REVELISE

Alteplase is a recombinant tissue plasminogen activator (rt-PA) used as a thrombolytic agent.

It cleaves plasminogen to form plasmin, an enzyme involved in the degradation of fibrin clots.

In the absence of fibrin, the alteplase-mediated conversion of plasminogen is limited, thanks to the high affinity between alteplase and fibrin. 3, 6 Alteplase is a purified glycoprotein of 527 amino acids expressed in Chinese hamster ovary (CHO) cells. 5, 6 It was first approved by the FDA in for the management of thromboembolic disease, including acute myocardial infarction (AMI).

The use of alteplase to manage

AMI has decreased thanks to the availability of safer treatments such as angioplasty and stenting.

However, its use for the treatment of acute ischemic stroke (AIS) has increased over the years.

New thrombolytic agents derived from tissue plasminogen activator, such as desmoteplase, tenecteplase and reteplase, have also been developed. 1, 5 Alteplase is also available as Cathflo Activase (intracatheter instillation) for the restoration of function to central venous access devices.

Alteplase is indicated for the treatment of acute ischemic stroke (AIS) and for use in acute myocardial infarction (AMI) for the reduction of mortality and incidence of heart failure.

Alteplase is also indicated for the lysis of acute massive pulmonary embolism, defined as acute pulmonary emboli obstructing blood flow to a lobe or multiple lung segments, and acute pulmonary emboli accompanied by unstable hemodynamics.

Alteplase binds to fibrin and plasminogen.

Alteplase specificity for fibrin is achieved thanks to its high affinity for lysine residues.

Also, it can bind plasminogen via loop structures called kringles, stabilized by three disulphide linkages similar to the ones in plasminogen.

The specificity of alteplase for plasminogen bound to fibrin allows this drug to act in a clot.

• or fibrin-specific manner, leading to low concentrations of circulating plasmin and a lower risk of hemorrhagic transformation. 1, 3 In patients with acute myocardial infarction, alteplase reduces fibrinogen levels 3-6 hours after treatment.

In patients with acute ischemic stroke, patients treated with alteplase have a significantly higher resolution of hyperdense artery sign, a marker of clot formation in the proximal middle cerebral artery, compared to those treated with placebo.

The use of alteplase increases the risk of bleeding and thromboembolic events.

Rare cases of cholesterol embolism have also been reported.

Plasminogen Activator Fibrinogen alpha chain Binder

Fibrinogen gamma chain Binder.

Healthy volunteers with a baseline endogenous tissue plasminogen activator (t-PA) of 3.3 ng/ml had a 290-fold increase in baseline concentrations after receiving alteplase at an infusion rate of 0.25 mg/kg for 30 min; with an infusion rate of 0.5 mg/kg, a 550-fold increase was observed.

Acute myocardial infarction patients (n=12) given 10 mg of alteplase in a 2-minute infusion reached a peak plasma concentration of 3310 ng/ml. This was followed by 50 mg of alteplase in 1 h and 30 mg in 1.5 h, resulting in steady-state plasma levels of 2210 ng/ml and 930 ng/ml, respectively.

The initial volume of distribution approximates plasma volume.

The average volume of distribution of the central compartment goes from 3.9-4.3 L, and the volume of distribution at steady state goes from 7.2-12 L.

Alteplase is mainly metabolized by the liver.

The carbohydrate and polypeptide domains of alteplase interact with hepatic glycoprotein receptors, leading to receptor-mediated endocytosis.

In vivo studies suggest that alteplase follows zero-order kinetics, meaning that its metabolism is saturable at higher plasma concentrations.

In healthy volunteers, more than 80% of alteplase is eliminated through urine 18 hours after administration.

Alteplase has an initial half-life of less than 5 minutes in patients with acute myocardial infarction (AMI).

The dominant initial plasma half-life of the 3-hour and the accelerated regimens for AMI are similar.

Alteplase has a plasma clearance between and 570 mL/min.

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information regarding alteplase is not readily available.

Patients experiencing an overdose are at an increased risk of severe adverse effects such as risk of bleeding and thromboembolic events.

Symptomatic and supportive measures are recommended.

The carcinogenic potential of alteplase or its effect on fertility have not been evaluated.

In vivo studies evaluating tumorigenicity and in vitro studies evaluating mutagenicity were negative.

It has been estimated that the acute oral and dermal toxicity of alteplase is above 5,000 mg/kg.

Activase should not be administered to patients with known hypersensitivity to Alteplase or any component of the formulation See DESCRIPTION.

Cathflo ® Activase ® (Alteplase) is for instillation into the dysfunctional catheter at a concentration of 1 mg/mL.

• Patients weighing ≥30 kg: 2 mg in 2 mL.

• Patients weighing <30 kg: 110% of the internal lumen volume of the catheter, not to exceed 2 mg in 2 mL If catheter function is not restored at 120 minutes after 1 dose of Cathflo Activase, a second dose may be instilled.

There is no efficacy or safety information on dosing in excess of 2 mg per dose for this indication.

Studies have not been performed with administration of total doses greater than 4 mg (two 2‑mg doses).

Instructions for Administration Preparation of Solution Reconstitute Cathflo Activase to a final concentration of 1 mg/mL: Aseptically withdraw 2.2 mL of Sterile Water for Injection, USP (diluent is not provided).

Do not use Bacteriostatic Water for

Inject the 2.2 mL of Sterile Water for Injection, USP, into the Cathflo Activase vial, directing the diluent stream into the powder.

Slight foaming is not unusual; let the vial stand undisturbed to allow large bubbles to dissipate.

Mix by gently swirling until the contents are completely dissolved.

Complete dissolution should occur within 3 minutes.

The reconstituted preparation results in a colorless to pale yellow transparent solution containing 1 mg/mL Cathflo Activase at a pH of approximately 7.3.

Activase contains no antibacterial preservatives and should be reconstituted immediately before use.

The solution may be used for intracatheter instillation within 8 hours following reconstitution when stored at 2–30°C (36–86°F).

No other medication should be added to solutions containing Cathflo Activase.

Instillation of Solution into the Catheter

Inspect the product prior to administration for foreign matter and discoloration.

Withdraw 2 mL (2 mg) of solution from the reconstituted vial.

Instill the appropriate dose of Cathflo

Activase See DOSAGE AND ADMINISTRATION into the occluded catheter.

After 30 minutes of dwell time, assess catheter function by attempting to aspirate blood.

If the catheter is functional, go to Step 7.

If the catheter is not functional, go to Step 5.

After 120 minutes of dwell time, assess catheter function by attempting to aspirate blood and catheter contents.

If the catheter is not functional, go to Step 6.

If catheter function is not restored after one dose of Cathflo Activase, a second dose of equal amount may be instilled.

Repeat the procedure beginning with

Step 1 under Preparation of Solution.

If catheter function has been restored, aspirate 4–5 mL of blood in patients ≥10 kg or 3 mL in patients <10 kg to remove Cathflo Activase and residual clot, and gently irrigate the catheter with 0.9% Sodium Chloride Injection, USP.

Any unused solution should be discarded.

Stability and Storage Store lyophilized Cathflo

Activase at refrigerated temperature (2–8°C/36–46°F).

Do not use beyond the expiration date on the vial.

Protect the lyophilized material during extended storage from excessive exposure to light.

Activase (Alteplase) for injection is supplied as a sterile, lyophilized powder in 2 mg vials.

Cathflo ® Activase ® is available in a carton that contains one 2 mg vial of Cathflo ® Activase ® (Alteplase): NDC 50242‑041‑64 or a carton that contains ten 2 mg vials of Cathflo ® Activase ® (Alteplase): NDC 50242-041-10.

Alteplase has been shown to have an embryocidal effect due to an increased postimplantation loss rate in rabbits when administered intravenously during organogenesis at a dose (3 mg/kg) approximately 50 times human exposure (based on AUC) at the dose for restoration of function to occluded CVADs.

No maternal or fetal toxicity was evident at a dose (1 mg/kg) approximately 16 times human exposure at the dose for restoration of function to occluded CVADs.

There are no adequate and well‑controlled studies in pregnant women.

Activase should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

It is not known whether Cathflo

Activase is excreted in human milk.

Because many drugs are excreted in human milk, caution should be exercised when Cathflo Activase is administered to a nursing woman.

A total of 432 subjects under age 17 have received Cathflo Activase in the three trials.

Rates of serious adverse events were similar in the pediatric and adult patients, as were the rates of catheter function restoration.

In 312 patients enrolled who were age 65 years and over, no incidents of intracranial hemorrhage (ICH), embolic events, or major bleeding events were observed.

One hundred three of these patients were age 75 years and over, and were age 85 years and over.

The effect of

Alteplase on common age-related comorbidities has not been studied.

In general, caution should be used in geriatric patients with conditions known to increase the risk of bleeding.