Marcain Spinal Heavy

Bupivacaine Hydrochloride:

• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Patient counseling information
• Marcain Spinal Heavy (Bupivacaine Hydrochloride) reviews

Marcain Spinal Heavy (Bupivacaine Hydrochloride) is indicated for administration into the surgical site to produce postsurgical analgesia.

Marcain Spinal Heavy (Bupivacaine Hydrochloride) has not been studied for use in patients younger than 18 years of age.

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

2. DOSAGE AND ADMINISTRATION

Marcain Spinal Heavy is intended for single-dose administration only.

The recommended dose of Marcain Spinal Heavy (Bupivacaine Hydrochloride) is based on the following factors:

• Size of the surgical site
• Volume required to cover the area
• Individual patient factors that may impact the safety of an amide local anesthetic
• Maximum dose of 266 mg (20 mL)

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 Marcain Spinal Heavy (Bupivacaine Hydrochloride) 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 Marcain Spinal Heavy (Bupivacaine Hydrochloride) 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.

Marcain Spinal Heavy (Bupivacaine Hydrochloride) is intended for single-dose administration only.

The recommended dose of Marcain Spinal Heavy (Bupivacaine Hydrochloride) is based on the following factors:

• Size of the surgical site
• Volume required to cover the area
• Individual patient factors that may impact the safety of an amide local anesthetic
• Maximum dose of 266 mg (20 mL)

Inject Marcain Spinal Heavy (Bupivacaine Hydrochloride) slowly into soft tissue via infiltration (2.1).

2.1 Injection Instructions

Marcain Spinal Heavy (Bupivacaine Hydrochloride) 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.

• Marcain Spinal Heavy (Bupivacaine Hydrochloride) is intended for single-dose administration only.
• Different formulations of Marcain Spinal Heavy (Bupivacaine Hydrochloride) are not bioequivalent even if the milligram strength is the same. Therefore, it is not possible to convert dosing from any other formulations of Marcain Spinal Heavy (Bupivacaine Hydrochloride) to Marcain Spinal Heavy (Bupivacaine Hydrochloride).
• Marcain Spinal Heavy (Bupivacaine Hydrochloride) should be administered with a 25 gauge or larger bore needle.
• The maximum dosage of Marcain Spinal Heavy (Bupivacaine Hydrochloride) should not exceed 266 mg (20 mL, 1.3% of undiluted drug).
• Marcain Spinal Heavy (Bupivacaine Hydrochloride) can be administered undiluted or diluted to increase volume up to a final concentration of 0.89 mg/mL (i.e. 1:14 dilution by volume) with normal (0.9%) saline or lactated Ringer’s solution.
• Vials of Marcain Spinal Heavy (Bupivacaine Hydrochloride) should be inverted multiple times to re-suspend the particles immediately prior to withdrawal from the vial
• Diluted suspensions of Marcain Spinal Heavy (Bupivacaine Hydrochloride) should be used within 4 hours of preparation in a syringe.
• Do not administer Marcain Spinal Heavy (Bupivacaine Hydrochloride) if the product is discolored.
• Do not administer Marcain Spinal Heavy (Bupivacaine Hydrochloride) if it is suspected that the vial has been frozen or exposed to high temperature (greater than 40°C or 104°F) for an extended period.

2.2 Compatibility Considerations

Some physicochemical incompatibilities exist between Marcain Spinal Heavy and certain other drugs. Direct contact of Marcain Spinal Heavy (Bupivacaine Hydrochloride) with these drugs results in a rapid increase in free (unencapsulated) Marcain Spinal Heavy (Bupivacaine Hydrochloride), altering Marcain Spinal Heavy (Bupivacaine Hydrochloride) characteristics and potentially affecting the safety and efficacy of Marcain Spinal Heavy (Bupivacaine Hydrochloride). Therefore, admixing Marcain Spinal Heavy (Bupivacaine Hydrochloride) 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 Marcain Spinal Heavy (Bupivacaine Hydrochloride) from Marcain Spinal Heavy (Bupivacaine Hydrochloride) if administered together locally. The administration of Marcain Spinal Heavy (Bupivacaine Hydrochloride) may follow the administration of lidocaine after a delay of 20 minutes or more.
• Marcain Spinal Heavy (Bupivacaine Hydrochloride) HCl administered together with Marcain Spinal Heavy (Bupivacaine Hydrochloride) may impact the pharmacokinetic and/or physicochemical properties of Marcain Spinal Heavy (Bupivacaine Hydrochloride), and this effect is concentration dependent. Therefore, Marcain Spinal Heavy (Bupivacaine Hydrochloride) HCl and Marcain Spinal Heavy (Bupivacaine Hydrochloride) may be administered simultaneously in the same syringe, and Marcain Spinal Heavy (Bupivacaine Hydrochloride) HCl may be injected immediately before Marcain Spinal Heavy (Bupivacaine Hydrochloride) as long as the ratio of the milligram dose of Marcain Spinal Heavy (Bupivacaine Hydrochloride) HCl solution to Marcain Spinal Heavy (Bupivacaine Hydrochloride) 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 Warnings and Precautions (5.1) and Overdosage (10)].

• When a topical antiseptic such as povidone iodine (e.g., Betadine^®) is applied, the site should be allowed to dry before Marcain Spinal Heavy (Bupivacaine Hydrochloride) is administered into the surgical site. Marcain Spinal Heavy (Bupivacaine Hydrochloride) should not be allowed to come into contact with antiseptics such as povidone iodine in solution.

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

When administered in recommended doses and concentrations, Marcain Spinal Heavy (Bupivacaine Hydrochloride) HCl does not ordinarily produce irritation or tissue damage and does not cause methemoglobinemia.

2.3 Non-Interchangeability with Other Formulations of Marcain Spinal Heavy (Bupivacaine Hydrochloride)

Different formulations of Marcain Spinal Heavy (Bupivacaine Hydrochloride) are not bioequivalent even if the milligram dosage is the same. Therefore, it is not possible to convert dosing from any other formulations of Marcain Spinal Heavy (Bupivacaine Hydrochloride) to Marcain Spinal Heavy (Bupivacaine Hydrochloride) 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

Marcain Spinal Heavy (Bupivacaine Hydrochloride) (bupivacaine liposome injectable suspension)

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

Marcain Spinal Heavy (Bupivacaine Hydrochloride) (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

Marcain Spinal Heavy (Bupivacaine Hydrochloride) is contraindicated in obstetrical paracervical block anesthesia. While Marcain Spinal Heavy (Bupivacaine Hydrochloride) has not been tested with this technique, the use of Marcain Spinal Heavy (Bupivacaine Hydrochloride) HCl with this technique has resulted in fetal bradycardia and death.

Marcain Spinal Heavy (Bupivacaine Hydrochloride) is contraindicated in obstetrical paracervical block anesthesia (4).

5. WARNINGS AND PRECAUTIONS

• Monitoring of cardiovascular and neurological status, as well as vital signs should be performed during and after injection of Marcain Spinal Heavy as with other local anesthetic products (5.1).
• Because amide-type local anesthetics, such as Marcain Spinal Heavy (Bupivacaine Hydrochloride), are metabolized by the liver, Marcain Spinal Heavy (Bupivacaine Hydrochloride) 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 (5.1).
• Other formulations of Marcain Spinal Heavy (Bupivacaine Hydrochloride) should not be administered within 96 hours following administration of Marcain Spinal Heavy (Bupivacaine Hydrochloride) (5.2).

5.1 Warnings and Precautions for Marcain Spinal Heavy (Bupivacaine Hydrochloride) Containing Products

The safety and effectiveness of Marcain Spinal Heavy (Bupivacaine Hydrochloride) 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 Marcain Spinal Heavy (Bupivacaine Hydrochloride), 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 Marcain Spinal Heavy (Bupivacaine Hydrochloride) 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.

Marcain Spinal Heavy (Bupivacaine Hydrochloride) 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 Marcain Spinal Heavy (Bupivacaine Hydrochloride) 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 Marcain Spinal Heavy (Bupivacaine Hydrochloride), 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 Marcain Spinal Heavy

As there is a potential risk of severe life-threatening adverse effects associated with the administration of Marcain Spinal Heavy (Bupivacaine Hydrochloride), Marcain Spinal Heavy (Bupivacaine Hydrochloride) 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 Marcain Spinal Heavy (Bupivacaine Hydrochloride). Convulsions and cardiac arrest have occurred following accidental intravascular injection of Marcain Spinal Heavy (Bupivacaine Hydrochloride) and other amide-containing products.

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

Marcain Spinal Heavy (Bupivacaine Hydrochloride) 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

Marcain Spinal Heavy (Bupivacaine Hydrochloride) 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

The ability of Marcain Spinal Heavy (Bupivacaine Hydrochloride) to achieve effective anesthesia has not been studied. Therefore, Marcain Spinal Heavy (Bupivacaine Hydrochloride) 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 Marcain Spinal Heavy administration were nausea, constipation, and vomiting (6.2).

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 Marcain Spinal Heavy (Bupivacaine Hydrochloride) and all amide-type local anesthetics that demand immediate counter-measures are related to the central nervous and cardiovascular systems.

High plasma concentrations of Marcain Spinal Heavy (Bupivacaine Hydrochloride) can occur from overdosage, unintended intravascular injection, or accumulation of Marcain Spinal Heavy (Bupivacaine Hydrochloride) 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 Marcain Spinal Heavy (Bupivacaine Hydrochloride) 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 Marcain Spinal Heavy (Bupivacaine Hydrochloride) 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 Marcain Spinal Heavy (Bupivacaine Hydrochloride). In these studies, the most common adverse reactions (incidence greater than or equal to 10%) following Marcain Spinal Heavy (Bupivacaine Hydrochloride) administration were nausea, constipation, and vomiting.

The common adverse reactions (incidence greater than or equal to 2% to less than 10%) following Marcain Spinal Heavy (Bupivacaine Hydrochloride) 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 Marcain Spinal Heavy (Bupivacaine Hydrochloride) 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 Marcain Spinal Heavy (Bupivacaine Hydrochloride) surgical site infiltration studies, adverse reactions with an incidence greater than or equal to 1% in the Nervous System Disorders system organ class following Marcain Spinal Heavy (Bupivacaine Hydrochloride) 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 Marcain Spinal Heavy (Bupivacaine Hydrochloride) 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 Marcain Spinal Heavy (Bupivacaine Hydrochloride) 1.3% (106 mg) to placebo and 20 mL Marcain Spinal Heavy (Bupivacaine Hydrochloride) 1.3% (266 mg) to placebo are shown in Table 1.

7. DRUG INTERACTIONS

Marcain Spinal Heavy (Bupivacaine Hydrochloride) 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. Marcain Spinal Heavy (Bupivacaine Hydrochloride) must not be diluted with water or other hypotonic agents as it will result in disruption of the liposomal particles.

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

Marcain Spinal Heavy (Bupivacaine Hydrochloride) HCl administered together with Marcain Spinal Heavy (Bupivacaine Hydrochloride) may impact the pharmacokinetic and/or physicochemical properties of Marcain Spinal Heavy (Bupivacaine Hydrochloride), and this effect is concentration dependent. Therefore, Marcain Spinal Heavy (Bupivacaine Hydrochloride) HCl and Marcain Spinal Heavy (Bupivacaine Hydrochloride) may be administered simultaneously in the same syringe, and Marcain Spinal Heavy (Bupivacaine Hydrochloride) HCl may be injected immediately before Marcain Spinal Heavy (Bupivacaine Hydrochloride) as long as the ratio of the milligram dose of Marcain Spinal Heavy (Bupivacaine Hydrochloride) HCl solution to Marcain Spinal Heavy (Bupivacaine Hydrochloride) 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 Marcain Spinal Heavy (Bupivacaine Hydrochloride) as noted above, Marcain Spinal Heavy (Bupivacaine Hydrochloride) should not be admixed with other drugs prior to administration.

• Marcain Spinal Heavy (Bupivacaine Hydrochloride) should not be admixed with lidocaine or other non-bupivacaine-based local anesthetics.
• Marcain Spinal Heavy (Bupivacaine Hydrochloride) may be administered after at least 20 minutes or more have elapsed following local administration of lidocaine.
• Marcain Spinal Heavy (Bupivacaine Hydrochloride) HCl, when injected immediately before or admixed with Marcain Spinal Heavy (Bupivacaine Hydrochloride), may impact the pharmacokinetic and/or physicochemical properties of the drugs (7).

8. USE IN SPECIFIC POPULATIONS

• Pregnancy: Based on animal data, may cause fetal harm.
• Pediatric Use: Safety and effectiveness in pediatric patients below the age of 18 have not been established (8.4).

8.1 Pregnancy

There are no studies conducted with Marcain Spinal Heavy (Bupivacaine Hydrochloride) in pregnant women. In animal reproduction studies, embryo-fetal deaths were observed with subcutaneous administration of Marcain Spinal Heavy (Bupivacaine Hydrochloride) to rabbits during organogenesis at a dose equivalent to 1.6 times the maximum recommended human dose (MRHD) of 266 mg. Subcutaneous administration of Marcain Spinal Heavy (Bupivacaine Hydrochloride) 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

Marcain Spinal Heavy (Bupivacaine Hydrochloride) is contraindicated for obstetrical paracervical block anesthesia. While Marcain Spinal Heavy (Bupivacaine Hydrochloride) has not been studied with this technique, the use of Marcain Spinal Heavy (Bupivacaine Hydrochloride) for obstetrical paracervical block anesthesia has resulted in fetal bradycardia and death.

Marcain Spinal Heavy (Bupivacaine Hydrochloride) 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

Marcain Spinal Heavy (Bupivacaine Hydrochloride) 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

Limited published literature reports that Marcain Spinal Heavy 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 Marcain Spinal Heavy (Bupivacaine Hydrochloride) and any potential adverse effects on the breastfed infant from Marcain Spinal Heavy (Bupivacaine Hydrochloride) 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 Marcain Spinal Heavy surgical site 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 Marcain Spinal Heavy (Bupivacaine Hydrochloride) 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. Marcain Spinal Heavy (Bupivacaine Hydrochloride) is known to be substantially excreted by the kidney, and the risk of toxic reactions to Marcain Spinal Heavy (Bupivacaine Hydrochloride) 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 Marcain Spinal Heavy (Bupivacaine Hydrochloride).

8.6 Hepatic Impairment

Because amide-type local anesthetics, such as Marcain Spinal Heavy (Bupivacaine Hydrochloride), 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

Marcain Spinal Heavy (Bupivacaine Hydrochloride) 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 Marcain Spinal Heavy (Bupivacaine Hydrochloride).

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 (C_max) values of approximately 34,000 ng/mL were reported and likely reflected inadvertent intravascular administration of Marcain Spinal Heavy (Bupivacaine Hydrochloride) or systemic absorption of Marcain Spinal Heavy (Bupivacaine Hydrochloride) at the surgical site. The plasma Marcain Spinal Heavy (Bupivacaine Hydrochloride) measurements did not discern between free and liposomal-bound Marcain Spinal Heavy (Bupivacaine Hydrochloride) making the clinical relevance of the reported values uncertain; however, no discernible adverse events or clinical sequelae were observed in these patients.

11. DESCRIPTION

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

11.1 Active Ingredient

Marcain Spinal Heavy (Bupivacaine Hydrochloride) 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, Marcain Spinal Heavy (Bupivacaine Hydrochloride) is 1-butyl-N-(2,6-dimethylphenyl)-2-piperidinecarboxamide with a molecular weight of 288.4. Marcain Spinal Heavy (Bupivacaine Hydrochloride) 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 Marcain Spinal Heavy (Bupivacaine Hydrochloride) 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 Marcain Spinal Heavy (Bupivacaine Hydrochloride) 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 Marcain Spinal Heavy (Bupivacaine Hydrochloride).

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 Marcain Spinal Heavy (Bupivacaine Hydrochloride) results in significant systemic plasma levels of Marcain Spinal Heavy (Bupivacaine Hydrochloride) which can persist for 96 hours [See Warnings and Precautions (5.2)]. Systemic plasma levels of Marcain Spinal Heavy (Bupivacaine Hydrochloride) following administration of Marcain Spinal Heavy (Bupivacaine Hydrochloride) are not correlated with local efficacy.

Absorption

The rate of systemic absorption of Marcain Spinal Heavy (Bupivacaine Hydrochloride) is dependent upon the total dose of drug administered, the route of administration, and the vascularity of the administration site.

Pharmacokinetic parameters of Marcain Spinal Heavy (Bupivacaine Hydrochloride) after local administration were evaluated following surgical procedures. Descriptive statistics of pharmacokinetic parameters of representative Marcain Spinal Heavy (Bupivacaine Hydrochloride) doses in each study are provided in Table 2.

Distribution

After Marcain Spinal Heavy (Bupivacaine Hydrochloride) has been released from Marcain Spinal Heavy (Bupivacaine Hydrochloride) and is absorbed systemically, Marcain Spinal Heavy (Bupivacaine Hydrochloride) distribution is expected to be the same as for any Marcain Spinal Heavy (Bupivacaine Hydrochloride) HCl solution formulation.

Local anesthetics including Marcain Spinal Heavy (Bupivacaine Hydrochloride) 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 Marcain Spinal Heavy (Bupivacaine Hydrochloride) 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. Marcain Spinal Heavy (Bupivacaine Hydrochloride) 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 Marcain Spinal Heavy (Bupivacaine Hydrochloride) readily enter the fetal blood from the maternal circulation.

Metabolism

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

The kidney is the main excretory organ for most local anesthetics and their metabolites. Only 6% of Marcain Spinal Heavy (Bupivacaine Hydrochloride) 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 Marcain Spinal Heavy (Bupivacaine Hydrochloride) pharmacokinetics following administration of Marcain Spinal Heavy (Bupivacaine Hydrochloride) were studied in patients with moderate hepatic impairment. Consistent with the hepatic clearance of Marcain Spinal Heavy (Bupivacaine Hydrochloride), 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 C_max and the area under the curve (AUC), respectively.

Because amide-type local anesthetics, such as Marcain Spinal Heavy (Bupivacaine Hydrochloride), 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

Marcain Spinal Heavy (Bupivacaine Hydrochloride) 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 Marcain Spinal Heavy (Bupivacaine Hydrochloride) [See Use in Specific Populations (8.7)].

Age

Various pharmacokinetic parameters of the local anesthetics such as Marcain Spinal Heavy (Bupivacaine Hydrochloride) 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.

Marcain Spinal Heavy (Bupivacaine Hydrochloride) 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 Marcain Spinal Heavy (Bupivacaine Hydrochloride) [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 Marcain Spinal Heavy (Bupivacaine Hydrochloride) have not been conducted.

Mutagenesis. The mutagenic potential of Marcain Spinal Heavy (Bupivacaine Hydrochloride) has not been determined.

Impairment of Fertility. The effect of Marcain Spinal Heavy (Bupivacaine Hydrochloride) on fertility has not been determined.

14. CLINICAL STUDIES

The efficacy of Marcain Spinal Heavy 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 (8 mL) Marcain Spinal Heavy (Bupivacaine Hydrochloride) 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 Marcain Spinal Heavy (Bupivacaine Hydrochloride) 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 Marcain Spinal Heavy (Bupivacaine Hydrochloride) compared to placebo. Marcain Spinal Heavy (Bupivacaine Hydrochloride) 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) Marcain Spinal Heavy (Bupivacaine Hydrochloride) 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 Marcain Spinal Heavy (Bupivacaine Hydrochloride) 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 Marcain Spinal Heavy (Bupivacaine Hydrochloride) compared to placebo. See Figure 1 for the mean pain intensity over time for the Marcain Spinal Heavy (Bupivacaine Hydrochloride) 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 Marcain Spinal Heavy (Bupivacaine Hydrochloride) 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 Marcain Spinal Heavy (Bupivacaine Hydrochloride) and 29 mg for patients treated with placebo.

The median time to rescue analgesic use was for 15 hours for patients treated with Marcain Spinal Heavy (Bupivacaine Hydrochloride) and one hour for patients treated with placebo.

16. HOW SUPPLIED/STORAGE AND HANDLING

Marcain Spinal Heavy (Bupivacaine Hydrochloride) (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

Marcain Spinal Heavy (Bupivacaine Hydrochloride) vials should be stored refrigerated between 2°C to 8°C (36°F to 46°F). Marcain Spinal Heavy (Bupivacaine Hydrochloride) 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.

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

Handling

• Vials of Marcain Spinal Heavy (Bupivacaine Hydrochloride) should be inverted to re-suspend the particles immediately prior to withdrawal from the vial. Multiple inversions may be necessary to re-suspend the particles if the contents of the vial have settled.
• Vials should be visually inspected before use.
• Do not filter.
• Do not heat before use.
• Do not autoclave.
• Following withdrawal from the vial, Marcain Spinal Heavy (Bupivacaine Hydrochloride) may be stored at controlled room temperature of 20°C to 25°C (68°F to 77°F) for up to 4 hours prior to administration.
• Discard any unused portion in an appropriate manner.

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 Marcain Spinal Heavy (Bupivacaine Hydrochloride) 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)

Package Label - 10 mL Vial Label

Package Label - 10 mL 10-count Carton Label

Package Label - 10 mL 4-count Carton Label

Package Label - 20 mL Vial Label

Package Label - 20 mL 10-count Carton Label

Package Label - 20 mL 4-count Carton Label

Dextrose:

• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• Directions for use of pharmacy bulk package container
• How supplied
• Marcain Spinal Heavy (Dextrose) reviews

INDICATIONS AND USAGE

70% Marcain Spinal Heavy (Dextrose) Injection USP is indicated as a caloric component in a parenteral nutrition regimen. 70% Marcain Spinal Heavy (Dextrose) Injection USP is used with an appropriate protein (nitrogen) source in the prevention of nitrogen loss or in the treatment of negative nitrogen balance in patients where: (1) the alimentary tract cannot or should not be used, (2) gastrointestinal absorption of protein is impaired, or (3) metabolic requirements for protein are substantially increased, as with extensive burns.

CONTRAINDICATIONS

The infusion of 70% Marcain Spinal Heavy (Dextrose) Injection USP is contraindicated in patients having intracranial or intraspinal hemorrhage, in patients who are severely dehydrated, in patients who are anuric, and in patients in hepatic coma.

Solutions containing Marcain Spinal Heavy (Dextrose) may be contraindicated in patients with hypersensitivity to corn products.

WARNINGS

This injection is for compounding only, not for direct infusion.

Dilute before use to a concentration which will, when administered with an amino acid (nitrogen) source, result in an appropriate calorie to gram of nitrogen ratio and which has an osmolarity consistent with the route of administration.

Unless appropriately diluted, the infusion of hypertonic Marcain Spinal Heavy (Dextrose) injection into a peripheral vein may result in vein irritation, vein damage, and thrombosis. Strongly hypertonic nutrient solutions should only be administered through an indwelling intravenous catheter with the tip located in a large central vein such as the superior vena cava.

Use of 70% Marcain Spinal Heavy (Dextrose) Injection USP to prepare parenteral nutritional admixtures may be incompatible with other components, especially calcium and phosphate salts and lipid emulsions. Incompatibility of admixed components can produce precipitates which may cause particulate emboli. Use 70% Marcain Spinal Heavy (Dextrose) Injection USP only to prepare formulations that are known to be stable: refer to standard texts for further information.

The administration of intravenous solutions can cause fluid and/or solute overload resulting in dilution of serum electrolyte concentrations, overhydration, congested states or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentration.

WARNING: 70% Marcain Spinal Heavy (Dextrose) Injection USP contains aluminum that may be toxic. Aluminum may reach toxic levels with prolonged parenteral administration if kidney function is impaired. Premature neonates are particularly at risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which contain aluminum.

Research indicates that patients with impaired kidney function, including premature neonates, who receive parenteral levels of aluminum at greater than 4 to 5 µg/kg/day accumulate aluminum at levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration.

Prolonged infusion of isotonic or hypotonic Marcain Spinal Heavy (Dextrose) in water may increase the volume of extracellular fluid and cause water intoxication.

Solutions containing Marcain Spinal Heavy (Dextrose) without electrolytes should not be administered simultaneously with blood through the same infusion set because of the possibility of agglomeration.

Excessive administration of potassium-free Marcain Spinal Heavy (Dextrose) solutions may result in significant hypokalemia. Serum potassium levels should be maintained and potassium supplemented as required.

In very low birth weight infants, excessive or rapid administration of Marcain Spinal Heavy (Dextrose) injection may result in increased serum osmolality and possible intracerebral hemorrhage.

PRECAUTIONS

General

This solution should be used with care in patients with hypervolemia, renal insufficiency, urinary tract obstruction, or impending or frank cardiac decompensation.

Solutions containing Marcain Spinal Heavy should be used with caution in patients with overt or known subclinical diabetes mellitus or carbohydrate intolerance for any reason.

Essential electrolytes, minerals, and vitamins should be supplied as needed.

Hypokalemia may develop during parenteral administration of hypertonic Marcain Spinal Heavy (Dextrose) solutions. Sufficient amounts of potassium should be added to Marcain Spinal Heavy (Dextrose) solutions administered to fasting patients with good renal function, especially those on digitalis therapy.

To minimize the risk of possible incompatibilities arising from mixing this solution with other additives that may be prescribed, the final infusate should be inspected for cloudiness or precipitation immediately after mixing, prior to administration, and periodically during administration. See WARNINGS .

Do not use plastic container in series connection.

If administration of 70% Marcain Spinal Heavy (Dextrose) Injection USP after admixture or dilution is controlled by a pumping device, care must be taken to discontinue pumping action before the container runs dry or air embolism may result. If administration is not controlled by a pumping device, refrain from applying excessive pressure (>300mmHg) causing distortion to the container such as wringing or twisting. Such handling could result in breakage of the container.

This solution is intended for intravenous administration after admixture or dilution using sterile equipment. When using an automated compounding device replace all disposable components as recommended by manufacturer and at least every 24 hours.

Aseptic technique is essential with the use of sterile preparations for compounding nutritional admixtures. Discard container within 4 hours of entering closure.

Administration of hypertonic Marcain Spinal Heavy (Dextrose) and amino acid solutions via central venous catheter may be associated with complications which can be prevented or minimized by careful attention to all aspects of the procedure. This includes attention to solution preparation, administration and patient monitoring.

It is essential that a carefully prepared protocol, based upon current medical practice, be followed, preferably by an experienced team. The package insert of the protein (nitrogen) source should be consulted for dosage and all precautionary information.

Use only if solution is clear and container and seals are intact.

70% Marcain Spinal Heavy (Dextrose) Injection USP contains no more than 25 µg/L of aluminum.

Laboratory Tests

Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid-base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Significant deviations from normal concentrations may require tailoring of the electrolyte pattern, in these or alternative solutions.

Drug Interactions

Caution must be exercised in the administration of 70% Marcain Spinal Heavy Injection USP to patients receiving corticosteroids or corticotropin. Some additives may be incompatible. Consult with pharmacist. When introducing additives, use aseptic techniques. Mix thoroughly. Do not store. Dispose of any unused product. See WARNINGS .

Carcinogenesis, Mutagenesis, Impairment of Fertility

Studies with Marcain Spinal Heavy (Dextrose) Injections USP have not been performed to evaluate carcinogenic potential, mutagenic potential or effects on fertility.

Pregnancy

Pregnancy Category C

There are no adequate and well controlled studies with Marcain Spinal Heavy Injections, USP in pregnant women and animal reproduction studies have not been conducted with this drug. Therefore, it is not known whether Marcain Spinal Heavy (Dextrose) Injections USP can cause fetal harm when administered to a pregnant woman. Marcain Spinal Heavy (Dextrose) Injections USP should be given during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Labor and Delivery

Intrapartum maternal intravenous infusion of glucose-containing solutions may produce maternal hyperglycemia with subsequent fetal hyperglycemia and fetal metabolic acidosis. Fetal hyperglycemia can result in increased fetal insulin levels which may result in neonatal hypoglycemia following delivery. Consider the potential risks and benefits for each specific patient before administering Marcain Spinal Heavy (Dextrose) Injection, USP.

Nursing Mothers

It is not known if this drug is present in human milk. Because many drugs are present in human milk, caution should be exercised when Marcain Spinal Heavy Injections USP are administered to a nursing woman.

Pediatric Use

The use of Marcain Spinal Heavy (Dextrose) in pediatric patients is based on clinical practice (see DOSAGE AND ADMINISTRATION ). Because of their hypertonicity, 70% Marcain Spinal Heavy (Dextrose) Injections must be diluted prior to administration.

Newborns – especially those born premature and with low birth weight - are at increased risk of developing hypo- or hyperglycemia and therefore need close monitoring during treatment with intravenous glucose solutions to ensure adequate glycemic control in order to avoid potential long term adverse effects. Hypoglycemia in the newborn can cause prolonged seizures, coma and brain damage. Hyperglycemia has been associated with intraventricular hemorrhage, late onset bacterial and fungal infection, retinopathy of prematurity, necrotizing enterocolitis, bronchopulmonary dysplasia, prolonged length of hospital stay, and death.

Geriatric Use

An evaluation of literature revealed no clinical experience identifying differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

This drug 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, and it may be useful to monitor renal function.

See WARNINGS .

ADVERSE REACTIONS

Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. Incompatibility of admixed components can produce precipitates which may cause particulate emboli.

Hyperosmolar syndrome, resulting from excessively rapid administration of concentrated Marcain Spinal Heavy (Dextrose) may cause hypovolemia, dehydration, mental confusion and/or loss of consciousness. Too rapid infusion of hypertonic solutions may cause local pain and venous irritation. Rate of administration should be adjusted according to tolerance. Use of the largest peripheral vein and a small bore needle is recommended. (See DOSAGE AND ADMINISTRATION .)

Hypersensitivity reactions, including anaphylaxis and chills.

If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary.

OVERDOSAGE

In the event of a fluid or solute overload during parenteral therapy, reevaluate the patient’s condition and institute appropriate corrective treatment.

DOSAGE AND ADMINISTRATION

This solution is for intravenous use only after admixture or dilution.

70% Marcain Spinal Heavy Injection USP is designed for use with automated compounding devices for preparing intravenous nutritional admixtures or for the filling of empty sterile syringes. Dosages will be in accordance with the recommendation of the prescribing physician. 70% Marcain Spinal Heavy (Dextrose) Injection USP is not intended for direct infusion. Admixtures should be made by, or under the direction of, a pharmacist using strict aseptic technique under a laminar flow hood. Compounded admixtures may be stored under refrigeration for up to 24 hours. Administration of admixtures should be completed within 24 hours after removal from refrigeration.

Dosage is to be directed by a physician and is dependent upon age, weight, clinical condition of the patient and laboratory determinations. Frequent laboratory determinations and clinical evaluation are essential to monitor changes in blood glucose and electrolyte concentrations, and fluid and electrolyte balance during prolonged parenteral therapy.

Fluid administration should be based on calculated maintenance or replacement fluid requirements for each patient.

Pediatric Use

The dosage selection and constant infusion rate of intravenous Marcain Spinal Heavy (Dextrose) must be selected with caution in pediatric patients, particularly neonates and low birth weight infants, because of the increased risk of hyperglycemia/hypoglycemia. Frequent monitoring of serum glucose concentrations is required when Marcain Spinal Heavy (Dextrose) is prescribed to pediatric patients, particularly neonates and low birth weight infants. The infusion rate and volume depends on the age, weight, clinical and metabolic conditions of the patient, concomitant therapy and should be determined by the consulting physician experienced in pediatric intravenous fluid therapy.

Directions for Use of Pharmacy Bulk Package Container

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration or admixture and final infusate should be inspected for cloudiness or precipitation immediately after mixing, prior to administration, and periodically during administration, whenever solution and container permit. Use of a final filter is recommended during administration of all parenteral solutions where possible.

70% Marcain Spinal Heavy (Dextrose) Injection USP in the Pharmacy Bulk Package is intended for use in the preparation of sterile, intravenous admixtures.

Refer to standard texts and guidelines on the preparation of parenteral nutritional admixtures.

When compounding admixtures, use aseptic technique. Mix thoroughly.

Do not store any unused portion of 70% Marcain Spinal Heavy (Dextrose) Injection USP.

TO OPEN:

• Inspect overwrap. Do not use if overwrap has been damaged.
• Do not use unless solution is clear and closure is intact.
• Tear overwrap starting from the tear notches. (Figure 1)
  

• Inspect the container for minute leaks by squeezing inner bag firmly. If leaks are found, discard the bag as sterility may be impaired.
• For compounding only. Do not use for direct infusion
  

  PREPARATION FOR ADMIXING
  

  Note: Important Admixing Information
  

  
  

• The Pharmacy Bulk Package is to be used only in a suitable work area such as a laminar air flow hood (or an equivalent clean air compounding area).
• The contents are restricted to the preparation of admixtures for infusion or, through a sterile transfer device, for the filling of empty sterile syringes.
• Additives may be incompatible with the fluid withdrawn from this container. When compounding admixtures, use aseptic technique, mix thoroughly and do not store.
• Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution container permits. (see PRECAUTIONS, General )

• Do not use/penetrate blocked port.
  

• Remove aluminum foil of set port at the bottom of container.
• Attach suitable transfer device or compounding set (Figure 2). Refer to complete directions accompanying device.
• Hang bag on suitable fixture (Figure 3).
• Once container closure has been penetrated, withdrawal of content should be completed within 4 hours.

HOW SUPPLIED

70% Marcain Spinal Heavy (Dextrose) Injection USP is supplied in 2000 mL Pharmacy Bulk Package containers packaged 4 per case.

NDC REF SIZE

0264-7387-50 S8705 2000 mL

Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. Protect from freezing. It is recommended that the product be stored at room temperature (25°C); however, brief exposure up to 40°C does not adversely affect the product.

Rx only

Initiated: February 2015

B. Braun Medical Inc.

Bethlehem, PA 18018-3524 USA

1-800-227-2862

www.bbraun.com

Y36-002-865 LD-355-2