Nitroglycerin injection is available as a 5-mg/mL concentrate for injection in 10-mL single-dose vials.3706 The concentrate for injection also contains alcohol 30% (v/v) and propylene glycol 30% in water for injection.3706 The pH may have been adjusted during manufacturing with sodium hydroxide and/or hydrochloric acid.3706 The concentrate for injection must be diluted prior to use.3706
Nitroglycerin also is available premixed in dextrose 5% at concentrations of 100, 200, and 400 mcg/mL in glass bottles containing 250 mL and packaged under vacuum.3705 The premixed infusions also contain propylene glycol and alcohol with citric acid hydrous as a buffer and sodium hydroxide and, if necessary, hydrochloric acid to adjust the pH during manufacturing.3705 Bottles should only be used if a vacuum is present.3705 Unused portions should be discarded.3705
pH
The concentrate for injection has a pH of 3 to 6.5.3706
The premixed infusion solutions have a pH of 4 (range 3 to 5).3705
Osmolarity
The calculated osmolarities of the nitroglycerin 100-, 200-, and 400-mcg/mL premixed infusion solutions in dextrose 5% are 428, 440, and 465 mOsm/L, respectively.3705
Nitroglycerin injection is administered by continuous intravenous infusion.3705; 3706
The concentrate for injection must be diluted prior to administration.3706 To prepare the initial dilution, 50 mg of nitroglycerin should be diluted in 500 mL of dextrose 5% or sodium chloride 0.9% contained in glass bottles to yield a solution with a final nitroglycerin concentration of 100 mcg/mL.3706 A 50-mcg/mL dilution also may be prepared by diluting 5 mg of nitroglycerin in 100 mL of dextrose 5% or sodium chloride 0.9%.3706 The fluid requirements of the patient and the expected duration of therapy both should be considered in selecting the appropriate concentration for any subsequent maintenance dilutions.3706 If fluid restriction is necessary, a more concentrated dilution may be used following the initial dosage titration period; however, the nitroglycerin concentration should not exceed 400 mcg/mL.3706
Diluted solutions for infusion and premixed solutions should be administered using only a pump that is capable of maintaining a constant rate of infusion.3705; 3706 One manufacturer states that if a peristaltic action infusion pump is used, an appropriate administration set with a drip chamber that delivers approximately 60 microdrops per mL should be used; if a volumetric infusion pump is used, an appropriate volumetric infusion pump connector set should be used.3706
Because of nitroglycerin sorption into polyvinyl chloride (PVC) plastic, dosage of nitroglycerin is affected by the type of infusion set used.3705 While usual initial adult dosages of nitroglycerin in published studies have been 25 mcg or more per minute, most of these published studies used PVC tubing and thus the delivered dosage was much less than those dosages reported.3705 Relatively nonadsorptive administration sets are available, and nitroglycerin should be administered using the least adsorptive infusion tubing (i.e., non-polyvinyl chloride [non-PVC]) available.3705; 3706 When nonadsorptive tubing is used, dosages based upon published studies that used PVC tubing must be reduced.3705 (See Sorption.)
Inaccurate nitroglycerin dosing may occur with nonabsorbing high-density polyethylene plastic administration sets; such tubing is less pliable than PVC and may not work well with some infusion control devices designed for PVC tubing, resulting in overinfusion.729; 730; 731; 1120
Manufacturers state that intracoronary injection of nitroglycerin has not been studied.3705; 3706
Both the concentrate for injection and the premixed solutions are clear and practically colorless.3705; 3706 The solutions are not explosive.3705; 3706
The concentrate for injection should be stored at controlled room temperature in the carton to protect from light until time of use.3706 The premixed solutions should be stored at room temperature and should be protected from freezing and from light until time of use; exposure to heat should be minimized and excessive heat should be avoided.3705 While light protection is recommended by manufacturers, exposure to light, even high intensity light, does not adversely affect nitroglycerin stability.506; 510; 928; 930; 1941
pH Effects
The rate of nitroglycerin hydrolysis becomes significant at low pH values and is also quite rapid in alkaline solutions.933 In neutral to weakly acidic solutions, the drug is stable. No loss was observed over 136 days at room temperature at pH 3 to 5.1072
Syringes
Plastic syringes having polypropylene barrels and polyethylene plungers (Pharma-Plast) and all-glass containers were compared in an investigation of the possible sorption of nitroglycerin. After 24 hours of storage of aqueous nitroglycerin solutions (concentrations unspecified), no drug loss was found in either the plastic syringes or glass containers. The authors indicated that these plastic syringes could be substituted for glass syringes for use with syringe pumps.782
Nitroglycerin (DuPont) (concentration unspecified) was filled into 3-mL plastic syringes (Becton Dickinson, Sherwood Monoject, and Terumo) and stored at -20, 4, and 25°C in the dark. Nitroglycerin losses in 1 day ranged from 10 to 15% at 25°C, from 2 to 3% at 4°C, and from 0 to 2% at -20°C. Long-term storage for 7 days at 4°C and 30 days at -20°C resulted in losses of 5 to 7% and 2% or less, respectively. The losses were presumably due to sorption to surfaces and/or the elastomeric plunger.1562
Nitroglycerin (DuPont) 50 mg/50 mL in dextrose 5% exhibited no change in appearance and about a 3.6% loss when stored in 60-mL plastic syringes (Becton Dickinson) for 24 hours at 25°C.1579
Nitroglycerin 5 mg/mL concentrates for injection from 4 manufacturers (Abbott, DuPont, Goldline, Marion) was filled as 10 mL in 10-mL glass syringes (Becton Dickinson) and in 10-mL (Becton Dickinson) and 12-mL (Monoject) polypropylene plastic syringes. No loss of nitroglycerin content occurred in 23 hours when stored at 25°C protected from light. Mean nitroglycerin concentrations were greater than 99% and were the same for both the glass and plastic syringes.2055
Nitroglycerin 110 mcg/mL prepared from nitroglycerin 100 mcg/mL in dextrose 5% injection (Hospira) and nitroglycerin 5 mg/mL concentrate for injection (American Regent) and packaged as 10.1 mL in 12-mL polypropylene syringes (Terumo) was tested for stability at a controlled room temperature of 23 to 27°C protected from light.2976 The solution exhibited no change in appearance and about an 8% loss at 14 days; calculated time to 10% loss was 24 days.2976
Sorption
Nitroglycerin readily undergoes sorption to many plastics, including PVC, which is commonly used for intravenous administration sets.3705; 3706
The rate of loss to conventional PVC tubing has been 40 to 80% in published studies.3705 Many factors including flow rate, concentration, and length of the set affect the extent of sorption.3705; 3706 A slow rate of flow, high nitroglycerin concentration, and long tubing length increase the loss.3705; 3706 The greatest amount of sorption occurs early in the infusion. Simple calculations or corrections cannot be applied to this complex phenomenon to determine or control the actual amount of nitroglycerin delivered through PVC tubing.503; 506; 508; 509; 510; 511; 721; 723; 724; 725; 726; 727; 728; 769; 770; 797; 930; 931; 932; 934; 943; 1027; 1121; 1122; 1392; 1510; 1511; 1512; 1796; 2143; 2289; 2660; 2792; 3705; 3706
In addition to PVC bags and infusion tubing, nitroglycerin has been demonstrated to undergo similar sorption to cellulose propionate drip chambers,725; 931; 1027; 1512 polystyrolbutadiene burettes,1512 PVC pulmonary artery catheters937 and central venous pressure catheters (Intracath, Deseret),938 a polyurethane sponge used to defoam blood in a bubble oxygenator,939 a silicone rubber membrane in a membrane oxygenator,940 an infusion pump cassette (Accuset C-924, IMED),941 and silicone rubber microbore intravenous infusion tubing.942
However, the clinical importance of the sorption to PVC has been questioned because nitroglycerin administration is titrated to clinical response, not in a fixed dosage.1120; 1123; 2015; 2016; 2054 A 25 to 35% loss to PVC tubing was reported at rates of nitroglycerin administration of 80 and 60 mcg/min, respectively. Polyethylene tubing delivered essentially 100% of the nitroglycerin. Nevertheless, there was no statistically significant difference in physiologic response in patients when a variety of parameters were evaluated. The type of tubing used does not influence the ultimate hemodynamic responses significantly, because even the PVC delivered a significant amount of the drug. It was advised that physiologic endpoints be monitored in patients on intravenous nitroglycerin.1120
A number of similar results were also reported.2015; 2016; 2054 Adequate clinical response was achieved using PVC containers and tubing. However, changes in patient hemodynamic status could occur if containers for nitroglycerin infusions were changed during the treatment course; switching from PVC to glass or vice versa could require substantial adjustment in the rate of administration to achieve a similar clinical response.2016
Filtration
Manufacturers state that some in-line filters adsorb nitroglycerin and that such filters should be avoided.3705; 3706
Filtration of 250 mL of a 485-mcg/mL aqueous solution of nitroglycerin through 3 different 142-mm, 0.2-µm filters was performed. A loss of 55% resulted with the Gelman GA filter composed of cellulose triacetate. Losses of only 5% occurred with a Millipore GS filter (a mixture of cellulose acetate and cellulose nitrate), and 2% losses occurred with a Gelman Tuffryn filter (a high-temperature aromatic polymer).724
In one study, a filter material specially treated with a proprietary agent was evaluated for a possible reduction in nitroglycerin binding. Nitroglycerin (Abbott) 62.5 mg/250 mL in dextrose 5% and in sodium chloride 0.9% was run through an administration set with a treated 0.22-µm cellulose ester inline filter at a rate of 3 mL/min. Cumulative nitroglycerin losses of less than 6% occurred from 200 mL of either solution. However, equilibrium binding studies showed no significant differences in drug affinity between treated and untreated filter material in either solution.904 Ivex integral filter and extension sets use the treated filter material.1074
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 Nitroglycerin3635; 3636
| Patient Population | Concentration Standards | Dosing Units |
|---|---|---|
| Adults | 200 mcg/mL | mcg/minute |
| Pediatric patients (50 kg) | 200 mcg/mL 400 mcg/mL | mcg/kg/minute |
For a list of references cited in the text of this monograph, search the monograph titled References.