Importation of US-Authorized Methotrexate for Injection, USP Due to the Current Shortage of Canadian-Authorized Methotrexate Injection BP, 25 mg/mL

Given the shortage of Methotrexate Injection BP (without preservative), 25 mg/mL in Canada, and to maintain continuity of supply, Health Canada has authorized the exceptional, temporary importation and sale of US-authorized Methotrexate for Injection, USP (preservative free) with English-only labels by Fresenius Kabi Canada Ltd.

 

Audience

Healthcare professionals including pharmacists, oncologists, hematologists, rheumatologists, dermatologists, and nurses.  

 

Key messages

• Due to a shortage of Methotrexate Injection BP (without preservative), 25 mg/mL in Canada, and given the medical importance of this drug, Health Canada has permitted the exceptional, temporary importation and sale of US-authorized Methotrexate for Injection, USP (preservative free) with English-only labels by Fresenius Kabi Canada Ltd.
• There are important differences between the US-authorized Methotrexate for Injection, USP (preservative free) and the Canadian-authorized Methotrexate Injection BP (without preservative), 25 mg/mL by Accord Healthcare Inc. (DIN 02474891) (see the Information for healthcare professionals section).
• Healthcare professionals are advised to:
  • Be aware that the US-authorized product is supplied as a lyophilized powder and must be reconstituted prior to use.
  • Be aware that the reconstituted product should be used immediately and not stored after reconstitution.
  • Be aware that the US-authorized product will have a concentration of 50 mg/mL after reconstitution, unlike the Canadian-authorized product, which is supplied as a 25 mg/mL solution.
  • Be aware that the US-authorized product has not been approved for intracerebroventricular administration, unlike the Canadian-authorized product.
  • Ensure that pharmacies review worksheets used in the preparation of methotrexate to ensure that they instruct pharmacy staff on the proper reconstitution, dilution, and storage of the US-authorized product.
  • Refer to the US-authorized product Prescribing Information, available in English and French (see the Information for healthcare professionals section), for reconstitution instructions and storage information.
  • Refer to the Canadian Product Monograph for Methotrexate Injection BP (without preservative), 25 mg/mL by Accord Healthcare Inc. (DIN 02474891), available in English and French on Health Canada’s Drug Product Database, for information on authorized indications, contraindications, dosage and administration and other safety information.

 

Background information

In Canada, methotrexate injection is used alone or in combination with other medicines to treat certain types of cancers. It may also be used to treat other diseases such as severe psoriasis and severe rheumatoid arthritis in adults.

 

Information for healthcare professionals

This product should be administered by appropriately trained healthcare professionals, familiar with its actions, characteristics, and hazards.

The US-authorized product has the same active ingredient (methotrexate) as Accord Healthcare Inc.’s Canadian-authorized Methotrexate Injection BP (without preservative), 25 mg/mL (DIN 02474891). However, there are differences in the dosage form, the need for reconstitution and concentration, among other characteristics, which are important to note (see Table 1). Proper selection of the intended product must be verified to avoid confusion with other products and prevent errors.

 

Table 1: Key differences between US-authorized Methotrexate for Injection, USP (preservative free) and Canadian-authorized Methotrexate Injection BP (without preservative), 25 mg/mL
 

	Drug product for importation	Canadian drug product
Product Brand Name, Dosage Form and Strength	Methotrexate for Injection, USP Vial of lyophilized powder containing methotrexate sodium equivalent to 1 g methotrexate. Sterile. For single use only. Concentration of 50 mg/mL, after reconstitution.	Methotrexate Injection BP Sterile solution. Single use vial. 25 mg/mL
Identifying Code	NDC: 63323-122-50	DIN 02474891
Route of Administration	Intramuscular, intravenous, intra-arterial, intrathecal	Intramuscular, intravenous, intra-arterial, intrathecal, intracerebroventricular
Reconstitution	Reconstitute immediately prior to use. Reconstitute with an appropriate sterile, preservative free medium such as 5% Dextrose Solution, or Sodium Chloride Injection. The 1 g vial should be reconstituted with 19.4 mL to a concentration of 50 mg/mL. When high doses of methotrexate are administered by IV infusion, the total dose is diluted in 5% Dextrose Solution. For intrathecal injection, reconstitute to a concentration of 1 mg/mL with an appropriate sterile, preservative free medium such as Sodium Chloride Injection.	None
Non-Medicinal Ingredients	Prior to reconstitution: Sodium hydroxide, hydrochloric acid	Sodium chloride, sodium hydroxide, hydrochloric acid and water for injection.
Preservative	Preservative-free Reconstitute with preservative free medium to be considered clinically equivalent to the Canadian product.	Preservative-free
Storage	Prior to reconstitution: Store at 20° to 25°C (68° to 77°F). Protect from light. Retain in carton until time of use. Discard unused portion. Storage after reconstitution: Reconstitute immediately prior to use. The reconstituted product should not be stored after reconstitution.	Store vials between 15° to 25°C. Protect from light and freezing. Discard unused portion. Dilutions should be used within 24 hours if kept at 20° to 25°C (room temperature). Unused solution should be discarded after this time in order to avoid risk of microbial contamination.

Healthcare professionals are advised that:

• The US-authorized product is supplied as a vial containing 1 g of lyophilized methotrexate sodium powder that must be reconstituted immediately before use. In accordance with the US label, reconstitute with 19.4 mL of an appropriate sterile, preservative-free medium (such as 5% Dextrose Solution, or Sodium Chloride Injection) to achieve a concentration of 50 mg/mL. In contrast, the Canadian-authorized product is supplied as a 25 mg/mL solution that does not require reconstitution.
• The US-authorized reconstituted product should be used immediately and not stored after reconstitution.
• The US-authorized product has not been approved for intracerebroventricular administration, unlike the Canadian-authorized product.
• The US-authorized product should not be used as a disease-modifying antirheumatic drug (DMARD) in pediatric patients in Canada. Unlike the US-authorized product, the Canadian-authorized product is not indicated for juvenile arthritis in Canada.
• The US-authorized product Prescribing Information, available in English and French, should be consulted for reconstitution instructions and storage information.
• The Canadian Product Monograph for Methotrexate Injection BP (without preservative), 25 mg/mL by Accord Healthcare Inc. (DIN 02474891), available in English and French on Health Canada’s Drug Product Database, should be consulted for information on authorized indications, contraindications, dosage and administration and other safety information.

The US-authorized product labels (see Appendix 1) are in English-only and do not include French text.

Healthcare professionals can find additional information about the US-authorized product in:

• English: https://www.fresenius-kabi.com/en-ca/methotrexate-for-injection--usp-1-gram-per-vial
• French: https://www.fresenius-kabi.com/fr-ca/methotrexate-for-injection--usp-1-gram-per-vial

Pharmacies should review worksheets used in the preparation of methotrexate to ensure that they instruct pharmacy staff on the proper reconstitution, dilution, and storage of the US-authorized product.

Additionally, the US-authorized product does not have a Drug Identification Number (DIN) or a barcode that scans in medication management systems in Canada. A facility-generated sticker is recommended to enable barcode scanning and allow proper identification of the product being dispensed and administered. It is the responsibility of the receiving organization to create this sticker.  

 

Action taken by Health Canada

To help mitigate the shortage of Methotrexate Injection BP (without preservative), 25 mg/mL in Canada, Health Canada has permitted the exceptional, temporary importation and sale of US-authorized Methotrexate for Injection, USP (preservative free) by Fresenius Kabi Canada Ltd. and added this product to the List of Drugs for Exceptional Importation and Sale.

Health Canada has worked with Fresenius Kabi Canada Ltd. to prepare this alert for methotrexate for injection. Health Canada is communicating this important safety information to healthcare professionals and Canadians via the  Recalls and Safety Alerts Database on the Healthy Canadians Web Site. This communication update will be further distributed through the MedEffect™ e-Notice email notification system.

 

Report health or safety concerns

Managing marketed health product-related side effects depends on healthcare professionals and consumers reporting them. Any case of serious or unexpected side effects in patients receiving methotrexate for injection should be reported to Fresenius Kabi Canada Ltd. or Health Canada.

Fresenius Kabi Canada Ltd.
165 Galaxy Blvd, Suite 100
Toronto, Ontario M9W 0C8, Canada
Telephone: 1-877-779-7760
Fax:1-844-605-4465
Email: Canada_Medinfo@fresenius-kabi.com

To correct your mailing address or fax number, contact Fresenius Kabi Canada Ltd.

You can report any suspected adverse reactions associated with the use of health products to Health Canada by:

• Calling toll-free at 1-866-234-2345; or
• Visiting MedEffect Canada's Web page on Adverse Reaction Reporting (http://www.hc-sc.gc.ca/dhp-mps/medeff/report-declaration/index-eng.php) for information on how to report online, by mail or by fax.

For other health product inquiries related to this communication, contact Health Canada at:

Regulatory Operations and Enforcement Branch

E-mail:  hpce-cpsal@hc-sc.gc.ca

Telephone: 1-800-267-9675

 

Original signed by

Prachi Chandel

National Safety Officer, Manager, Vigilance and Medical

 

Appendix 1

A. Image of US-Authorized Methotrexate for Injection, USP, Vial

 

B . Image of US-Authorized Methotrexate for Injection, USP, Inner Label

 

C. Image of US-Authorized Methotrexate for Injection, USP, Outer Label