 2

A multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trial evaluated the safety and efficacy of 266 mg (20 mL) Marcaine Polyamp in 189 patients undergoing hemorrhoidectomy. The mean age was 48 years (range 18 to 86).

Study medication was administered directly into the site (greater than or equal to 3 cm) at the conclusion of the surgery. Dilution of 20 mL of Marcaine Polyamp with 10 mL of saline, for a total of 30 mL, was divided into six 5 mL aliquots. A field block was performed by visualizing the anal sphincter as a clock face and slowly infiltrating one aliquot to each of the even numbers.

Pain intensity was rated by the patients on a 0 to 10 NRS at multiple time points up to 72 hours. Postoperatively, patients were allowed rescue medication (morphine sulfate 10 mg intramuscular every 4 hours as needed).

The primary outcome measure was the AUC of the NRS pain intensity scores (cumulative pain scores) collected over the first 72 hour period.

There was a significant treatment effect for Marcaine Polyamp compared to placebo. See Figure 1 for the mean pain intensity over time for the Marcaine Polyamp and placebo treatment groups for the 72-hour efficacy period.

Figure 1. Mean Pain Intensity versus Time plot for hemorrhoidectomy study (C-316)

This resulted in a decrease in opioid consumption, the clinical benefit of which was not demonstrated.

Twenty-eight percent of patients treated with Marcaine Polyamp required no rescue medication at 72 hours compared to 10% treated with placebo. For those patients who did require rescue medication, the mean amount of morphine sulfate intramuscular injections used over 72 hours was 22 mg for patients treated with Marcaine Polyamp and 29 mg for patients treated with placebo.

The median time to rescue analgesic use was for 15 hours for patients treated with Marcaine Polyamp and one hour for patients treated with placebo.

16. HOW SUPPLIED/STORAGE AND HANDLING

Marcaine Polyamp (bupivacaine liposome injectable suspension) is available in single-use vials for infiltration.

20 mL single use vial, 1.3% (13.3 mg/mL) (NDC 65250-266-20) packaged in cartons of 10 (NDC 65250-266-09) and cartons of 4 (NDC 65250-266-04)

10 mL single use vial, 1.3% (13.3 mg/mL) (NDC 65250-133-10) packaged in cartons of 10 (NDC-65250-133-09) and cartons of 4 (NDC 65250-133-04)

Storage

Marcaine Polyamp vials should be stored refrigerated between 2°C to 8°C (36°F to 46°F). Marcaine Polyamp may be held at a controlled room temperature of 20°C to 25°C (68°F to 77°F) for up to 30 days in sealed, intact (unopened) vials. Vials should not be re-refrigerated.

Marcaine Polyamp should not be frozen or exposed to high temperatures (greater than 40°C or 104°F) for an extended period. Do not administer Marcaine Polyamp if it is suspected of having been frozen or exposed to high temperatures. Do not use the vial if the stopper is bulging.

Handling

17. PATIENT COUNSELING INFORMATION

Patients should be informed in advance that bupivacaine-containing products can cause temporary loss of sensation or motor activity in the area infiltrated. Physicians should discuss adverse reactions in the Marcaine Polyamp prescribing information with their patients.

Pacira Pharmaceuticals, Inc.

San Diego, CA 92121 USA

Patent Numbers:

6,132,766

5,766,627

5,891,467

8,182,835

Trademark of Pacira Pharmaceuticals, Inc.

PACIRA

PHARMACEUTICALS, INC.

For additional information call 1-855-RX-EXPAREL (1-855-793-9727)

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References

  1. Dailymed."A3080-27 SPINAL () C47916 [SMITHS MEDICAL ASD, INC.]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. Dailymed."BUPIVACAINE: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  3. "bupivacaine". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Marcaine Polyamp?

Depending on the reaction of the Marcaine Polyamp after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Marcaine Polyamp not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Marcaine Polyamp addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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The information was verified by Dr. Rachana Salvi, MD Pharmacology


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