Cathflo Activase

Vial Reconstitution

Use only the accompanying sterile water for injection (without preservatives); do not use bacteriostatic water for injection

Reconstitute using aseptic technique

Do not add other medication to resulting solution

Reconstitute no more than 8 hr before use (does not contains antibacterial preservatives)

Slight foaming is not unusual; let stand undisturbed for several minutes to allow large bubbles to dissipate

Inspect parenteral drug products for particulate matter and discoloration prior to administration whenever solution and container permit

Activase may be administered as reconstituted at 1 mg/mL or further diluted immediately before administration in an equal volume of 0.9% NaCl or D5W, to yield a concentration of 0.5 mg/mL, using either PVC bags or glass vials

Avoid excessive agitation during dilution; mix by gently swirling and/or slow inversion

50-mg vials

• Do not use if vacuum is not present
• Using a large bore needle (eg, 18 gauge) and a syringe, reconstitute by adding the contents of the accompanying 50 mL vial of sterile water for injection (SWFI) to the 50 mg vial, directing the SWFI stream into the lyophilized cake

100-mg vials

• The 100 mg vials do not contain vacuum
• Using the transfer device provided, reconstitute by adding the contents of the accompanying 100 mL vial of SWFI to the 100 mg vial
• 1. Use aseptic technique
• 2. Remove the protective flip-caps from 1 vial of Activase and 1 vial of SWFI
• 3. Open the package containing the transfer device by peeling the paper label off the package
• 4. Remove the protective cap from 1 end of the transfer device and keeping the vial of SWFI upright, insert the piercing pin vertically into the center of the stopper of the vial of SWFI
• 5. Remove the protective cap from the other end of the transfer device; do NOT invert the vial of SWFI
• 6. Hold the vial of Activase upside down, position it so that the center of the stopper is directly over the exposed piercing pin of the transfer device, and push the vial of Activase down so that the piercing pin is inserted through the center of the Activase vial stopper
• 7. Invert the 2 vials so that the vial of Activase is on the bottom (upright) and the vial of SWFI is upside-down, allowing the SWFI to flow down through the transfer device; allow the entire contents of the vial of SWFI to flow into the Activase vial (approximately 0.5 mL of SWFI will remain in the diluent vial)
• 8. Remove the transfer device and the empty SWFI vial from the Activase vial and discard
• 9. Swirl gently to dissolve the Activase powder; do NOT shake

Bolus Dose Preparation

Prepare the bolus dose in 1 of the following ways

50-mg vials

• Remove the appropriate volume from the reconstituted vial (1 mg/mL) using a syringe and needle
• If this method is used with the 50 mg vials (contains vacuum), the syringe should not be primed with air and the needle should be inserted into the vial stopper

100-mg vials

• If the 100 mg vial (no vacuum) is used, the needle should be inserted away from the puncture mark made by the transfer device
• Remove the appropriate volume from a port (second injection site) on the infusion line after the infusion set is primed
• Program an infusion pump to deliver the appropriate volume as a bolus at the initiation of the infusion

Cathflo Activase preparation

Reconstitute 2 mg vial by adding 2.2 mL SWI (do not use bacteriostatic water for injection); yields final concentration of 1 mg/mL

Mix by gently swirling until completely dissolved; complete dissolution occurs within 3 minutes; do NOT shake

Use within 8 hr if stored at room temperature

Alteplase is a thrombolytic (THROM-bo-LIT-ik) drug, sometimes called a "clot-busting" drug. It helps your body produce a substance that dissolves unwanted blood clots.

Alteplase is used to treat a stroke caused by a blood clot or other obstruction in a blood vessel. Alteplase is also used to prevent death from a heart attack (acute myocardial infarction).

Alteplase is also used to treat a blood clot in the lung (pulmonary embolism).

Alteplase is also used to dissolve blood clots that have formed in or around a catheter placed inside a blood vessel. This improve the flow of medicines injected in through the catheter, or blood drawn out through the catheter.

Alteplase may also be used for purposes not listed in this medication guide.

If possible before you receive alteplase, tell your doctor if you have a brain tumor or aneurysm, high blood pressure, stomach bleeding, hemophilia or other bleeding disorder, or if you have recently had a head injury, brain or spinal surgery, or other major surgery or serious injury.

In an emergency situation it may not be possible to tell your caregivers about your health conditions. Make sure any doctor caring for you afterward knows you have received this medicine.

Alteplase injection is used to dissolve blood clots that have formed in the blood vessels. It is used immediately after symptoms of a heart attack occur to improve patient survival. It is also used after symptoms of a stroke and to treat blood clots in the lungs (pulmonary embolism).

Alteplase is used to dissolve blood clots in tubes (catheters) that are placed in large blood vessels (central venous access devices).

This medicine is available only with your doctor's prescription.

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor or nurse immediately if any of the following side effects occur:

• Bleeding from puncture sites and wounds
• bleeding gums
• coughing up blood
• difficulty with breathing or swallowing
• dizziness
• headache
• increased menstrual flow or vaginal bleeding
• nosebleeds
• paralysis
• prolonged bleeding from cuts
• red or black, tarry stools
• red or dark brown urine

• Chills
• confusion
• fainting
• fast heartbeat
• fever
• lightheadedness
• pain in the chest, groin, or legs, especially the calves
• pain, redness, or swelling in the arm or leg
• rapid, shallow breathing
• severe, sudden headache
• slurred speech
• sudden loss of coordination
• sudden, severe weakness or numbness in the arm or leg
• sudden, unexplained shortness of breath
• vision changes

• Anxiety
• blue lips and fingernails
• blue or pale skin
• blurred vision
• chest pain or discomfort
• chest pain, possibly moving to the left arm, neck, or shoulder
• convulsions
• cool, sweaty skin
• cough
• coughing that sometimes produces a pink frothy sputum
• decreased urine output
• dilated neck veins
• extreme fatigue
• hives or welts, itching, or skin rash
• hoarseness
• increased sweating
• large, hive-like swelling on the mouth, lips, or tongue
• loss of bladder control
• muscle spasm or jerking of all extremities
• nausea or vomiting
• pain or discomfort in the arms, jaw, back, or neck
• puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue
• redness of the skin
• slow or irregular breathing or heartbeat
• sudden loss of consciousness
• sweating
• swelling of the face, fingers, feet, lower legs, or ankles
• unconsciousness
• unusual tiredness or weakness
• weight gain

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Cathflo® Activase® (Alteplase) is a tissue plasminogen activator (t‑PA) produced by recombinant DNA technology. It is a sterile, purified glycoprotein of 527 amino acids. It is synthesized using the complementary DNA (cDNA) for natural human tissue‑type plasminogen activator (t‑PA) obtained from an established human cell line. The manufacturing process involves secretion of the enzyme Alteplase into the culture medium by an established mammalian cell line (Chinese hamster ovary cells) into which the cDNA for Alteplase has been genetically inserted. Fermentation is carried out in a nutrient medium containing the antibiotic gentamicin sulfate, 100 mg/L. The presence of the antibiotic is not detectable in the final product.

Cathflo Activase is a sterile, white to pale yellow, lyophilized powder for intracatheter instillation for restoration of function to central venous access devices following reconstitution with Sterile Water for Injection, USP.

Each vial of Cathflo Activase contains 2.2 mg of Alteplase (which includes a 10% overfill), 77 mg of L‑arginine, 0.2 mg of polysorbate 80, and phosphoric acid for pH adjustment. Each reconstituted vial will deliver 2 mg of Cathflo Activase, at a pH of approximately 7.3.

NDC 50242-041-64

10147268
US License No.: 1048

cathflo®
activase®
(ALTEPLASE) 2 mg

For Use in Central Venous Access Devices

Rx only
KEEP REFRIGERATED

Genentech

Ask your doctor before taking aspirin or ibuprofen (Motrin, Advil) shortly after you have received alteplase. These medications can increase your risk of bleeding.

Avoid activities that may increase your risk of bleeding or injury. Use extra care to prevent bleeding while shaving or brushing your teeth.

Tell your doctor about all your current medicines and any you start or stop using, especially:

• any medication used to prevent blood clots;
• a blood thinner (heparin, warfarin, Coumadin, Jantoven); or
• NSAIDs (nonsteroidal anti-inflammatory drugs)--aspirin, ibuprofen (Advil, Motrin), naproxen (Aleve), celecoxib, diclofenac, indomethacin, meloxicam, and others.

This list is not complete. Other drugs may interact with alteplase, including prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed in this medication guide.

Applies to alteplase: intravenous powder for solution

Along with its needed effects, alteplase (the active ingredient contained in Cathflo Activase) may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor or nurse immediately if any of the following side effects occur while taking alteplase:

• Bleeding from puncture sites and wounds
• bleeding gums
• coughing up blood
• difficulty with breathing or swallowing
• dizziness
• headache
• increased menstrual flow or vaginal bleeding
• nosebleeds
• paralysis
• prolonged bleeding from cuts
• red or black, tarry stools
• red or dark brown urine

• Chills
• confusion
• fainting
• fast heartbeat
• fever
• lightheadedness
• pain in the chest, groin, or legs, especially the calves
• pain, redness, or swelling in the arm or leg
• rapid, shallow breathing
• severe, sudden headache
• slurred speech
• sudden loss of coordination
• sudden, severe weakness or numbness in the arm or leg
• sudden, unexplained shortness of breath
• vision changes

• Anxiety
• blue lips and fingernails
• blue or pale skin
• blurred vision
• chest pain or discomfort
• chest pain, possibly moving to the left arm, neck, or shoulder
• convulsions
• cool, sweaty skin
• cough
• coughing that sometimes produces a pink frothy sputum
• decreased urine output
• dilated neck veins
• extreme fatigue
• hives or welts, itching, or skin rash
• hoarseness
• increased sweating
• large, hive-like swelling on the mouth, lips, or tongue
• loss of bladder control
• muscle spasm or jerking of all extremities
• nausea or vomiting
• pain or discomfort in the arms, jaw, back, or neck
• puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue
• redness of the skin
• slow or irregular breathing or heartbeat
• sudden loss of consciousness
• sweating
• swelling of the face, fingers, feet, lower legs, or ankles
• unconsciousness
• unusual tiredness or weakness
• weight gain

Applies to alteplase: injectable powder for injection, intravenous powder for injection

Hematologic

The incidence of major hemorrhagic events among heparinized patients with acute myocardial infarction who underwent cardiac catheterization in the Thrombolysis in Myocardial Infarction (TIMI) study significantly increased with age, averaging 8.7% and 24.7% for patients less than 65 years and 70 to 76 years old, respectively. These values agree with GISSI-2 data, where the overall incidence of bleeding associated with alteplase (the active ingredient contained in Cathflo Activase) with and without heparin was 8.5% (0.5% major, 8.0% minor). Concomitant administration of heparin did not increase the incidence of stroke, although the incidence of major bleeding was greater in patients who received both thrombolytic (alteplase or streptokinase) and heparin therapy.

In one large study of 139 patients with acute thrombotic or embolic stroke, the incidence of hemorrhagic infarction averaged 20.2%. Parenchymal hematoma was observed in 10.6% of patients in this study, and neurological worsening accompanied by either hemorrhagic infarction or brain parenchymal hematoma was observed in 9.6% of patients. Limited data in which 100 mg of alteplase was given to 32 patients with documented middle cerebral artery and/or intracranial internal carotid artery occlusion reveal an incidence of hemorrhagic infarction without clinical deterioration in 28%, fatal parenchymal hemorrhage in 9%, and serious puncture site hemorrhage in 6% of patients.

In general, the overall incidence of alteplase-induced symptomatic intracerebral hemorrhage (ICH) in most studies has ranged between 3% and 7%. It appears that the overall risk of symptomatic ICH with the use of IV alteplase therapy is dependent on the expertise of the treating clinician. In one report, the risk of symptomatic ICH was 4% if protocol guidelines were strictly followed, but more than 10% when deviating from protocol guidelines. Other studies have confirmed these findings. The risk of ICH appears to be higher in elderly patients treated with thrombolytics for acute MI. An alternative reperfusion strategy (i.e., angioplasty) may be considered in this patient population.[Ref]

The hematologic side effect, bleeding, is the most common adverse event in all approved indications.

The incidence of bleeding among patients with acute myocardial infarction who received alteplase (often with aspirin and heparin) ranged from 8% to 77% (0.5% to 10% serious). Blood loss of greater than 250 mL occurred in up to 5% of patients, and typically affected the gastrointestinal tract (5%) or genitourinary tract (4%). Ecchymosis, epistaxis, gingival, or retroperitoneal bleeding occurred in up to 1% of patients.

The incidence of alteplase-associated intracranial hemorrhagic (ICH) in patients with acute myocardial infarction is dose-related and has averaged about 1%. Administration of 100 mg over 3 hours resulted in an incidence of stroke of 0.4%, at 100 mg over 90 minutes the rate was 0.7%, and at 150 mg over 90 minutes the rate of ICH was 1.3%. ICH in patients with acute ischemic stroke was significantly greater in patients receiving alteplase (15.4%) compared to placebo (6.4%). Symptomatic ICH (defined as sudden clinical worsening followed by subsequent CT verification of ICH) occurred in 8% (6.4% within 36 hours of receiving alteplase).

Stroke occurred in 1.2% to 1.6% of patients experiencing an AMI and receiving alteplase as a 3 hour infusion or an accelerated infusion, respectively.

Rare cases of atheroembolic events have been associated with the use of this drug and other lytic agents.

If bleeding occurs during therapy with alteplase and cannot be controlled by pressure, it is recommended that alteplase (and heparin, if applicable) should be discontinued immediately. Arterial punctures are of particular concern and an upper extremity accessible to manual compression is preferred. The usual precautions and procedures following arterial catheterization are extremely important. It is recommended that other invasive procedures be avoided or minimized. Non-compressible venous sites should be avoided.[Ref]

Cardiovascular

Cardiovascular-related side effects may occur more frequently in patient with an acute myocardial infarction (AMI) or pulmonary embolism. These events may be a sequelae of the disease and their relationship to the drug is not always clear. Reperfusion arrhythmias, including sinus bradycardia, accelerated idioventricular rhythm, premature ventricular depolarizations, or ventricular tachycardia commonly have occurred. Alteplase has been shown to significantly reduce the incidence of in-hospital mortality, left ventricular failure, postinfarction angina, reinfarction, and all ischemic events in patients with AMI.

Alteplase-associated cases of recurrent thrombosis or reinfarction have been reported. Rarely, reinfarction may be due to embolization of partially lysed thrombi. Reformation of thrombi may be due to elevated thrombin-antithrombin-III levels during alteplase (the active ingredient contained in Cathflo Activase) therapy. Theoretically, adjunctive therapy with continuous heparin will significantly decrease the risk of an alteplase-induced hypercoagulable state.

Angioedema has also been reported (1% to 2%) during alteplase therapy in patients with acute ischemic stroke, particularly when alteplase was used in combination with an angiotensin-converting enzyme inhibitor. Orolingual angioedema has, in most cases, been mild, transient, and spontaneously reversible; however, it can be rapidly progressive requiring urgent intubation.

Recurrent hemopericardium, cardiac tamponade, massive hemorrhagic MI and death from cardiogenic shock have been associated with the use of some thrombolytic agents.

Rarely, cholesterol embolization syndrome presenting as peripheral cyanosis has been associated with alteplase therapy.[Ref]

The mortality rate among patients in the Thrombolysis in Myocardial Infarction (TIMI) study significantly increased with age, averaging 3.5% and 12% for patients less than 65 years and 70 to 76 years old, respectively. Risk factors for death were female gender, diabetes mellitus, extensive coronary artery disease, history of congestive heart failure, persistent chest pain after alteplase administration, low systolic blood pressure at presentation, and advanced age.[Ref]

Nervous system

A potentially life-threatening nervous system side effect, hemorrhagic stroke, has occurred in approximately 1% of patients with an acute myocardial infarction. Administration of 100 mg over 3 hours resulted in a 0.4% incidence of stroke, at 100 mg over 90 minutes the incidence was 0.7%, and at 150 mg over 90 minutes the rate of ICH was 1.3%. The incidence is significantly increased in patients with thrombotic stroke, with reports as high as 31% (4% to 10% experience worsening neurologic status). See "Hematologic" side effects. Rare cases of intracerebral hemorrhage associated with the use of t-PA in patients with cerebral amyloid angiopathy and cases of headache or subdural hematoma have been associated with alteplase (the active ingredient contained in Cathflo Activase)

Recurrent intracerebral embolization following alteplase has been reported in a patient with dilated cardiomyopathy. Alteplase may promote lysis and embolization of detached intracranial thrombi.

Stroke has occurred in 1.2% to 1.6% of patients experiencing an AMI and receiving alteplase as a 3 hour infusion or an accelerated infusion, respectively.

Rare cases of atheroembolic events have been associated with the use of this drug and other lytic agents.[Ref]

A retrospective meta-analysis of patients with intracranial hemorrhage (ICH) who had received alteplase (n = 88) versus no alteplase (n = 148) revealed the following independent predictors for ICH (odds ratio): age over 65 years (2.2), body weight below 70 kg (2.1), and hypertension on admission (2.0). Furthermore, the probability of ICH increased with the number of risk factors present. Other studies have corroborated these data, with some finding a higher Killip classification and the occurrence of anterior myocardial infarction as additional risk factors. These data do not account for other possible risk factors, such as extensive peripheral vascular disease, diabetes, or the use of oral anticoagulants.[Ref]

Hypersensitivity

A 69-year-old beekeeper with acute myocardial infarction developed urticaria and gross facial, tongue, and neck edema within 25 minutes following administration of glyceryl trinitrate, nifedipine, aspirin, and alteplase (the active ingredient contained in Cathflo Activase) Investigations revealed normal complement (qualitative and quantitative measurements), the absence of circulating immune complexes, normal levels of circulating IgE, and absence of t-PA antibodies by ELISA. Intradermal skin testing with each drug revealed no allergic response. This anaphylactoid reaction did not appear to be due to an antibody-antigen or direct chemical reaction. This patient had a history of atopy. The authors suggested that clinicians who administer alteplase to strongly atopic individuals consider the possibility of an anaphylactoid reaction and have resuscitative measures available.

A 51-year-old woman with systemic lupus erythematosus and deep vein thrombosis developed throat tightness, dyspnea and dysphagia within 24 hours after receiving alteplase therapy. Subconjunctival bullous edema of the left eye and angioedema of the tongue, face, neck and upper lip were also observed. Associated laboratory findings included markedly decreased C4 and C1 esterase inhibitor levels relative to baseline. The patient's angioedema resolved within six hours after discontinuation of alteplase and initiation of steroid and antihistamine therapy.

A separate report documented two cases of anaphylactic reactions following treatment of 105 consecutive patients receiving alteplase for the treatment of ischemic stroke.[Ref]

Hypersensitivity reactions have occurred in less than 0.02% of patients. A cause-and-effect relationship between anaphylaxis and alteplase has not been clearly established.[Ref]

Gastrointestinal

Gastrointestinal (GI) side effects generally have been limited to GI bleeding.[Ref]

Renal

Renal biopsy in a 76-year-old man with a history of angina, hypertension, and hypercholesterolemia who developed acute renal failure after alteplase (the active ingredient contained in Cathflo Activase) therapy for an acute myocardial infarction revealed needle-shaped cholesterol crystals in small artery intima. There was mild focal segmental mesangial cell proliferation, tubular atrophy, and interstitial fibrosis. The patient required maintenance hemodialysis.[Ref]

Rare cases of cholesterol crystal embolization syndrome-associated renal failure have occurred during alteplase therapy.[Ref]

General

Bleeding has been the most frequent side effect noted with alteplase (the active ingredient contained in Cathflo Activase) therapy. Arterial punctures are of particular concern and an upper extremity accessible to manual compression is preferred if arterial puncture is required. The usual precautions and procedures following arterial catheterization are extremely important. It is recommended that other invasive procedures be avoided or minimized. Non-compressible venous sites should be avoided.[Ref]

Hepatic

Hepatic side effects have been limited to rare (at least two cases) reports of hepatic cholesterol embolization syndrome.[Ref]

Local

Local inflammation and/or ecchymosis may occur with extravasation during alteplase (the active ingredient contained in Cathflo Activase) infusion.[Ref]

Some side effects of Cathflo Activase may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.