Cathflo Activase

Cathflo Activase

- 90-min (accelerated) dosage regimen (see " Method of administration and dosage») - for patients in whom treatment can be initiated within 6 hours after the development of symptoms,

reduces mortality in the first 30 days after the onset of a heart attack,

thrombolytic therapy of massive pulmonary embolism, accompanied by unstable hemodynamics. This diagnosis should, if possible, be confirmed objectively (for example, by angiography of the pulmonary artery) or by non-invasive methods (for example, by tomography of the lungs). No clinical studies have been conducted on mortality and long-term treatment outcomes for pulmonary embolism,

thrombolytic therapy of ischemic stroke in the acute period. Treatment should begin as early as possible, within 4.5 hours after the onset of stroke symptoms and after the exclusion of intracranial bleeding by an adequate imaging method (using appropriate imaging methods, such as brain CT or other diagnostic method sensitive to the detection of bleeding (such as MRI). The effect of treatment depends on the time of its beginning, i.e. earlier treatment increases the probability of a favorable result.

1. Myocardial infarction

a) a 90-minute (accelerated) dosage regimen for patients with myocardial infarction, in which treatment can be initiated within 6 hours after the onset of symptoms:

- 50 mg-intravenous infusion for the first 30 minutes, followed by 35 mg infusion for 60 minutes until the maximum dose is reached-100 mg.

- 15 mg-in/in, jet,

- 0.75 mg / kg (maximum-50 mg) for 30 minutes in / in drip, followed by an infusion of 0.5 mg/kg (maximum 35 mg) for 60 minutes.

b) a 3-hour dosage regimen for patients in whom treatment can be initiated between 6 and 12 hours after the development of symptoms:

- 50 mg-intravenous infusion for 1 hour, followed by intravenous infusion at a rate of 10 mg for 30 minutes, until a maximum dose of 100 mg is reached within 3 hours.

The total dose of 100 mg should be administered within 2 hours. The greatest experience is obtained when using the following dosage regimen:

- 90 mg intravenously for 2 hours.

^® in the event that the APTT values are less than 2 times higher than the ULN, the infusion of heparin should be started (or continued). The dose of heparin should be adjusted to maintain the APTT between 50-70 s (values should exceed the initial 1.5–2.5 times).

3. Ischemic stroke (acute period)

Adjunctive therapy: the safety and efficacy of the above-mentioned treatment regimen, used in combination with heparin and acetylsalicylic acid, in the first 24 hours after the onset of symptoms, have not been sufficiently studied. In this regard, in the first 24 hours after the start of Actilize therapy the use of acetylsalicylic acid or intravenous administration of heparin should be avoided. If the use of heparin is required for other indications (for example, for the prevention of DVT), its dose should not exceed 10,000 IU per day, while the drug is administered n / K.

Dry substance contained in the Actilize bottle^®

containing a dry substance, the entire volume of the supplied solvent must be added.

When preparing the preparation from the appropriate amount of powder and solvent, the resulting mixture should only be carefully mixed until completely dissolved. It is necessary to avoid strong shaking (foam formation is possible).

alteplase should be 0.2 mg / ml.

^® do not mix with other drugs (even with heparin) either in the infusion bottle or in the general system for intravenous administration.

^®

^® do not use in cases where there is an increased risk of bleeding:

- extensive bleeding at present or during the previous 6 months, hemorrhagic diathesis,

- simultaneous effective treatment with oral anticoagulants, such as warfarin (INR >1,3) (see " Special instructions», ),

- prolonged or traumatic cardiopulmonary resuscitation (>2 min), delivery within the previous 10 days, recently performed puncture of an uncompremated blood vessel (for example, the subclavian or jugular vein),

- severe liver diseases, including liver failure, cirrhosis, portal hypertension (including esophageal varicose veins) and active hepatitis,

- confirmed gastric or duodenal ulcer within the last 3 months,

- hypersensitivity to the components of the drug.

In the case of using the drug for the treatment of acute myocardial infarction and pulmonary embolism, in addition to the above, there are the following contraindications:

- hemorrhagic stroke or stroke of unknown etiology in the anamnesis,

- ischemic stroke or transient ischemic attack during the last 6 months, with the exception of the current acute ischemic stroke for 4.5 hours.

- the onset of symptoms of ischemic stroke more than 4.5 hours before the start of the infusion or the lack of accurate information about the time of onset of symptoms,

- rapid improvement in acute ischemic stroke or mild symptoms by the time the infusion begins,

>25 (National Institutes of Health Stroke Scale)

- convulsions at the beginning of a stroke,

- the presence of a history of stroke of any etiology in patients with diabetes mellitus,

- the use of heparin for 48 hours before the onset of a stroke, if at a given time the APTT is increased,

- platelet count less than 100,000 / µl,

- blood glucose concentration <2.77 or >22.2 mmol / l,

- children and adolescents under 18 years of age (for the treatment of acute stroke).

"With caution»).

In the following cases, when prescribing Actilize

- a recent IV injection or minor recent interventions, such as a biopsy (with a needle), puncture (with a needle) of large vessels, cardiac massage during resuscitation,

- simultaneous administration of oral anticoagulants: treatment with Actilize^® it can be considered only in the case when laboratory indicators of anticoagulant activity are not clinically significant.

- sAD >160 mmHg.,

- old age, at which the risk of intracranial hemorrhage may increase. Since elderly patients are also more likely to have a positive outcome of this treatment, a careful assessment of the benefit-risk ratio is necessary.

In the treatment of acute ischemic stroke, the following special warnings and precautions should also be kept in mind: application of Actilize

- all conditions characterized by a high risk of bleeding,

- the presence of small asymptomatic cerebral aneurysms,

- delayed start of treatment,

- in patients who have previously been treated with acetylsalicylic acid or other antiplatelet agents, there may be an increased risk of intracerebral hemorrhage, especially if the use of Actilize started at a later date. Given the increased risk of cerebral hemorrhage, the applied dose of alteplase should not exceed 0.9 mg / kg (the maximum dose is 90 mg),

- in patients over 80 years of age, compared with younger patients, the risk of cerebral hemorrhage may increase and the overall benefit of treatment may decrease. Therefore, the question of the use of Actilize it should be carefully considered and decided individually, taking into account the expected risk.

Treatment should not be started later than 4.5 hours after the onset of symptoms due to an unfavorable benefit / risk ratio, due to the following circumstances:

- the positive effect of treatment decreases with a late start of therapy,

- mortality increases mainly in patients previously treated with acetylsalicylic acid,

WARNINGS

None.

PRECAUTIONS

General

Catheter dysfunction may be caused by a variety of conditions other than thrombus formation, such as catheter malposition, mechanical failure, constriction by a suture, and lipid deposits or drug precipitates within the catheter lumen. These types of conditions should be considered before treatment with Cathflo Activase.

Because of the risk of damage to the vascular wall or collapse of softwalled catheters, vigorous suction should not be applied during attempts to determine catheter occlusion.

Excessive pressure should be avoided when Cathflo Activase is instilled into the catheter. Such force could cause rupture of the catheter or expulsion of the clot into the circulation.

Bleeding

The most frequent adverse reaction associated with all thrombolytics in all approved indications is bleeding^3,4. Cathflo Activase has not been studied in patients known to be at risk for bleeding events that may be associated with the use of thrombolytics. Caution should be exercised with patients who have active internal bleeding or who have had any of the following within 48 hours: surgery, obstetrical delivery, percutaneous biopsy of viscera or deep tissues, or puncture of noncompressible vessels. In addition, caution should be exercised with patients who have thrombocytopenia, other hemostatic defects (including those secondary to severe hepatic or renal disease), or any condition for which bleeding constitutes a significant hazard or would be particularly difficult to manage because of its location, or who are at high risk for embolic complications (e.g., venous thrombosis in the region of the catheter). Death and permanent disability have been reported in patients who have experienced stroke and other serious bleeding episodes when receiving pharmacologic doses of a thrombolytic.

Should serious bleeding in a critical location (e.g., intracranial, gastrointestinal, retroperitoneal, pericardial) occur, treatment with Cathflo Activase should be stopped and the drug should be withdrawn from the catheter.

Infections

Cathflo Activase should be used with caution in the presence of known or suspected infection in the catheter. Using Cathflo Activase in patients with infected catheters may release a localized infection into the systemic circulation (see ADVERSE REACTIONS). As with all catheterization procedures, care should be used to maintain aseptic technique.

Re-Administration

In clinical trials, patients received up to two 2 mg/2 mL doses (4 mg total) of Alteplase. Additional readministration of Cathflo Activase has not been studied. Antibody formation in patients receiving one or more doses of Cathflo Activase for restoration of function to CVADs has not been studied.

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Longterm studies in animals have not been performed to evaluate the carcinogenic potential or the effect on fertility. Short-term studies that evaluated tumorigenicity of Alteplase and effect on tumor metastases were negative in rodents. Studies to determine mutagenicity (Ames test) and chromosomal aberration assays in human lymphocytes were negative at all concentrations tested. Cytotoxicity, as reflected by a decrease in mitotic index, was evidenced only after prolonged exposure at high concentrations exceeding those expected to be achieved with Cathflo Activase.

Pregnancy (Category C)

Alteplase has been shown to have an embryocidal effect due to an increased postimplantation loss rate in rabbits when administered intravenously at doses approximately 100 times (3 mg/kg) the human dose for restoration of function to occluded CVADs. No maternal or fetal toxicity was evident at 33 times (1 mg/kg) the human dose for restoration of function to occluded CVADs in pregnant rats and rabbits dosed during the period of organogenesis.

There are no adequate and wellcontrolled studies in pregnant women. Cathflo Activase should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

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.

Pediatric Use

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.

Geriatric Use

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 12 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 (see PRECAUTIONS, Bleeding).

REFERENCES

3. Califf RM, Topol EJ, George BS, Boswick JM, Abbottsmith C, Sigmon KN, et al., and the Thrombolysis and Angioplasty in Myocardial Infarction Study Group. Hemorrhagic complications associated with the use of intravenous tissue plasminogen activator in treatment of acute myocardial infarction. Am J Med 1988;85:353–9.

4. Bovill EG, Terrin ML, Stump DC, Berke AD, Frederick M, Collen D, et al. Hemorrhagic events during therapy with recombinant tissue-type plasminogen activator, heparin, and aspirin for acute myocardial infarction: results of the thrombolysis in myocardial infarction (TIMI), phase II trial. Ann Int Med 1991;115:256–65.

SIDE EFFECTS

In the clinical trials, the most serious adverse events reported after treatment were sepsis (see PRECAUTIONS, Infections), gastrointestinal bleeding, and venous thrombosis.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Trials 1 And 2

The data described for Trials 1 and 2 reflect exposure to Cathflo Activase in 1122 patients, of whom 880 received a single dose and 242 received two sequential doses of Cathflo Activase.

In the Cathflo Activase Trials 1 and 2, only limited, focused types of serious adverse events were recorded, including death, major hemorrhage, intracranial hemorrhage, pulmonary or arterial emboli, and other serious adverse events not thought to be attributed to underlying disease or concurrent illness. Major hemorrhage was defined as severe blood loss ( > 5 mL/kg), blood loss requiring transfusion, or blood loss causing hypotension. Nonserious adverse events and serious events thought to be due to underlying disease or concurrent illness were not recorded. Patients were observed for serious adverse events until catheter function was deemed to be restored or for a maximum of 4 or 6 hours depending on study. For most patients the observation period was 30 minutes to 2 hours. Spontaneously reported deaths and serious adverse events that were not thought to be related to the patient's underlying disease were also recorded during the 30 days following treatment.

Four catheter-related sepsis events occurred from 15 minutes to 1 day after treatment with Alteplase, and a fifth sepsis event occurred on Day 3 after Alteplase treatment. All 5 patients had positive catheter or peripheral blood cultures within 24 hours after symptom onset.

Three patients had a major hemorrhage from a gastrointestinal source from 2 to 3 days after Alteplase treatment. One case of injection site hemorrhage was observed at 4 hours after treatment in a patient with pre-existing thrombocytopenia. These events may have been related to underlying disease and treatments for malignancy, but a contribution to occurrence of the events from Alteplase cannot be ruled out. There were no reports of intracranial hemorrhage.

Three cases of subclavian and upper extremity deep venous thrombosis were reported 3 to 7 days after treatment. These events may have been related to underlying disease or to the long-term presence of an indwelling catheter, but a contribution to occurrence of the events from Alteplase treatment cannot be ruled out. There were no reports of pulmonary emboli.

There were no gender-related differences observed in the rates of adverse reactions. Adverse reactions profiles were similar across all age subgroups.

Trial 3

In Trial 3 all serious adverse events were recorded with a specific interest in intracranial hemorrhage, major hemorrhage, thrombosis, embolic events, sepsis and catheter related complications. Major hemorrhage was defined as severe blood loss ( > 5 mL/kg), blood loss requiring transfusion, or blood loss causing hypotension. Non-serious adverse events were not recorded. Patients were observed until catheter function was deemed to be restored or for a maximum of 4 hours after the first dose. Additionally, serious adverse events were elicited from patients at 48 hours (up to 96 hours) following completion of treatment.

No pediatric patients in Trial 3 experienced an intracranial hemorrhage, major hemorrhage, thrombosis, or an embolic event.

Three cases of sepsis occurred 2 to 44 hours after treatment with Cathflo Activase. All of these patients had evidence of infection prior to administration of Cathflo Activase. An additional patient developed fever and lethargy within one day of Cathflo Activase administration, which required outpatient intravenous antibiotics. In one subject, the lumen of the catheter, placed 2 years previously, ruptured with infusion of the study drug.

There were no gender-related differences observed in the rates of adverse reactions. Adverse reactions profiles were similar across all age groups.

Allergic Reactions

No allergic-type reactions were observed in the trials in patients treated with Alteplase. If an anaphylactic reaction occurs, appropriate therapy should be administered.

DRUG INTERACTIONS

The interaction of Cathflo Activase with other drugs has not been formally studied. Concomitant use of drugs affecting coagulation and/or platelet function has not been studied.

Drug/Laboratory Test Interactions

Potential interactions between Cathflo Activase and laboratory tests have not been studied.

The frequency of adverse reactions that may occur during therapy is given as the following gradation: very often (≥1/10), often (≥1/100, <1/10), infrequently (≥1/1, 000, <1/100), rarely (≥1/10 000, <1/1 000), very rare (<1/10, 000), unspecified frequency (frequency cannot be estimated from available data).

Use in acute myocardial infarction, PE and ischemic stroke

^®

- external bleeding (usually from punctures or damage to blood vessels),

The indication of a fat embolism that was not observed in the population of patients who participated in clinical trials is based on a spontaneous report.

In comparison with studies in myocardial infarction, the number of patients with PE and stroke who participated in clinical trials (within 0-4. 5 hours from the onset of symptoms of these diseases) was very small. Therefore, the small numerical differences noted when compared with the data obtained in myocardial infarction were most likely the result of a small sample size. In addition to intracranial hemorrhage (as a side effect) in stroke and reperfusion arrhythmias (as a side effect in myocardial infarction), there are no clinical grounds to assume qualitative and quantitative differences in the spectrum of side effects of the drug Actilize^®

On the part of the immune system:

(in low titers), but the clinical significance of this phenomenon is not established.

rarely-hemorrhages in the eyes.

infrequently-bleeding from the respiratory tract (such as bleeding from the pharynx, hemoptysis, nasal bleeding).

From the gastrointestinal tract: often-gastrointestinal bleeding (such as gastric bleeding, bleeding from a stomach ulcer, bleeding from the rectum, bloody vomiting, melena, bleeding from the oral cavity), infrequently - bleeding from the gums, rarely-retroperitoneal bleeding (for example, retroperitoneal hematoma), nausea, unspecified frequency — vomiting. Nausea and vomiting may also be symptoms of a myocardial infarction.

From the skin and subcutaneous fat: often-ecchymoses.

often-bleeding at the puncture site, bleeding at the injection site (for example, a hematoma at the catheter site, bleeding at the catheter site).

Reactions identified in special studies:

unspecified frequency-fat embolism.

unspecified frequency — the need for transfusions.

infrequently-reperfusion arrhythmias (arrhythmia, extrasystole, atrial fibrillation, AV block from I degree to complete block, bradycardia, tachycardia, ventricular arrhythmia, ventricular fibrillation, ventricular tachycardia). Reperfusion arrhythmias can lead to cardiac arrest, endanger life, and require the use of conventional antiarrhythmic therapy.

Use in myocardial infarction and PE

From the nervous system: often-intracranial hemorrhages (such as cerebral hemorrhage, cerebral hematoma, hemorrhagic stroke, hemorrhagic transformation of stroke, intracranial hematoma, subarachnoid hemorrhage).

often-intracranial hemorrhages (such as cerebral hemorrhage, cerebral hematoma, hemorrhagic stroke, hemorrhagic transformation of stroke, intracranial hematoma, subarachnoid bleeding).

The main undesirable phenomenon was symptomatically expressed intracranial hemorrhages (their frequency reached 10%). However, there was no increase in the incidence of complications or overall mortality.

Treatment: in most cases, it is sufficient to stop the administration of Actilize

Active ingredient of Actilize - alteplase - is a recombinant human tissue plasminogen activator, a glycoprotein that directly activates the conversion of plasminogen to plasmin. After intravenous administration, alteplase remains relatively inactive in the circulation system. It is activated by binding to fibrin, which causes the conversion of plasminogen to plasmin and leads to the dissolution of the fibrin clot.

Patients with acute myocardial infarction (AMI). Two dosage regimens of Actilize were studied in patients with AMI^®

4 modes of thrombolytic therapy were studied. Application of Actilize^®

3-hour infusion in patients with AMI.^®, there was an increase in 30-day survival, improvement in left ventricular function when assessing the ejection fraction using contrast ventriculography, there was a decrease in the size of the infarction, there were significantly fewer episodes of cardiogenic shock, ventricular fibrillation, pericarditis compared to patients receiving placebo.

In a study conducted in patients with angiographically documented acute massive PE, it was found that treatment leads to a significant decrease in the frequency of pulmonary hypertension caused by PE.

Clinically pronounced intracranial hemorrhages were observed in 5.9% of patients treated with Actilize, and in 1.1% of patients treated with placebo, which depended on the age of the patients, but not on the time elapsed from the onset of symptoms to the start of treatment. This analysis also confirmed that the rapid start of the use of Actilize

In normal clinical settings, the safety and efficacy of Actilize were evaluated in acute stroke, if treatment is started within 3 hours of the onset of symptoms. It was found that the frequency of clinically pronounced intracranial bleeding (within 24 hours) in these studies was comparable, it was 7.3 and 8.6%, mortality (after 3 months) was 11.3 and 17%.

A favorable result of treatment was found in a larger number of patients receiving alteplase (52.4%), compared with patients receiving placebo (45.2%). Patients treated with alteplase also had an improved "global outcome", but the frequency of clinically pronounced any intracranial bleeding was higher in the case of alteplase compared to placebo. Systematic intracranial bleeding (ECASS III) they were 2.4% compared to 0.2% placebo (p=0.008). Mortality was low, and there were no significant differences between patients treated with alteplase (7.7%) or placebo (8.4%). Thus, Actilize^®

Safety and effectiveness of the use of Actilize^® in the treatment of acute ischemic stroke, which is undertaken for up to 4.5 hours after the onset of symptoms, continues to be evaluated in the registry

Actilize^® it is rapidly excreted from the bloodstream and metabolized mainly in the liver (plasma clearance is 550-680 ml / min). T_1/2β is about 40 min.

When Actilize it is used to restore the patency of non-functioning catheters installed in the central veins, the achievement of pharmacological concentrations in the plasma is not expected.

Special studies of the interaction of Actilize^® other medications commonly used in acute myocardial infarction have not been compared.

The use of drugs that affect blood clotting or alter the function of platelets, before, during or after the start of Actilize therapy may increase the risk of bleeding.

Concomitant use of ACE inhibitors may increase the risk of anaphylactoid reactions. These reactions were observed in a relatively large proportion of patients treated with ACE inhibitors.