Streptase
Status: formerly approved in the U.S. and Europe
Organizations involved:
ZLB Behring AG – Manuf.; Tech.
CSL Ltd. – Parent
Astra Pharmaceuticals – USA Mark.
Alternate Site Distributors, Inc. (ASD) – USA Mark.
Astra AB – Parent; Intl. mark.
Behringwerke AG – R&D; Tech.; Former
Cross ref: See the entry above (#623) for Streptokinase Products, and the entry for Fibrinolytic and Thrombolytic Enzymes (#613).
Description: Streptase refers to lyophilized (freeze-dried) and aqueous formulations of Streptokinase purified from fermentation of group C beta-homolytic Streptococci bacteria.
Streptase powder is packaged in vials containing 100,000, 250,000 IU, 750,000 IU, or 1.5 million IU for intravenous administration and containing no preservatives. Streptase in aqueous solution is available in 1.5 million IU infusion bottles. Streptase is also packaged in sizes of 5,000 IU (for resistance testing only). Streptase vials and infusion bottles both contain stabilizers – 25 mg of cross-linked gelatin polypeptides (bovine origin), 25 mg sodium L-glutamate, sodium hydroxide to adjust pH, and 100 mg Albumin (Human). The dating period is three years at room temperature storage.
Companies.: Streptokinase is manufactured by ZLB Behring AG, previously Aventis Behring GmbH (originally developed and manufactured by Behring-werke AG, est. no. 0097, later Hoechst Marion Roussel Deutsch-land GmbH). ZLB Behring AG is a subsidiary of CSL Ltd.
Streptase was marketed in the U.S. by Alternate Site Distributors, Inc. (ASD) on behalf of Astra Pharmaceuticals. It was originally marketed in the U.S. by Hoechst-Roussel Pharmaceuticals, Inc., later Hoechst Marion Roussel (now Sanofi Aventis). It is marketed internationally by Astra AB.
Besides sales by Aventis Behring to Astra, streptokinase had been purchased in bulk by Wülfing Pharma GmbH for use in the manufacture of another fibrinolytic/thrombolytic product, Anistreplase (Eminase) or Lys-Plasminogen-Streptokinase activator complex, p-anisoylated derivative (see entry #606).
Manufacture: Beta-hemolytic streptococci from a seed stock are cultured in a standard bouillon media (bovine source) at constant temperature and pH. When peak streptokinase concentration is obtained in the media, fermentation is stopped, and the bacteria are removed (e.g., by centrifugation, filtration). Streptokinase is purified from media by precipitation, chromatography, and adsorption techniques. Final formulation consists of mixing the streptokinase with modified gelatin and L-glutamate. This solution is sterile filtered, filled, and lyophilized.
The modified gelatin used for stabilization of streptokinase is derived from beef (bovine) bones and thermally degraded. Small molecular weigh gelatin (collagen) derivatives are chemically cross-linked, heat-sterilized, and filtered.
The final product is tested for streptokinase potency (enzyme activity) as well as for contaminating streptococcal enzymes [hyaluronidase, deoxyribonuclease (DNase), and streptolysin O] by standard methods. The final product is tested for general safety, pyrogens, sterility, moisture, glutamate content, and the presence of gelatin.
FDA class: Biologic PLA
CBER class: Antitoxins, Antivenins, Enzymes and Venoms
CBER to CDER: Among the products transferred within FDA on June 30, 2003
Approvals: Date = 19770818, first approval, PLA/ELA (ref. 74-351 and 75-229) granted to Behringwerke AG; Indication = venous thrombosis, pulmonary embolism and removals of clots from arterio-venous cannulae
Date = 19871105; PLA supplement, ref. no, 85-54; Indication = for management of myocardial infarction in adults when administered by intravenous route
Date = 19900705; PLA supplement, ref. no. 87-547; Indication = addition of statement in the product insert/labeling regarding reduction of infarct size and the reduction in the incidence of congestive heart failure
Date = 19971015; approval revoked from Behringwerke and granted (reissued) to new owner, Hoechst Marion Roussel Deutschland GmbH
Indications: [extract from the product insert/labeling]:
for management of acute myocardial infarction (AMI) in adults, for the lysis of thrombi obstructing coronary arteries, the reduction of infarct size, the improvement of ventricular function following AMI, and the reduction of mortality associated with AMI
Status: Astra reported (4/2005) that the product is still marketed and available in the U.S. (indicating it was still approved; or available for off-label use). But in recent years, the product no longer appears on CBER/FDA approval lists. As with many other products involving significant exposure to animal-derived components, this product has presumably been withdrawn voluntarily from major markets.
No centralized EU approval. Approvals were country-by-country in Europe.
Tech. transfer: Any relevant patents are presumed to have expired, likely ≥20 years ago.
Medical: For acute myocardial infarction (AMI) intracoro-nary thrombi, ventricular improvement, and reduction of mortality associated with AMI, Streptase may be administered by intravenous or intracoronary injection. For the reduction of infarct size and congestive heart failure associated with AMI, Steptase is administered intravenously. Streptase is often administered as a loading dose followed by intravenous infusion.
Market: The 2007 Average Wholesale Price (AWP) is $562.50/1.5 million IU vial; $93.75/250,000 IU vial; and $281.25/750,000 IU vial (unchanged since 2004).
The market size and share for Streptase had been decreasing in recent years, particularly, in the U.S. and other developed countries with the introduction of more recombinant thrombolytic products. However, streptokinase was generally less expensive than these products.
Companies involvement:
Full monograph
624 Streptokinase/Astra
Nomenclature:
Streptokinase/Astra [BIO]
Streptase [TR]
Streptokinase [FDA INN BAN]
81669-57-0 [CAS RN]
9002-01-1 [CAS RN]
Anistreplase [SY]
NDC 0186-1170-01; NDC 0186-1171-01; NDC 0186-1172-01; NDC 0186-1173-01; NDC 0186-1174-01 [NUM NDC]
FDA Class: Biologic PLA
Year of approval (FDA) = 1977
Date of 1st FDA approval = 19770818
(in format YYYYMMDD)
Biosimilars/biobetters-related U.S. Patents: | long expired; 1990 arbitrarily used as the expiration date |
U.S. Patent Expiration Year: | 2011 |
U.S. Biosimilars Data Exclusivity Expiration: | 1989 |
U.S. Biosimilars Orphan Exclusivity Expiration: | 1984 |
U.S. Biosimilars Launchability Year: | 1990 |
U.S. Biobetters Launchability Year: | 1990 |
Biosimilars/biobetters-related EU Patents: | long expired; 1990 arbitrarily used as the expiration date |
EU Patent Expiration Year: | 1990 |
EU Biosimilars Data Exclusivity Expiration: | |
EU Biosimilars Orphan Exclusivity Expiration: | |
EU Biosimilars Launchability Year: | |
EU Biobetters Launchability Year: | 1990 |
Index Terms:
biopharmaceutical products
bovine materials used<!-- bovinesource -->
enzymes
enzymes, fibrinolytic/thrombolytic
human materials used<!-- humansource -->
bacterial culture <!-- bacterialculture -->
bouillon (beef)
Streptococcus, group C beta-hemolytic
Albumin (Human)
deoxyribonuclease (DNase)
gelatin (bovine source)
glutamate
hyaluronidase
lyophilized (freeze-dried)
sodium glutamate
sodium hydroxide
streptolysin O
approval dates uncertain (FDA reports erroneous, conflicting, or simply has lost the original approval dates) (FDAapproved)
catheter clearance
EU200 Currently Approved in EU
UM001 Marketed Product in US
US200 Currently Approved in US
EM001 Marketed Product in EU
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