Anectine

Contraindications ( 4 ) 11/2023 Warnings and Precautions ( 5.5 ) 11/2023

1 INDICATIONS AND USAGE ANECTINE 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. ANECTINE is a depolarizing neuromuscular blocker indicated in adults and pediatric patients: • as an adjunct to general anesthesia ( 1 ) • to facilitate tracheal intubation ( 1 ) • to provide skeletal muscle relaxation during surgery or mechanical ventilation ( 1 ).

2 DOSAGE AND ADMINISTRATION • For intravenous or intramuscular use only ( 2.1 ). • Individualize dosage after careful assessment of the patient ( 2.1 ) • 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 ( 2.1 ). • See full prescribing information for ANECTINE dosage recommendations, preparation instructions, and administration information ( 2.2 , 2.3 , 2.4 , 2.5 ). 2.1 Important Dosage and Administration Information • ANECTINE is for intravenous or intramuscular use only. • ANECTINE must be titrated to effect by or under supervision of experienced clinicians who are familiar with its actions and with appropriate neuromuscular monitoring techniques. • ANECTINE 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 carbon dioxide. The clinician must be prepared to assist or control respiration. • The dosage of ANECTINE should be individualized and should always be determined by the clinician after careful assessment of the patient. • 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. • The occurrence of bradyarrhythmias with administration of ANECTINE 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 ANECTINE by infusion [see Dosage and Administration (2.2) ] . • Visually inspect ANECTINE for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not administer solutions which are not clear and colorless. 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 [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 ANECTINE given intravenously. The optimum intravenous dose will vary among patients and may be from 0.3 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. 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) [see Prolonged Neuromuscular Block due to Phase II Block and Tachyphylaxis ( 5.8 ), Overdose ( 10 ), and Pharmacodynamics ( 12.2 )]. A 5 to 10 mg test dose 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 dose of ANECTINE administered by intravenous infusion depends upon the duration of the surgical procedure and the need for muscle relaxation. The average rate for an adult range between 2.5 and 4.3 mg per minute. Diluted ANECTINE solutions containing from 1 to 2 mg/mL succinylcholine have commonly been used for continuous infusion [see Dosage and Administration (2.4) ] . The more dilute solution (1 mg/mL) is probably preferable from the standpoint of ease of control of the rate of administra …

3 DOSAGE FORMS AND STRENGTHS ANECTINE (Succinylcholine Chloride Injection, USP) is supplied as a clear, colorless solution: • 200 mg/10 mL (20 mg/mL) in multiple-dose vials contains: 20 mg of succinylcholine anhydrous (equivalent to 22.65 mg of Succinylcholine Chloride, USP). Injection: 200 mg/ 10 mL (20 mg/mL) in multiple-dose vials ( 3 )

4 CONTRAINDICATIONS ANECTINE is contraindicated in patients with: • Known or suspected genetic susceptibility to malignant hyperthermia [see WARNINGS, Malignant Hyperthermia ( 5.5 ), CLINICAL PHARMACOLOGY, Pharmacogenomics ( 12.5 )] • Skeletal muscle myopathies [see WARNINGS, Ventricular Dysrhythmias, Cardiac Arrest, and Death From Hyperkalemic Rhabdomyolysis in Pediatric Patients ( 5.1 )] • Known hypersensitivity to succinylcholine [see Warnings and Precautions (5.2) ] . • 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 and Precautions (5.4) ] . • Skeletal muscle myopathies ( 4 ) • Known hypersensitivity to succinylcholine ( 4 ) • After the acute phase of injury following major burns, multiple trauma, extensive denervation of skeletal muscle, or upper motor neuron injury ( 4 ) • Known or suspected genetic susceptibility to malignant hyperthermia ( 4 )

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) ] • Increased 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 Adverse reactions reported with succinylcholine are cardiac arrest, malignant hyperthermia, arrhythmias, bradycardia, tachycardia, hypertension, hypotension, hyperkalemia, prolonged respiratory depression or apnea ( 6 ). To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

7 DRUG INTERACTIONS Drugs that may Enhance the Neuromuscular Blocking Action of Succinylcholine: promazine, oxytocin, aprotinin, certain non-penicillin antibiotics, quinidine, β-adrenergic blockers, procainamide, lidocaine, trimethaphan, lithium carbonate, magnesium salts, quinine, chloroquine, isoflurane, desflurane, metoclopramide, terbutaline, and drugs that reduce plasma cholinesterase activity. ( 7.1 ) 7.1 Drugs that May Affect the Neuromuscular Blocking Action of ANECTINE Drugs that may enhance the neuromuscular blocking action of succinylcholine include: promazine, oxytocin, aprotinin, certain non-penicillin antibiotics, β-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 Warnings and Precautions (5.9) ] . If other neuromuscular blocking agents are to be used during the same procedure, the possibility of a synergistic or antagonistic effect should be considered.

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 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 Maternal Adverse Reactions Plasma cholinesterase levels are decreased by approximately 24% during pregnancy and for several days postpartum which can prolong the effect of ANECTINE. Therefore, some pregnant or newly postpartum patients may experience prolonged apnea following administration of ANECTINE. 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 ANECTINE and any potential adverse effects on the breastfed infant from ANECTINE or from the underlying maternal condition. 8.4 Pediatric Use Safety and effectiveness of succinylcholine chloride have been established in pediatric patients age groups, neonate to adolescent. Since there is a risk of ventricular dysrhythmias, cardiac arrest, and death from hyperkalemic rhabdomyolysis in pediatric patients, reserve the use of ANECTINE 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 ANECTINE in infants or pediatric patients 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 ANECTINE 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 did not include sufficient numbers of subjects aged 65 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.

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.

11 DESCRIPTION ANECTINE (Succinylcholine Chloride Injection, USP) is a short-acting depolarizing neuromuscular blocker, for intravenous (IV) or intramuscular administration. Anectine contains succinylcholine chloride as the active pharmaceutical ingredient. Succinylcholine Chloride, USP is chemically assigned as C 14 H 30 Cl 2 N 2 O 4 with a molecular weight of 361.305 g/mol. 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: chemical-structure

10 OVERDOSAGE Overdosage with ANECTINE 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 ANECTINE 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) ] .

16 HOW SUPPLIED/STORAGE AND HANDLING ANECTINE (Succinylcholine Chloride Injection, USP) is supplied as a clear, colorless solution in multiple-dose vials. 200 mg/10 mL (20 mg/mL) Carton of 10 Vials NDC 72572-750-10 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. Manufactured for: Civica, Inc., Lehi, Utah 84043 Manufactured by: Delpharm Boucherville Canada Inc. 145 Rue Jules-Leger Street Boucherville, QC, J4B 7K8