Sodium Chloride

INDICATIONS AND USAGE: Sodium Chloride Injection, USP, 23.4%, is indicated as an additive in parenteral fluid therapy for use in patients who have special problems of sodium electrolyte intake or excretion. It is intended to meet the specific requirements of the patient with unusual fluid and electrolyte needs. After available clinical and laboratory information is considered and correlated, the appropriate number of milliequivalents of sodium chloride required can be withdrawn from Sodium Chloride Injection, USP, 23.4% and diluted for use. Sodium Chloride Injection is indicated for the treatment of sodium, chloride and water deficiencies that commonly occur in many diseases. Isotonic Sodium Chloride Injection should be limited to cases in which the chloride loss is greater than the sodium loss, as in vomiting from pyloric obstruction, or in which the loss is about equal, as in vomiting from duodenal, jejunal or ileal obstruction and in the replacement of aspirated gastrointestinal fluids. The toxic symptoms that follow various forms of intestinal obstruction are accompanied by a marked reduction of blood chloride and often sodium chloride has a lifesaving effect. Symptoms of sodium chloride deficiency are very similar to those of Addison’s disease and large doses of sodium chloride will produce temporary alleviation of the symptoms. Other disorders in which sodium chloride is therapeutically useful include extensive burns, failure of gastric secretion and postoperative intestinal paralysis.

DOSAGE AND ADMINISTRATION 23.4% Sodium Chloride Injection, USP Additive Solution is administered intravenously only after addition to a larger volume of fluid. The dose, dilution and rate of injection are dependent upon the individual needs of each patient. In solutions for total parenteral nutrition (TPN), 120 mEq of sodium/day (range: 75–180 mEq/day) is the recommended adult dosage, whereas the recommended dosage is 3–4 mEq/kg/day for preterm infants. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Discard unused portion. Additives may be incompatible with the fluid dispensed from this container. Consult with pharmacist, if available. When admixing, use aseptic technique, mix thoroughly and do not store. Directions for Proper Use of Pharmacy Bulk Package Use Aseptic Technique 1. For hanger application, peel off the paper liner from both ends of the tape hanger to expose 3/4 in. long adhesive portions. Adhere each end to the label on the bottle. 2. During use, container must be stored and all manipulations performed in an appropriate laminar flow hood. 3. Remove cover from container and cleanse closure with antiseptic. 4. Insert suitable sterile dispensing set or transfer device and suspend unit in a laminar flow hood. The closure should be entered only once and after initial entry, the withdrawal of container contents should be completed promptly in one continuous operation. Should this not be possible, a maximum time of 4 hours from initial closure puncture is permitted to complete fluid transfer operations; i.e., discard container no later than 4 hours after initial closure puncture. 5. Sequentially dispense aliquots of 23.4% Sodium Chloride Injection, USP into intravenous containers using appropriate transfer device. During fluid transfer operations, the Pharmacy Bulk Package should be maintained under the storage conditions recommended in the labeling. 6. Inspect solution after admixing. Discard if the solution is discolored or particulates are observed.

WARNINGS Hypersensitivity Hypersensitivity and infusion reactions, including hypotension, pyrexia, tremor, chills, urticaria, rash, and pruritus have been reported with 0.9% Sodium Chloride Injection, USP. Stop the infusion immediately if signs or symptoms of a hypersensitivity reaction develop, such as tachycardia, chest pain, dyspnea and flushing. Appropriate therapeutic countermeasures must be instituted as clinically indicated. Electrolyte Imbalances Fluid Overload Depending on the volume and rate of infusion, and the patient’s underlying clinical condition, intravenous administration of Sodium Chloride Injection, USP can cause fluid disturbances such as overhydration/ hypervolemia and congested states, including pulmonary congestion and edema. Avoid 0.9% Sodium Chloride Injection, USP in patients with or at risk for fluid and/or solute overloading. If use cannot be avoided, monitor fluid balance, electrolyte concentrations, and acid base balance, as needed and especially during prolonged use. Hyponatremia Sodium Chloride Injection, USP may cause hyponatremia. Hyponatremia can lead to acute hyponatremic encephalopathy characterized by headache, nausea, seizures, lethargy, and vomiting. Patients with brain edema are at particular risk of severe, irreversible and life-threatening brain injury. The risk of hospital-acquired hyponatremia is increased in patients with cardiac or pulmonary failure, and in patients with non-osmotic vasopressin release (including SIADH) treated with high volume of Sodium Chloride Injection, USP. The risk for hyponatremia is increased in pediatric patients, elderly patients, postoperative patients, those with psychogenic polydipsia, and in patients treated with medications that increase the risk of hyponatremia (such as diuretics, certain antiepileptic and psychotropic medications). See DRUG INTERACTIONS . Patients at increased risk for developing complications of hyponatremia such as hyponatremic encephalopathy, include pediatric patients, women (in particular pre­-menopausal women), patients with hypoxemia, and patients with underlying central nervous system disease. Avoid Sodium Chloride Injection, USP in patients with or at risk for hyponatremia. If use cannot be avoided, monitor serum sodium concentrations. Rapid correction of hyponatremia is potentially dangerous with risk of serious neurologic complications. Brain adaptations reducing risk of cerebral edema make the brain vulnerable to injury when chronic hyponatremia is too rapidly corrected, which is known as osmotic demyelination syndrome (ODS). To avoid complications, monitor serum sodium and chloride concentrations, fluid status, acid-base balance, and signs of neurologic complications. Hypernatremia Hypernatremia may occur with Sodium Chloride Injection, USP. Conditions that may increase the risk of hypernatremia, fluid overload and edema (central and peripheral), include patients with: primary hyperaldosteronism; secondary hyperaldosteronism associated with, for example, hypertension, congestive heart failure, liver disease (including cirrhosis), renal disease (including renal artery stenosis, nephrosclerosis); and pre-eclampsia. Certain medications, such as corticosteroids or corticotropin, may also increase risk of sodium and fluid retention, see DRUG INTERACTIONS . Avoid Sodium Chloride Injection, USP in patients with, or at risk for, hypernatremia. If use cannot be avoided, monitor serum sodium concentrations. Rapid correction of hypernatremia is potentially dangerous with risk of serious neurologic complications. Excessively rapid correction of hypernatremia is also associated with a risk for serious neurologic complications such as osmotic demyelination syndrome (ODS) with risk of seizures and cerebral edema. Hypersensitivity Hypersensitivity and infusion reactions, including hypotension, pyrexia, tremor, chills, urticaria, rash, and pruritus have been reported with 0.9% Sodium Chloride Injection, USP. Stop the infusion immediately if signs or symptoms of a hypersensitivity reaction develop, such as tachycardia, chest pain, dyspnea and flushing. Appropriate therapeutic countermeasures must be instituted as clinically indicated. Electrolyte Imbalances Fluid Overload Depending on the volume and rate of infusion, and the patient’s underlying clinical condition, intravenous administration of Sodium Chloride Injection, USP can cause fluid disturbances such as overhydration/ hypervolemia and congested states, including pulmonary congestion and edema. Avoid 0.9% Sodium Chloride Injection, USP in patients with or at risk for fluid and/or solute overloading. If use cannot be avoided, monitor fluid balance, electrolyte concentrations, and acid base balance, as needed and especially during prolonged use. Hyponatremia Sodium Chloride Injection, USP may cause hyponatremia. Hyponatremia can lead to acute hyponatremic encephalopathy characterized by headache, nausea, seizures, lethargy, and vomiting. Patients with brain edema are at particular risk of severe, irreversible and life-threatening brain injury. The risk of hospital-acquired hyponatremia is increased in patients with cardiac or pulmonary failure, and in patients with non-osmotic vasopressin release (including SIADH) treated with high volume of Sodium Chloride Injection, USP. The risk for hyponatremia is increased in pediatric patients, elderly patients, postoperative patients, those with psychogenic polydipsia, and in patients treated with medications that increase the risk of hyponatremia (such as diuretics, certain antiepileptic and psychotropic medications). See DRUG INTERACTIONS . Patients at increased risk for developing complications of hyponatremia such as hyponatremic encephalopathy, include pediatric patients, women (in particular pre­-menopausal women), patients with hypoxemia, and patients with underlying central nervous system disease. Avoid Sodium Chloride Injection, USP in patients with or at risk for hyponatremia. If use cannot be avoided, monitor serum sodium concentrations. Rapid correction of hyponatremia is potentially dangerous with risk of serious neurologic complications. Brain adaptations reducing risk of cerebral edema make the brain vulnerable to injury when chronic hyponatremia is too rapidly corrected, which is known as osmotic demyelination syndrome (ODS). To avoid complications, monitor serum sodium and chloride concentrations, fluid status, acid-base balance, and signs of neurologic complications. Hypernatremia Hypernatremia may occur with Sodium Chloride Injection, USP. Conditions that may increase the risk of hypernatremia, fluid overload and edema (central and peripheral), include patients with: primary hyperaldosteronism; secondary hyperaldosteronism associated with, for example, hypertension, congestive heart failure, liver disease (including cirrhosis), renal disease (including renal artery stenosis, nephrosclerosis); and pre-eclampsia. Certain medications, such as corticosteroids or corticotropin, may also increase risk of sodium and fluid retention, see DRUG INTERACTIONS . Avoid Sodium Chloride Injection, USP in patients with, or at risk for, hypernatremia. If use cannot be avoided, monitor serum sodium concentrations. Rapid correction of hypernatremia is potentially dangerous with risk of serious neurologic complications. Excessively rapid correction of hypernatremia is also associated with a risk for serious neurologic complications such as osmotic demyelination syndrome (ODS) with risk of seizures and cerebral edema.

CONTRAINDICATIONS Due to the potential toxicity of benzyl alcohol in neonates, solutions containing benzyl alcohol must not be used in this patient population. Parenteral preparations with benzyl alcohol should not be used for fluid or sodium chloride replacement. Parenteral preparations containing benzyl alcohol should not be used in epidural or spinal anesthetic procedures.

DRUG INTERACTIONS Caution must be exercised in the administration of Sodium Chloride Injection, USP to patients receiving corticosteroids or corticotropin. Carcinogenesis, Mutagenesis, Impairment of Fertility Studies have not been performed with Sodium Chloride Injection, USP to evaluate the potential for carcinogenesis, mutagenesis or impairment of fertility. Pregnancy: Teratogenic Effects Pregnancy Category C Animal reproduction studies have not been conducted with Sodium Chloride Injection, USP. It is also not known whether Sodium Chloride Injection, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Sodium Chloride Injection, USP should be given to a pregnant woman only if clearly needed. Labor and Delivery Studies have not been conducted to evaluate the effects of Sodium Chloride Injection, USP on labor and delivery. Caution should be exercised when administering this drug during labor and delivery. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Sodium Chloride Injection, USP is administered to a nursing mother. Pediatric Use The use of Sodium Chloride Injection, USP in pediatric patients is based on clinical practice. Plasma electrolyte concentrations should be closely monitored in the pediatric population as this population may have impaired ability to regulate fluids and electrolytes. The infusion of hypotonic fluids (0.45% Sodium Chloride Injection, USP) together with the non-osmotic secretion of ADH may result in hyponatremia in patients with acute volume depletion. Hyponatremia can lead to headache, nausea, seizures, lethargy, coma, cerebral edema and death, therefore acute symptomatic hyponatremic encephalopathy is considered a medical emergency. Geriatric Use Clinical studies of Sodium Chloride Injection, USP 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 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 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. Do not administer unless solution is clear and container is undamaged. Discard unused portion.

ADVERSE REACTIONS Post-Marketing Adverse Reactions The following adverse reactions have been identified during postapproval use of 0.9% Sodium Chloride Injection, USP. Because these reactions are 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. The following adverse reactions have been reported in the post-marketing experience during use of 0.9% Sodium Chloride Injection, USP and include the following: Hypersensitivity reactions : hypersensitivity/infusion reactions, including hypotension, pyrexia, tremor, chills, urticaria, rash, and pruritus. General disorders and administration site condition s: infusion site reactions, such as infusion site erythema, injection site streaking, burning sensation, and infusion site urticaria. Metabolism and nutrition disorders : hypernatremia, hyperchloremic metabolic acidosis, and hyponatremia, which may be symptomatic. Nervous System Disorders : Hyponatremic encephalopathy. 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.

CLINICAL PHARMACOLOGY: Sodium chloride comprises over 90% of the inorganic constituents of the blood serum. Both its ions are physiologically important. Sodium, more than any other ion, determines the osmotic pressure of interstitial fluids and the degree of hydration of tissues. When the intake of the chloride ion is less than is excreted, there is a relative increase in the blood bicarbonate level, producing the condition known as alkalosis. Other symptoms of sodium chloride deficiency are nausea, vomiting and increased irritability of muscles, evidenced by cramps and, possibly, convulsions. It is well known that excessive sweating will cause ‘‘heatcramps,’’ i.e., muscle cramps in the abdomen and extremities, which can be completely relieved only by ingestion of a weak salt solution. Approximately 25% of the total body sodium is found in the bone. The regulation of salt and water metabolism is governed by different mechanisms; however, changes in the intake, distribution and output of salt are, in health, associated with collateral shifts of water so that electrolyte concentrations are maintained within a narrow range. In the presence of disease affecting the cardiovascular, hepatic or renal system or in certain endocrinologic disorders, changes in the rate of excretion of salt and water will disturb the homeostatic equilibrium. Frequently, abnormalities in the metabolism of water or salt may occur as a result of vomiting, diarrhea, gastrointestinal suction and fever. Excessive sweating will produce loss of water or salt, but since the electrolyte concentration is hypotonic, loss of water will predominate. The normal salt intake ranges from 5 to 15 grams daily, most of which is excreted by the kidneys. The control of water and salt excretion in urine is very intricate, involving filtration by the glomerulus and reabsorption by the tubules of approximately 99% of the filtered load. The actual quantities excreted depends on the requirements prevailing at the moment. The finer adjustments of the tubular absorptive mechanisms are influenced by osmotic interrelationships between cell water, plasma and urine and by certain steroid hormones influencing electrolyte excretion and the posterior pituitary hormone regulating water excretion. When food intake ceases or salt is withheld, the content of sodium chloride in urine diminishes rapidly so that the body stores are retained. Similar renal retention of electrolytes occurs when salt is lost via gastrointestinal secretion through vomiting, etc. In other conditions, such as congestive heart failure, cirrhosis, nephritis or hypersecretion of the adrenal cortical hormones, the kidney fails to eliminate sufficient sodium. This results in retention of both salt and water, producing an excessive accumulation of extracellular fluid, which may be effectively combated by a sharp restriction of salt intake and use of a diuretic. Depletion of body salt may be caused in many ways, one of which is too energetic treatment of fluid and sodium retention. Besides this, diabetic acidosis, burns, excessive sweating with free drinking of water, repeated paracentesis for removal of ascitic fluid, adrenal cortical hypofunction and certain forms of nephritis, as well as abnormal losses of gastrointestinal secretions, will cause marked salt depletion. With salt loss, there is a reduction of the osmotic pressure of the extracellular fluid; the urine volume may be retained but it is free of sodium chloride.