Alteplase (Activase, Genentech) is available as a lyophilized powder in 50- and 100-mg vials.3639 The products also contain L-arginine, phosphoric acid, and polysorbate 80.3639 Intact 50-mg vials contain a vacuum, but the 100-mg vials do not; 50-mg vials should not be used if the vacuum is not present.3639
The alteplase vials are accompanied by 50- and 100-mL vials of sterile water for injection for the 50- and 100-mg sizes, respectively.3639 Alteplase should be reconstituted only with the accompanying sterile water for injection (without preservatives) diluent; bacteriostatic water for injection should not be used.3639 Use of the accompanying diluent results in a reconstituted solution with a 1-mg/mL concentration.3639 For reconstitution of the contents of 50-mg vials, the manufacturer recommends use of a large bore needle (e.g., 18 gauge) to direct the stream of diluent into the lyophilized cake.3639 For reconstitution of the 100-mg vials, the provided special transfer device should be used; specific product labeling should be consulted for details on reconstitution using the provided special transfer device.3639 Following addition of the diluent, vials should be swirled gently to dissolve the drug; vials should not be shaken.3639 Slight foaming is not unusual; vials should be allowed to stand undisturbed for several minutes to allow large bubbles to dissipate.3639
Alteplase may be administered as the 1-mg/mL reconstituted solution or may be further diluted immediately prior to administration in an equal volume of sodium chloride 0.9% or dextrose 5% for a diluted solution with a final alteplase concentration of 0.5 mg/mL.3639 Diluted solutions should be mixed by swirling gently and/or slow inversion; excessive agitation should be avoided.3639
Alteplase (Cathflo Activase, Genentech) also is available for intracathether instillation in vials containing alteplase 2.2 mg with L-arginine 77 mg, polysorbate 80 0.2 mg, and phosphoric acid to adjust pH.3640 Vials should be reconstituted with 2.2 mL of sterile water for injection (not provided), directing the diluent stream into the powder; bacteriostatic water for injection should not be used.3640 Vials should be gently swirled until the contents are completely dissolved to yield a 1-mg/mL solution; vials should not be shaken.3640 Slight foaming is not unusual; vials should be allowed to stand undisturbed for several minutes to allow the large bubbles to dissipate.3640
Specific Activity
Alteplase is a purified glycoprotein with a specific activity of 580,000 international units/mg.3639 The 50-mg vial contains 29 million international units, and the 100-mg vial contains 58 million international units.3639
pH
The 1-mg/mL reconstituted solution of alteplase has a pH of approximately 7.3.3639
Osmolality
The 1-mg/mL reconstituted solution of alteplase has an osmolality of approximately 215 mOsm/kg.3639
Trade Name(s)
Activase
Alteplase is administered by intravenous infusion, directly after reconstitution to a 1-mg/mL concentration or diluted with an equal volume of sodium chloride 0.9% or dextrose 5% to a 0.5-mg/mL concentration.3639 Dilution to a lower concentration may result in precipitation.1425
Alteplase has been effective and well tolerated in catheter clearance.2328; 2329; 2330; 2446; 2635; 3640
Activase, a white to off-white lyophilized powder, becomes a colorless to pale yellow solution on reconstitution.3639 Intact vials should be stored at room temperature with protection from extended exposure to light.3639
Cathflo Activase, a white to pale yellow lyophilized powder, becomes a colorless to pale yellow solution on reconstitution.3640 Intact vials should be stored under refrigeration.3640
Alteplase contains no antibacterial preservatives.3639; 3640 The manufacturer states that Cathflo Activase should be reconstituted immediately prior to use;3640 however, they also state that alteplase should be used within 8 hours following reconstitution when stored at 2 to 30°C.3639; 3640
The manufacturer states that bacteriostatic water for injection should not be used for reconstitution of alteplase.3639 Even so, alteplase was reconstituted with sterile water for injection and also bacteriostatic water for injection (containing benzyl alcohol 0.9%) to yield a 1-mg/mL solution. The test solutions were stored at 37°C and remained clear and colorless. In vitro clot lysis testing found activity was retained for at least 7 days. The USP antimicrobial effectiveness test was performed as well. The samples reconstituted with sterile water failed the test while the samples reconstituted with bacteriostatic water for injection passed.2668
Freezing Solutions
A 50-mg vial of alteplase (Genentech), reconstituted with sterile water for injection to a concentration of 1 mg/mL, was diluted with balanced saline solution to a final alteplase concentration of 250 mcg/mL. Then 0.3-mL (75 mcg) portions of the diluted solution were drawn into 1-mL tuberculin syringes and frozen at -70°C. Alteplase activity was retained for at least 1 year.2157
However, others have objected to frozen storage of diluted alteplase solution. It was noted that the alteplase formulation has been designed for optimal stability, and dilution to an alteplase concentration lower than 500 mcg/mL might adversely affect the drug's solubility by diluting the formulation's solubilizing components. Furthermore, it was noted that the calcium or magnesium salts contained in some diluents might interact with the phosphates present in the alteplase formulation to form a precipitate. Indeed, precipitated protein has been found in diluted alteplase after room temperature storage for 24 hours. Frozen storage at -20°C with subsequent thawing has resulted in changed patterns of light scattering as well. It was recommended that dilution with balanced saline solution and storage of dilutions for any length of time at room temperature or frozen should be avoided.2158
Use of a diluent containing polysorbate 80, L-arginine, and phosphoric acid to reconstitute and dilute alteplase to 50 mcg/mL has been reported to permit frozen storage. Although the report did not specify the exact concentrations of the diluent components, it may have duplicated the alteplase vehicle after reconstitution. Use of this diluent for dilution prevented precipitation of the protein upon frozen storage at -20°C. In addition, the activity in ophthalmic use was found to be unchanged after storage for 6 months in the frozen state.2159
Alteplase (Genentech) concentrations of 0.5, 1, and 2 mg/mL in sterile water for injection were packaged as 1 mL of solution in 5-mL polypropylene syringes and sealed with rubber tip caps. Sample syringes were stored frozen at -70 and -25°C for up to 14 days as well as refrigerated at 2°C. Frozen samples were thawed at room temperature and stored under refrigeration for determination of fibrinolytic activity. Fibrinolytic activity after frozen storage at both -70 and -25°C remained near nominal initial concentrations for at least 14 days. Furthermore, the activity remained greater than 90% for up to 48 hours in all thawed samples subsequently stored at 2°C and was comparable to the activity of refrigerated solutions that had never been frozen. However, substantial and unacceptable losses of activity occurred after 72 hours under refrigeration whether previously frozen or not.2327
Genentech evaluated the activity of alteplase 1 mg/mL when reconstituted with sterile water for injection, packaged in glass vials, and stored frozen at -20°C for 32 days, followed by thawing at room temperature. The frozen alteplase solution remained physically and chemically comparable to newly reconstituted alteplase for at least 8 hours at room temperature after thawing.2328
Alteplase (Genentech) 1 mg/mL in sterile water for injection packaged in polypropylene syringes was frozen at -20°C for 6 months. Similar solutions in glass vials were frozen at -70°C for 2 weeks, thawed and kept at 23°C for 24 hours, and then refrozen at -70°C for 19 days. Little or no loss of alteplase bioactivity was found.2400
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 Alteplase3635; 3636
| Patient Population | Concentration Standards | Dosing Units |
|---|---|---|
| Adults | 1 mg/mL | mg/hour |
| Pediatric patients (50 kg) | 1 mg/mL | mg/kg/hour |
For a list of references cited in the text of this monograph, search the monograph titled References.