Sanofi Canada
Tetanus and Diphtheria Toxoids Adsorbed - Td Vaccine; Tenivac
Status: FDA approval withdrawn, reapproved in 2008
Organizations involved:
Sanofi Pasteur Ltd. – Manuf.; R&D; Tech.
Sanofi Pasteur S.A. – World mark.; Parent
Cross ref: See the entries for components of this vaccine – Tetanus Toxoid and Tetanus Toxoid Adsorbed, including those from Sanofi Pasteur. See also the entry for Td vaccine manufactured by Sanofi Pasteur Inc. (USA).
Description: Tetanus and Diphtheria Toxoids Adsorbed for Adult Use is an aqueous formulation of a suspension of formaldehyde-inactivated diphtheria and tetanus toxoids (inactivated toxins) adsorbed on aluminum phosphate adjuvant in an isotonic sodium chloride solution containing sodium phosphate buffer to control pH. Note, unlike the comparable Td vaccine manufactured by Sanofi Pasteur Inc. in the U.S., this vaccine is adjuvanted with aluminum phosphate, not alum (and does not contain thimerosal as a preservative).
The tetanus toxoid is prepared from Clostridium tetani toxin produced in culture medium consisting of a tryptic digest of casein (bovine-derived), supplemented with cystine, dextrose, uracil, inorganic salts and vitamins. The toxin is converted to toxoid (inactivated) by the addition of formalin (formaldehyde), concentrated, and purified. The diphtheria toxoid is prepared from Corynebacterium diphtheriae toxin produced from a C. diphtheriae strain in submerged culture with aeration. The culture medium consists of a tryptic digest of casein (bovine origin), supplemented with cystine, maltose, inorganic salts, and vitamins. The toxin is purified by precipitation, converted to toxoid by the addition of formalin (formaldehyde), and concentrated by ultrafiltration. The two toxoids are mixed, formulated, and packaged.
The vaccine is packaged in single-dose vials containing 0.5 mL of vaccine and in 5.0 mL ten-dose vials for intramuscular injection only. Each 0.5 mL dose contains 5 Lf of tetanus toxoid and 2 Lf of diphtheria toxoid. Other ingredients per dose include 3 mg of 2-phenoxyethanol as preservative, 1.5 mg of aluminum phosphate (equivalent to 0.33 mg of aluminum) as the adjuvant, and no more than 0.1 mg of residual formaldehyde. When tested in guinea pigs, the tetanus component induces at >2 neutralizing units/mL of serum, and the diphtheria component induces at least 0.5 neutralizing units/mL of serum. The vaccine is stored at 2-8°C (35-46°F; refrigerated), with a dating period (upon approval) of 18 months from date of manufacture, defined as the date of initiation of the last valid potency test of the diphtheria or tetanus component of the final formulated bulk vaccine, whichever is earliest.
Nomenclature: Tetanus & Diphtheria Toxoids/Sanofi Canada [BIO]; Tenivac [TR]; Tetanus and Diphtheria Toxoids Adsorbed for Adult Use [FDA, as originally approved]; Tetanus and Diphtheria Toxoids Adsorbed [FDA, current]; NDC 49281-210-11 [NDC]
Companies.: This vaccine is manufactured by Sanofi Pasteur Ltd., CBER/FDA lic. no. 1726, formerly Aventis Pasteur Ltd. FDA class: Biologic PLA
Manufacture: In the Clinical Review for the 2003 original approval, FDA noted, " The manufacturing processes for both the tetanus and diphtheria toxoid components of the candidate Tetanus and Diphtheria Toxoids Adsorbed for Adult Use (Td) are essentially identical to those used in the manufacture of Aventis Pasteur Limited’s Diphtheria and Tetanus Toxoids Adsorbed (For Pediatric Use) (DT) and for DAPTACEL, both of which are licensed in the U.S. These products have a higher amount of diphtheria toxoid than the candidate Td. The DT manufactured by Aventis Pasteur Limited contains thimerosal as a preservative; DAPTACEL contains 2-phenoxyethanol."
FDA class: Biologic PLA BLA
CBER class: Multiple Antigen Preparations
Approvals: Date = 20031103; BLA (BL 103171/0); Indications: = primary and booster immunization of persons 7 - 59 years of age against tetanus and diphtheria
Date = 20080605; BLA supplement; Indications: = include use in adults 60 years of age and older for active immunization for the prevention of tetanus and diphtheria.
Indications: [full text of the "INDICATIONS AND USAGE” section of product insert/labeling]:
TENIVAC is a vaccine indicated for active immunization for the prevention of tetanus and diphtheria in persons 7 years of age and older.
Status: The original application (PLA #86-0205) was submitted April 1986. CBER issued a non-approval letter March 1994. The clinical data submitted to support lot consistency of the candidate Td vaccine are insufficient. The company submitted response to the CBER review in 2001-2003.
This Td vaccine was apparently never launched in the U.S., at least prior to its 2008 (re)approval. It may have been used as component of Sanofi Pasteur DTaP vaccines and/or marketed internationally. FDA approval was withdrawn in recent years, but somehow reactivated and the product granted a sBLA in 2008.
Sanofi Aventis, the largest vaccine company, presumably manufactures its own diphtheria toxoid vaccine components, but no diphtheria toxoid monovalent vaccine from the company is currently approved. Thus, the source for the approval of the diphtheria toxoid (D) component of this combination vaccine is unclear. The approval for this Td vaccine (or DTaP or another Sanofi Pasteur vaccine containing diphtheria toxoid) may effectively cover approval of the diphtheria toxoid component of this and other diphtheria toxoid-containing vaccines from the company.
As a condition of its original approval, Aventis Pasteur agreed to conduct a safety and immunogenicity postmarketing study in approximately 3,000 subjects, with a final study protocol to be submitted by Dec. 2003 and the study initiated by April 2004 or 2 weeks after CBER releases the first commercial batch of vaccine, whichever is later. The company also agreed to complete patient accrual 20 months after the first patient is enrolled in the study and to complete the study 6 months after the last patient has been enrolled, with the final study report to be submitted 1 year after the last patient completed the study.
In some respects, this may be considered a biogeneric (biosimilar, follow-on, etc) biologics approval, with approval based on abbreviated trials showing bioequivalence to an already approved product, not full Phase III-type efficacy and safety studies. The product insert states, “The efficacy of tetanus toxoid and diphtheria toxoid used in Tetanus and Diphtheria Toxoids Adsorbed For Adult Use, manufactured by Aventis Pasteur Limited, was determined on the basis of immunogenicity studies.”
Tenivac was (re)approved, receiving a supplemental BLA, in June 2008. As part of the approval, FDA noted that Sanofi Pasteur had fulfilled its "commitment to conduct a safety and immunogenicity post-marketing study in approximately 3,000 subjects receiving TENIVAC, to include a subset of subjects 60 years of age and older as stated in commitment #1 of the November 3, 2003, approval letter."
Medical: Td vaccine is used only as a booster (not for primary immunization) of adults previously having completed a pediatric DTP or DTaP regimen of five doses, or otherwise previously having received a course of tetanus vaccination.
Market: See the Status section above.
Companies involvement:
Full monograph
556 Tetanus & Diphtheria Toxoids/
Nomenclature:
Diphtheria & Tetanus Toxoids/Sanofi Canada [BIO]
Tenivac [TR]
Diphtheria & Tetanus Toxoids Adsorbed [FDA]
Diphtheria & Tetanus Toxoids Adsorbed USP (For Pediatric Use) [FDA used on insert/labeling]
DT vaccine [SY]
[NDC]
FDA Class: Biologic PLA
Year of approval (FDA) = 1997
Date of 1st FDA approval = 19970411
(in format YYYYMMDD)
Index Terms:
biopharmaceutical products
vaccines, bacterial
vaccines, combination
vaccines, toxoids (inactivated toxins)
bacterial culture <!-- bacterialculture -->
Clostridium tetani
Corynebacterium diphtheriae
Mueller and Miller medium
peptone (medium)
aluminum potassium sulfate (alum)
ammonium sulfate
Diphtheria Toxoid
formaldehyde
Tetanus Toxoid
approval dates uncertain (FDA reports erroneous, conflicting, or simply has lost the original approval dates) (FDAapproved)
North American coral snake
North American coral snake
EU000 Not yet/Never filed with EU
UM999 Not Available/Not Marketed in US
US200 Currently Approved in US
EM999 Not Available/Not Marketed in EU
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