Status: approvals withdrawn

Organizations involved:

Wülfing Pharma GmbH – Manuf.

Shire Richwood Inc. – World mark.

Sigma-Tau S.p.A. – Europe mark.

Beecham Labs. – Former

Roberts Pharmaceutical Corp. – Former

Shire Pharmaceuticals Group plc – Parent

Pharmacia & Upjohn Co. – Former

SmithKline Beecham Pharma GmbH – Former

SmithKline Beecham plc – Parent

Cross ref: See the separate entries for Lys-Plasminogen (#620) and streptokinase (Streptokinase Products, #623), the main components that form Anistreplase. See the Fibrinolytic and Thrombolytic Products entry (#613).

Description: Eminase is a lyophilized (freeze-dried) formulation of anistreplase, the p-anisoyl derivative of the primary Lys-plasminogen-streptokinase activator complex (a complex of Lys-plasminogen and streptokinase). A p-anisoyl group is chemically conjugated to a complex of bacterial-derived streptokinase and human Plasma-derived Lys-plasminogen proteins. This derivatized streptokinase/Lys-Plasminogen enzyme complex has fibrinolytic and thrombolytic activity. Anistreplase is manufactured by acylation of (attaching a p-anisole group to) human Plasma-derived, purified, heat-treated (viral inactivated) Lys-Plasminogen (see entry #620) complexed with purified Streptokinase enzyme (see entry #623, and also #624 and #625) obtained by fermentation of group C beta-hemolytic Streptococci bacteria. Anistreplase has a molecular weight of about 131 kDa. Anistreplase resembles the complex formed in vivo in humans after administration of streptokinase, with streptokinase forming a complex primarily with glu-plasminogen. Fibrinolytic potency of Eminase is expressed in units of anistreplase using a reference standard specific for Eminase (not comparable with other fibrin-olytics).

After intravenous administration, deacylation (removal of the p-anisole group) of Anistreplase in vivo provides the enzymatically active Lys-plasminogen–streptokinase complex with fibrinolytic activity. Thus, Anistreplase is a prodrug of (metabolized to) or a zymogen (inactivated form) of the active Lys-plasminogen-streptokinase enzyme complex. Anistrep-lase is essentially an inactive derivative of a fibrinolytic enzyme complex with the catalytic center of its activate region complex temporarily blocked by an anisoyl group (which does not affect the high fibrin-binding ability of the complex). The acyl group blocking the catalytic site is removable in vivo by hydrolysis at an optimal rate.

Eminase is a sterile, lyophilized, white to off-white powder for reconstitution with 5 mL Sterile Water for Injection, USP, for intravenous injection. Each vial contains 30 units of Anistrep-lase, < 3 mg dimethylsulfoxide (DMSO), < 0.2 mg sodium hydroxide, with buffers and stabilizers; 150 µg p-amin-di-no--phenyl-p-anisate (residual acylating agent); 100 mg mannitol; 46 mg L-Lysine; 30 mg Albumin (Human); < 2 mg glycerol; and 1.3 mg epsilon-aminocaproic acid. Eminase contains no preservatives. Eminase is stored at 2-8˚C (refrigerated).

Biological.: Anistreplase is degraded in vivo to the active fibrinolytic/thrombolytic Lys-Plasminogen-Streptokinase activator complex by release of the anisoyl group (deacylation), a non-enzy-matic first-order process. Deacylation starts immediately when Eminase is reconstituted and injected. The fibrinolytic enzyme activity of the resulting complex converts plasmin to plasminogen, either within the thrombus (blood clot) or in the bloodstream. Catalytic activity within the thrombus is more efficient, but enzyme activity in the bloodstream may contribute to efficacy. Anistreplase has an in vivo half life of about two hours. The in vivo half-life of thrombolytic activity is 70-120 minutes (mean 94 minutes).

Nomenclature: Anistreplase [BIO FDA]; Eminase [TR]; Lys-plasminogen-streptokinase activator complex, p-anisoy-lated derivative [CAS]; 81669-57-0 [CAS RN]; APSAC [SY]; apsaplase [SY]; BRL 26921 [SY]; plasminogen-streptokinase activator complex, p-anisoylated [SY]; Iminiase [TR]; Multilase [TR in Italy]; Fibrit [TR in Portugal]; NDC 54092-543-30 [NDC]

Companies.: Eminase is manufactured by Wülfing Pharma GmbH (also reported as Wuelfing; formerly SmithKline Beecham Pharma GmbH, prior to that Beecham Wülfing GmbH & Co.). Exclusive worldwide marketing rights have been licensed to Roberts Pharmaceutical, now Shire Richwood Inc., a subsidiary of Shire Pharmaceuticals Group plc. Eminase was formerly marketed in the U.S. by Beecham Labs. (became SmithKline Beecham) and co-marketed in the U.S. by Upjohn Co. Roberts/Shire has sublicensed marketing in some countries, e.g., Sigma-Tau in Italy.

Eminase was formerly manufactured in the same facilities by SmithKline Beecham Pharma GmbH, from March 1992. In July 1996, this establishment became the Wülfing Institute through a management buyout. The establishment operated under the name Beecham Wülfing GmbH & Co. prior to March 1992.

Raw materials for anistreplase are/have been obtained from other companies. Lys-plasminogen (see related entry) was manu-factured by Oesterreichisches Institut fur Haemo-derivate GmbH (OIH), later Immuno AG, now Baxter AG. FDA approval of this product was revoked in 2000, subsequent to the acquisition of OIH by Baxter Hyland Immuno. Wülfing may now be manufacturing lys-plasminogen in-house or obtaining it from another manufacturer (not showing up in FDA approval listings). Streptokinase (see entry #624) is manufactured by Sanofi Aventis Pharma Deutschland GmbH. This same streptokinase is marketed in the U.S. by Astra Pharmaceuticals.

Manufacture: As described in Example 2 of U.S. 4,808,405 (see Tech. transfer section), lyophilized p-anisoyl-(streptokinase-plasminogen) activator complex (Eminase) is produced by mixing Streptokinase solution with a lysine/mannitol buffer at pH 7.0 and glycerol; stirring; addition of a sterile filtered solution of p-amidinophenyl p-anisate dissolved in dimethyl sulfoxide (DMSO); addition of the human Plasma-derived lys-plasminogen; addition of Albumin (Human) as stabilizer and lysine/mannitol buffer; diafiltration; sterile filtration (0.22 µm filter); filling of vials; lyophilization (freeze drying); and capping. Bulk processing is performed at 4˚C.

FDA class: Biologic PLA

CBER to CDER: Among the products transferred within FDA on June 30, 2003

Approvals: Date = 19891127, 1st approval, PLA/ELA

Date = 1996128; PLA/ELA revoked and granted (reissued) to new owner, Wülfing Pharma GmbH

Indications: [full text of the "INDICATIONS AND USAGE” section of product insert/labeling]:

Eminase is indicated for use in the 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. Treatment should be initiated as soon as possible after the onset of AMI symptoms (see CLINICAL PHARMACOLOGY).

Status: FDA approval was voluntarily revoked in recent years. The product may still be manufactured and marketed in Europe and/or internationally (but manufacturing most likely has stopped).

Tech. transfer: U.S. 4,808,405, Smith, et al., “p-Anisoyl Streptokinase/Plasminogen Complex,” Feb. 28, 1989, assigned to Beecham Group plc, describes various aspects of the manufacture of Eminase. The first three claims are: “1. p-anisoyl streptokinase/plasminogen complex without internal peptide bond cleavage. 2. The complex of claim 1, wherein said plasminogen is human lys-plasminogen. 3. A pharmaceutical composition for the prevention and/or treatment of thromboses, which comprises a thrombolytically effective amount of a p-anisoyl streptokinase/plasminogen complex without internal peptide bond cleavage together with a pharmaceutically acceptable carrier.” Patents including WO 9108768 and EP 0504239 assigned to Beecham Group PLC cover methods for treatment of stroke using anistreplase.

Based on time during clinical trials and FDA review (under 35 USC §156), the expiration date for U.S. 4,285,932, originally assigned to Beecham Group, was extended from Aug. 20, 1989 to Aug. 20, 1991. This patent describes enzyme complexes with thrombolytic activity.

Medical: The normal dosage is the full single-dose vial (30 Units) reconstituted in 5 mL of Sterile Water for Injection, USP, and injected intravenously over 2-5 minutes. Heparin for anticoagulation is routinely administered 4-6 hours after treatment with Eminase. Multiple clinical trials have demonstrated the efficacy of Eminase as a thrombolytic agent when administered within six hours of onset of symptoms of acute myocardial infarction (AMI).

Market: Other, more modern fibrinolytics, e.g., Activase, Retavase and TNKase, offer improved efficacy and safety and have replaced Eminase,