PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

PRINCIPAL DISPLAY PANEL - 20 mg/mL Vial Label

NDC 75834-151-02

Succinylcholine Chloride Injection, USP
200 mg /10mL (20 mg/mL)

WARNING: Paralyzing Agent
For Intravenous or Intramuscular use

Nivagen
10 mL Multiple-Dose Vial; Rx only

PRINCIPAL DISPLAY PANEL - 20 mg/mL Vial Tray

25 X 10 mL Multiple-Dose Vials
NDC 75834-151-25

Succinylcholine Chloride Injection, USP
200 mg /10mL (20 mg/mL)

Rx only
WARNING: Paralyzing Agent

Store in refrigerator 2° to 8°C (36° to 46°F).
Manufactured for: Nivagen Pharmaceuticals, Inc., Sacramento, CA 95827 USA Toll free number: 1-877-977-0687

Nivagen

**WARNING: VENTRICULAR DYSRHYTHMIAS, CARDIAC ARREST, AND DEATH FROM

HYPERKALEMIC RHABDOMYOLYSIS IN PEDIATRIC PATIENTS**

1 INDICATIONS AND USAGE

Succinylcholine Chloride Injection is indicated in adults and pediatric patients:

• as an adjunct to general anesthesia
• to facilitate tracheal intubation
• to provide skeletal muscle relaxation during surgery or mechanical ventilation.

4 CONTRAINDICATIONS

Succinylcholine Chloride Injection is contraindicated:

• in patients with skeletal muscle myopathies [see Warnings and Precautions (5.1)]
• in patients with known hypersensitivity to succinylcholine. Severe anaphylactic reactions to succinylcholine have been reported [see Warnings and Precautions (5.2)]
• after the acute phase of injury following major burns, multiple trauma, extensive denervation of skeletal muscle, or upper motor neuron injury, which may result in severe hyperkalemia and cardiac arrest [see Warnings and Precautions (5.4)]
• in patients with known or suspected genetic susceptibility to malignant hyperthermia [see Warnings and Precautions (5.5), Clinical Pharmacology (12.5)]

6 ADVERSE REACTIONS

The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling:

• Ventricular Dysrhythmias, Cardiac Arrest, and Death from Hyperkalemic Rhabdomyolysis in Pediatric Patients [see Warnings and Precautions (5.1)]
• Anaphylaxis [see Warnings and Precautions (5.2)]
• Hyperkalemia [see Warnings and Precautions (5.4)]
• Malignant Hyperthermia [see Warnings and Precautions (5.5)]
• Bradycardia [see Warnings and Precautions (5.6)]
• Increase in Intraocular Pressure [see Warnings and Precautions (5.7)]
• Prolonged Neuromuscular Block due to Phase II Block and Tachyphylaxis [see Warnings and Precautions (5.8)]

The following adverse reactions associated with the use of succinylcholine were identified in clinical studies or postmarketing reports. Because some of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure:

Cardiovascular disorders: Cardiac arrest, arrhythmias, bradycardia, tachycardia, hypertension, hypotension

Electrolyte disorders: Hyperkalemia

Eye disorders: Increased intraocular pressure

Gastrointestinal disorders: Excessive salivation

Immune system disorders: Hypersensitivity reactions including anaphylaxis (in some cases life-threatening and fatal)

Musculoskeletal disorders: Malignant hyperthermia, rhabdomyolysis with possible myoglobinuric acute renal failure, muscle fasciculation, jaw rigidity, postoperative muscle pain
Respiratory disorders: Prolonged respiratory depression or apnea

Skin disorders: Rash

7 DRUG INTERACTIONS

7.1 Drugs that May Affect the Neuromuscular Blocking Action of

Succinylcholine Chloride Injection

Drugs that may enhance the neuromuscular blocking action of succinylcholine include: promazine, oxytocin, aprotinin, certain non-penicillin antibiotics, quinidine, β-adrenergic blockers, procainamide, lidocaine, trimethaphan, lithium carbonate, magnesium salts, quinine, chloroquine, isoflurane, desflurane, metoclopramide, and terbutaline.

The neuromuscular blocking effect of succinylcholine may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase [see Warnings and Precautions (5.9)].

If other neuromuscular blocking agents are to be used during the same procedure, consider the possibility of a synergistic or antagonistic effect.

2 DOSAGE AND ADMINISTRATION

2.1 Important Dosage and Administration Information

• Succinylcholine Chloride Injection is for intravenous or intramuscular use only.
• Succinylcholine Chloride Injection must be titrated to effect by or under supervision of experienced clinicians who are familiar with its actions and with appropriate neuromuscular monitoring techniques.
• Succinylcholine Chloride Injection should be administered only by those skilled in the management of artificial respiration and only when facilities are instantly available for tracheal intubation and for providing adequate ventilation of the patient, including the administration of oxygen under positive pressure and the elimination of CO2. The clinician must be prepared to assist or control respiration.
• The dosage of Succinylcholine Chloride Injection should be individualized and should always be determined by the clinician after careful assessment of the patient.
• To avoid distress to the patient, do not administer Succinylcholine Chloride Injection before unconsciousness has been induced [see Warnings and Precautions (5.14)].
• The occurrence of bradyarrhythmias with administration of Succinylcholine Chloride Injection may be reduced by pretreatment with anticholinergics (e.g., atropine) [see Warnings and Precautions (5.6)].
• Monitor neuromuscular function with a peripheral nerve stimulator when using Succinylcholine Chloride Injection by infusion [see Dosage and Administration (2.2), Warnings and Precautions (5.8)].
• Visually inspect Succinylcholine Chloride Injection for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not administer solutions that are not clear and colorless.
• Succinylcholine Chloride Injection supplied in multiple-dose vials does not require dilution before use [see Dosage and Administration (2.5)].

Risk of Medication Errors

Accidental administration of neuromuscular blocking agents may be fatal. Store Succinylcholine Chloride Injection with the cap and ferrule intact and in a manner that minimizes the possibility of selecting the wrong product [see Warnings and Precautions (5.3)].

2.2 Dosage Recommendations for Intravenous Use in Adults

For Short Surgical Procedures

The average dose required to produce neuromuscular blockade and to facilitate tracheal intubation is 0.6 mg/kg Succinylcholine Chloride Injection given intravenously. The optimum intravenous dose of Succinylcholine Chloride Injection will vary among patients and may be from 0.3 mg/kg to 1.1 mg/kg for adults. Following intravenous administration of doses in this range, neuromuscular blockade develops in about 1 minute; maximum blockade may persist for about 2 minutes, after which recovery takes place within 4 to 6 minutes. A 5 to 10 mg intravenous test dose of Succinylcholine Chloride Injection may be used to determine the sensitivity of the patient and the individual recovery time [see Warnings and Precautions (5.9)].

For Long Surgical Procedures

Continuous Intravenous Infusion

The dosage of Succinylcholine Chloride Injection administered by continuous intravenous infusion depends upon the duration of the surgical procedure and the need for muscle relaxation.

Diluted Succinylcholine Chloride Injection solutions containing from 1 mg/mL to 2 mg/mL succinylcholine have commonly been used for continuous intravenous infusion [see Dosage and Administration (2.5)]. The more dilute solution (1 mg/mL) is probably preferable from the standpoint of ease of control of the rate of administration of Succinylcholine Chloride Injection and, hence, of relaxation. This diluted Succinylcholine Chloride Injection solution containing 1 mg/mL succinylcholine may be administered intravenously at a rate of 0.5 mg (0.5 mL) per minute to 10 mg (10 mL) per minute to obtain the required amount of relaxation. The amount required per minute will depend upon the individual response as well as the degree of relaxation required. The average rate of continuous intravenous infusion for an adult ranges between 2.5 mg per minute and 4.3 mg per minute.

Monitor neuromuscular function with a peripheral nerve stimulator when using Succinylcholine Chloride Injection by infusion in order to avoid overdose, detect development of Phase II block, follow its rate of recovery, and assess the effects of reversing agents [see Warnings and Precautions (5.8)].

Intermittent Intravenous Injection

Intermittent intravenous injections of Succinylcholine Chloride Injection may also be used to provide muscle relaxation for long procedures. An intravenous injection of 0.3 mg/kg to 1.1 mg/kg may be given initially, followed, at appropriate intervals, by further intravenous injections of 0.04 mg/kg to 0.07 mg/kg to maintain the degree of relaxation required.

2.3 Dosage Recommendations for Intravenous Use in Pediatric Patients

For emergency tracheal intubation or in instances where immediate securing of the airway is necessary, the intravenous dose of Succinylcholine Chloride Injection is 2 mg/kg for infants and other small pediatric patients; for older pediatric patients and adolescents the intravenous dose is 1 mg/kg [see Warnings and Precautions (5.1), Use in Specific Populations (8.4)]. The effective dose of Succinylcholine Chloride Injection in pediatric patients may be higher than that predicted by body weight dosing alone. For example, the usual adult intravenous dose of 0.6 mg/kg is comparable to a dose of 2 mg/kg to 3 mg/kg in neonates and infants up to 6 months of age and 1 mg/kg to 2 mg/kg in infants up to 2 years of age [see Clinical Pharmacology (12.3)].

2.4 Dosage Recommendations for Intramuscular Use in Adults and Pediatric

Patients

If a suitable vein is inaccessible, Succinylcholine Chloride Injection may be administered intramuscularly at a dose of up to 3 mg/kg to 4 mg/kg to infants, older pediatric patients, or adults. The total dose administered by the intramuscular route should not exceed 150 mg. The onset of effect of succinylcholine given intramuscularly is usually observed in about 2 to 3 minutes.

2.5 Preparation of Succinylcholine Chloride Injection

Succinylcholine Chloride Injection supplied in multiple-dose vials does not require dilution before use.

Succinylcholine Chloride Injection may be diluted to 1 mg/mL or 2 mg/mL in a solution such as:

• 5% Dextrose Injection, USP, or
• 0.9% Sodium Chloride Injection, USP

Prepare the diluted Succinylcholine Chloride Injection solution for single patient use only. Store the diluted Succinylcholine Chloride Injection solution in a refrigerator [2 °C to 8 °C (36 °F to 46 °F)] and use within 24 hours after preparation. Visually inspect the diluted Succinylcholine Chloride Injection solution for particulate matter and discoloration prior to administration. Do not administer solutions that are not clear and colorless. Discard any unused portion of the diluted Succinylcholine Chloride Injection solution.

2.6 Drug Incompatibility

Succinylcholine Chloride Injection is acidic (pH is between 3.0 and 4.5) and may not be compatible with alkaline solutions having a pH greater than 8.5 (e.g., barbiturate solutions). Therefore, do not mix Succinylcholine Chloride Injection with alkaline solutions.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Succinylcholine is a depolarizing neuromuscular blocker. As does acetylcholine, it combines with the cholinergic receptors of the motor end plate to produce depolarization. This depolarization may be observed as fasciculations. Subsequent neuromuscular transmission is inhibited so long as adequate concentration of succinylcholine remains at the receptor site. Onset of flaccid paralysis is rapid (less than one minute after intravenous administration), and with single administration lasts approximately 4 to 6 minutes.

The paralysis following administration of succinylcholine is progressive, with differing sensitivities of different muscles. This initially involves consecutively the levator muscles of the face, muscles of the glottis and finally the intercostals and the diaphragm and all other skeletal muscles.

12.2 Pharmacodynamics

Depending on the dose and duration of succinylcholine administration, the characteristic depolarizing neuromuscular block (Phase I block) may change to a block with characteristics superficially resembling a non-depolarizing block (Phase II block). This may be associated with prolonged respiratory muscle paralysis or weakness in patients who manifest the transition to Phase II block. Tachyphylaxis occurs with repeated administration [see Warnings and Precautions (5.8)]. The transition from Phase I to Phase II block has been reported in 7 of 7 patients studied under halothane anesthesia after an accumulated dose of 2 to 4 mg/kg succinylcholine (administered in repeated, divided doses). The onset of Phase II block coincided with the onset of tachyphylaxis and prolongation of spontaneous recovery. In another study, using balanced anesthesia (N2O/O2/narcotic-thiopental) and succinylcholine infusion, the transition was less abrupt, with great individual variability in the dose of succinylcholine required to produce Phase II block. Of 32 patients studied, 24 developed Phase II block. Tachyphylaxis was not associated with the transition to Phase II block, and 50% of the patients who developed Phase II block experienced prolonged recovery [see Warnings and Precautions (5.8)].

Succinylcholine has no direct effect on the myocardium. Succinylcholine stimulates both autonomic ganglia and muscarinic receptors which may cause changes in cardiac rhythm, including cardiac arrest. Changes in rhythm, including cardiac arrest, may also result from vagal stimulation, which may occur during surgical procedures, or from hyperkalemia, particularly in pediatric patients [see Warnings and Precautions (5.1, 5.4, 5.6), Use in Specific Populations (8.4)]. These effects are enhanced by halogenated anesthetics.

Succinylcholine causes an increase in intraocular pressure immediately after its injection and during the fasciculation phase, and increases which may persist after onset of complete paralysis [see Warnings and Precautions (5.7)].

Succinylcholine may cause increases in intracranial pressure immediately after its injection and during the fasciculation phase [see Warnings and Precautions (5.11)].

As with other neuromuscular blocking agents, the potential for releasing histamine is present following succinylcholine administration. Signs and symptoms of histamine-mediated release such as flushing, hypotension and bronchoconstriction are, however, uncommon with normal clinical usage.

Succinylcholine has no effect on consciousness, pain threshold or cerebration [see Warnings and Precautions (5.14)].

Succinylcholine has no direct action on the uterus or other smooth muscle structures.

12.3 Pharmacokinetics

Elimination

Succinylcholine levels were reported to be below the detection limit of 2 μg/mL after 2.5 minutes of an intravenous bolus dose of 1 or 2 mg/kg in 14 anesthetized patients.

Metabolism

Succinylcholine is rapidly hydrolyzed by plasma cholinesterase to succinylmonocholine (which possesses clinically insignificant depolarizing muscle relaxant properties) and then more slowly to succinic acid and choline.

Excretion

About 10% of the drug is excreted unchanged in the urine.

Specific Populations

Pediatric Patients

Due to the relatively large volume of distribution in the pediatric patient versus the adult patient, the effective dose of Succinylcholine Chloride Injection in pediatric patients may be higher than that predicted by body weight dosing alone [see Dosage and Administration (2.3)].

12.5 Pharmacogenomics

RYR1 and CACNA1S are polymorphic genes and multiple pathogenic variants have been associated with malignant hyperthermia susceptibility (MHS) in patients receiving succinylcholine, including Succinylcholine Chloride Injection. Case reports as well as ex-vivo studies have identified multiple variants in RYR1 and CACNA1S associated with MHS. Variant pathogenicity should be assessed based on prior clinical experience, functional studies, prevalence information, or other evidence [see Contraindications (4), Warnings and Precautions (5.5)].

RECENT MAJOR CHANGES

Contraindications (4) 11/2022

Warnings and Precautions, Malignant Hyperthermia (5.5) 11/2022

3 DOSAGE FORMS AND STRENGTHS

Succinylcholine Chloride Injection, USP is supplied as a clear, colorless solution as follows:

200 mg/10 mL (20 mg/mL) in multiple-dose fliptop vials contains: 20 mg of succinylcholine anhydrous (equivalent to 22.65 mg of Succinylcholine Chloride, USP).

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Available data from published literature from case reports and case series over decades of use with succinylcholine during pregnancy have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Succinylcholine is used commonly during delivery by caesarean section to provide muscle relaxation. If succinylcholine is used during labor and delivery, there is a risk for prolonged apnea in some pregnant women (see Clinical Considerations). Animal reproduction studies have not been conducted with succinylcholine chloride.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Clinical Considerations

Maternal Adverse Reactions

Plasma cholinesterase levels are decreased by approximately 24% during pregnancy and for several days postpartum which can prolong the effect of succinylcholine. Therefore, some pregnant patients may experience prolonged apnea.

Fetal/Neonatal Adverse Reactions

Apnea and flaccidity may occur in the newborn after repeated high doses to, or in the presence of atypical plasma cholinesterase in, the mother.

Labor or Delivery

Succinylcholine is commonly used to provide muscle relaxation during delivery by caesarean section. Succinylcholine is known to cross the placental barrier in an amount that is dependent on the concentration gradient between the maternal and fetal circulation.

8.2 Lactation

Risk Summary

There are no data on the presence of succinylcholine or its metabolite in either human or animal milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Succinylcholine Chloride Injection and any potential adverse effects on the breastfed infant from Succinylcholine Chloride Injection or from the underlying maternal condition.

8.4 Pediatric Use

Safety and effectiveness of succinylcholine chloride have been established in pediatric patient age groups, neonate to adolescent. Because of a risk of ventricular dysrhythmias, cardiac arrest, and death from hyperkalemic rhabdomyolysis in pediatric patients, reserve the use of Succinylcholine Chloride Injection in pediatric patients for emergency intubation or instances where immediate securing of the airway is necessary, e.g., laryngospasm, difficult airway, full stomach, or for intramuscular use when a suitable vein is inaccessible [see Warnings and Precautions (5.1)].

Intravenous bolus administration of Succinylcholine Chloride Injection in pediatric patients (including infants) may result in profound bradycardia or, rarely, asystole. The incidence and severity of bradycardia is higher in pediatric patients than adults [see Warnings and Precautions (5.6)].

The effective dose of Succinylcholine Chloride Injection in pediatric patients may be higher than that predicted by body weight dosing alone [see Dosage and Administration (2.3)].

8.5 Geriatric Use

Clinical studies of Succinylcholine Chloride Injection did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified 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.

10 OVERDOSAGE

Overdosage with Succinylcholine Chloride Injection may result in neuromuscular block beyond the time needed for surgery and anesthesia. This may be manifested by skeletal muscle weakness, decreased respiratory reserve, low tidal volume, or apnea. The primary treatment is maintenance of a patent airway and respiratory support until recovery of normal respiration is assured. Depending on the dose and duration of Succinylcholine Chloride Injection administration, the characteristic depolarizing neuromuscular block (Phase I) may change to a block with characteristics superficially resembling a non-depolarizing block (Phase II) [see Warnings and Precautions (5.8)].

11 DESCRIPTION

Succinylcholine Chloride Injection, USP is a sterile, nonpyrogenic solution to be used as a short-acting, depolarizing neuromuscular blocker for intravenous or intramuscular use. Succinylcholine Chloride Injection contains succinylcholine chloride as the active pharmaceutical ingredient.

Succinylcholine Chloride, USP is chemically designated C14H30Cl2N2O4 and its molecular weight is 361.31. The chemical name of succinylcholine chloride is ethanaminium, 2,2'-[(1,4-dioxo-1,4 butanediyl)bis(oxy)]bis[N,N,N-trimethyl-], dichloride. Succinylcholine chloride is a diquaternary base consisting of the dichloride salt of the dicholine ester of succinic acid. It is a white or almost white, odorless, hygroscopic, crystalline powder, freely soluble in water, slightly soluble in alcohol and in chloroform, practically insoluble in ether. The drug is incompatible with alkaline solutions but relatively stable in acid solutions. Solutions of the drug lose potency unless refrigerated. It has the following structural formula:


Succinylcholine Chloride Injection 200 mg/10 mL (20 mg/mL) is intended for multiple-dose administration and contains preservative. Each 1 mL of Succinylcholine Chloride Injection 200 mg/10 mL (20 mg/mL) multiple-dose fliptop vials contains: 20 mg of succinylcholine anhydrous (equivalent to 22.65 mg of Succinylcholine Chloride, USP), 1.8 mg of methylparaben and 0.2 mg of propylparaben as preservatives, 4.6 mg of sodium chloride as iso-osmotic agent, and sodium hydroxide and hydrochloric acid as pH adjusters in water for injection. The pH of the solution is between 3.0 and 4.5, with an osmolarity of 0.338 mOsm/mL (calc.).

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

There have been no long-term studies performed in animals to evaluate carcinogenic potential of succinylcholine.

Mutagenesis

Adequate studies have not been completed to evaluate the genotoxic potential of succinylcholine.

Impairment of Fertility

There are no studies to evaluate the potential impact of succinylcholine on fertility.

16 HOW SUPPLIED/STORAGE AND HANDLING

Succinylcholine Chloride Injection, USP is supplied as a clear, colorless solution in the following concentrations and packages:

NDC No.	Container	Size (mL)	mg/mL	mg (total)	mOsmol/mL (calc.)
Multiple-dose 75834-151-02
Fliptop Vial	10	20	200	0.338
Multiple-dose 75834-151-25
Fliptop Vial	10	20	200	0.338

Refrigeration of undiluted Succinylcholine Chloride Injection will assure full potency until expiration date.

Store in refrigerator 2 °C to 8 °C (36 °F to 46 °F). The multiple-dose vials are stable for up to 14 days at room temperature without significant loss of potency.

Manufactured For:
Nivagen Pharmaceuticals, Inc.
Sacramento, CA 95827, USA
Toll free number: 1-877-977-0687

Rev. 11/2022