12:12.12 alpha- and beta-Adrenergic Agonists
Generic Name
Norepinephrine bitartrate is available as a 1-mg/mL concentrate for injection in 4-mL single-dose amber glass vials.4055 Each mL of the concentrate contains norepinephrine 1 mg (equivalent to norepinephrine bitartrate, anhydrous 1.89 mg), sodium metabisulfite not more than 0.2 mg as an antioxidant, and sodium chloride for isotonicity in water for injection.4055 The air in the vials is replaced with nitrogen at the time of manufacture.4055 Norepinephrine bitartrate concentrate must be diluted prior to administration.4055 To prepare a 4-mcg/mL solution, 4 mL of the concentrate should be added to 1000 mL of dextrose 5% or sodium chloride solutions containing 5% dextrose; product labeling states administration in sodium chloride solution alone is not recommended.4055 The manufacturer states higher concentrations may be used when fluid restriction is required.4055
Norepinephrine bitartrate is also available as a ready-to-use solution for infusion in single-dose flexible containers containing norepinephrine 4, 8, or 16 mg in 250 mL of dextrose or sodium chloride solution.4045; 4053; 4054 Each mL of ready-to-use solution contains norepinephrine 16, 32, or 64 mcg (equivalent to approximately 32, 64, or 128 mcg of norepinephrine bitartrate monohydrate, respectively) in dextrose 5% or sodium chloride 0.9% and may contain hydrochloric acid and/or sodium hydroxide for pH adjustment.4045; 4053; 4054 Some formulations of norepinephrine bitartrate in sodium chloride ready-to-use solutions also contain edetate disodium (EDTA).4045
pH
Concentrate (1 mg/mL): 3 to 4.5.77; 4055
Ready-to-use solution in dextrose: 3.7.4053
Ready-to-use solution in sodium chloride: 3.4 to 44054 or 3.5 to 4.5.4045
Trade Name(s)
Levophed
Norepinephrine bitartrate is administered by intravenous infusion into a large vein.4055; 4045; 4053; 4054 Extravasation may cause tissue damage and should be avoided.4045; 4053; 4054; 4055
Norepinephrine bitartrate concentrate and ready-to-use solutions in intact containers should be stored at controlled room temperature in the original carton or overwrap to protect from light.4053; 4054; 4055; 4045 After removal from the overwrap, product labeling states ready-to-use solutions may be stored at room temperature for up to 30 days (norepinephrine bitartrate in dextrose) or 7 days (norepinephrine bitartrate in sodium chloride).4045; 4053; 4054
Dextrose 5% and sodium chloride solutions that contain 5% dextrose are recommended diluents for norepinephrine bitartrate concentrate because dextrose reduces loss of potency due to oxidation.4055 Contact of norepinephrine bitartrate solutions with oxidizing agents, iron salts, or alkalis should be avoided.4045; 4053; 4054; 4055
Norepinephrine bitartrate concentrate is stated to be a colorless solution.4055 Norepinephrine bitartrate in dextrose ready-to-use solution is stated to be a colorless to slightly yellow.4053 Norepinephrine bitartrate in sodium chloride ready-to-use solution is clear and colorless.4045; 4054 Solutions should not be used if a pinkish or darker than slightly yellow color or a precipitate is present.4053; 4055
Manufacturer labeling states diluted solutions prepared from the concentrate may be stored for up to 24 hours at room temperature (20 to 25°C) protected from light.4055
pH Effects
Norepinephrine bitartrate is stable at pH 3.6 to 6 in dextrose 5%.48; 77 The pH of a solution is the primary determinant of catecholamine stability in intravenous admixtures.527 At a concentration of 5 mg/L in dextrose 5% at pH 6.5, norepinephrine bitartrate loses 5% in 6 hours; at pH 7.5, it loses 5% in 4 hours.77 The rate of loss also increases with exposure to increasing temperatures.1929
Caution should be employed in mixing additives that may result in a final pH above 6 since norepinephrine bitartrate is alkali labile.6; 24; 77
Visual inspection for color change may be inadequate to assess compatibility of admixtures. In one evaluation with aminophylline stored at 25°C, a color change was not noted until 48 hours had elapsed. However, no intact norepinephrine bitartrate was present in the admixture at 48 hours.527
Syringes
Norepinephrine bitartrate (Aguettant) 0.24 mg/mL in sodium chloride 0.9% was packaged in 50-mL polypropylene syringes (Becton Dickinson) and stored at 2 to 8°C with light protection.3508 Solutions were physically stable with less than 10% loss in 30 days.3508
Norepinephrine bitartrate (manufacturer unspecified) prepared at norepinephrine concentrations of 0.5 and 1.16 mg/mL in dextrose 5% was packaged as 48 mL in 50-mL clear polypropylene and amber polypropylene syringes (Becton Dickinson) and stored at 20 to 25°C.3509 Solutions both with and without light protection were physically stable with little to no loss of drug in 48 hours.3509
Noradrenaline (as the tartrate salt) (Aguettant) prepared at norepinephrine concentrations of 6 mg/50 mL and 12 mg/50 mL in sodium chloride 0.9% in a 50-mL polypropylene syringe (BD) was physically stable for 48 hours at room temperature.3545
Filtration
Norepinephrine bitartrate 4 mg/L in dextrose 5% and sodium chloride 0.9% was filtered at a rate of 120 mL/hr for 6 hours through a 0.22-µm cellulose ester membrane filter (Ivex-2). No significant drug loss due to binding to the filter was noted.533
Central Venous Catheter
Norepinephrine bitartrate prepared at a norepinephrine concentration of 0.1 mg/mL in dextrose 5% was found to be compatible with the ARROWg+ard Blue Plus (Arrow International) chlorhexidine-bearing triple-lumen central catheter. Essentially complete delivery of the drug was found with little or no drug loss occurring. Furthermore, chlorhexidine delivered from the catheter remained at trace amounts with no substantial increase due to the delivery of the drug through the catheter.2335
Standardize 4 Safety
One or more standardized concentrations for this drug have been established through Standardize 4 Safety (S4S), a national patient safety initiative to reduce medication errors, especially during transitions of care. (See Standardize 4 Safety in Users Guide.) Recommendations developed to date through this initiative are available at www.ashp.org/pharmacy-practice/standardize-4-safety-initiative.
Table 1. Standardize 4 Safety Continuous IV Infusion Standard Concentrations for Norepinephrine3635; 3636
| Patient Population | Concentration Standardsa | Dosing Units |
|---|---|---|
| Adults | 16 mcg/mL 32 mcg/mL 128 mcg/mL | mcg/kg/minute |
| Pediatric patients (50 kg) | 16 mcg/mLb 32 mcg/mL 64 mcg/mL | mcg/kg/minute |
aThe concentrations for epinephrine and norepinephrine are intentionally different to avoid confusion as recommended by the S4S panel and ISMP.bBabies weighing under 500 grams may require a lower concentration.
For a list of references cited in the text of this monograph, search the monograph titled References.