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DRUGS & SUPPLEMENTS
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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)
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.
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.
Heparin and Rapilysin are incompatible. Do not administer Rapilysin through an intravenous line containing heparin.
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)
Because thrombolytic therapy increases the risk of bleeding, Rapilysin is contraindicated in the following situations:
Do not use in patients with:
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.
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.
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.
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.
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 .
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 Site | 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.
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.
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.
Safety and effectiveness of Rapilysin in pediatric patients have not been established.
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 |
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.
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.
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.
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.
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 mortality | 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 1 | ||||
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 |
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
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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The information was verified by Dr. Rachana Salvi, MD Pharmacology