Fortelyzin^® (Lyophilisate) Instructions for Use

Marketing Authorization Holder

Supragen, LLC (Russia)

Manufactured By

Ferment Firm, LLC (Russia)

Packaging and Quality Control Release

Ferment Firm, LLC (Russia)

Or

Supragen, LLC (Russia)

ATC Code

B01AD (Enzyme preparations)

Dosage Form

Fortelyzin®

Lyophilizate for preparation of solution for intravenous administration 5 mg (745000 IU): vial 1 pc. in a set with solvent

Dosage Form, Packaging, and Composition

Lyophilizate for preparation of solution for intravenous administration in the form of an amorphous mass or a lyophilized cake, white or almost white in color; the supplied solvent is a colorless transparent liquid; the reconstituted solution is a colorless transparent or slightly opalescent liquid.

Excipients: L-arginine – 15 mg, L-histidine – 2 mg, glycine – 30 mg, povidone-17 – 20 mg, polysorbate-20 – 0.4 mg.

Solvent composition (1 ampoule): sodium chloride injection 0.9% – 5 ml.

5 mg – neutral glass vials with a capacity of 5 ml (1) in a set with solvent (amp. 5 ml 1 pc.) – contour polymer packaging (1) – cardboard packs.

Clinical-Pharmacological Group

Thrombolytic

Pharmacotherapeutic Group

Fibrinolytic agent – plasminogen activator

Pharmacological Action

Fibrinolytic agent – plasminogen activator. Recombinant protein containing the amino acid sequence of staphylokinase (substance Fortelase). It is a single-chain molecule consisting of 138 amino acids, with a molecular weight of 15.5 kDa.

It activates plasminogen to form a stoichiometric complex in a 1:1 ratio. It reacts only with plasminogen bound to partially degraded fibrin located in the area of the thrombus (so-called γ-plasminogen), and does not interact with plasminogen in the systemic circulation, which explains the high fibrin selectivity of this agent.

The mechanism of fibrinolytic action is due to its initial binding of this substance to plasmin located on the fibrin clot, followed by activation of γ-plasminogen and the formation of a triple complex Fortelase-plasmin-plasminogen, which lyses (dissolves) fibrin clots in the thrombus. Due to this fibrin-selective mechanism of action, there is no dependence of the dose of this substance on the patient’s body weight.

The fibrin selectivity of the substance Fortelase is also due to the high rate of neutralization of its complex with plasmin in the blood plasma compared to the thrombus, so the fibrinolytic effect is not accompanied by a decrease in blood fibrinogen. When using this agent, neutralizing antistaphylokinase antibodies are not formed in the blood due to the amino acid substitutions made in the immunodominant epitope of native staphylokinase. In rare cases, transient formation of antibodies to this substance (in low titers) may be observed.

After intravenous administration, a slight decrease in blood fibrinogen, less than 10%, is noted within 1 day after its administration.

Clinical studies have shown that the use of this substance leads to the restoration of coronary blood flow in at least 80% of patients with acute myocardial infarction with ST-segment elevation; it is effective for any location, pathogenetic subtype and severity of ischemic stroke, including in patients with mild stroke.

According to a clinical study, the use of this substance in patients with massive pulmonary embolism at very high risk of mortality (30%) according to the PESI scale contributes to the stabilization of hemodynamics, reduction of pulmonary hypertension and reduction of signs of right ventricular dysfunction. All-cause mortality on day 30 was 4%. The use of this substance was not accompanied by the development of hemorrhagic stroke and major bleeding.

The use of this substance was also effective in patients with massive pulmonary embolism with a history of the novel SARS-CoV-2 coronavirus infection.

Pharmacokinetics

It is eliminated from the bloodstream by binding to receptors in the liver. After a single bolus injection at a dose of 15 mg in patients with acute myocardial infarction with ST-segment elevation, biphasic elimination of the active substance was noted. It is characterized by a short T_1/2. The initial predominant T_1/2α is 5.77±0.72 min (mean ± standard deviation). T_1/2β is 32.08±4.11 min. After a single bolus injection at a dose of 10 mg in patients with ischemic stroke, T_1/2α is 5.11±0.56 min, and in the terminal phase T_1/2β is 32.67±2.12 min. It is excreted with bile, so it can be assumed that impaired renal function does not lead to a change in the pharmacokinetics of this substance.

Indications

Acute myocardial infarction with ST-segment elevation (within the first 12 hours after the onset of symptoms); ischemic stroke (within the first 4.5 hours after the onset of symptoms); massive pulmonary embolism.

ICD codes

Dosage Regimen

Administer only intravenously as a bolus injection. Do not administer by intramuscular or other routes.

For acute myocardial infarction with ST-segment elevation, use a single dose of 15 mg. Initiate therapy within the first 12 hours after symptom onset.

For ischemic stroke, use a single dose of 10 mg. Initiate therapy within the first 4.5 hours after symptom onset.

For massive pulmonary embolism, use a single dose of 15 mg.

Reconstitute the 5 mg (745,000 IU) lyophilizate immediately before use with the supplied 5 ml ampoule of 0.9% sodium chloride injection. Gently swirl the vial until the lyophilizate is completely dissolved. Do not shake vigorously.

Inspect the reconstituted solution visually for particulate matter and discoloration prior to administration. The solution should be colorless, transparent, or slightly opalescent. Discard the solution if it is cloudy or contains visible particles.

Administer the total dose as a single intravenous bolus over several minutes. The dose is not dependent on patient body weight.

Do not mix Fortelyzin^® with other medications in the same syringe or infusion line.

After administration, carefully monitor the patient for signs of bleeding, particularly at vascular puncture sites.

Adverse Reactions

Immune system disorders: very rarely – anaphylactoid reactions (anaphylactic shock), skin itching.

Nervous system disorders: often – intracranial hemorrhages (subarachnoid hemorrhage, hemorrhagic stroke).

Cardiac disorders: infrequently – reperfusion arrhythmias (arrhythmia, bradycardia, ventricular fibrillation, ventricular tachycardia).

Respiratory system disorders: rarely – nosebleed.

Gastrointestinal disorders: infrequently – gastrointestinal bleeding (gastric bleeding, bleeding from a gastric ulcer), gum bleeding; very rarely – nausea, vomiting.

Renal and urinary disorders: infrequently – hematuria, bleeding from the urinary tract.

General disorders: rarely – bleeding from vascular puncture sites.

Contraindications

General contraindications: hypersensitivity to the recombinant protein containing the amino acid sequence of staphylokinase; diseases manifested by increased bleeding, or conditions with a high risk of bleeding; major surgical interventions or major trauma (within the last 4 weeks); severe liver diseases with pronounced disorders of the hemostatic system (liver failure, cirrhosis of the liver, portal hypertension, esophageal varices) and active hepatitis; recent punctures of decompressible vessels (jugular vein, subclavian vein); suspected aortic dissection; septic endocarditis, pericarditis; simultaneous effective use of indirect anticoagulants, for example warfarin (INR >1.3); ongoing severe or life-threatening bleeding (including recently suffered); vascular aneurysm; intracranial or spinal surgical interventions (within the last 2 months); acute pancreatitis, gastric and duodenal ulcer (within 3 months from the moment of exacerbation); history of CNS diseases (neoplasms, aneurysm, surgery on the brain and spinal cord); neoplasms with an increased risk of bleeding; age under 18 years (efficacy and safety have not been established).

Additional contraindications for acute myocardial infarction with ST-segment elevation and massive pulmonary embolism: hemorrhagic stroke (less than 6 months ago).

Additional contraindications for ischemic stroke:
Neuroimaging signs (detected by CT), MRI signs of intracranial hemorrhage, brain tumor, arteriovenous malformation, brain abscess, cerebral vessel aneurysm; signs of severe stroke – clinical (NIHSS stroke score >25), neuroimaging according to CT and/or MRI of the brain; use of direct anticoagulants (unfractionated heparin, low molecular weight heparins, heparinoids) in the 48 hours preceding the stroke with APTT values above normal; significant regression of neurological symptoms during patient observation or mild severity of symptoms at the time of initiation of thrombolytic therapy; history of strokes of any etiology in patients with diabetes mellitus; blood glucose less than 2.7 mmol/l or more than 22.2 mmol/l; platelet count less than 100,000/µl; evidence of bleeding or acute trauma (fracture) at the time of examination; seizure at the onset of the disease, if there is no certainty that the attack is a clinical manifestation of ischemic stroke with postictal residual deficit; major surgical interventions or major trauma (within the last 14 days); prolonged or traumatic cardiopulmonary resuscitation lasting more than 2 minutes; previous hemorrhagic stroke or severe traumatic brain injury within 3 months; systolic BP greater than 185 mm Hg or diastolic BP greater than 110 mm Hg or the need for intravenous administration of drugs to reduce BP to these limits.

With caution

Diseases not listed in the “Contraindications” section that increase the risk of bleeding (if it is necessary to use this agent, the expected benefit for the patient and the possible risk of bleeding should be carefully assessed); arterial hypertension; age over 75 years (for acute myocardial infarction with ST-segment elevation); age over 80 years (for ischemic stroke).

Use in Pregnancy and Lactation

Preclinical studies have shown that this agent does not have embryotoxic, teratogenic, or reprotoxic properties. It is not recommended for use during pregnancy except in cases where the expected benefit of therapy for the mother outweighs the potential risk to the fetus.

There are no data on the excretion of this agent in breast milk. If it is necessary to use during lactation, breastfeeding should be discontinued.

Use in Hepatic Impairment

Contraindicated in severe liver diseases with pronounced disorders of the hemostatic system (liver failure, cirrhosis of the liver, portal hypertension, active hepatitis).

Use in Renal Impairment

The drug is approved for use in renal impairment.

Pediatric Use

Contraindicated for use in children and adolescents under 18 years of age.

Geriatric Use

With caution: age over 75 years for acute myocardial infarction with ST-segment elevation; age over 80 years for ischemic stroke.

Special Precautions

This agent is recommended to be administered as early as possible from the onset of clinical symptoms of acute myocardial infarction or ischemic stroke.

During treatment, monitoring of sites of possible bleeding, including the catheter insertion and puncture site, is necessary.

The use of this agent in therapeutic doses, as a rule, does not lead to the development of arterial hypotension, but the possibility of its occurrence cannot be excluded.

Drug Interactions

When used concomitantly with antiplatelet agents and drugs affecting the blood coagulation system, the risk of bleeding increases.

Fortelase should not be mixed with other drugs in the same infusion vial or in a common system for intravenous administration.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.