AHFS Class:

20:12.04.16 Heparins

Generic Name

• Heparin Sodium

Heparin sodium injection is available in concentrations ranging from 1000 to 20,000 units/mL, packaged in sizes ranging from 0.5- to 1-mL as vials, prefilled syringes, or syringe cartridges, to 30-mL multiple-dose vials.³⁷⁸⁷; ³⁷⁸⁸; ³⁷⁸⁹; ³⁸⁰⁴ Some products are preservative-free; others may contain benzyl alcohol or parabens as preservatives.³⁷⁸⁷; ³⁷⁸⁸; ³⁷⁸⁹; ³⁸⁰⁴ Hydrochloric acid and/or sodium hydroxide may have been added to adjust pH.³⁷⁸⁷; ³⁷⁸⁸; ³⁷⁸⁹; ³⁸⁰⁴ Sodium chloride may have been added to some products for isotonicity.³⁷⁸⁸

Heparin sodium injection also is available as a premixed infusion solution in the following concentrations: 40, 50, or 100 units/mL in dextrose 5%;³⁸⁰⁰ 2 units/mL in sodium chloride 0.9%;³⁸⁰¹ and 50 or 100 units/mL in sodium chloride 0.45%.³⁸⁰⁵ Heparin sodium 40, 50, or 100 units/mL in dextrose 5% premixed infusion solution also contains, in each 100 mL, dibasic sodium phosphate 410 mg, anhydrous citric acid 93 mg, and sodium metabisulfite 68.6 mg.³⁸⁰⁰ Heparin sodium 2 units/mL in sodium chloride 0.9% premixed infusion solution also contains, in each 100 mL, dibasic sodium phosphate heptahydrate 434 mg and citric acid monohydrate 40 mg.³⁸⁰¹ Heparin sodium 50 or 100 units/mL in sodium chloride 0.45% premixed infusion solution also contains, in each 100 mL, anhydrous edetate disodium 10 mg with hydrochloric acid and/or sodium hydroxide to adjust pH.³⁸⁰⁵

Heparin sodium also is available as a heparin lock flush solution in concentrations of 1, 10, and 100 units/mL in packaged in vials or syringes in various sizes ranging from 1 to 10 mL.³⁸⁰²; ³⁸⁰³

pH

From 5 to 7.5.³⁷⁸⁷; ³⁷⁸⁸; ³⁷⁸⁹; ³⁸⁰²; ³⁸⁰⁴

Osmolality

The osmolality of heparin sodium (Elkins-Sinn) 1000 units/mL was determined to be 384 mOsm/kg by freezing-point depression and 283 mOsm/kg by vapor pressure.¹⁰⁷¹

Heparin lock flush solution is isotonic.³⁸⁰²; ³⁸⁰³

Osmolarity

Heparin sodium premixed infusion solutions in sodium chloride 0.45% or dextrose 5% have calculated osmolarities of 155 or 315 mOsm/L, respectively.³⁸⁰⁰; ³⁸⁰⁵ Heparin sodium injection 2 units/mL in sodium chloride 0.9% has a calculated osmolarity of 378 mOsm/L.³⁸⁰¹

Heparin sodium injection is administered by deep subcutaneous injection, by intermittent intravenous injection either undiluted or diluted in 50 to 100 mL of sodium chloride 0.9%, or by continuous intravenous infusion following dilution in 1000 mL of a compatible infusion solution.³⁷⁸⁷; ³⁷⁸⁸ Following addition of heparin sodium injection to an infusion solution, the container should be inverted at least 6 times to ensure adequate mixing and prevent pooling of the drug.³⁷⁸⁷; ³⁷⁸⁸

Intramuscular injection is not recommended because of higher risk of local irritation, erythema, pain, hematoma, or ulceration at the injection site.³⁷⁸⁷; ³⁷⁸⁸

Care is required when adding heparin sodium to infusion solutions, especially in flexible containers. When heparin sodium was added to a flexible polyvinyl chloride (PVC) container of sodium chloride 0.9% hanging in the use position, pooling of the heparin resulted; 97% of the heparin was delivered in the first 30% of the solution. Repeated inversion and agitation of the containers to effect thorough mixing eliminates this pooling (and the danger of overdosage), yielding an even distribution and a constant delivery concentration.⁸⁵

Heparin sodium injection should not be used if the solution is discolored or contains a precipitate.³⁷⁸⁷ Intact containers of heparin sodium injection should be stored at controlled room temperature³⁷⁸⁷; ³⁷⁸⁸; ³⁷⁸⁹ and protected from freezing.³⁸⁰⁴; ³⁸⁰⁵ In a study of hospital-manufactured heparin sodium 1 unit/mL in sodium chloride 0.9%, full anticoagulant activity was retained for at least 12 months after sterilization by autoclaving and subsequent storage at room temperature exposed to daylight.⁶⁷⁵

Heparin lock flush solution should be stored at controlled room temperature and protected from freezing.³⁸⁰²; ³⁸⁰³ The solution should not be used if it is cloudy or hazy or contains a precipitate.³⁸⁰²

pH Effects

A pH profile of heparin sodium 20,000 units/L in dextrose 5% over a pH range of 3.8 to 7.6 did not reveal a loss during the 24-hour study.²¹ In another report, heparin sodium in sodium chloride 0.9% was tested at pH 3.2 (adjusted with hydrochloric acid) and 9.2 (adjusted with sodium hydroxide). No loss was noted in 24 hours.⁵⁷ However, a pH profile of heparin sodium 660 units/mL, when autoclaved for 10 minutes at 10 pounds/inch² at 115°C, showed loss of activity at pH values above 8.5 and especially below 5.²⁴³

Syringes

The stability of 50 mL of a 500-unit/mL heparin sodium solution in sodium chloride 0.9% packaged in 50-mL polypropylene syringes was studied. Storage both at room temperature and at 0 to 4°C showed an overall trend to lower activity by about 8% after 3 weeks.

When glass containers were compared to plastic syringes, the glass containers consistently showed lower retained activity in as little as 2 hours after preparation. The possibility of adsorption to glass surfaces was noted⁶⁷⁶ but has not been demonstrated.

Heparin sodium 1 unit/mL, prefilled into Injekt (Braun) all-plastic syringes having polyethylene barrels and polypropylene plungers, showed no significant activity loss over 52 weeks at 37°C due to decomposition or sorption. However, plastic syringes with rubber-tipped plungers, such as Plastipak (Becton Dickinson) and Perfusor (Braun), exhibited extra ultraviolet peaks, presumably due to leaching of rubber components.¹⁴⁹¹

Heparin sodium (Leo) 300 units/mL in dextrose 5% or water for injection was drawn into 50-mL polypropylene syringes (Plastipak, Becton Dickinson) and stored for 8 hours at room temperature and 4°C. No loss in either solvent occurred.¹⁷⁹⁹

The stability of heparin sodium repackaged in 10-mL polypropylene syringes for use in CADD-Micro syringe pumps was evaluated. 10 mL of heparin sodium 1000 units/mL (Elkins-Sinn) and 40,000 units/mL (Schein) were packaged in the test syringes and capped. Syringes were stored at a near-body temperature of 30°C for 30 days. Little or no loss of heparin sodium content occurred; actual activity in prolonging blood clotting was not evaluated.²²⁷⁵

Sorption

Heparin sodium, BP, 2000 units/2 mL was stored for 18 hours at room temperature in plastic syringes: Brunswick (Sherwood Medical), Plastipak (Becton Dickinson), Steriseal (Needle Industries), and Sabre (Gillette U.K.). The first 3 syringes have polypropylene barrels; the Sabre has a combination polypropylene-polystyrene barrel. No significant loss of heparin occurred due to sorption.⁷⁸⁴

Heparin sodium (Leo) 300 units/mL in dextrose 5% or water for injection was delivered at 4 mL/hr by syringe pump through PVC and polyethylene-lined PVC infusion tubing for 12 hours at room temperature. No loss occurred due to sorption to the polyethylene-lined tubing. However, losses of about 15 to 25% occurred with the PVC tubing and were especially high during the first 15 minutes of infusion.¹⁷⁹⁹

Filtration

Heparin sodium (Abbott) 10,000 units/L in dextrose 5% and sodium chloride 0.9% was filtered at 120 mL/hr for 6 hours through a 0.22-µm cellulose ester membrane filter (Ivex-2). No significant loss due to binding to the filter was noted.⁵³³

Central Venous Catheter

Heparin sodium (Elkins-Sinn) 100 units/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 Heparin³⁶³⁵; ³⁶³⁶

^aThe S4S panel recommends trying to standardize dosing units but understands that some protocols may use “flat” dosing while others may require weight-based dosing.

Solution Compatibility

Additive Compatibility

Drugs in Syringe Compatibility

Y-Site Injection Compatibility (1:1 Mixture)

Additional Compatibility Information

Parenteral Nutrition Admixtures

In solutions of amino acids 5% and dextrose 5 or 25% with vitamins or trace elements, heparin activity was retained for 24 hours at 25°C. However, the activity fell significantly after 24 hours.⁹⁰⁰

Flocculation of lipid emulsion (Kabi-Vitrum) was reported during Y-site administration into a line being used to infuse a parenteral nutrition solution containing both calcium gluconate and heparin sodium. Subsequent evaluation indicated that the combination of calcium gluconate (0.46 and 1.8 mM/125 mL) plus heparin sodium (25 and 100 units/125 mL) in amino acids plus dextrose would induce flocculation of the lipid emulsion within 2 to 4 minutes at concentrations that resulted in no visually apparent flocculation in 30 minutes with either agent alone.¹²¹⁴

Calcium chloride concentrations of 1 to 20 mM normally result in slow flocculation of lipid emulsion 20%, intravenous, over a period of hours. When heparin sodium 5 units/mL was added, the flocculation rate accelerated greatly; a cream layer was observed visually in a few minutes. This effect was not observed when sodium ion was substituted for the divalent calcium.¹⁴⁰⁶

Destabilization of lipid emulsion (Intralipid 20%) was observed when administered simultaneously with a parenteral nutrition admixture. The damage, detected by viscosity measurement, occurred immediately upon contact at the Y-site. The extent of the destabilization was dependent on the concentration of the heparin and the presence of MVI Pediatric with its surfactant content. In addition to the viscosity changes, phase separation was observed in 2 hours. Parenteral nutrition admixtures containing heparin should never be premixed with lipid emulsion as a 3-in-1 total nutrient admixture because of this emulsion destabilization. The damage might be minimized during Y-site co-administration as long as the heparin was kept at a sufficiently low concentration (no visible separation occurred at a heparin concentration of 0.5 unit/mL) and the length of tubing between the Y-site and the patient was minimized.²²⁸²

However, because the damage to emulsion integrity has been found to occur immediately upon mixing with heparin in the presence of the calcium ions in parenteral nutrition admixtures¹²¹⁴; ²²¹⁵; ²²⁸² and no evaluation and documentation of the clinical safety of using such destabilized emulsions has been performed, use of such damaged emulsions in patients is suspect.

Peritoneal Dialysis Solutions

The activity of heparin 35,000 units/L was evaluated in peritoneal dialysis fluids containing 1.5 and 2.5% dextrose (Dianeal, Travenol). Storage at 25°C resulted in an apparent temporary 50% loss of heparin activity in 4 hours with recovery in 6 hours. Heparin activity was then retained for 14 days at 4°C.⁹⁰⁰

Gentamicin sulfate 10 mg/L with heparin sodium 1000 units/L in Dianeal with dextrose 5% had no significant reduction in gentamicin sulfate concentration or of heparin sodium in 4 to 6 hours.²²⁸ However, a marked reduction in the anticoagulant activity of heparin sodium occurred if opalescence or a precipitate is formed, which results if the undiluted drugs are combined, even if the precipitate redissolves. Heparin activity was retained if one drug was added to a dilute solution of the other and no precipitate formed.²⁹⁵

Vancomycin hydrochloride (Lilly) 15 mg/L to 5.3 g/L in Dianeal with dextrose 2.5 or 4.25% was physically compatible with heparin sodium (Organon) 500 to 14,300 units/L for 24 hours at 25°C under fluorescent light. However, a white precipitate formed immediately in combinations of heparin sodium with vancomycin hydrochloride 6.9 to 14.3 g/L.¹³²²

Ceftazidime (GlaxoSmithKline Australia) 125 mg/L with heparin sodium (Hospira Australia) 500 units/Lwas evaluated for stability in Dianeal with dextrose 2.5% (Baxter), Dianeal with dextrose 4.25% (Baxter), and Extraneal with icodextrin 7.5% (Baxter) stored at 4°C for 120 hours, then 25°C for 6 hours, and 37°C for 12 hours.³⁸⁰⁶ The combination also was evaluated in Balance with dextrose 2.3% (Fresenius), a 2-compartment peritoneal dialysis bag at an initial concentration of ceftazidime 250 mg/L with heparin sodium 1000 units/L in the non-dextrose compartment stored at 4°C for 120 hours, then 25°C for 6 hours; the 2 compartments were then combined, resulting in a concentration of ceftazidime 125 mg/L with heparin sodium 500 units/L, and stored at 37°C for 12 hours.³⁸⁰⁶ Throughout the study, no color change or particle formation was observed and no meaningful pH changes occurred.³⁸⁰⁶ For all solutions, losses of both drugs were less than 5% after 120 hours at 4°C and 6 hours at 25°C and less than 10% after an additional 12 hours at 37°C.³⁸⁰⁶ Heparin activity was retained with less than 2% loss of anti-factor Xa activity after 120 hours at 4°C, 6 hours at 25°C, and 12 hours at 37°C.³⁸⁰⁶

Heparin Locks

Heparin locks, weak heparin solutions instilled or “locked” into infusion ports or sets through a resealing latex diaphragm, are useful in providing an established intravenous route for intermittent intravenous injections. To maintain patency, a weak heparin solution is left in the tubing. Concentrations of heparin sodium used have varied from about 10 to 1000 units/mL of sodium chloride 0.9%, with 10 and 100 units/mL being the most common. The volume of dilute heparin sodium in sodium chloride 0.9% usually used to flush the set is 0.2 to 1 mL.²⁵⁵; ²⁵⁶; ²⁵⁷; ²⁵⁸; ⁴⁰⁵; ⁶⁷⁷; ⁶⁷⁸; ⁹⁰¹; ²¹¹⁹ However, the use of sodium chloride 0.9% instead of a solution containing heparin has been suggested to maintain patency. Studies have found sodium chloride 0.9% to be as effective in maintaining patency as 10- and 100-unit/mL solutions of heparin.⁹⁰²; ⁹⁰³; ¹¹⁰⁹; ¹²⁶⁶; ¹²⁶⁷; ¹²⁶⁸; ¹²⁶⁹; ¹⁶³⁹; ¹⁶⁴⁰; ¹⁶⁴¹; ¹⁶⁵⁶; ¹⁸³⁹; ¹⁹⁵⁹; ²⁰⁰³; ²¹¹⁹ Other investigators reported that even small amounts of heparin solution are more effective than sodium chloride 0.9% alone.⁶⁷⁸; ¹²⁷⁰; ²¹²⁰; ²¹²¹

Evaluations of the use of heparinized solutions as locks or continuous flow solutions to help maintain patency in central venous catheters and arterial catheters have resulted in similarly variable results and recommendations.²¹²²; ²¹²³; ²¹²⁴; ²¹²⁵; ²¹²⁶ Although use of such heparinized solutions has been generally considered a benign technique causing minimal problems, a number of adverse effects have been reported, especially from solutions with a high heparin concentration and/or numerous heparin flushes.²¹²⁷; ²¹²⁸; ²¹²⁹; ²¹³⁰; ²¹³¹; ²¹³²

Vancomycin hydrochloride (Lilly) 25 mcg/mL and heparin sodium (Elkins-Sinn) 100 units/mL in 0.9% sodium chloride injection as a catheter flush solution was evaluated for stability when stored at 4°C for 14 days. The flush solution was visually clear, and vancomycin activity and heparin activity were retained throughout the storage period. However, an additional 24 hours at 37°C to simulate use conditions resulted in losses of both agents ranging from 20 to 37%.¹⁹³³

Vancomycin hydrochloride 25 mcg/mL combined with heparin sodium (Hospira) 10 units/mL in sterile water for injection for use as a lock solution was found to be physically compatible. Little or no vancomycin loss occurred in 3 days at 4°C. However, losses of 8% occurred in 3 days at 27°C and 1 day at 40°C.²⁸²⁰

If ciprofloxacin (Sicor) 2 mg/mL was added to this flush solution, a white precipitate appeared within 1 day. Losses of both ciprofloxacin and vancomycin occurred as well.²⁸²⁰

A combination of daptomycin (Cubist) 5 mg/mL and heparin sodium (Hospira) 100 units/mL in Ringer’s injection, lactated was evaluated for stability as a lock solution stored in 5-mL aliquots in 5-mL polypropylene syringes (Becton Dickinson) at 4 and -20°C.²⁹⁷⁸ The solution remained clear and colorless on visual inspection and little or no loss of either drug occurred throughout the 14-day study period.²⁹⁷⁸

Methylprednisolone

The compatibility of methylprednisolone sodium succinate (Upjohn) with heparin sodium added to an auxiliary medication infusion unit has been studied. Primary admixtures were prepared by adding heparin sodium 10,000 units/L to dextrose 5%, dextrose 5% in sodium chloride 0.9%, and Ringer’s injection, lactated. Up to 100 mL of the primary admixture was added along with methylprednisolone sodium succinate (Upjohn) to the auxiliary medication infusion unit with the following results:³²⁹

Reteplase

Heparin and reteplase are stated to be incompatible; reteplase should not be administered through an intravenous line containing heparin.²⁷¹⁹

For a list of references cited in the text of this monograph, search the monograph titled References.

ASHP^® Injectable Drug Information^TM. Selected Revisions December 5, 2024. © Copyright, 2024. American Society of Health-System Pharmacists^®, 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.