Alteplase

(BAN, USAN, rINN)
Synonyms: Alteplaasi; Alteplas; Alteplasa; Altéplase; Alteplasum; Alteplaz; G11035; G-11044; G-11021 (2-chain form); Recombinant Tissuetype Plasminogen Activator; rt-PA.
Cyrillic synonym: Альтеплаза.

💊 Chemical information

CAS — 105857-23-6.
ATC — B01AD02; S01XA13.
ATC Vet — QB01AD02; QS01XA13.

Description.

Alteplase is a glycosylated protein of 527 residues having the amino acid sequence of human tissue plasminogen activator (t-PA) and produced by recombinant DNA technology.

Pharmacopoeias.

In US. Eur. includes Alteplase for Injection.

Ph. Eur. 6.2

(Alteplase for Injection; Alteplasum ad Iniectabile). A sterile, freeze-dried preparation of alteplase, a tissue plasminogen activator produced by recombinant DNA technology. It has a potency of not less than 500 000 units/mg of protein. It is a white or slightly yellow powder or friable mass. The reconstituted preparation has a pH of 7.1 to 7.5. Store in colourless glass containers, under vacuum or an inert gas, at a temperature between 2° and 30°. Protect from light. Alteplase consists of 527 amino acids with carbohydrate moieties attached.

USP 31

(Alteplase). A highly purified glycosylated serine protease with fibrin-binding properties and plasminogen-specific proteolytic activities. It is produced by recombinant DNA synthesis in mammalian cell culture. It has a potency of 522 000 to 667 000 USP units/mg of protein. Store in airtight containers in the frozen state at a temperature of −20° or below.

Incompatibility and stability.

Alteplase has been reported 1 to be incompatible with dobutamine, dopamine, glyceryl trinitrate, and heparin, although a subsequent study found no incompatibility between alteplase and glyceryl trinitrate. 2 Another study 3 found that dilution of a proprietary preparation of alteplase (Activase) to 0.09 and 0.16 mg/mL with glucose 5% resulted in precipitation of the drug. Alteplase is formulated with arginine as a solubilising agent, and dilution with glucose 5% to concentrations below 0.5 mg/mL of alteplase makes precipitation possible. Dilution with sodium chloride 0.9% is possible to concentrations down to 0.2 mg/mL before precipitation becomes a risk. Studies 4,5 have suggested that a 1 mg/mL solution of alteplase retains its activity when frozen at −20° or below for up to 6 months. 1. Lee CY, et al. Visual and spectrophotometric determination of compatibility of alteplase and streptokinase with other injectable drugs. Am J Hosp Pharm 1990; 47: 606–8. 2. Lam XM, et al. Stability and activity of alteplase with injectable drugs commonly used in cardiac therapy. Am J Health-Syst Pharm 1995; 52: 1904–9. 3. Frazin BS. Maximal dilution of Activase. Am J Hosp Pharm 1990; 47: 1016. 4. Calis KA, et al. Bioactivity of cryopreserved alteplase solutions. Am J Health-Syst Pharm 1999; 56: 2056–7. 5. Wiernikowski JT, et al. Stability and sterility of recombinant tissue plasminogen activator at −30°C. Lancet 2000; 355: 2221–2.

💊 Units

The activity of alteplase can be measured in terms of international units using the third International Standard for tissue plasminogen activator recombinant, human, established in 1999, although doses are generally expressed by weight.

💊 Adverse Effects, Treatment, and Precautions

As for Streptokinase. Allergic reactions are less likely with alteplase than with streptokinase and repeated use may be possible.

Hypersensitivity.

An anaphylactoid reaction to alteplase occurred in a patient with a history of atopy.1 For comment on this unexpected reaction, see Hypersensitivity under Adverse Effects of Streptokinase. (See also ACE Inhibitors under Interactions, below).
1. Purvis JA, et al. Anaphylactoid reaction after injection of alteplase. Lancet 1993; 341: 966–7.

Thrombin generation.

Alteplase produces considerable thrombin generation which may result from direct activation of the coagulation system by plasmin or by positive feedback of the coagulation system by clot-bound thrombin. This excessive thrombin generation was considered a possible cause of myocardial infarction in a patient undergoing thrombolytic therapy with alteplase for venous thrombosis.1 Streptokinase produced no evidence of excessive thrombin generation.
1. Baglin TP, et al. Thrombin generation and myocardial infarction during infusion of tissue-plasminogen activator. Lancet 1993; 341: 504–5.

💊 Interactions

ACE inhibitors.

Angioedema has been reported rarely in patients treated with alteplase, but the risk may be increased in those taking

ACE inhibitors.

A prospective study1 found that out of 176 patients treated with alteplase for acute stroke, 9 developed angioedema; the risk was strongly associated with use of an ACE inhibitor (7 of the 9).
1. Hill MD, et al. Hemi-orolingual angioedema and ACE inhibition after alteplase treatment of stroke. Neurology 2003; 60: 1525–7.

Glyceryl trinitrate.

Although thrombolytics and nitrates are both frequently used in acute myocardial infarction a report suggested that this combination may result in impaired thrombolysis. Giving alteplase and glyceryl trinitrate intravenously to 36 patients with acute myocardial infarction produced lower plasma-antigen concentrations of tissue-plasminogen activator than alteplase given alone to 11 patients.1 Reperfusion was sustained in only 44% of patients receiving both drugs compared with 91% of patients given alteplase alone. The authors of a subsequent study2 suggested that these lower plasma concentrations may be due to increased hepatic metabolism of alteplase as a result of glyceryl trinitrate’s effect of increasing hepatic blood flow.
1. Nicolini FA, et al. Concurrent nitroglycerin therapy impairs tissue-type plasminogen activator-induced thrombolysis in patients with acute myocardial infarction. Am J Cardiol 1994; 74: 662–6
2. Romeo F, et al. Concurrent nitroglycerin administration reduces the efficacy of recombinant tissue-type plasminogen activator in patients with acute anterior wall myocardial infarction. Am Heart J 1995; 130: 692–7.

💊 Pharmacokinetics

Alteplase is cleared rapidly from the plasma, mainly by metabolism in the liver. It has an initial half-life of 4 to 5 minutes and a terminal half-life of about 40 minutes.
1. Krause J. Catabolism of tissue-type plasminogen activator (tPA), its variants, mutants and hybrids. Fibrinolysis 1988; 2: 133–42.

💊 Uses and Administration

Alteplase is a thrombolytic drug. It is a mainly singlechain form of the endogenous enzyme tissue plasminogen activator and is produced by recombinant DNA technology. Like endogenous tissue plasminogen activator, alteplase converts fibrin-bound plasminogen to the active form plasmin, resulting in fibrinolysis and dissolution of clots. Alteplase has relatively little effect on circulating, unbound plasminogen and thus may be termed a fibrin-specific thrombolytic. Alteplase is used similarly to streptokinase in the treatment of thromboembolic disorders, particularly myocardial infarction and venous thromboembolism, and to clear occluded catheters (see below). Alteplase may also be used in patients with acute ischaemic stroke. In the treatment of acute myocardial infarction, alteplase is given intravenously as soon as possible after the onset of symptoms in a total dose of 100 mg; the total dose should not exceed 1.5 mg/kg in patients weighing less than 65 kg. The total dose may be given either over 1 1 ⁄ 2 hours (accelerated or ‘front-loaded’ al teplase) or over 3 hours. The accelerated schedule has been recommended if given within 6 hours of myocardial infarction, while the 3-hour schedule has been recommended when used more than 6 hours after myocardial infarction. The schedule over 1 1 ⁄ 2 hours is as follows: 15 mg as an intravenous bolus, then 0.75 mg/kg, up to a maximum of 50 mg, by intravenous infusion over 30 minutes, followed by the remainder infused over the subsequent 60 minutes. The schedule over 3 hours is as follows: 10 mg as an intravenous bolus, then 50 mg by intravenous infusion over 1 hour, followed by the remainder infused over the subsequent 2 hours. In the treatment of acute, massive pulmonary embolism a total dose of 100 mg is given; the total dose should not exceed 1.5 mg/kg in patients weighing less than 65 kg. The first 10 mg is given as an intravenous bolus and the remainder by intravenous infusion over 2 hours. In acute ischaemic stroke, alteplase is given within 3 hours of the onset of symptoms in a dose of 0.9 mg/kg up to a maximum total dose of 90 mg. The dose is given intravenously over 60 minutes with 10% of it as a bolus during the first minute. To restore function in central venous lines, alteplase is instilled into the catheter at a concentration of 1 mg/mL. The usual dose is 2 mg, repeated after 2 hours if necessary. A total dose of 4 mg should not be exceeded. For patients weighing less than 30 kg, the dose is 110% of the internal lumen volume of the catheter, but should not exceed 2 mg, and may be repeated after 2 hours if necessary.
1. Gillis JC, et al. Alteplase: a reappraisal of its pharmacological properties and therapeutic use in acute myocardial infarction. Drugs 1995; 50: 102–36
2. Wagstaff AJ, et al. Alteplase: a reappraisal of its pharmacology and therapeutic use in vascular disorders other than acute myocardial infarction. Drugs 1995; 50: 289–316
3. Semba CP, et al. Society of Cardiovascular and Interventional Radiology (SCVIR). Alteplase and tenecteplase: applications in the peripheral circulation. Tech Vasc Interv Radiol 2001; 4: 99–106
4. Lindley RI, et al. Alteplase and ischaemic stroke: have new reviews of old data helped? Lancet Neurol 2005; 4: 249–53
5. De Keyser J, et al. Intravenous alteplase for stroke: beyond the guidelines and in particular clinical situations. Stroke 2007; 38: 2612–8
6. Quinn TJ, et al. Past, present and future of alteplase for acute ischemic stroke. Expert Rev Neurother 2008; 8: 181–92.

Arterial and venous thromboembolism.

For the use of alteplase for arterial or venous thromboembolism in children, see Administration in Children under Streptokinase.

Catheters and cannulas.

Alteplase has been used successfully to clear thrombi in central venous catheters.1,2 Typical doses have been 2 mg injected as a bolus into the blocked catheter. Children have been treated similarly; in one study3 where patients’ weight started from 3 kg, doses ranged from 0.1 to 2.0 mg (as a 1 mg/mL solution), depending on the size of the catheter. Similarly, a later study using a 1 mg/mL solution gave doses of 2 mg to children weighing 30 kg or more, and a volume equal to 110% of the calculated internal volume of the catheter (rounded to the nearest 0.1 mL and not to exceed 2 mL in total) in children weighing less than 30 kg.4 The dwell time was up to 2 hours, and doses were repeated once in patients in whom catheter function was not restored after this period. A cohort study5 used doses of 0.5 mg for children weighing 10 kg or under, and 1 to 2 mg above this weight, with a dwell time of 2 to 4 hours. In another report, 2 children6 were successfully treated with intravenous alteplase in doses of 0.01 to 0.05 mg/kg per hour for venous thrombosis associated with indwelling intravascular catheters. Alteplase has also been instilled into central haemodialysis lines to preserve patency between dialysis sessions.7 Urokinase has been used similarly in children with long-term venous access devices for antineoplastic therapy.8 For reports covering the use of alteplase to treat intracardiac thrombosis resulting from the placement of central venous lines, see Intracardiac Thrombosis, below.
1. Paulsen D, et al. Use of tissue plasminogen activator for reopening of clotted dialysis catheters. Nephron 1993; 64: 468–9
2. Haire WD, et al. Urokinase versus recombinant tissue plasminogen activator in thrombosed central venous catheters: a doubleblinded, randomized trial. Thromb Haemost 1994; 72: 543–7
3. Jacobs BR, et al. Recombinant tissue plasminogen activator in the treatment of central venous catheter occlusion in children. J Pediatr 2001; 139: 593–6
4. Blaney M, et al. CAPS Investigators. Alteplase for the treatment of central venous catheter occlusion in children: results of a prospective, open-label, single-arm study (The Cathflo Activase Pediatric Study). J Vasc Interv Radiol 2006; 17: 1745–51
5. Choi M, et al. The use of alteplase to restore patency of central venous lines in pediatric patients: a cohort study. J Pediatr 2001; 139: 152–6
6. Doyle E, et al. Thrombolysis with low dose tissue plasminogen activator. Arch Dis Child 1992; 67: 1483–4
7. Gittins NS, et al. Comparison of alteplase and heparin in maintaining the patency of paediatric central venous haemodialysis lines: a randomised controlled trial. Arch Dis Child 2007; 92: 499–501
8. Dillon PW, et al. Prophylactic urokinase in the management of long-term venous access devices in children: a Children’s Oncology Group study. J Clin Oncol 2004; 22: 2718–23.

Intracardiac thrombosis.

Alteplase has been used, in a dose of 100 mg given intravenously over 2 hours, for thrombosis of prosthetic heart valves.1 Alteplase has been used successfully in a neonate to treat intracardiac thrombosis associated with the use of a central venous line.2 A dose of 500 micrograms/kg given over 10 minutes was followed by infusion of 200 micrograms/kg per hour for 3 days. In another report,3 4 preterm infants were treated successfully. All received 400 to 500 micrograms/kg of alteplase in a 20 to 30 minute bolus. This was followed in one case by a 3-hour infusion at 100 micrograms/kg per hour. Although thrombolytics are usually contra-indicated in patients with infective endocarditis, alteplase has been used successfully in children with indwelling catheters who developed infective endocarditis; coagulation was monitored and fresh frozen plasma was given to maintain fibrinogen concentrations.4
1. Astengo D, et al. Recombinant tissue plasminogen activator for prosthetic mitral-valve thrombosis. N Engl J Med 1995; 333: 259
2. Van Overmeire B, et al. Intracardiac thrombus formation with rapidly progressive heart failure in the neonate: treatment with tissue type plasminogen activator. Arch Dis Child 1992; 67: 443–5
3. Ferrari F, et al. Early intracardiac thrombosis in preterm infants and thrombolysis with recombinant tissue type plasminogen activator. Arch Dis Child Fetal Neonatal Ed 2001; 85: F66–F69
4. Levitas A, et al. Successful treatment of infective endocarditis with recombinant tissue plasminogen activator. J Pediatr 2003; 143: 649–52.

Microvessel thrombosis.

Alteplase has been used in conditions where the underlying pathology is occlusion of small blood vessels by microthrombi. Purpura and loss of circulation in the hands of a patient recovering from fulminant meningococcaemia1 responded to intra-arterial infusion of alteplase 20 to 40 micrograms/kg per hour for 22 hours in the right hand, and 20 micrograms/kg per hour for 11 hours in the left. Perfusion was successfully restored to both hands, and full function subsequently attained in them. Improvement was also achieved when alteplase was given to 2 infants with septic shock and purpura fulminans caused by meningococcal infection.2 Six patients3 with ulcers caused by livedoid vasculitis and refractory to conventional treatment were treated with alteplase 10 mg infused intravenously over 4 hours daily for 14 days. Most ulcers healed rapidly; one patient required re-treatment with concomitant anticoagulation. Healing of ulcers associated with calciphylaxis has also been reported4 with a similar alteplase regimen. A 4-year-old girl5 with haemolytic-uraemic syndrome responded to treatment with an intravenous infusion of alteplase 200 micrograms/kg per hour for 5 hours, subsequently reduced to 50 micrograms/kg per hour for 14 days. Alteplase use has been reviewed6 and mixed results found, in patients with veno-occlusive disease of the liver, a serious complication of bone marrow transplantation that may be caused by diffuse thrombi in the hepatic venules. Although results in patients with established veno-occlusive disease have been disappointing,7 one study8 suggested that alteplase given early in the course of the disease improves response rate.
1. Keeley SR, et al. Tissue plasminogen activator for gangrene in fulminant meningococcaemia. Lancet 1991; 337: 1359
2. Zenz W, et al. Recombinant tissue plasminogen activator treatment in two infants with fulminant meningococcemia. Pediatrics 1995; 96: 44–8
3. Klein KL, Pittelkow MR. Tissue plasminogen activator for treatment of livedoid vasculitis. Mayo Clin Proc 1992; 67: 923–33
4. Sewell LD, et al. Low-dose tissue plasminogen activator for calciphylaxis. Arch Dermatol 2004; 140: 1045–8
5. Kruez W, et al. Successful treatment of haemolytic uraemic syndrome with recombinant tissue-type plasminogen activator. Lancet 1993; 341: 1665–6
6. Terra SG, et al. A review of tissue plasminogen activator in the treatment of veno-occlusive liver disease after bone marrow transplantation. Pharmacotherapy 1997; 17: 929–37
7. Bearman SI, et al. Treatment of hepatic venocclusive disease with recombinant human tissue plasminogen activator and heparin in 42 marrow transplant patients. Blood 1997; 89: 1501–6
8. Schriber J, et al. Tissue plasminogen activator (tPA) as therapy for hepatotoxicity following bone marrow transplantation. Bone Marrow Transplant 1999; 24: 1311–14.

Ocular disorders.

Intra-ocular alteplase has been used to treat postoperative fibrinous deposits that can form after procedures such as surgery for cataracts1 or glaucoma,2 including cataracts in children.3 Doses ranging from 6 to 25 micrograms have been used. Intra-ocular bleeding has occurred as a complication of such use.2,4 Alteplase has also been used prophylactically in children undergoing surgery for congenital cataracts.5 Intra-ocular alteplase has also been used for treatment of subhyaloid haemorrhage,6,7 including that seen in shaken baby syndrome.8 Successful treatment of subretinal macular haemorrhage with alteplase injected directly into the subretinal area around the clot has also been reported.9
1. Heiligenhaus A, et al. Recombinant tissue plasminogen activator in cases with fibrin formation after cataract surgery: a prospective randomised multicentre study. Br J Ophthalmol 1998; 82: 810–15
2. Lundy DC, et al. Intracameral tissue plasminogen activator after glaucoma surgery: indications, effectiveness, and complications. Ophthalmology 1996; 103: 274–82
3. Mehta JS, Adams GGW. Recombinant tissue plasminogen activator following paediatric cataract surgery. Br J Ophthalmol 2000; 84: 983–6
4. Azuara-Blanco A, Wilson RP. Intraocular and extraocular bleeding after intracameral injection of tissue plasminogen activator. Br J Ophthalmol 1998; 82: 1345–6
5. Siatiri H, et al. Intracameral tissue plasminogen activator to prevent severe fibrinous effusion after congenital cataract surgery. Br J Ophthalmol 2005; 89: 1458–61
6. Schmitz K, et al. Therapy of subhyaloidal haemorrhage by intravitreal application of rtPA and SF gas. Br J Ophthalmol 2000; 84: 1324–5
7. Koh HJ, et al. Treatment of subhyaloid haemorrhage with intravitreal tissue plasminogen activator and C F gas injection. Br J Ophthalmol 2000; 84: 1329–30
8. Conway MD, et al. Intravitreal tPA and SF promote clearing of premacular subhyaloid hemorrhages in shaken and battered baby syndrome. Ophthalmic Surg Lasers 1999; 30: 435–41
9. Singh RP, et al. Management of subretinal macular haemorrhage by direct administration of tissue plasminogen activator. Br J Ophthalmol 2006; 90: 429–31.

Peripheral arterial thromboembolism.

Thrombolytics, including alteplase, may be used in the management of peripheral arterial thromboembolism. Alteplase has been injected intravenously or intra-arterially directly into the clot as an alternative to surgical treatment of the occlusion. It has also been infused intra-arterially to remove distal clots during a surgical procedure. Alteplase is claimed to produce more rapid thrombolysis than streptokinase although studies have been too small to provide evidence of reduced limb loss or mortality.1 The most common dose range is 0.5 to 1 mg/hour given intra-arterially.1-3 An intravenous dose of 500 micrograms/kg per hour for the first hour followed by 250 micrograms/kg per hour until clot lysis occurred has been used in infants.4 Treatment of arterial thrombosis in neonates has been reported, using doses of alteplase ranging from 100 to 500 micrograms/kg per hour intravenously.5,6 The BNFC recommends a dose for any intravascular thrombosis in neonates and children of 100 to 500 micrograms/kg per hour by intravenous infusion over 3 to 6 hours; a second dose may be given if needed. The maximum daily dose should not exceed 100 mg. However, a retrospective study7 of 80 infants and children with arterial or venous thrombi found that although treatment with alteplase may be effective, it is associated with a low safety margin and an unknown risk-benefit ratio. Where a thrombolytic is used to remove distal clots during a surgical procedure alteplase has been given intra-arterially as three doses of 5 mg at 10-minute intervals.8
1. Wolfe JH. Critical limb ischaemia. Prescribers’ J 1994; 34: 50–8
2. Anonymous. Non-coronary thrombolysis. Lancet 1990; 335: 691–3
3. Ward AS, et al. Peripheral thrombolysis with tissue plasminogen activator: results of two treatment regimens. Arch Surg 1994; 129: 861–5
4. Zenz W, et al. Tissue plasminogen activator (alteplase) treatment for femoral artery thrombosis after cardiac catheterisation in infants and children. Br Heart J 1993; 70: 382–5
5. Weiner GM, et al. Successful treatment of neonatal arterial thromboses with recombinant tissue plasminogen activator. J Pediatr 1998; 133: 133–6
6. Farnoux C, et al. Recombinant tissue-type plasminogen activator therapy of thrombosis in 16 neonates. J Pediatr 1998; 133: 137–40
7. Gupta AA, et al. Safety and outcomes of thrombolysis with tissue plasminogen activator for treatment of intravascular thrombosis in children. J Pediatr 2001; 139: 682–8
8. Chester JF, et al. Peroperative t-PA thrombolysis. Lancet 1991; 337: 861–2.

💊 Preparations

USP 31: Alteplase for Injection.

Proprietary Preparations

Arg.: Actilyse; Austral.: Actilyse; Austria: Actilyse; Belg.: Actilyse; Braz.: Actilyse; Canad.: Activase; Cathflo; Chile: Actilyse; Cz.: Actilyse; Denm.: Actilyse; Fin.: Actilyse; Fr.: Actilyse; Ger.: Actilyse; Gr.: Actilyse; Hong Kong: Actilyse; Hung.: Actilyse; India: Actilyse; Indon.: Actilyse; Irl.: Actilyse; Israel: Actilyse; Ital.: Actilyse; Jpn: Activacin; Malaysia: Actilyse; Mex.: Actilyse; Neth.: Actilyse; Norw.: Actilyse; NZ: Actilyse; Philipp.: Actilyse; Pol.: Actilyse; Port.: Actilyse; Rus.: Actilyse (Актилизе); S.Afr.: Actilyse; Singapore: Actilyse; Spain: Actilyse; Swed.: Actilyse; Switz.: Actilyse; Thai.: Actilyse; Turk.: Actilyse; UK: Actilyse; USA: Activase; Venez.: Actilyse.
Published November 07, 2018.