1.1 In Intravenous Fluids to Correct Hypophosphatemia

POTASSIUM PHOSPHATES INJECTION is indicated as a source of phosphorus in intravenous fluids to correct hypophosphatemia in adults and pediatric patients 12 years of age and older when oral or enteral replacement is not possible, insufficient or contraindicated.

1.2 For Parenteral Nutrition

POTASSIUM PHOSPHATES INJECTION is indicated as a source of phosphorus for parenteral nutrition in adults weighing at least 45 kg and pediatric patients 12 years of age and older weighing at least 40 kg when oral or enteral nutrition is not possible, insufficient or contraindicated.

Limitations of Use
Safety has not been established for parenteral nutrition in adults weighing less than 45 kg or pediatric patients less than 12 years of age or weighing less than 40 kg due to the risk of aluminum toxicity [see Warnings and Precautions (5.5), Use in Specific Population (8.4)].

2.1 Preparation and Administration in Intravenous Fluids to Correct Hypophosphatemia

Preparation

• POTASSIUM PHOSPHATES INJECTION is for intravenous infusion into a central or peripheral vein only after dilution.
• Using aseptic technique, withdraw the required dose from the vial and add to 100 mL to 250 mL of 0.9% Sodium Chloride Injection, USP (normal saline) or 5% Dextrose Injection, USP (D5W).
• The concentration of the diluted solution should take into consideration the amounts of phosphorus and potassium to be administered and is dependent upon whether administration will be through a peripheral or central venous catheter. The recommended maximum concentration is:

• phosphorus 6.4 mmol/100 mL (potassium 10 mEq/100 mL) for peripheral administration
• phosphorus 18 mmol/100 mL (potassium 28.2 mEq/100mL) for central administration

• Visually inspect the solution for particulate matter and discoloration before and after dilution and prior to administration. Do not administer unless solution is clear, and seal on the vial is intact.

Administration

• Check serum potassium and calcium concentrations prior to administration. Normalize the calcium before administering POTASSIUM PHOSPHATES INJECTION [see Contraindications (4), Warnings and Precautions (5.3,5.4)].
• POTASSIUM PHOSPHATES INJECTION is only for administration to a patient with a serum potassium concentration less than 4 mEq/dL[see Warnings and Precautions (5.3)]. If the potassium concentration is 4 mEq/dL or more, use an alternative source of phosphate.
• Do not infuse with calcium-containing intravenous fluids [see Warnings and Precautions (5.4)].
• The rate of administration may be dependent on the patient and the specific institution policy [see Dosage and Administration (2.2)].

Storage and Stability

• For single use only. Discard used vial, including any unused contents.
• After dilution, the solution is stable for 48 hours under refrigeration at 2°C to 8°C (36°F to 46°F) or at room temperature from 20°C to 25°C (68°F to 77°F).

2.2 Dosage for Administration in Intravenous Fluids to Correct Hypophosphatemia

POTASSIUM PHOSPHATES INJECTION provides phosphorus 3 mmol/mL (potassium 4.7 mEq/mL).

The dosage is dependent upon the individual needs of the patient, and the contribution of phosphorus and potassium from other sources.

Initial or Single Dose
The phosphorus doses in Table 1 are general recommendations for an initial or single dose and are intended for most patients. Based upon clinical requirements, some patients may require a lower or higher dose. The maximum initial or single dose of phosphorus is 45 mmol (potassium 71 mEq) [see Warnings and Precautions (5.1)].

In patients with moderate renal impairment (eGFR ≥30 mL/min/1.73 m2 to <60 mL/min/1.73 m2), start at the low end of the dose range [see Use in Specific Populations (8.6)].

Monitor serum phosphorus, potassium, calcium and magnesium serum concentrations.

a Serum phosphorus reported using 2.5 mg/dL as the lower end of the reference range for healthy adults. Serum phosphorus concentrations may vary depending on the assay used and the laboratory reference range.
b Weight is in terms of actual body weight. Limited information is available regarding dosing of patients significantly above ideal body weight; consider using an adjusted body weight for these patients.
c up to a maximum of phosphorus 45 mmol (potassium 71 mEq) as a single dose.

Concentration and Intravenous Infusion Rate

• The concentration of the diluted solution and the infusion rate is dependent upon whether administration will be through a peripheral or central venous catheter.

Peripheral administration:

• The maximum recommended concentration is phosphorus 6.4 mmol/100 mL (potassium10 mEq/100 mL).
• The maximum recommended infusion rate is approximately phosphorus 6.4 mmol/hour (potassium 10 mEq/hour).

Central administration:

• The maximum recommended concentration is phosphorus 18 mmol/100 mL (potassium 28.2 mEq/100 mL).
• The maximum recommended infusion rate is approximately phosphorus 15 mmol/hour (potassium 23.5 mEq/hour).

• Continuous electrocardiographic (ECG) monitoring and infusion through a central venous catheter is recommended for infusion rates of potassium higher than 10 mEq/hour in adults and 0.5 mEq/kg/hour in pediatric patients 12 years of age and older.

Repeated Dosing
Additional dose(s) following the initial dose may be needed in some patients. Prior to administration of additional doses, assess the patient clinically and obtain serum phosphorous, calcium and potassium concentrations and adjust the dose accordingly.

2.3 Preparation and Administration in Parenteral Nutrition

• POTASSIUM PHOSPHATES INJECTION is for intravenous infusion into a peripheral or central vein only after dilution and admixing.
• POTASSIUM PHOSPHATES INJECTION is to be prepared only in a suitable work area such as a laminar flow hood (or an equivalent clean air compounding area). The key factor in the preparation is careful aseptic technique to avoid inadvertent touch contamination during mixing of solutions and addition of other nutrients.
• Transfer the required amount of POTASSIUM PHOSPHATES INJECTION to the parenteral nutrition solution following the admixture of amino acids, dextrose, electrolytes solutions, and prior to lipids (if added).
• Because additives may be incompatible, evaluate all additions to the parenteral nutrition container for compatibility and stability of the resulting preparation.
• Calcium and phosphate ratios must be considered. Excess addition of calcium and phosphate, especially in the form of mineral salts, may result in the formation of calcium-phosphate precipitates [see Warnings and Precautions (5.2)]. Calcium-phosphate stability in parenteral nutrition solutions is dependent upon the pH of the solution, temperature, and relative concentration of each ion. Discard if any precipitates are observed.
• Inspect the final parenteral solution containing POTASSIUM PHOSPHATES INJECTION to ensure that:
  
  • precipitates have not formed during mixing or addition of additives and inspect again before administration.
  • the emulsion has not separated, if lipids have been added. Separation of the emulsion can be visibly identified by a yellowish streaking or the accumulation of yellowish droplets in the admixed emulsion.
• The final parenteral nutrition solution is for intravenous infusion into a peripheral or central vein. The choice of a peripheral or central venous route should depend on the osmolarity of the final infusate. Solutions with osmolarity of 900 mOsm/L or greater must be infused through a central catheter [see Warnings and Precautions (5.7)].

Storage and Stability

• For single use only. Discard used vial, including any unused contents.
• Use parenteral nutrition solution promptly after mixing. Any storage of the admixture should be under refrigeration from 2°C to 8°C (36°F to 46°F) and limited to a brief period of time, no longer than 24 hours. After removal from refrigeration, bring to room temperature and use promptly and complete the infusion within 24 hours. Discard any remaining admixture.
• Protect the parenteral nutrition solution from light during storage.

2.4 Dosage for Administration in Parenteral Nutrition

POTASSIUM PHOSPHATES INJECTION provides phosphorus 3 mmol/mL (potassium 4.7 mEq/mL).

The recommended and maximum daily dosage in parenteral nutrition is shown in Table 2. Individualize the dosage based upon the patient’s clinical condition, nutritional requirements, and the contribution of oral or enteral phosphorus and potassium intake. The amount of phosphorus that can be added to parenteral nutrition may be limited by the amount of calcium that is also added to the solution.

a see Warnings and Precautions (5.5), Use in Specific Populations (8.4)
b In patients with moderate renal impairment (eGFR ≥30 mL/min/1.73 m2 to <60 mL/min/1.73 m2), start at the low end of the dosage range.

Monitoring

5.1 Serious Cardiac Adverse Reactions with Undiluted, Bolus or Rapid Intravenous Administration

Intravenous administration of potassium phosphates to correct hypophosphatemia in single doses of phosphorus 50 mmol and greater and/or at rapid infusion rates (over 1 to 3 hours) in intravenous fluids has resulted in death, cardiac arrest, cardiac arrhythmia (including QT prolongation), hyperkalemia, hyperphosphatemia, and seizures [see Overdosage (10)]. In addition, inappropriate intravenous administration of undiluted or insufficiently diluted potassium phosphates as a rapid “IV push” has resulted in cardiac arrest, cardiac arrhythmias, hypotension, and death.

POTASSIUM PHOSPHATES INJECTION is for intravenous infusion only after dilution or admixing. The maximum initial or single dose of POTASSIUM PHOSPHATES INJECTION in intravenous fluids to correct hypophosphatemia is phosphorus 45 mmol (potassium 71 mEq). The recommended infusion rate is approximately phosphorus 6.4 mmol/hour (potassium 10 mEq/hour). Continuous electrocardiographic (ECG) monitoring is recommended for higher infusion rates [see Dosage and Administration (2.1, 2.2)].

5.2 Pulmonary Embolism due to Pulmonary Vascular Precipitates

Pulmonary vascular emboli and pulmonary distress related to precipitates in the pulmonary vasculature have been described in patients receiving admixed products containing calcium and phosphates or parenteral nutrition. The cause of precipitate formation has not been determined in all cases; however, in some fatal cases, pulmonary emboli occurred as a result of calcium phosphate precipitates. Precipitation has occurred following passage through an in-line filter; in vivo precipitate formation may also have occurred. If signs of pulmonary distress occur, stop the parenteral nutrition infusion and initiate a medical evaluation. In addition to inspection of the solution [see Dosage and Administration (2.1, 2.3)], the infusion set and catheter should also periodically be checked for precipitates.

5.3 Hyperkalemia

POTASSIUM PHOSPHATES INJECTION may increase the risk of hyperkalemia, including life-threatening cardiac events, especially when administered in excessive doses, undiluted or by rapid intravenous infusion [see Warnings and Precautions (5.1)]. Patients with severe renal impairment and end stage renal disease are at increased risk of developing life-threatening hyperkalemia, when administered intravenous potassium [see Contraindications (4)]. Other patients at increased risk of hyperkalemia include those with severe adrenal insufficiency or treated concurrently with other drugs that cause or increase the risk of hyperkalemia [see Drug Interactions (7.1)]. Patients with cardiac disease may be more susceptible to the effects of hyperkalemia.

Consider the amount of potassium from all sources when determining the dose of POTASSIUM PHOSPHATES INJECTION and do not exceed the maximum age-appropriate recommended daily amount of potassium. In patients with moderate renal impairment (eGFR ≥30 mL/min/1.73 m2 to <60 mL/min/1.73 m2), start at the low end of the dose range and monitor serum potassium, phosphorus, calcium, and magnesium concentrations [see Dosage and Administration (2.2, 2.4), Use in Specific Populations (8.6)].

When administering POTASSIUM PHOSPHATES INJECTION in intravenous fluids to correct hypophosphatemia, check the serum potassium concentration prior to administration. If the potassium concentration is 4 mEq/dL or more, do not administer POTASSIUM PHOSPHATES INJECTION and use an alternative source of phosphate [see Dosage and Administration (2.1)]. The maximum initial or single dose of POTASSIUM PHOSPHATES INJECTION in intravenous fluids to correct hypophosphatemia is phosphorus 45 mmol (potassium 71 mEq). The recommended infusion rate of potassium is 10 mEq/hour. Continuous electrocardiographic (ECG) monitoring is recommended for higher infusion rates of potassium [see Dosage and Administration (2.2)].

5.4 Hyperphosphatemia and Hypocalcemia

Hyperphosphatemia can occur with intravenous administration of potassium phosphates, especially in patients with renal impairment.
Hyperphosphatemia can cause the formation of insoluble calcium phosphorus products with consequent hypocalcemia, neurological irritability with tetany, nephrocalcinosis with acute kidney injury and more rarely, cardiac irritability with arrhythmias.

Obtain serum calcium concentrations prior to administration and normalize the calcium before administering POTASSIUM PHOSPHATES INJECTION. POTASSIUM PHOSPHATES INJECTION is contraindicated in patients with hyperphosphatemia and/or hypercalcemia [see Contraindications (4)].

Monitor serum phosphorus and calcium concentrations during treatment with POTASSIUM PHOSPHATES INJECTION [see Dosage and Administration (2.2)].

5.5 Aluminum Toxicity

POTASSIUM PHOSHATES INJECTION contains aluminum that may be toxic.

Aluminum may reach toxic levels with prolonged parenteral administration in patients with renal impairment. Preterm infants are particularly at risk for aluminum toxicity because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which also contain aluminum.

Patients with renal impairment, including preterm infants, who receive greater than 4 to 5 mcg/kg/day of parenteral aluminum can accumulate aluminum to levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration.

Exposure to aluminum from POTASSIUM PHOSPHATES INJECTION is not more than 4.9 mcg/kg/day when:

• adults weighing at least 45 kg are administered the recommended maximum dosage of phosphorus (45 mmol/day) for parenteral nutrition.
• pediatric patients 12 years of age and older weighing at least 40 kg are administered the recommended maximum dosage of phosphorus (40 mmol/day) for parenteral nutrition [see Dosage and Administrations (2.4), Description (11)].

When prescribing POTASSIUM PHOSPHATES INJECTION for use in parenteral nutrition solutions containing other small volume parenteral products, the total daily patient exposure to aluminium from the admixture should be considered and maintained at no more than 5 mcg/kg/day [see Use in Specific Populations (8.4)].

POTASSIUM PHOSPHATES INJECTION for parenteral nutrition is not recommended in adults weighing less than 45 kg or pediatric patients less than 12 years of age or weighing less than 40 kg due to the risks of aluminum toxicity [see Indications and Usage (1.2)].

5.6 Hypomagnesemia

Intravenous infusion of phosphate has been reported to cause a decrease in serum magnesium (and calcium) concentrations when administered to patients with hypercalcemia and diabetic ketoacidosis. Monitor serum magnesium concentrations during treatment.

5.7 Vein Damage and Thrombosis

POTASSIUM PHOSPHATES INJECTION must be diluted and administered in intravenous fluids or used as an admixture in parenteral nutrition. It is not for direct intravenous infusion. The infusion of hypertonic solutions into a peripheral vein may result in vein irritation, vein damage, and/or thrombosis. The primary complication of peripheral administration is venous thrombophlebitis, which manifests as pain, erythema, tenderness or a palpable cord. Remove the catheter as soon as possible and initiate appropriate medical treatment if thrombophlebitis develops.

When administered peripherally in intravenous fluids to correct hypophosphatemia, a generally recommended maximum concentration is phosphorus 6.4 mmol/100 mL (potassium 10 mEq/100 mL) [see Dosage and Administration (2.1)]

Parenteral nutrition solutions with an osmolarity of 900 mOsm/L or greater must be infused through a central catheter [see Dosage and Administration (2.3)].

5.8 Laboratory Monitoring

Monitor serum phosphorus, potassium, calcium and magnesium concentrations during treatment [see Dosage and Administration (2.2, 2.4)].

7.1 Other Products that Increase Serum Potassium

Administration of POTASSIUM PHOSPHATES INJECTION to patients treated concurrently or recently with products that increase serum potassium (e.g., potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists, digoxin, or the immunosuppressants tacrolimus and cyclosporine) increases the risk of severe and potentially fatal hyperkalemia, in particular in the presence of other risk factors for hyperkalemia [see Warnings and Precautions (5.2)]. Avoid use of POTASSIUM PHOSPHATES INJECTION in patients receiving such products. If use cannot be avoided, closely monitor serum potassium concentrations [see Dosage and Administration (2.2, 2.3)].

8.1 Pregnancy

Risk Summary
Administration of the approved recommended dose of POTASSIUM PHOSPHATES INJECTION is not expected to cause major birth defects, miscarriage, or adverse maternal or fetal outcomes. Animal reproduction studies have not been conducted with intravenous potassium phosphates.

The estimated background risk of major birth defects and miscarriage for the indicated populations 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
Disease-associated Maternal and/or Embryo-Fetal Risk
Phosphorus is an essential mineral element. Parenteral supplementation with potassium phosphates should be considered if a pregnant woman’s requirements cannot be fulfilled by oral or enteral intake.

8.2 Lactation

Risk Summary
Phosphorus and potassium are present in human milk. Administration of the approved recommended dose of POTASSIUM PHOSPHATES INJECTION is not expected to cause harm to a breastfed infant. There is no information on the effects of potassium phosphates on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for POTASSIUM PHOSPHATES INJECTION and any potential adverse effects on the breastfed infant from POTASSIUM PHOSPHATES INJECTION or from the underlying maternal condition.

8.4 Pediatric Use

Safety and effectiveness of POTASSIUM PHOSPHATES INJECTION have been established in:

• pediatric patients 12 years and older as a source of phosphorus in intravenous fluids to correct hypophosphatemia when oral or enteral replacement is not possible, insufficient, or contraindicated.
• pediatric patients 12 years and older weighing at least 40 kg as a source of phosphorus for parenteral nutrition when oral or enteral nutrition is not possible, insufficient, or contraindicated.

The safety of POTASSIUM PHOSPHATES INJECTION for parenteral nutrition has not been established in pediatric patients less than 12 years of age or in adolescents weighing less than 40 kg due to the risk of aluminum toxicity [see Indications and Usage (1.2), Warnings and Precautions (5.5)].

8.5 Geriatric Use

In general, dose selection of POTASSIUM PHOSPHATES INJECTION for an elderly patient should be cautious, starting at the low end of the dosing range because of the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. It may be useful to monitor renal function during treatment [see Use in Specific Populations (8.6)].

8.6 Renal Impairment

Potassium and phosphorus are known to be substantially excreted by the kidney and the risk of adverse reactions to POTASSIUM PHOSPHATES INJECTION may be greater in patients with impaired renal function [see Warnings and Precautions (5.3, 5.4, 5.5)].

POTASSIUM PHOSPHATES INJECTION is contraindicated due to the risk of hyperkalemia in patients with severe renal impairment (eGFR less than 30 mL/min/1.73 m2) or end stage renal disease [see Contraindications (4)].

In patients with moderate renal impairment (eGFR ≥ 30 mL/min/1.73 m2 to < 60 mL/min/1.73 m2), start at the low end of the dosage range and monitor serum potassium, phosphorus, calcium, and magnesium concentrations [see Dosage and Administration (2.2, 2.4)].

12.1 Mechanism of Action

Phosphorus in the form of organic and inorganic phosphate has a variety of biochemical functions in all organs and tissues, including critical roles in nucleic acid structure, energy storage and transfer, cell signaling, cell membrane composition and structure, acid-base balance, mineral homeostasis and bone mineralization.

12.3 Pharmacokinetics

Distribution
Approximately 85% of serum phosphates is free and ultra-filterable and 15% is protein-bound.

Elimination
Intravenously infused phosphates not taken up by the tissues are excreted almost entirely in the urine. Serum phosphorus is believed to be filterable by the renal glomeruli and the major portion of filtered phosphorus (greater than 80%) is actively reabsorbed by the tubules.