Rapilysin

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Rapilysin uses


1 INDICATIONS AND USAGE

Rapilysin is indicated for use in acute ST-elevation myocardial infarction (STEMI) to reduce the risk of death and heart failure.

Limitation of Use: The risk of stroke may outweigh the benefit produced by thrombolytic therapy in patients whose STEMI puts them at low risk for death or heart failure.

Rapilysin is a tissue plasminogen activator (tPA) indicated for treatment of acute ST-elevation myocardial infarction (STEMI) to reduce the risk of death and heart failure. (1)

Limitation of Use: The risk of stroke may outweigh the benefit produced by thrombolytic therapy in patients whose STEMI puts them at low risk for death or heart failure. (1)

2 DOSAGE AND ADMINISTRATION

2.1 Dosing Information and Administration

As soon as possible after the onset of STEMI, administer 10 units intravenously over 2 minutes. Administer a second dose of 10 units 30 minutes after the first dose.

2.2 Reconstitution

Reconstitute Rapilysin immediately before administration.

Reconstitute Rapilysin only with the supplied Sterile Water for Injection. Slight foaming upon reconstitution may occur; if necessary allow the vial to stand undisturbed for several minutes to allow dissipation of any large bubbles. Prior to administration, inspect the product for particulate matter and discoloration.

Use aseptic technique throughout.

Step 1: Open the package containing the reconstitution spike. Remove the protective cap from the luer lock port of the reconstitution spike and remove the protective cap on the end of the sterile 10 mL pre-filled syringe. Remove the protective flip-cap from one vial of Rapilysin.

Step 2: Clean the rubber closure with an alcohol wipe.

Step 3: Connect the sterile pre-filled syringe to the reconstitution spike.

Step 4: Remove the protective cap from the spike end of the reconstitution spike and firmly insert the spike into the vial of Rapilysin.

Step 5: Connect the syringe plunger to the sterile 10 mL pre-filled syringe by screwing the plunger into the rubber stopper.

Step 6: Transfer the 10 mL of Sterile Water for Injection through the reconstitution spike into the vial of Rapilysin.

Step 7: With the reconstitution spike and empty pre-filled syringe still attached to the vial, swirl the vial gently to dissolve the Rapilysin. DO NOT SHAKE. The resulting solution concentration is 1 unit/mL and delivers 10 mL (10 units Rapilysin).

Step 8: Disconnect the empty pre-filled syringe from the reconstitution spike and connect the plastic, graduated syringe to the reconstitution spike that is still attached to the vial.

Step 9: Withdraw 10 mL of Rapilysin reconstituted solution into the graduated syringe. A small amount of solution will remain in the vial due to overfill. Detach the graduated syringe from the reconstitution spike.

2.3 Heparin Incompatibility

Heparin and Rapilysin are incompatible. Do not administer Rapilysin through an intravenous line containing heparin.

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3 DOSAGE FORMS AND STRENGTHS

For Injection: 10 units as a lyophilized powder in single-use vials for reconstitution co-packaged with Sterile Water for Injection, USP in 10 mL prefilled syringe.

For Injection: 10 units as a lyophilized powder in single-use vials for reconstitution co-packaged with Sterile Water for Injection, USP in 10 mL prefilled syringe. (3)

4 CONTRAINDICATIONS

Because thrombolytic therapy increases the risk of bleeding, Rapilysin is contraindicated in the following situations:

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5 WARNINGS AND PRECAUTIONS

5.1 Bleeding

Rapilysin can cause significant and sometimes fatal bleeding. Avoid intramuscular injections and other trauma to a patient administered Rapilysin. Minimize venipunctures. Avoid puncturing noncompressible veins, such as the internal jugular and subclavian. If an arterial puncture is necessary, use an upper extremity vessel that is accessible to manual compression, apply pressure for at least 30 minutes, and monitor the puncture site closely. As fibrin is lysed during Rapilysin therapy, bleeding from recent puncture sites or other recent trauma may occur.

Should serious bleeding (not controllable by local pressure) occur, terminate concomitant anticoagulant therapy. Withhold the second Rapilysin dose if serious bleeding occurs before it is administered.

5.2 Hypersensitivity Reactions

Hypersensitivity reactions have been reported with Rapilysin administration. Signs and symptoms observed included rash, pruritis, erythema, glossal edema, hypotension and respiratory distress. If an anaphylactoid reaction occurs, withhold the second dose of Rapilysin and initiate appropriate therapy.

5.3 Cholesterol Embolization

Cholesterol embolism has been reported in patients treated with thrombolytic agents. Cholesterol embolism may present with livedo reticularis, “purple toe” syndrome, acute renal failure, gangrenous digits, hypertension, pancreatitis, myocardial infarction, cerebral infarction, spinal cord infarction, retinal artery occlusion, bowel infarction, and rhabdomyolysis and can be fatal. It is also associated with invasive vascular procedures (e.g., cardiac catheterization, angiography, vascular surgery) and/or anticoagulant therapy.

5.4 Drug/Laboratory Test Interactions

Coagulation tests and measures of fibrinolytic activity are unreliable during Rapilysin therapy unless specific precautions are taken to prevent in vitro artifacts. When present in blood at pharmacologic concentrations, Rapilysin remains active under in vitro conditions, which can result in degradation of fibrinogen in blood samples removed for analysis.

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6 ADVERSE REACTIONS

The following adverse reactions are discussed in greater detail in the other sections of the label:


The most common adverse reaction (>5%) is bleeding. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Chiesi USA, Inc. at 1-888-661-9260 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Clinical Trials Experience

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.

Bleeding

The most frequent adverse reaction associated with Rapilysin is bleeding.


In the INJECT clinical trial, the overall rate of in-hospital, intracranial hemorrhage was 0.8%. The risk for intracranial hemorrhage is increased in patients with advanced age (2.2% among patients >70 years old) or with elevated blood pressure (2.4% among patients with systolic blood pressure >160 mmHg).


The incidence of other types of bleeding events in clinical studies of Rapilysin varied depending upon the use of arterial catheterization or other invasive procedures and whether the study was performed in Europe or the USA. The overall incidence of any bleeding event in patients treated with Rapilysin in clinical studies (n = 3,805) was 21.1%. The rates for bleeding events, regardless of severity, for the 10 + 10 unit Rapilysin regimen from controlled clinical studies are summarized in Table 1.

Table 1: Rapilysin Hemorrhage Rates


Bleeding Site


INJECT


RAPID 1 and RAPID 2


Europe

N = 2,965


USA

N = 210


Europe

N =113


Injection Siteincludes the arterial catheterization site (all patients in the RAPID studies underwent arterial catheterization).



4.6%


48.6%


19.5%


Gastrointestinal


2.5%


9.0%


1.8%


Genitourinary


1.6%


9.5%


0.9%


Anemia, site unknown


2.6%


1.4%


0.9%


In these studies the severity and sites of bleeding events were similar for Rapilysin and the comparison thrombolytic agents.

Allergic Reactions

Among the 2,965 patients receiving Rapilysin in the INJECT trial, serious allergic reactions were noted in 3 patients, with one patient experiencing dyspnea and hypotension.

Among the 9,938 patients that received Rapilysin in a postmarketing clinical study, 8 patients experienced allergic and/or anaphylactoid reactions. Signs and symptoms observed included rash, pruritis, erythema, glossal (tongue) edema, hypotension, and respiratory distress.

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8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Limited published data with Rapilysin use in pregnant women are insufficient to inform a drug associated risk of adverse developmental outcomes. In animal reproduction studies, Rapilysin administered to pregnant rabbits resulted in hemorrhaging in the genital tract, leading to abortions in mid-gestation in doses 3 times the human dose; however, there was no evidence of fetal anomalies in rats at doses up to 15 times the human dose.

The estimated background risk of major birth defects and miscarriage for the indicated population(s) are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Clinical Considerations

Maternal Adverse Reactions

The most common complication of thrombolytic therapy is bleeding and pregnancy may increase this risk.

Data

Animal Data

Rapilysin was administered to pregnant rabbits in doses 3 times the human dose (0.86 units/kg) resulting in hemorrhaging in the genital tract, leading to abortions in mid-gestation. In animal developmental studies in rats at Rapilysin doses up to 15 times the human dose (4.31 units/kg), there was no evidence of fetal anomalies.

8.2 Lactation

Risk Summary

There are no data on the presence of Rapilysin in either human or animal milk, the effects on the breastfed infant, or the effects on milk production. RETEVASE has not been studied in nursing mothers.

8.4 Pediatric Use

Safety and effectiveness of Rapilysin in pediatric patients have not been established.

11 DESCRIPTION

Rapilysin is a non-glycosylated deletion mutein of tissue plasminogen activator (tPA), containing the kringle 2 and the protease domains of human tPA. Reteplase contains 355 of the 527 amino acids of native tPA (amino acids 1-3 and 176-527). Reteplase is produced by recombinant DNA technology in E. coli. The protein is isolated as inactive inclusion bodies from E. coli, converted into its active form by an in vitro folding process and purified by chromatographic separation. The molecular weight of Rapilysin is 39,571 daltons.

Potency is expressed in units (U) using a reference standard which is specific for Rapilysin and is not comparable with units used for other thrombolytic agents.

Rapilysin (reteplase) for Injection is a sterile, white, lyophilized powder for intravenous injection after reconstitution with Sterile Water for Injection, USP (without preservatives). Following reconstitution with 10 mL of Sterile Water for Injection, the resulting concentration is 1 unit/mL to allow for delivery of 10 mL (10 units Rapilysin). The pH is 6.0 ± 0.3. Rapilysin is supplied with overfill to ensure sufficient drug for administration of each 10 unit injection.

Each single-use vial delivers:


Rapilysin


10 units


Dipotassium Hydrogen Phosphate


131 mg


Phosphoric Acid


49.3 mg


Polysorbate 80


5 mg


Sucrose


350 mg


Tranexamic Acid


8 mg


12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Rapilysin is a recombinant plasminogen activator which catalyzes the cleavage of endogenous plasminogen to generate plasmin. Plasmin in turn degrades the fibrin matrix of the thrombus, thereby exerting its thrombolytic action.

12.2 Pharmacodynamics

In a controlled trial, 36 of 56 patients treated for myocardial infarction had a decrease in fibrinogen levels to below 100 mg/dL by 2 hours following the administration of Rapilysin as two intravenous injections in which 10 units was followed 30 minutes later by a second dose of 10 units. The mean fibrinogen level returned to the baseline value by 48 hours.

12.3 Pharmacokinetics

Based on the measurement of thrombolytic activity, Rapilysin is cleared from plasma at a rate of 250-450 mL/min, with an effective half-life of 13-16 minutes. Rapilysin is cleared primarily by the liver and kidney.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis and Mutagenesis

Long-term studies in animals have not been performed to evaluate the carcinogenic potential of Rapilysin. Studies to determine mutagenicity, chromosomal aberrations, gene mutations, and micronuclei induction were negative at all concentrations tested.

14 CLINICAL STUDIES

Rapilysin was evaluated in three controlled clinical studies comparing Rapilysin to other thrombolytic agents. In all three studies, patients were treated with aspirin (initial doses of 160 mg to 350 mg and subsequent doses of 75 mg to 350 mg) and heparin (a 5,000 unit IV bolus prior to the administration of Rapilysin or control, followed by a 1000 unit/hour continuous IV infusion for at least 24 hours).

The INJECT study compared Rapilysin to streptokinase on mortality rates at 35 days following acute ST-elevation myocardial infarction (STEMI). INJECT was a double-blind study in which 6,010 patients with no more than 12 hours of chest pain consistent with coronary ischemia and either ST segment elevation or bundle branch block on ECG were randomized 1:1 to Rapilysin (10 + 10 unit) or streptokinase (1.5 million units over 60 minutes). Patients with cerebrovascular or other bleeding risks or with systolic blood pressure >200 mm Hg or diastolic blood pressure >100 mm Hg were excluded from enrollment. The study was designed to determine whether the effect of Rapilysin on survival was noninferior to that of streptokinase by ruling out with 95% confidence that 35-day mortality among Rapilysin patients was no more than 1% higher than among streptokinase patients. The results of the primary endpoint (mortality at 35 days), 6-month mortality, and selected other in-hospital endpoints are shown in Table 2.

Table 2: INJECT Study: Selected Results


Endpoint


Rapilysin

N = 2,965


Streptokinase

N = 2,971


RETAVASE-Streptokinase ∆

(95% CI)


35-day mortalityKaplan-Meier estimates


8.9%


9.4%


-0.5 (-2.0, 0.9)


6-month mortality


11.0%


12.1%


-1.1 (-2.7, 0.6)


Cardiogenic shock


4.6%


5.8%


-1.2 (-2.4, -0.1)


Heart failure in-hospital


24.8%


28.1%


-3.3 (-5.6, -1.1)


Any stroke in-hospital


1.4%


1.1%


0.3 (-0.3, 0.8)


Intracranial hemorrhage in-hospital


0.8%


0.4%


0.4 (0.0, 0.8)


More patients treated with Rapilysin experienced hemorrhagic strokes than did patients treated with streptokinase. An exploratory analysis indicated that the incidence of intracranial hemorrhage was higher among older patients or those with elevated blood pressure.

The other two studies (RAPID 1 and RAPID 2) compared coronary artery patency of Rapilysin to two regimens of alteplase in patients with STEMI. In RAPID 1 patients within 6 hours of the onset of symptoms were randomized to open-label administration of one of three regimens of Rapilysin (doses of 10 + 10 unit, 15 unit, or 10 + 5 unit) or to alteplase (100 mg over 3 hours). In RAPID 2 patients within 12 hours of the onset of symptoms were randomized to open-label administration of either Rapilysin (10 + 10 unit) or alteplase (100 mg over 1.5 hours). The primary endpoint for both studies was patency of the infarct-related artery 90 minutes after initiation of therapy. Interpretation of coronary angiograms was blinded.

A higher percentage of subjects administered RETEVASE had complete flow (TIMI grade 3) and partial or complete flow (TIMI grades 2 or 3) compared to both regimens of alteplase. The relationship between coronary artery patency and clinical efficacy has not been established.

In both clinical trials the re-occlusion rates were similar for Rapilysin and alteplase.

Table 3: RAPID 1 and RAPID 2 Studies: Angiographic Results


90 minute patency rates


RAPID 2


RAPID 1p values represent one of multiple dose comparisons.


Rapilysin

(10 +10 unit)

N = 157


Alteplase

(100 mg over 1.5 hours)

N = 146


p - value


Rapilysin

(10 +10 unit)

N = 142


Alteplase

(100 mg over 3 hours)

N = 145


p - value


TIMI 2 or 3


83%


73%


0.03


85%


77%


0.08


TIMI 3


60%


45%


0.01


63%


49%


0.02


16 HOW SUPPLIED/STORAGE AND HANDLING

Rapilysin (reteplase) for Injection is supplied as a sterile, preservative-free, lyophilized powder in 10 unit vials without a vacuum, in the following packaging configurations:

Rapilysin Kit (NDC 10122-141-02): 2 single-use Rapilysin vials 10 units, 2 single-use prefilled syringes for reconstitution (10 mL Sterile Water for Injection, USP), 2 syringe plungers, 2 sterile 10 mL graduated syringes, 2 sterile reconstitution spikes, 1 quick reference guide and 1 package insert.

Rapilysin Half-Kit (NDC 10122-143-01): 1 single-use Rapilysin vial 10 units, 1 single-use prefilled syringe for reconstitution (10 mL Sterile Water for Injection, USP), 1 syringe plunger, 1 sterile 10 mL graduated syringe, 1 sterile reconstitution spike, 1 quick reference guide and 1 package insert.

Storage: Store Rapilysin at 2°C to 25°C (36°F to 77°F). The box should remain sealed until use to protect the lyophilisate from exposure to light.

Distributed by:

Chiesi USA, Inc.

Cary, NC 27518

Manufactured by:

EKR Therapeutics, Inc.

Cary, NC 27518

U.S. License No. 1814

Retavase® manufactured at Actavis Italy, S.p. A. Nerviano, Italy 20014

To report an adverse event, record the lot number and call Medical Information at 1-888-661-9260.

RETAVASE® is a registered trademark of EKR Therapeutics, Inc.

The trademarks Streptase®, Activase®, and Actilyse® referenced herein are the property of their respective owners and are not affiliated with, connected to, or sponsored by Chiesi USA, Inc.

CTR-001-0415-00-SPL-1

Rapilysin Full Kit

Rapilysin Full Kit

Rapilysin Half Kit

Rapilysin Half Kit

Rapilysin pharmaceutical active ingredients containing related brand and generic drugs:

Active ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.


Rapilysin available forms, composition, doses:

Form of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.


Rapilysin destination | category:

Destination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.


Rapilysin Anatomical Therapeutic Chemical codes:

A medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.


Rapilysin pharmaceutical companies:

Pharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.


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References

  1. Dailymed."RETAVASE (RETEPLASE) KIT [CHIESI USA, INC.]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. "Reteplase". https://pubchem.ncbi.nlm.nih.gov/su... (accessed August 28, 2018).
  3. "Reteplase - DrugBank". http://www.drugbank.ca/drugs/DB0001... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Rapilysin?

Depending on the reaction of the Rapilysin after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Rapilysin not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Rapilysin addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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Review

sdrugs.com conducted a study on Rapilysin, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Rapilysin consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

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The information was verified by Dr. Rachana Salvi, MD Pharmacology

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