This drug should be used only by individuals familiar with its actions, characteristics, and hazards.

DESCRIPTION

ANECTINE (succinylcholine chloride) is an ultra short-acting depolarizingtype, skeletal muscle relaxant for intravenous (IV) administration.

Succinylcholine chloride is a white, odorless, slightly bitter powder and very soluble in water. The drug is unstable in alkaline solutions but relatively stable in acid solutions, depending upon the concentration of the solution and the storage temperature. Solutions of succinylcholine chloride should be stored under refrigeration to preserve potency. ANECTINE injection is a sterile nonpyrogenic solution for intravenous injection where each mL contains 20 mg succinylcholine chloride as active, 1 mg methylparaben as a preservative, 4.5 mg sodium chloride as an isotonic agent and pH adjusted to 3.5 with hydrochloric acid and sodium hydroxide.

The chemical name for succinylcholine chloride is 2,2’-[(1,4-dioxo-1,4- butanediyl)bis(oxy)]bis[N,N,N-trimethylethanaminium] dichloride, and the structural formula is:

CLINICAL PHARMACOLOGY

Succinylcholine is a depolarizing skeletal muscle relaxant. 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 1 minute after IV administration), and with single administration lasts approximately 4 to 6 minutes.

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 (see PRECAUTIONS). About 10% of the drug is excreted unchanged in the urine. The paralysis following administration of 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.

Succinylcholine has no direct action on the uterus or other smooth muscle structures. Because it is highly ionized and has low fat solubility, it does not readily cross the placenta.
Tachyphylaxis occurs with repeated administration (see PRECAUTIONS).

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 nondepolarizing 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. When this diagnosis is confirmed by peripheral nerve stimulation, it may sometimes be reversed with anticholinesterase drugs such as neostigmine (see PRECAUTIONS). Anticholinesterase drugs may not always be effective. If given before succinylcholine is metabolized by cholinesterase, anticholinesterase drugs may prolong rather than shorten paralysis.

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 PRECAUTIONS: Pediatric Use). These effects are enhanced by halogenated anesthetics.

Succinylcholine causes an increase in intraocular pressure immediately after its injection and during the fasciculation phase, and slight increases
which may persist after onset of complete paralysis (see WARNINGS). Succinylcholine may cause slight increases in intracranial pressure
immediately after its injection and during the fasciculation phase (see  PRECAUTIONS).
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 in normal clinical usage. 
Succinylcholine has no effect on consciousness, pain threshold, or cerebration. It should be used only with adequate anesthesia (see WARNINGS).

Pharmacogenomics

RYR1 and CACNA1S are polymorphic genes, and multiple pathogenic variants have been associated with malignant hyperthermia susceptibility  (MHS) in patients receiving succinylcholine, including Anectine. 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, WARNINGS).

INDICATIONS AND USAGE

Succinylcholine chloride is indicated as an adjunct to general anesthesia, to facilitate tracheal intubation, and to provide skeletal muscle relaxation during surgery or mechanical ventilation.

CONTRAINDICATIONS

ANECTINE is contraindicated in patients with:
• Known or suspected genetic susceptibility to malignant hyperthermia (see  WARNINGS; Malignant Hyperthermia, CLINICAL PHARMACOLOGY;
Pharmacogenomics)
• Skeletal muscle myopathies
• Known hypersensitivity to succinylcholine (see WARNINGS; Anaphylaxis)
• After the acute phase of injury following major burns, multiple trauma, extensive denervation of the skeletal muscle, or upper neuron injury because succinylcholine administered to such individuals may result in severe hyperkalemia, which may result in cardiac arrest (see WARNINGS; Hyperkalemia)

WARNINGS

Succinylcholine should be used 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 carbon dioxide. The clinician must be prepared to assist or control respiration.

To avoid distress to the patient, succinylcholine should not be administered before unconsciousness has been induced. In emergency situations, however, it may be necessary to administer succinylcholine before unconsciousness is induced.

Succinylcholine is metabolized by plasma cholinesterase and should be used with caution, if at all, in patients known to be or suspected of being homozygous for the atypical plasma cholinesterase gene.

Drug Interactions

Drugs which may enhance the neuromuscular blocking action of succinylcholine include: promazine, oxytocin, aprotinin, certain nonpenicillin antibiotics, quinidine, ß-adrenergic blockers, procainamide, lidocaine, trimethaphan, lithium carbonate, magnesium salts, quinine, chloroquine, diethylether, 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 PRECAUTIONS).

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

Carcinogenesis, Mutagenesis, Impairment of Fertility
There have been no long-term studies performed in animals to evaluate carcinogenic potential of succinylcholine. Genetic toxicology studies have not been completed to evaluate the genotoxic potential of succinylcholine. There are no studies to evaluate the potential impact of succinylcholine on fertility.

Pregnancy

Risk Summary
It is also not known whether succinylcholine can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Animal reproduction studies have not been conducted with succinylcholine chloride. Succinylcholine should be given to a pregnant woman only if clearly needed.

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 to 4% and 15 to 20%, respectively.

Clinical Considerations
Plasma cholinesterase levels are decreased by approximately 24% during pregnancy and for several days postpartum. Therefore, a higher proportion of patients may be expected to show increased sensitivity (prolonged apnea) to succinylcholine when pregnant than when nonpregnant.
Labor and Delivery
Succinylcholine is commonly used to provide muscle relaxation during delivery by Cesarean section. While small amounts of succinylcholine are known to cross the placental barrier, under normal conditions the quantity of drug that enters fetal circulation after a single dose of 1 mg/kg to the mother should not endanger the fetus. However, since the amount of drug that crosses the placental barrier is dependent on the concentration gradient between the maternal and fetal circulations, residual neuromuscular blockade (apnea and flaccidity) may occur in the neonate after repeated high doses to, or in the presence of atypical plasma cholinesterase in, the mother.

Nursing Mothers
It is not known whether succinylcholine is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised following succinylcholine administration to a nursing woman.

Pediatric Use

There are rare reports of ventricular dysrhythmias and cardiac arrest secondary to acute rhabdomyolysis with hyperkalemia in apparently healthy pediatric patients who receive succinylcholine (see BOX WARNING). Many of these pediatric patients were subsequently found to have a skeletal muscle myopathy such as Duchenne’s muscular dystrophy whose clinical signs were not obvious. The syndrome often presents as sudden cardiac arrest within minutes after the administration of succinylcholine. These pediatric patients are usually, but not exclusively, males, and most frequently 8 years of age or younger. There have also been reports in adolescents. There may be no signs or symptoms to alert the practitioner to which patients are at risk. A careful history and physical may identify developmental delays suggestive of a myopathy. A preoperative creatine kinase could identify some but not all patients at risk. Due to the abrupt onset of this syndrome, routine resuscitative measures are likely to be unsuccessful. Careful monitoring of the electrocardiogram may alert the practitioner to peaked T-waves (an early sign). Administration of IV calcium, bicarbonate, and glucose with insulin, with hyperventilation have resulted in successful resuscitation in some of the reported cases. Extraordinary and prolonged resuscitative efforts
have been effective in some cases. In addition, in the presence of signs of malignant hyperthermia, appropriate treatment should be initiated concurrently (see WARNINGS). Since it is difficult to identify which patients are at risk, it is recommended that the use of succinylcholine in pediatric patients should be reserved 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.

As in adults, the incidence of bradycardia in pediatric patients is higher following the second dose of succinylcholine. The incidence and severity of bradycardia is higher in pediatric patients than in adults. Pretreatment with anticholinergic agents, e.g., atropine, may reduce the occurrence of bradyarrhythmias.

ADVERSE REACTIONS

Adverse reactions to succinylcholine consist primarily of an extension of its pharmacological actions. Succinylcholine causes profound muscle relaxation resulting in respiratory depression to the point of apnea; this effect may be prolonged. Hypersensitivity reactions, including anaphylaxis, may occur in rare instances. The following additional adverse reactions have been reported: cardiac arrest, malignant hyperthermia, arrhythmias, bradycardia, tachycardia, hypertension, hypotension, hyperkalemia, prolonged respiratory depression or apnea, increased intraocular pressure, muscle fasciculation, jaw rigidity, postoperative muscle pain, rhabdomyolysis with possible myoglobinuric acute renal failure, excessive salivation, and rash.

There have been post-marketing reports of severe allergic reactions (anaphylactic and anaphylactoid reactions) associated with use of neuromuscular blocking agents, including ANECTINE. These reactions, in some cases, have been life-threatening and fatal. Because these reactions were reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency (see WARNINGSand  PRECAUTIONS).

OVERDOSAGE

Overdosage with succinylcholine 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 administration, the characteristic depolarizing neuromuscular block (Phase I) may change to a block with characteristics superficially resembling a nondepolarizing block (Phase II) (see PRECAUTIONS). 

DOSAGE AND ADMINISTRATION

The dosage of succinylcholine should be individualized and should always be determined by the clinician after careful assessment of the patient (see WARNINGS).

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Solutions which are not clear and colorless should not be used.

Risk of Medication Errors
Accidental administration of neuromuscular blocking agents may be fatal. Store ANECTINE with the cap and ferrule intact and in a manner that minimizes the possibility of selecting the wrong product.

Adults
For Short Surgical Procedures
The average dose required to produce neuromuscular blockade and to facilitate tracheal intubation is 0.6 mg/kg ANECTINE Injection given intravenously. The optimum dose will vary among individuals and may be from 0.3 to 1.1 mg/kg for adults. Following 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. However, very large doses may result in more prolonged blockade. A 5- to 10-mg test dose may be used to determine the sensitivity of the patient and the individual recovery time (see  PRECAUTIONS).

For Long Surgical Procedures
The dose of succinylcholine administered by infusion depends upon the duration of the surgical procedure and the need for muscle relaxation. The average rate for an adult ranges between 2.5 and 4.3 mg per minute.

Solutions containing from 1 to 2 mg per mL succinylcholine have commonly been used for continuous infusion. The more dilute solution (1 mg per mL) is probably preferable from the standpoint of ease of control of the rate of administration of the drug and, hence, of relaxation. This IV solution containing 1 mg per mL may be administered at a rate of 0.5 mg (0.5 mL) 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. Avoid overburdening the circulation with a large volume of fluid. It is recommended that neuromuscular function be carefully monitored with a peripheral nerve stimulator when using succinylcholine 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 PRECAUTIONS).

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

Pediatrics

For emergency tracheal intubation or in instances where immediate securing of the airway is necessary, the IV dose of succinylcholine is 2 mg/kg for infants and small pediatric patients; for older pediatric patients and adolescents the dose is 1 mg/kg (see BOX WARNING and PRECAUTIONS: Pediatric Use).

Rarely, IV bolus administration of succinylcholine in infants and pediatric patients may result in malignant ventricular arrhythmias and cardiac arrest secondary to acute rhabdomyolysis with hyperkalemia. In such situations, an underlying myopathy should be suspected.

Intravenous bolus administration of succinylcholine in infants or pediatric patients may result in profound bradycardia or, rarely, asystole. As in adults, the incidence of bradycardia in pediatric patients is higher following a second dose of succinylcholine. The occurrence of bradyarrhythmias may be reduced by pretreatment with atropine (see  PRECAUTIONS: Pediatric Use).

Intramuscular Use 

If necessary, succinylcholine may be given intramuscularly to infants, older pediatric patients, or adults when a suitable vein is inaccessible. A dose of up to 3 to 4 mg/kg may be given, but not more than 150 mg total dose should be administered by this route. The onset of effect of succinylcholine given intramuscularly is usually observed in about 2 to 3 minutes.

Compatibility and Admixtures

Succinylcholine is acidic (pH 3.5) and should not be mixed with alkaline solutions having a pH greater than 8.5 (e.g., barbiturate solutions).  ANECTINE Injection is stable for 24 hours after dilution to a final concentration of 1 to 2 mg/mL in 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP. Aseptic techniques should be used to prepare the diluted product. Admixtures of ANECTINE should be prepared for single patient use only. The unused portion of diluted ANECTINE should be discarded.

HOW SUPPLIED

ANECTINE (Succinylcholine Chloride Injection, USP) is supplied as a clear, colorless solution in Multiple-dose vials 200 mg/10 mL (20 mg/mL), box of 10 vials (NDC 0781-9053-95).

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

Novaplus is a registered trademark of Vizient, Inc.
Distributed by

Sandoz Inc., Princeton, NJ 08540

Rev. November 2022

46314243

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