Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antithrombotic agents, ATC-code: B01AD02.

Mechanism of action
The active ingredient of Actilyse is alteplase, a recombinant human tissue-type plasminogen activator, a glycoprotein, which activates plasminogen directly to plasmin. When administered intravenously, alteplase remains relatively inactive in the circulatory system. Once bound to fibrin, it is activated, inducing the conversion of plasminogen to plasmin leading to the dissolution of the fibrin clot.

Pharmacodynamic effects
Due to its relative fibrin-specificity, alteplase at a dose of 100 mg leads to a modest decrease of the circulating fibrinogen levels to about 60 % at 4 hours, which is generally reverted to more than 80 % after 24 hours. Plasminogen and alpha-2-antiplasmin decrease to about 20 % and 35 % respectively after 4 hours and increase again to more than 80 % at 24 hours. A marked and prolonged decrease of the circulating fibrinogen level is only seen in few patients.

Clinical efficacy and safety
In a study including more than 40,000 patients with an acute myocardial infarction (GUSTO) the administration of 100 mg alteplase over 90 minutes, with concomitant intravenous heparin infusion, led to a lower mortality after 30 days (6.3 %) as compared to the administration of streptokinase, 1.5 million U over 60 minutes, with subcutaneous or intravenous heparin (7.3 %). Actilyse-treated patients showed higher infarct related vessel patency rates at 60 and 90 minutes after thrombolysis than the streptokinase- treated patients. No differences in patency rates were noted at 180 minutes or longer.

30-day-mortality is reduced as compared to patients not undergoing thrombolytic therapy.

The release of alpha-hydroxybutyrate-dehydrogenase (HBDH) is reduced. Global ventricular function as well as regional wall motion is less impaired as compared to patients receiving no thrombolytic therapy.
Actilyse                                                               Updated Prescribing Information  20 mg, 50 mg                                                                                  Feb 2023
Acute myocardial infarction
A placebo controlled trial with 100 mg alteplase over 3 hours (LATE) showed a reduction of 30 day- mortality compared to placebo for patients treated within 6-12 hours after symptom onset. In cases, in which clear signs of myocardial infarction are present, treatment initiated up to 24 hours after symptom onset may still be beneficial.
Acute massive pulmonary embolism
In patients with acute massive pulmonary embolism with haemodynamic instability thrombolytic treatment with Actilyse leads to a fast reduction of the thrombus size and a reduction of pulmonary artery pressure. Mortality data are not available.
Acute ischaemic stroke Patients
In two USA studies (NINDS A/B) a significant higher proportion of patients, had a favourable outcome with alteplase, compared to placebo (no or minimal disability).

These findings were confirmed in the ECASS III trial (see paragraph below), after in the meantime two European studies and an additional USA study had failed to provide the respective evidence in settings essentially not compliant with the current EU product information.
The ECASS III trial was a placebo-controlled, double-blind trial conducted in patients with acute stroke in a time-window of 3 to 4.5 hours in Europe. Treatment administration in the ECASS III study was in line with the European SmPC for Actilyse in its stroke indication, except the upper end of the time of treatment window i.e. 4.5 hours. The primary end point was disability at 90 days, dichotomized for favourable (modified Rankin scale [mRS] 0 to 1) or unfavourable (mRS 2 to 6) outcome. A total of 821 patients (418 alteplase/403 placebo) were randomized. More patients achieved favourable outcome with alteplase (52.4%) vs. placebo (45.2%; odds ratio [OR] 1.34; 95% CI 1.02 - 1.76; P=0.038). The incidence of any ICH/SICH was higher with alteplase vs. placebo (any ICH 27.0% vs 17.6%, p=0.0012; SICH by ECASS III definition 2.4% versus 0.2 %, p = 0.008). Mortality was low and not significantly different between alteplase (7.7%) and placebo (8.4%; P=0.681). Subgroup results of ECASS III confirm that a longer OTT is associated with an increasing risk for mortality and symptomatic intracranial haemorrhage. The results of ECASS III show a positive net-clinical benefit for Actilyse in the 3 to 4.5 hour time window, while pooled data demonstrate that the net-clinical benefit is no longer favourable for alteplase in the time window beyond 4.5 hours.
The safety and efficacy of Actilyse for acute ischaemic stroke treatment up to 4.5 hours time stroke onset time to start of treatment (OTT) has been assessed by an ongoing registry (SITS-ISTR: The Safe Implementation of Thrombolysis in Stroke registry). In this observational study safety outcome data of 21.566 treated patients in the 0 to 3 hour time window were compared with data from 2.376 patients treated between 3 to 4.5 hours after onset of AIS. The incidence of symptomatic intracranial haemorrhage (according to the SITS-MOST definition) was found to be higher in the 3 to 4.5 hour time window (2.2%) as compared with the up to 3 hour time window (1.7%). Mortality rates at 3 months were similar comparing the 3 to 4.5 hour time window (12.0%) with the 0 to 3.0 hours time window (12.3%) with an unadjusted OR 0.97 (95% CI: 0.84-1.13, p=0.70) and an adjusted OR 1.26 (95% CI: 1.07-1.49, p=0.005. The SITS observational data support clinical trial evidence of stroke onset time to start of treatment (OTT) as an important predictor of outcome following acute stroke treatment with alteplase.

Elderly (> 80 years)
Individual patient data adjusted meta-analyses from 6,756 patients including those aged > 80 years in nine randomised trials comparing alteplase with placebo or open control were used to assess the benefit-risk of alteplase in patients > 80 years. The probability of a good stroke outcome (mRS 0 - 1 at day 90/180) was increased and was associated with a larger benefit when treated earlier for all age groups (p-value for interaction of 0.0203) and was independent of age.

The effect of alteplase treatment was similar for patients aged 80 years or younger [mean treatment delay 4.1 hours: 990/2512 (39%) alteplase treated vs 853/2515 (34%) controls achieved good stroke outcome at day 90/180; OR 1.25, 95% CI 1.10-1.42] and for those older than 80 years [mean treatment Actilyse                                                                Updated Prescribing Information  20 mg, 50 mg                                                                                   Feb 2023 delay 3.7 hours: 155/879 (18%) alteplase treated vs 112/850 (13%) controls achieved good stroke outcome; OR 1.56, 95% CI 1.17-2.08].

In patients older than 80 years treated with alteplase less or equal to 3 hours, a good stroke outcome was achieved in 55/302 (18.2%) vs 30/264 (11.4%) in controls (OR 1.86, 95% CI 1.11-3.13) and in those treated with alteplase 3 hours-4.5 hours 58/342 (17.0%) achieved a good stroke outcome vs 50/364 (13.7%) in controls (OR 1.36, 95% CI 0.87-2.14).

Type 2 parenchymal haemorrhage within 7 days occurred in 231 (6.8%) of 3,391 patients assigned to alteplase versus 44 (1.3%) of 3,365 assigned to control (OR 5.55, 95% CI 4.01-7.70).
Fatal type 2 parenchymal haemorrhage within 7 days occurred in 91 (2.7%) patients assigned to alteplase versus 13 (0.4%) assigned to control (OR 7.14, 95% CI 3.98-12.79).

In patients older than 80 years treated by alteplase a fatal intracranial haemorrhage within 7 days occurred in 32/879 (3.6%) vs 4/850 (0.5%) in controls (OR 7.95, 95% CI 2.79-22.60).

From a total of 8,658 patients > 80 years treated < 4.5 hours of stroke onset in the SITS-ISTR, the data of the 2,157 patients treated > 3 to 4.5 hours from stroke onset were compared to those of the 6,501 patients treated < 3 hours.
Three-month functional independence (mRS score 0 - 2) was 36 vs 37% (adjusted OR 0.79, 95% CI 0.68- 0.92), mortality was 29.0% vs 29.6% (adjusted OR 1.10, 95% CI 0.95-1.28), and sICH (per SITS-MOST definition) was 2.7% vs 1.6% (adjusted OR 1.62, 95% CI 1.12-2.34).

Paediatric population
Observational non-randomised and non-comparative data on stroke patients of 16 -17 years of age with confirmed alteplase treatment was obtained from SITS-ISTR (Safe Implementation of Treatments in Stroke - International Stroke Thrombolysis Register, an independent, international registry).
Between 2003 and the end of 2017, a total of 25 paediatric patients with confirmed alteplase use within the age group of 16 – 17 years were collected in the SITS registry. The median dose of alteplase used in this age group was 0.9mg/kg (range: 0.83 - 0.99mg/kg). 23 of 25 patients initiated treatment within the 4.5h after stroke symptoms onset (19 by 3h; 4 by 3 - 4.5h; 1 by 5 – 5.5h; 1 case not reported). The weight ranged from 56 – 90 kg. Most patients presented with moderate or moderate to severe stroke with a median NIHSS of 9.0 (range 1 – 30) at baseline.
Day 90 mRS scores were available in 21/25 patients. At day 90, 14/21 patients had a mRS score of 0-1 (no symptoms or no significant disability) and 5 further patients had mRS = 2 (slight disability). This means that 19/21 (over 90%) of the patients had a favourable outcome at day 90 according to mRS.
The remaining 2 patients had either a reported outcome of moderate severe disability (mRS=4; n=1), or death (mRS=6) within 7 days (n=1).
Four patients did not have a day 90 mRS score reported. The last available information showed that 2/4 patients had a mRS of 2 at day 7 and 2/4 patients reported a clear global improvement at day 7.
Safety data on adverse events for haemorrhages and oedema were also available in the registry. Of the 25 patients from age category 16 -17 years, none had symptomatic intracerebral haemorrhage (sICH,
ICH bleeding type PH2). 5 cases developed cerebral oedema after alteplase treatment. 4/5 patients with cerebral oedema had either a reported day 90 mRS between 0 and 2 or showed a global improvement at day 7 post treatment. One patient had a mRS=4 (moderate severe disability) reported at day 90. None of the cases experienced a fatal outcome.
In summary, there were 25 reports from the SITS Register of patients between 16 and 17 years of age with acute ischaemic stroke who have been treated according to adult recommendations with alteplase.
Although the small sample size precludes a statistical analysis, the overall results show a positive trend with the respective adult dose used in these patients. The data do not appear to show an increased risk of symptomatic intracerebral haemorrhage or oedema compared to adults.
Actilyse                                                                       Updated Prescribing Information  20 mg, 50 mg                                                                                          Feb 2023

Pharmacokinetic Properties

5.2 Pharmacokinetic properties
Alteplase is cleared rapidly from the circulating blood and metabolised mainly by the liver (plasma clearance 550 - 680 ml/min.). Under physiological conditions, the major portion of alteplase in the circulation is inhibitor-bound. Hepatic clearance of alteplase is not hindered by the presence of other proteins including alteplase inhibitors. Complexes of alteplase and its inhibitor are eliminated as free alteplase. The relevant plasma half-life t1/2 alpha is 4-5 minutes. This means that after 20 minutes less than 10% of the initial value is present in the plasma. For the residual amount remaining in a deep compartment, a beta-half-life of about 40 minutes was measured.