Lorazepam is available in 2- and 4-mg/mL solutions in 1-mL single-dose vials and 10-mL multiple-dose vials.3031 Both concentrations also are available in 1-mL disposable syringe cartridges.3033 Each mL of lorazepam injection solution also contains 0.18 mL of polyethylene glycol 400 and 2% benzyl alcohol in propylene glycol.3031; 3033
For intramuscular use, lorazepam may be injected undiluted.3031; 3033 For intravenous use, however, lorazepam must be diluted immediately prior to injection with an equal volume of a compatible diluent (e.g., sterile water for injection, dextrose 5%).3031; 3033
To dilute the dose in a syringe cartridge, all of the air should first be eliminated and the proper volume of a compatible diluent (e.g., sterile water for injection, dextrose 5%) should then be aspirated.3033 The plunger should then be pulled back slightly to provide some mixing space and the syringe cartridge should be repeatedly and gently inverted to mix the contents.3033 A similar procedure should be followed for diluting a dose withdrawn from a vial, taking care to repeatedly and gently invert the container until a homogenous solution results.3031 To avoid air entrapment, neither the syringe cartridge nor the container should be shaken vigorously.3031; 3033
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Ativan
Lorazepam may be administered by deep intramuscular injection; alternatively, the drug may be administered by intravenous injection, when diluted immediately prior to use with an equal volume of a compatible diluent (e.g., sterile water for injection, dextrose 5%);3031; 3033 the volume of the diluent to be added should not exceed the volume of the drug.3033 Intravenous injection should be made slowly (i.e., at a rate not exceeding 2 mg/min), with frequent aspiration, directly into a vein or into the tubing of a running intravenous infusion.3031; 3033
Lorazepam also has been administered by continuous intravenous infusion.3034
Care should be taken to ensure that intra-arterial administration or perivascular extravasation do not occur.3031; 3033
Intact vials and syringe cartridges of lorazepam should be refrigerated and stored in the original carton to protect from light.3031; 3033 One manufacturer had previously stated that the product could be stored for up to 2 weeks at room temperature1181 and other manufacturers had acknowledged that both physical and chemical stability were acceptable for 60 to 90 days at room temperature;1674; 2829 however, these recommendations for extended room temperature stability are no longer supported by manufacturers.3032
Lorazepam injection solution should be visually inspected for discoloration and particulate matter; if discolored or if a precipitate is present, the solution should not be used.3031; 3033
Precipitation
The choice of commercial lorazepam concentration to use in the preparation of dilutions is a critical factor in the physical stability of the dilutions.2207; 2208 Both the 2- and 4-mg/mL concentrations utilize the same concentrations of solubilizing solvents.1945; 1981; 2207; 3031; 3033 On admixture, the solvents that keep the aqueous insoluble lorazepam in solution are diluted twice as much using the 4-mg/mL concentration than if the 2-mg/mL were used, resulting in different precipitation potentials for the same concentration of lorazepam.1945; 1981; 2207 Care should be taken to ensure that the compounding procedure that is to be used for lorazepam admixtures has been demonstrated to result in solutions in which the lorazepam remains soluble.
Lorazepam concentrations up to 0.08 mg/mL have been reported to be physically stable, while occasional precipitate formation in admixtures of lorazepam 0.1 to 0.2 mg/mL has been reported. The precipitate has been observed in both containers and in administration set tubing.1943; 1979; 1980 In one case, a visible precipitate formed in a lorazepam 0.5-mg/mL admixture in sodium chloride 0.9% in a glass bottle.1945 However, a 0.5-mg/mL concentration may remain in solution longer if prepared from the 2-mg/mL concentration, yielding a higher concentration of organic solvents in the final admixture.1981; 2207 Concentrations of 1 and 2 mg/mL have been reported to be physically stable for up to 24 hours, as well as concentrations below 0.08 mg/mL.1980; 2208 Concentrations in the middle range of 0.08 to 1 mg/mL may be problematic.1980 In one report, use of lorazepam 2 mg/mL to prepare lorazepam 1-mg/mL admixtures in dextrose 5% or sodium chloride 0.9% was acceptable, but use of the lorazepam 4-mg/mL concentration to prepare the same solutions resulted in almost immediate precipitation.2207
Lorazepam solubility in common infusion solutions has been reported (Table 1). Solubility of lorazepam in sodium chloride 0.9% is approximately half that found in the other tested solutions. This result was attributed to the pH of the sodium chloride 0.9% solution (pH 6.3) being essentially the same as the isoelectric point of lorazepam (pH 6.4), where aqueous solubility would be the lowest. Dextrose 5% was the best diluent for lorazepam in this study.787
Table 1. Lorazepam Equilibrium Solubility787
| Solution | Lorazepam Solubility (mg/mL) | Solution pH |
|---|---|---|
| Deionized water | 0.054 | 7.09 |
| Dextrose 5% | 0.062 | 4.41 |
| Ringer’s injection, lactated | 0.055 | 7.21 |
| Sodium chloride 0.9% | 0.027 | 6.30 |
Bacteriostatic Water
Dilution of lorazepam (Wyeth) to 1 mg/mL with bacteriostatic water for injection (bacteriostat unspecified), packaged in glass vials, resulted in lorazepam losses. Losses of about 10% at 4°C and 12% at 22°C occurred in 7 days. Drug precipitated in varying periods after the first week of storage.1840
Syringes
Lorazepam (Wyeth) 2 mg/mL was packaged as 3 mL in 10-mL polypropylene infusion pump syringes (Pharmacia Deltec). About 12 to 14% loss occurred in 3 days and 25% loss occurred in 10 days at 5 and 30°C. The authors recommended against storing lorazepam in the syringes for these time periods.1967
Lorazepam (Wyeth) 1 mg/mL, prepared from the 2-mg/mL commercial concentration and diluted in dextrose 5% or in sodium chloride 0.9%, was filled as 40 mL in 60-mL polypropylene syringes (Becton Dickinson). The filled syringes were stored at 22°C for 28 hours. Visual inspection found that the solutions remained physically stable, and less than 3% drug loss occurred in this time period.2208
The physical and chemical stability of lorazepam (Wyeth-Ayerst) 0.2, 0.5, and 1 mg/mL in dextrose 5% and in sodium chloride 0.9% was evaluated when packaged in polypropylene syringes. When prepared using lorazepam 2 mg/mL, the solutions were found to be physically stable over 24 hours and chemically stable for 48 hours at room temperature. When prepared using lorazepam 4 mg/mL, the solutions consistently precipitated.2416
Lorazepam (Pfizer) 4 mg/24 mL (0.167 mg/mL) in sodium chloride 0.9%, prepared from the 4-mg/mL solution in 30-mL polypropylene syringes (Becton Dickinson) was physically stable for 48 hours at room temperature; however the study duration did not extend beyond 48 hours and drug concentration was not measured.3545 In another study, similar solutions of lorazepam (Pfizer) 4 mg/24 mL (0.167 mg/mL) in sodium chloride 0.9%, prepared from the 4-mg/mL solution in polypropylene syringes (Becton Dickinson) were physically stable with no change in pH and less than 10% drug loss in 4 days at room temperature with visible crystals forming in 7 days.4039 At 2 to 8°C, the solution was physically and chemically stable for 2 days, with visible crystals forming in 4 days.4039
Sorption
Lorazepam (Wyeth) 2- and 4-mg/mL concentrations were diluted 1:1 using dextrose 5%, sodium chloride 0.9%, and water for injection. A 2-mL sample of each dilution was injected into the Y-sites of administration sets from 5 different manufacturers through which dextrose 5%, sodium chloride 0.9%, Ringer’s injection, or Ringer’s injection, lactated was flowing at rates of 30 and 125 mL/hr. No differences were found among the various infusion sets, infusion solutions, or flow rates. All effluent solutions were visually acceptable and had no loss of lorazepam.786
In another study, lorazepam (Wyeth) 2 mg/50 mL in dextrose 5% was delivered at rates of 600, 200, and 100 mL/hr using an infusion controller fitted with 180 or 350 cm of polyvinyl chloride (PVC) tubing. Lorazepam loss due to sorption was greater with the longer tubing and at slower rates. Losses ranged from a high of 5% (350 cm, 100 mL/hr) to a low of 0.7% (180 cm, 600 mL/hr).787
In static sorption studies, lorazepam (Wyeth) 2 mg/50 mL in dextrose 5% was filled into PVC containers in the following amounts: 50 mL into 50-mL bags, 100 mL into 50-mL bags, and 100 mL into 250-mL bags. The bags were stored at 23°C. A rapid initial loss of lorazepam occurred (about 3.9 to 5.8% in the first hour) followed by a slower, approximately constant loss after 8 hours. Cumulative losses of 6 to 8% occurred in about 5 hours in the smaller bags with smaller bag surface area to volume ratios. The solution in the larger bags exhibited over a 10% loss in 2 hours.787
Plasticizer Leaching
Lorazepam (Wyeth-Ayerst) 0.1 mg/mL in dextrose 5% did not leach diethylhexyl phthalate (DEHP) plasticizer from 50-mL PVC bags in 24 hours at 24°C.1683
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 2. Standardize 4 Safety Continuous IV Infusion Standard Concentrations for Lorazepam3636
| Patient Population | Concentration Standards | Dosing Units |
|---|---|---|
| Adults | 1 mg/mL | mg/hour |
For a list of references cited in the text of this monograph, search the monograph titled References.