Methotrexate sodium injection is available as a solution containing methotrexate 25 mg/mL in vials of various sizes from 2 to 40 mL.2966; 2967 The products also contain sodium chloride and water for injection; sodium hydroxide and/or hydrochloric acid may have been added to adjust the pH.2966; 2967 Some products contain benzyl alcohol as a preservative.2966
Methotrexate sodium also is available as a lyophilized powder in single-use, preservative-free vials containing methotrexate sodium equivalent to 1 g of methotrexate.2968 The pH may have been adjusted during manufacturing with sodium hydroxide and/or hydrochloric acid.2968 The 1-g vial is reconstituted with 19.4 mL of sterile, preservative-free diluent (e.g., dextrose 5%, sodium chloride 0.9%) to yield a solution containing methotrexate 50 mg/mL.2968
Methotrexate (RediTrex) also is available as a 25-mg/mL preservative-free solution in single-dose prefilled syringes for subcutaneous use containing 7.5, 10, 12.5, 15, 17.5, 20, 22.5, or 25 mg of methotrexate.3743 The product also contains sodium chloride and water for injection; sodium hydroxide is added to adjust the pH.3743
Methotrexate (Rasuvo) also is available as a 50-mg/mL preservative-free solution in single-dose prefilled auto-injector syringes for subcutaneous use containing 7.5, 10, 12.5, 15, 17.5, 20, 22.5, 25, 27.5, or 30 mg of methotrexate.2970 The product also contains sodium chloride and water for injection; sodium hydroxide and/or hydrochloric acid may have been added to adjust the pH.2970
Methotrexate (Otrexup) also is available in preservative-free, prefilled auto-injector syringes for subcutaneous use containing 10, 12.5, 15, 17.5, 20, 22.5, or 25 mg of methotrexate per 0.4 mL.2969 The product also contains sodium chloride and water for injection; sodium hydroxide and/or hydrochloric acid may have been added to adjust the pH.2969
pH
Methotrexate sodium injection solution in vials: Approximately 8.5.2966; 2967
Methotrexate sodium lyophilized powder: From 8.5 to 8.7.2968
Methotrexate 25-mg/mL prefilled syringes (RediTrex): 8.2.3743
Methotrexate 50-mg/mL prefilled auto-injector syringes (Rasuvo): 8.5.2970
Methotrexate 0.4-mL prefilled auto-injector syringes (Otrexup): 8.2969
Tonicity
Methotrexate sodium injection solution in vials is isotonic.2966; 2967
Sodium Content
Methotrexate sodium preservative-free injection solution in vials contains sodium 0.43, 0.86, 1.72, 2.15, and 8.6 mEq in the 2-, 4-, 8-, 10-, and 40-mL vials, respectively.2967 The lyophilized product contains 7 mEq of sodium in the 1-g vial.2968
Trade Name(s)
Otrexup, Rasuvo, RediTrex
Methotrexate sodium may be administered by intramuscular, intra-arterial, subcutaneous, or intrathecal injection, by direct intravenous injection, or by intravenous infusion.2966; 2967; 2968; 2969; 2970 For intrathecal injection, a preservative-free form is diluted to a 1-mg/mL concentration in an appropriate preservative-free diluent (e.g., sodium chloride 0.9%, Elliott’s B solution, the patient’s own spinal fluid).4; 435; 830; 2966; 2967; 2968
For high-dose regimens, it is recommended that preservative-free forms of methotrexate sodium be used.241; 242; 2967; 2968 The manufacturer of methotrexate sodium lyophilized powder states that high doses of methotrexate administered by intravenous infusion should be diluted in dextrose 5%.2968 High doses of methotrexate sodium require leucovorin rescue.2967; 2968
Methotrexate products should be stored at controlled room temperature and protected from light.2966; 2967; 2968; 2969; 2970; 3743 Some manufacturers state that products should be retained in the original carton until use.2968; 3743
For intrathecal injection, the preservative-free dosage forms should be diluted immediately prior to use.2967 Although reconstitution of the lyophilized powder immediately prior to use is also recommended (because of the absence of antibacterial preservatives),2968 the reconstituted solution is stable for at least 1 week at room temperature.234
Multiple-dose vials contain a preservative and, after initial entry, should be stored under refrigeration and used within 30 days.2966
Solutions of methotrexate injection with preservative diluted in sodium chloride 0.9% should be used within 4 hours when stored at controlled room temperature or 24 hours when stored under refrigeration.2966
Immersion of a needle with an aluminum component in methotrexate sodium (Lederle) 25 mg/mL resulted in the formation of orange crystals on the aluminum surface after 36 hours at 24°C with protection from light.988
pH Effects
Methotrexate is most stable between pH 6 and 8. Drugs producing extremes of pH should not be added to methotrexate.1072; 1379
Freezing Solutions
Methotrexate sodium (Lederle) 50 mg/100 mL in polyvinyl chloride (PVC) bags of dextrose 5% (Travenol) was frozen at -20°C for at least 30 days and thawed by microwave radiation for 2 minutes with no significant change in concentration. Even after 5 repetitions of the freeze-thaw treatment, the methotrexate concentration showed no significant change.818
The stability of methotrexate 5 mg, 50 mg, and 1 g in 50 mL of sodium chloride 0.9% in PVC bags frozen at -20°C for up to 12 weeks and thawed in a microwave oven was evaluated. No loss was found in any of the concentrations.1281
Light Effects
Photolability, although unrecognized for many years, is a stability problem that is increased by dilution and mixture with sodium bicarbonate.1202
In dilute solutions of 0.1 mg/mL, methotrexate is reported to undergo photodegradation on exposure to light. Decomposition of 5 to 8% in 10 days and 11 to 17% in 20 days has been reported. This effect was not observed in the more concentrated solutions of the commercial preparation (25 mg/mL)433 or in admixtures of methotrexate during short-term light exposure. No significant loss of methotrexate occurred due to light exposure for 4 hours in solutions composed of 5 mg, 50 mg, or 1 g of methotrexate in 50 mL of sodium chloride 0.9% in PVC containers.1281
Little methotrexate loss was found from a 1-mg/mL solution in sodium chloride 0.9% in 3 burette drip chambers made of cellulose propionate (Avon A200 standard and A2000 Amberset) and methacrylate butadiene styrene (Avon A2001 Sureset) when exposed to normal mixed daylight and fluorescent lighting conditions for 24 hours. However, in 48 hours about 10 and 12% losses were observed in the A200 and A2001, respectively. With exposure to direct sunlight, an 11% loss occurred in the A200 in 7 hours. No loss occurred when the Amberset or Sureset was wrapped in foil and exposed to either light condition for 48 hours.1378
Exposure of methotrexate 1-mg/mL solution in PVC and polybutadiene tubing to mixed daylight and fluorescent light produced significant losses after 8 to 12 hours. The Amberset PVC tubing or foil wrapping for the polybutadiene tubing to protect solutions from light reduced losses to 12 to 16% in 48 hours.1378
Methotrexate sodium (R. Bellon), reconstituted to a concentration of 1 mg/mL with sodium chloride 0.9%, was evaluated for stability in translucent containers (Perfupack, Baxter) and 5 opaque containers (green PVC Opafuseur [Bruneau], white EVA Perfu-opaque [Baxter], orange PVC PF170 [Cair], white PVC V86 [Codan], and white EVA Perfecran [Fandre]) when exposed to sunlight for 28 days. Photodegradation was found after storage in the translucent Perfupack. Losses ranged from 18.5 to 27% after 24 hours at a methotrexate sodium concentration of 5 mg/mL. At 1 mg/mL, losses of 4% or less occurred in 24 hours in the opaque containers.1750
Intrathecal Injections
In a study of intrathecal injections, preservative-free methotrexate sodium (Ben Venue) was reconstituted to a concentration of 2.5 mg/mL with Elliott’s B solution (305 mOsm/kg, pH 7.2), sodium chloride 0.9% injection (303 mOsm/kg, pH 7.6), or Ringer’s injection, lactated (270 mOsm/kg, pH 7.6). In all 3 solutions, methotrexate exhibited no change in concentration over 7 days under fluorescent light at 30°C.327
In another study, the stability and compatibility of cytarabine (Upjohn), methotrexate (NCI), and hydrocortisone (Upjohn), mixed together in intrathecal injections, were evaluated. Two combinations were tested: (1) cytarabine 50 mg, methotrexate 12 mg (as the sodium salt), and hydrocortisone 25 mg (as the sodium succinate salt); and (2) cytarabine 30 mg, methotrexate 12 mg (as the sodium salt), and hydrocortisone 15 mg (as the sodium succinate salt). Each drug combination was added to 12 mL of Elliott’s B solution (NCI), sodium chloride 0.9% (Abbott), dextrose 5% (Abbott), and Ringer’s injection, lactated (Abbott) and stored for 24 hours at 25°C. Cytarabine and methotrexate were both chemically stable, with no drug loss after the full 24 hours in all solutions. Hydrocortisone was also stable in the sodium chloride 0.9%, dextrose 5%, and Ringer’s injection, lactated with about a 2% drug loss. However, in Elliott’s B solution, hydrocortisone was significantly less stable, with a 6% loss in the 25-mg concentration over 24 hours. The 15-mg concentration was worse, with a 5% loss in 10 hours and a 13% loss in 24 hours. The higher pH of Elliott’s B solution and the lower concentration of hydrocortisone may have been factors in this increased decomposition. All mixtures were physically compatible during this study, but a precipitate formed after several days of storage.819
Methotrexate sodium (Lederle) 2 mg/mL diluted in Elliott’s B solution (Orphan Medical) was packaged as 20 mL in 30-mL glass vials and 20-mL plastic syringes (Becton Dickinson) with Red Cap (Burron) Luer-Lok syringe tip caps. The solution was physically compatible and chemically stable exhibiting little loss during storage for 48 hours at 4 and 23°C.1976
Bacterially contaminated intrathecal solutions can pose very grave risks. Consequently, intrathecal solutions should be administered as soon as possible after preparation.328
Syringes
Methotrexate (Lederle) 50 mg/mL was stable for up to 8 months when stored in Monoject or Plastipak plastic syringes at 25°C. Because of possible alteration in water vapor permeability, use of Sabre and Steriseal plastic syringes is limited to 70 days at 25°C.1280
Methotrexate sodium (Lederle) 2.5 mg/mL was repackaged into 10-mL plastic syringes (Becton Dickinson) and stored at 4 and 25°C for 7 days. No loss of methotrexate was found. Furthermore, no contaminants from the syringes were observed.1913
Sorption
Methotrexate sodium 22.5 mg/100 mL and 12 g/500 mL in both dextrose 5% and sodium chloride 0.9% in PVC containers (Macoflex, Macopharma) exhibited no sorption loss during 30 days of storage at 4°C protected from light. Simulated infusion of methotrexate sodium 2.25 g/500 mL in dextrose 5% and sodium chloride 0.9% over 24 hours through opaque PVC infusion sets (Perfecran, Fandre) also showed no sorption loss to the PVC tubing.1867
Methotrexate sodium (Medac) 0.36 mg/mL in dextrose 5% and in sodium chloride 0.9% exhibited little or no loss due to sorption in polyethylene, PVC, and glass containers over 72 hours at room and refrigeration temperatures.2420; 2430
Central Venous Catheter
Methotrexate sodium (Immunex) 2.5 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
For a list of references cited in the text of this monograph, search the monograph titled References.