Phenytoin sodium is available as a 50-mg/mL solution in 2- and 5-mL single-dose vials.3376 Each mL of solution also contains propylene glycol 40% (v/v) and alcohol 10% (v/v) in water for injection.3376 Sodium hydroxide may have been added to adjust the pH.3376
CAUTION: Care should be taken to avoid confusion between phenytoin sodium and fosphenytoin sodium to prevent dosing errors.3280
pH
From 10 to 12.3.3376
Osmolality
The osmolality of phenytoin sodium 50 mg/mL was 9740 mOsm/kg by freezing-point depression and 6175 mOsm/kg by vapor pressure.1071 Another report indicated that the osmolality was 3035 mOsm/kg by freezing-point depression.1233
The osmolality of phenytoin sodium 500 mg in 50 and 100 mL of sodium chloride 0.9% was calculated to be 336 and 312 mOsm/kg, respectively.1054
Phenytoin sodium is preferably administered intravenously, directly into a large peripheral or central vein through a large-gauge catheter.3376 Prior to administration, patency of the intravenous catheter should be tested with a flush of sodium chloride.3376 Following each intravenous administration of phenytoin sodium, the same catheter used to administer the drug should be flushed with sodium chloride to avoid irritation caused by the alkalinity of the phenytoin sodium formulation.3376
For the treatment of status epilepticus, a loading dose of phenytoin sodium should be administered intravenously slowly.3376 For adults, the manufacturer recommends administration of phenytoin sodium at a rate not exceeding 50 mg/min.3376 For pediatric patients, the manufacturer recommends administration of phenytoin sodium at a rate not exceeding 1 to 3 mg/kg/min or 50 mg/min, whichever is slower.3376 The intramuscular route of administration should not be used in the treatment of status epilepticus.3376
For non-emergent indications, phenytoin sodium should be administered more slowly, either as a loading dose or by intermittent intravenous infusion.3376 When administered as an intravenous infusion, phenytoin sodium solution should be diluted in sodium chloride 0.9% to a final phenytoin sodium concentration no less than 5 mg/mL.3376 Administration of phenytoin sodium solution diluted in sodium chloride 0.9% should begin immediately after dilution through an inline filter with a pore size of 0.22 to 0.55 µm.3376
Although phenytoin sodium also may be administered by intramuscular injection, it can cause pain, necrosis, and abscess formation at the injection site and can result in erratic or delayed absorption of the drug.3376 The manufacturer states that the drug generally should not be administered intramuscularly because of these risks.3376 In addition, the intramuscular route of administration should not be used in the treatment of status epilepticus.3376
Purple glove syndrome, characterized by edema, discoloration, and pain distal to the site of infusion, has been reported following intravenous administration of phenytoin sodium through a peripheral vein and may or may not be associated with extravasation.3376
Intact vials should be stored at controlled room temperature.3376 If the undiluted solution is refrigerated or frozen, a precipitate may form; however, this precipitate will dissolve upon standing at room temperature.3376 On dissolution of the precipitate, the product is still suitable for use.3376 Also, a faint yellow color, which has no effect on concentration, may sometimes develop in the injection.3376
Phenytoin sodium solution diluted for infusion should not be refrigerated.3376 Infusion of phenytoin sodium solution diluted in sodium chloride 0.9% should begin immediately after dilution and must be completed within 1 to 4 hours after preparation.3376
Phenytoin sodium solution should be visually inspected for particulate matter and discoloration prior to administration.3376 Any unused portions should be discarded.3376
Precipitation
The solubility of phenytoin sodium is such that crystallization or precipitation may result if the special vehicle is altered or the pH is lowered.62; 63; 613 Unfortunately, direct intravenous injection of phenytoin sodium is inconvenient due to limitations on the rate of administration, and rapid administration increases the risk of severe adverse cardiovascular effects.3376 In spite of the caveat against dilution, some clinicians have advocated the infusion of phenytoin sodium443; 448; 611; 947; 948; 949; 950; 1295 or administration into the tubing of a running infusion solution.63; 65; 338; 445
There are a number of reports of phenytoin crystallization in infusion solutions within varying periods after dilution. While the time to crystal formation may be variable and difficult to predict, crystal formation is nonetheless inevitable.65; 66; 305; 306; 447; 449; 450; 451; 708; 709; 710; 1421
The relationship of phenytoin sodium solubility to various solution characteristics was explored. It was noted that the effect of the special solvent system could be disregarded in dilutions of 1:5 or more. The pH of the admixture was stated to be the primary determinant of the occurrence or absence of crystallization. With a given solution, the pH is dependent on the volume of dilution, with a lower pH resulting from greater dilution. Phenytoin becomes less soluble in aqueous solution as the pH drops. Equations for predicting the compatibility of phenytoin sodium in admixture solutions were presented, but it was noted that it is not possible to predict the time required to develop precipitation.713
Although some may feel that infusion of phenytoin sodium is, perhaps, too dangerous to perform clinically,452 others indicate that such administration may be feasible provided proper precautions are taken such as using a suitable vehicle (i.e., sodium chloride 0.9% or Ringer’s injection, lactated), using a sufficiently concentrated solution, starting the infusion immediately after preparation and completing administration within a relatively short time, using a 0.22-µm inline filter, and watching the admixture very carefully.305; 306; 453; 611; 612; 613; 708; 709; 710; 947; 948; 949; 950; 1295
Phenytoin may precipitate if the injection is mixed with dextrose or dextrose-containing solutions; mixing with these solutions should be avoided.3376 Such precipitation has been found to occlude catheters. Instilling 5 mL of 8.4% sodium bicarbonate injection at 15- to 30-minute intervals has cleared catheters occluded with phenytoin precipitate. The sodium bicarbonate apparently raised the pH enough to result in dissolution of a sufficient amount of the phenytoin precipitate to reopen the catheter;2299; 2300 however, the safety is uncertain because it is not known if some of the precipitated phenytoin is delivered into the bloodstream upon opening the occlusion.
Sorption
Phenytoin sodium was shown not to exhibit sorption to polyvinyl chloride (PVC) bags and tubing, polyethylene tubing, Silastic tubing, and polypropylene syringes.536; 606
Plasticizer Leaching
Phenytoin sodium 10 mg/mL in sodium chloride 0.9% did not leach diethylhexyl phthalate (DEHP) plasticizer from 50-mL PVC bags in 24 hours at 24°C.1683
Filtration
The manufacturer recommends the use of an inline filter with a pore size of 0.22 to 0.55 µm for administration of phenytoin sodium solution diluted for infusion.3376
Phenytoin sodium 250 mg/5 mL was filtered at a rate of 1 mL/min through a 5-µm stainless steel depth filter (Argyle Filter Connector). No reduction due to binding to the filter was observed.320
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