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קבזרה 200 מ"ג KEVZARA 200 MG (SARILUMAB)
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תת-עורי : S.C
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תמיסה להזרקה : SOLUTION FOR INJECTION
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מינוניםPosology התוויות
Indications תופעות לוואי
Adverse reactions התוויות נגד
Contraindications אינטראקציות
Interactions מינון יתר
Overdose הריון/הנקה
Pregnancy & Lactation אוכלוסיות מיוחדות
Special populations תכונות פרמקולוגיות
Pharmacological properties מידע רוקחי
Pharmaceutical particulars אזהרת שימוש
Special Warning עלון לרופא
Physicians Leaflet
Pharmacological properties : תכונות פרמקולוגיות
Pharmacodynamic Properties
5.1 Pharmacodynamic properties Pharmacotherapeutic group: Immunosupressants, Interleukin inhibitors, ATC code: L04AC14 Mechanism of action Sarilumab is a human monoclonal antibody (IgG1 subtype) that specifically binds to both soluble and membrane-bound IL-6 receptors (IL-6R), and inhibits IL-6-mediated signalling which involves ubiquitous signal-transducing glycoprotein 130 (gp130) and the Signal Transducer and Activator of Transcription-3 (STAT-3). In functional human cell-based assays, sarilumab was able to block the IL-6 signalling pathway, measured as STAT-3 inhibition, only in the presence of IL-6. IL-6 is a pleiotropic cytokine that stimulates diverse cellular responses such as proliferation, differentiation, survival, and apoptosis and can activate hepatocytes to release acute-phase proteins, including C-reactive protein (CRP) and serum amyloid A. Elevated levels of IL-6 are found in the synovial fluid of patients with rheumatoid arthritis and play an important role in both the pathologic inflammation and joint destruction which are hallmarks of RA. IL-6 is involved in diverse physiological processes such as migration and activation of T-cells, B-cells, monocytes, and osteoclasts leading to systemic inflammation, synovial inflammation, and bone erosion in patients with RA. The activity of sarilumab in reducing inflammation is associated with laboratory changes such as decrease in ANC and elevation in lipids (see section 4.4). Pharmacodynamic effects Following single-dose subcutaneous (SC) administration of sarilumab 200 mg and 150 mg in patients with RA rapid reduction of CRP levels was observed. Levels were reduced to normal as early as 4 days after treatment initiation. Following single-dose sarilumab administration, in patients with RA, ANC decreased to the nadir between 3 to 4 days and thereafter recovered towards baseline (see section 4.4). Treatment with sarilumab resulted in decreases in fibrinogen and serum amyloid A, and increases in haemoglobin and serum albumin. Rheumatoid Arthritis Clinical efficacy The efficacy and safety of sarilumab were assessed in three randomised, double-blind, controlled multicentre studies (MOBILITY and TARGET were placebo-controlled studies and MONARCH was an active comparator-controlled study) in patients older than 18 years with moderately to severely active rheumatoid arthritis diagnosed according to American College of Rheumatology (ACR) criteria. Patients had at least 8 tender and 6 swollen joints at baseline. Placebo-controlled studies MOBILITY evaluated 1197 patients with RA who had inadequate clinical response to MTX. Patients received sarilumab 200 mg, sarilumab 150 mg, or placebo every 2 weeks with concomitant MTX. The primary endpoints were the proportion of patients who achieved an ACR20 response at week 24, changes from baseline in Health Assessment Questionnaire – Disability Index (HAQ-DI) score at week 16, and change from baseline in van der Heijde-modified Total Sharp Score (mTSS) at week 52. TARGET evaluated 546 patients with RA who had an inadequate clinical response or were intolerant to one or more TNF-α antagonists. Patients received sarilumab 200 mg, sarilumab150 mg, or placebo every 2 weeks with concomitant conventional DMARDs (cDMARDs). The primary endpoints were the proportion of patients who achieved an ACR20 response at week 24 and the changes from baseline HAQ-DI score at week 12. Clinical response The percentages of sarilumab+ DMARDs-treated patients achieving ACR20, ACR50, and ACR70 responses in MOBILITY and TARGET are shown in Table 4. In both studies, patients treated with either 200 mg or 150 mg of sarilumab+ DMARDs every two weeks had higher ACR20, ACR50, and ACR70 response rates versus placebo-treated patients at week 24. These responses persisted through 3 years of therapy in an open-label extension study. In MOBILITY, a greater proportion of patients treated with sarilumab 200 mg or 150 mg every two weeks plus MTX achieved remission, defined as Disease Activity Score 28-C-Reactive Protein (DAS28-CRP) < 2.6 compared with placebo + MTX at week 52. Results at 24 weeks in TARGET were similar to the results at 52 weeks in MOBILITY (see Table 4). Table 4: Clinical response at weeks 12, 24, and 52 in placebo-controlled studies, MOBILITY and TARGET Percentage of patients MOBILITY TARGET MTX inadequate responders TNF inhibitor inadequate responders Placebo Sariluma Sarilumab Placebo Sarilumab Sarilumab + MTX b 150 mg 200 mg + cDMA 150 mg 200 mg N = 398 + MTX + MTX RDs* + cDMARD + cDMARD N = 400 N = 399 N = 181 s* s* N = 181 N = 184 Week 12 DAS28-CRP ††† ††† ††† ††† remission (< 2.6) 4.8% 18.0% 23.1% 3.9% 17.1% 17.9% ††† ††† † ††† ACR20 34.7% 54.0% 64.9% 37.6% 54.1% 62.5% ††† ††† ††† ††† ACR50 12.3% 26.5% 36.3% 13.3% 30.4% 33.2% †† ††† ††† ††† ACR70 4.0% 11.0% 17.5% 2.2% 13.8% 14.7% Week 24 DAS28-CRP ††† ††† ††† ††† remission (< 2.6) 10.1% 27.8% 34.1% 7.2% 24.9% 28.8% ††† ††† ††† ††† ACR20‡ 33.4% 58.0% 66.4% 33.7% 55.8% 60.9% ††† ††† ††† ††† ACR50 16.6% 37.0% 45.6% 18.2% 37.0% 40.8% ††† ††† †† † ACR70 7.3% 19.8% 24.8% 7.2% 19.9% 16.3% Week 52 DAS28-CRP ††† ††† remission (< 2.6) 8.5% 31.0% 34.1% NA§ NA§ NA§ ††† ††† ACR20 31.7% 53.5% 58.6% ††† ††† ACR50 18.1% 40.0% 42.9% ACR70 9.0% 24.8% 26.8% Major clinical ††† ††† response¶ 3.0% 12.8% 14.8% * cDMARDs in TARGET included MTX, sulfasalazine, leflunomide and hydroxychloroquine † p-value <0.01 for difference from placebo †† p-value <0.001 for difference from placebo ††† p-value <0.0001 for difference from placebo ‡ Primary endpoint § NA=Not Applicable as TARGET was a 24-week study ¶ Major clinical response = ACR70 for at least 24 consecutive weeks during the 52-week period In both MOBILITY and TARGET, higher ACR20 response rates were observed within 2 weeks compared to placebo and were maintained for the duration of the studies (see Figures 1 and 2). Figure 1: Percent of ACR20 response by visit for MOBILITY Figure 2: Percent of ACR20 response by visit for TARGET The results of the components of the ACR response criteria at week 24 for MOBILITY and TARGET are shown in Table 5. Results at 52 weeks in MOBILITY were similar to the results at 24 weeks for TARGET. Table 5: Mean reductions from baseline to week 24 in components of ACR score MOBILITY TARGET Placebo Sarilumab Sarilumab Placebo Sarilumab Sarilumab + MTX 150 mg 200 mg + 150 mg q2w* 200 mg q2w* Component (N = q2w* + q2w* + cDMARDs + cDMARDs + cDMARDs (range) 398) MTX MTX (N = 181) (N = 181) (N = 184) (N = 400) (N = 399) Tender Joints -14.38 -19.25††† -19.00††† -17.18 -17.30† -20.58††† (0-68) Swollen Joints -8.70 -11.84††† -12.43††† -12.12 -13.04†† -14.03††† (0-66) Pain VAS† -19.43 -30.75††† -34.35††† -27.65 -36.28†† -39.60††† (0-100 mm) Physician global VAS‡ -32.04 -40.69††† -42.65††† -39.44 -45.09††† -48.08††† (0-100 mm) Patient global VAS‡ (0-100 -19.55 -30.41††† -35.07††† -28.06 -33.88†† -37.36††† mm) HAQ-DI (0-3) -0.43 -0.62††† -0.64††† -0.52 -0.60† -0.69†† CRP -0.14 -13.63††† -18.04††† -5.21 -13.11††† -29.06††† * q2w = every 2 weeks ‡ Visual analogue scale †p-value <0.01 for difference from placebo ††p-value <0.001 for difference from placebo †††p-value <0.0001 for difference from placebo Radiographic response In MOBILITY, structural joint damage was assessed radiographically and expressed as change in van der Heijde-modified Total Sharp Score (mTSS) and its components, the erosion score, and joint space narrowing score at week 52. Radiographs of hands and feet were obtained at baseline, 24 weeks, and 52 weeks and scored independently by at least two well-trained readers who were blinded to treatment group and visit number. Both doses of sarilumab+ MTX were superior to placebo + MTX in the change from baseline in mTSS at 24 and 52 weeks (see Table 6). Less progression of both erosion and joint space narrowing scores at 24 and 52 weeks was reported in the sarilumab treatment groups compared to the placebo group. Treatment with sarilumab+ MTX was associated with significantly less radiographic progression of structural damage as compared with placebo. At week 52, 55.6% of patients receiving sarilumab 200 mg and 47.8% of patients receiving sarilumab 150 mg had no progression of structural damage (as defined by a change in the TSS of zero or less) compared with 38.7% of patients receiving placebo. Treatment with sarilumab 200 mg and 150 mg + MTX inhibited the progression of structural damage by 91% and 68%, respectively, compared to placebo + MTX at week 52. The efficacy of sarilumab with concomitant DMARDs on inhibition of radiographic progression that was assessed as part of the primary endpoints at week 52 in MOBILITY was sustained up to three years from the start of treatment. Table 6: Mean radiographic change from baseline at week 24 and week 52 in MOBILITY MOBILITY MTX Inadequate responders Placebo Sarilumab Sarilumab + MTX 150 mg q2w* 200 mg q2w* (N = 398) + MTX + MTX (N = 400) (N = 399) Mean change at week 24 Modified Total Sharp Score (mTSS) 1.22 0.54† 0.13†† Erosion score (0-280) 0.68 0.26† 0.02†† Joint space narrowing score 0.54 0.28 0.12† Mean change at week 52 Modified Total Sharp Score (mTSS) ‡ 2.78 0.90†† 0.25†† Erosion score (0-280) 1.46 0.42†† 0.05†† Joint space narrowing score 1.32 0.47† 0.20†† * q2w=every two weeks † p-value <0.001 †† p-value <0.0001 ‡ Primary end point Physical function response In MOBILITY and TARGET, physical function and disability were assessed by the Health Assessment Questionnaire Disability Index (HAQ-DI). Patients receiving sarilumab 200 mg or 150 mg + DMARDs every two weeks demonstrated greater improvement from baseline in physical function compared to placebo at week 16 and week 12 in MOBILITY and TARGET, respectively. MOBILITY demonstrated significant improvement in physical function, as measured by the HAQ-DI at week 16 compared to placebo (-0.58, -0.54, and -0.30 for sarilumab 200 mg + MTX, sarilumab 150 mg + MTX, and placebo + MTX, every two weeks, respectively). TARGET demonstrated significant improvement in HAQ-DI scores at week 12 compared to placebo (-0.49, -0.50, and -0.29 for sarilumab 200 mg + DMARDs, sarilumab 150 mg + DMARDs, and placebo + DMARDs, every two weeks, respectively). In MOBILITY, the improvement in physical functioning as measured by HAQ-DI was maintained up to week 52 (-0.75, -0.71, and -0.46 for sarilumab 200 mg + MTX, sarilumab 150 mg + MTX, and placebo + MTX treatment groups, respectively). Patients treated with sarilumab+ MTX (47.6% in the 200 mg treatment group and 47.0% in the 150 mg treatment group) achieved a clinically relevant improvement in HAQ-DI (change from baseline of ≥0.3 units) at week 52 compared to 26.1% in the placebo + MTX treatment group. Patient reported outcomes General health status was assessed by the Short Form health survey (SF-36). In MOBILITY and TARGET, patients receiving sarilumab 200 mg + DMARDs every two weeks or sarilumab 150 mg + DMARDs every two weeks demonstrated greater improvement from baseline compared to placebo + DMARDs in physical component summary (PCS) and no worsening on the mental component summary (MCS) at week 24. Patients receiving sarilumab 200 mg + DMARDs reported greater improvement relative to placebo in the domains of Physical Functioning, Role Physical, Bodily Pain, General Health Perception, Vitality, Social Functioning, and Mental Health. Fatigue was assessed by the FACIT-Fatigue scale. In MOBILITY and TARGET, patients receiving sarilumab 200 mg + DMARDs every two weeks or sarilumab 150 mg + DMARDs every two weeks demonstrated greater improvement from baseline compared to placebo + DMARDs. Active Comparator-controlled Study MONARCH was a 24 –week randomised double-blind, double-dummy study that compared sarilumab 200 mg monotherapy with adalimumab 40 mg monotherapy administered subcutaneously every two weeks in 369 patients with moderately to severely active RA who were inappropriate for treatment with MTX including those who were intolerant of or inadequate responders to MTX. Sarilumab mg was superior to adalimumab 40 mg in reducing disease activity and improving physical function, with more patients achieving clinical remission over 24 weeks (see Table 7). Table 7: Efficacy results for MONARCH Adalimumab Sarilumab 40 mg q2w* 200 mg q2w (N=185) (N=184) DAS28-ESR (primary endpoint) -2.20 (0.106) -3.28 (0.105) p-value versus adalimumab < 0.0001 DAS28-ESR remission (< 2.6), n (%) 13 (7.0%) 49 (26.6%) p-value versus adalimumab < 0.0001 ACR20 response, n (%) 108 (58.4%) 132 (71.7%) p-value versus adalimumab 0.0074 ACR50 response, n (%) 55 (29.7%) 84 (45.7%) p-value versus adalimumab 0.0017 ACR70 response, n (%) 22 (11.9%) 43 (23.4%) p-value versus adalimumab 0.0036 HAQ-DI -0.43(0.045) -0.61(0.045) p-value versus adalimumab 0.0037 *Includes patients who increased the frequency of dosing of adalimumab 40 mg to every week because of an inadequate response Polymyalgia Rheumatica The efficacy and safety of KEVZARA in PMR were assessed in a randomized, double-blind, placebo- controlled, 52-week, multicenter study (SAPHYR) (NCT03600818) in adults with PMR diagnosed according to American College of Rheumatology/European Union League against Rheumatism (ACR/EULAR) classification criteria. Patients had at least one episode of unequivocal PMR flare while attempting to taper corticosteroids. In SAPHYR, patients with active PMR were randomized to receive KEVZARA 200 mg every two weeks with a pre-defined 14-week taper of prednisone (n= 60) or placebo every two weeks with a pre- defined 52-week taper of prednisone (n=58). One participant was randomized but not treated in the KEVZARA 200 mg arm. Patients experiencing a disease flare or unable to adhere to the assigned prednisone tapering schedule could receive corticosteroids as rescue therapy. The primary endpoint was the proportion of patients with sustained remission at Week 52. Sustained remission was defined as achievement of disease remission no later than Week 12, absence of disease flare from Week 12 through Week 52, sustained reduction of CRP (to <10 mg/L) from Week 12 through Week 52, and successful adherence to prednisone taper from Week 12 through Week 52. An additional endpoint was total cumulative corticosteroid dose over 52 weeks. Clinical Response The proportion of participants achieving sustained remission at Week 52 was higher in the KEVZARA arm compared to the placebo arm; this difference was statistically significant. At 52 weeks, a higher proportion of patients in the KEVZARA arm achieved each component of the sustained remission endpoint compared to the placebo An analysis was conducted that removed all acute phase reactants (CRP and ESR) criteria from the definition of the sustained remission, given sarilumab’s direct impact on acute phase reactants. The results of this analysis were consistent with the primary analysis (see Table 8). Table 8 Clinical Response in Placebo-Controlled SAPHYR in Adults with Active PMR Placebo KEVZARA (N=58) (N=60) Sustained remission at Week 52 Number of patients with sustained remission, n 6 (10.3) 17 (28.3) (%) Proportion difference (95% CI) vs. placebo 18.0 (4.2, 31.8; p=0.0193) Components of sustained remission at Week 52 Absence of signs and symptoms and CRP < 10 22 (37.9) 28 (46.7) mg/L (disease remission*) no later than Week 12, n (%) Absence of disease flare‡ from Week 12 19 (32.8) 33 (55.0) through Week 52, n (%) Sustained reduction of CRP (<10 mg/L) from 26 (44.8) 40 (66.7) Week 12 through Week 52, n (%) Successful adherence to prednisone taper from 14 (24.1) 30 (50.0) Week 12 through Week 52, n (%) Sensitivity analysis removing acute phase reactants (CRP and ESR) from sustained remission at Week 52 Number of patients with sustained remission, n 8 (13.8) 19 (31.7) (%) Proportion difference (95% CI) for sarilumab 17.9 (3.1, 32.6) vs. placebo *Disease remission is defined as the resolution of signs and symptoms of PMR, and normalization of CRP (<10 mg/L). ‡Flare is defined as recurrence of signs and symptoms attributable to active PMR requiring an increase in corticosteroid dose, or elevation of ESR attributable to active PMR plus an increase in corticosteroid dose. Effect on Concomitant Corticosteroid Use The total actual cumulative corticosteroid dose included all corticosteroids taken during the study (i.e., prednisone taper regimen per protocol, add-on prednisone prior to Week 12, corticosteroid use due to rescue, or corticosteroid use during the treatment period to manage an adverse reaction not related to PMR). The total actual cumulative prednisone equivalent corticosteroid dose was lower in the KEVZARA arm (mean [SD] 1039.5 [612.2] mg and median 777 mg) relative to the placebo arm (mean [SD] 2235.8 [839.4] mg and median 2044 mg).
Pharmacokinetic Properties
5.2 Pharmacokinetic properties Rheumatoid Arthritis The pharmacokinetics of sarilumab were characterised in 2186 patients with RA treated with sarilumab which included 751 patients treated with 150 mg and 891 patients treated with 200 mg subcutaneous doses every two weeks for up to 52 weeks. Absorption The absolute bioavailability for sarilumab after SC injection was estimated to be 80% by population PK analysis. The median tmax after a single subcutaneous dose was observed in 2 to 4 days. After multiple dosing of 150 to 200 mg every two weeks, steady state was reached in 12 to 16 weeks with a 2- to 3-fold accumulation compared to single dose exposure. For the 150 mg every two weeks dose regimen, the estimated mean (± standard deviation, SD) steady- state area under curve (AUC), Cmin, and Cmax of sarilumab were 210 ± 115 mg.day/L, 6.95 ± 7.60 mg/L, and 20.4 ± 8.27 mg/L, respectively. For the 200 mg every two weeks dose regimen, the estimated mean (± SD) steady-state AUC, Cmin and Cmax of sarilumab were 396 ± 194 mg.day/L, 16.7 ± 13.5 mg/L, and 35.4 ± 13.9 mg/L, respectively. In a usability study sarilumab exposure after 200 mg Q2W was slightly higher (Cmax + 24-34%, AUC(0-2w) +7-21%) after use of a pre-filled pen compared to the pre-filled syringe. Distribution In patients with RA, the apparent volume of distribution at steady state was 8.3 L. Biotransformation The metabolic pathway of sarilumab has not been characterised. As a monoclonal antibody sarilumab is expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgG. Elimination Sarilumab is eliminated by parallel linear and non-linear pathways. At higher concentrations, the elimination is predominantly through the linear, non-saturable proteolytic pathway, while at lower concentrations, non-linear saturable target-mediated elimination predominates. These parallel elimination pathways result in an initial half-life of 8 to 10 days, and at steady-state an effective half- life of 21 days is estimated. After the last steady state dose of 150 mg and 200 mg sarilumab, the median times to non-detectable concentration are 30 and 49 days, respectively. Monoclonal antibodies are not eliminated via renal or hepatic pathways. Linearity/non-linearity A more than dose-proportional increase in pharmacokinetic exposure was observed in patients with RA. At steady state, exposure over the dosing interval measured by AUC increased approximately 2- fold with a 1.33-fold increase in dose from 150 to 200 mg every two weeks. Interactions with CYP450 substrates Simvastatin is a CYP3A4 and OATP1B1 substrate. In 17 patients with RA, one week following a single 200-mg subcutaneous administration of sarilumab, exposure of simvastatin and simvastatin acid decreased by 45% and 36%, respectively (see section 4.5). Polymyalgia Rheumatica The pharmacokinetic profile of subcutaneous sarilumab in PMR patients was determined using a population pharmacokinetic analysis on a data set including 58 PMR patients treated with repeated subcutaneous administration of sarilumab 200 mg every two weeks. In general, pharmacokinetic exposures were higher in patients with PMR when compared to patients with RA. For this dose regimen, the estimated mean (± SD) steady-state AUC, Cmin and Cmax of sarilumab were 551 ± 321 mg.day/L, 27.0 ± 21.5 mg/L, and 46.5 ± 23.0 mg/L, respectively. The median time to steady state in PMR patients was estimated to be 28 weeks. There was accumulation following subcutaneous administration of sarilumab 200 mg, with an accumulation ratio of approximately 6-fold based on the mean trough concentrations. Special populations Age, gender, ethnicity and body weight Population pharmacokinetic analyses in adult patients with RA (ranging in age from18 to 88 years with 14% over 65 years) showed that age, gender and race did not meaningfully influence the pharmacokinetics of sarilumab. Body weight influenced the pharmacokinetics of sarilumab. In patients with higher body weight (>100 Kg) both 150 mg and 200 mg doses demonstrated efficacy; however, patients weighing >100 Kg had greater therapeutic benefit with the 200 mg dose. Renal impairment No formal study of the effect of renal impairment on the pharmacokinetics of sarilumab was conducted. Mild to moderate renal impairment did not affect the pharmacokinetics of sarilumab. No dose adjustment is required in patients with mild to moderate renal impairment. Patients with severe renal impairment were not studied. Hepatic impairment No formal study of the effect of hepatic impairment on the pharmacokinetics of sarilumab was conducted (see section 4.2).
פרטי מסגרת הכללה בסל
א. התרופה תינתן לטיפול בארתריטיס ראומטואידית (Rheumatoid arthritis) כאשר התגובה לתכשירים ממשפחת ה-DMARDs איננה מספקת , בכפוף לתנאי פסקה (ב) ב. טיפול בתרופה לחולה העונה על תנאי פסקה (א), יינתן בהתקיים כל אלה: 1. קיימת עדות לדלקת פרקים (RA-Rheumatoid Arthritis) פעילה המתבטאת בשלושה מתוך אלה: א. מחלה דלקתית (כולל כאב ונפיחות) בארבעה פרקים ויותר; ב. שקיעת דם או CRP החורגים מהנורמה באופן משמעותי (בהתאם לגיל החולה); ג. שינויים אופייניים ל-RA בצילומי רנטגן של הפרקים הנגועים; ד. פגיעה תפקודית המוגדרת כהגבלה משמעותית בתפקודו היומיומי של החולה ובפעילותו בעבודה. 2. לאחר מיצוי הטיפול בתרופות השייכות למשפחת ה-NSAIDs ובתרופות השייכות למשפחת ה-DMARDs. לעניין זה יוגדר מיצוי הטיפול כהעדר תגובה קלינית לאחר טיפול קו ראשון בתרופות אנטי דלקתיות ממשפחת ה-NSAIDs וטיפול קו שני ב-3 תרופות לפחות ממשפחת ה-DMARDs שאחת מהן מתוטרקסאט, במשך 3 חודשים רצופים לפחות. 3. הטיפול יינתן באישור רופא מומחה בראומטולוגיה.
מסגרת הכללה בסל
התוויות הכלולות במסגרת הסל
התוויה | תאריך הכללה | תחום קליני | Class Effect | מצב מחלה |
---|---|---|---|---|
טיפול ב-Rheumatoid arthritis | ETANERCEPT, INFLIXIMAB, ABATACEPT, TOCILIZUMAB, TOFACITINIB, CERTOLIZUMAB PEGOL, SARILUMAB |
שימוש לפי פנקס קופ''ח כללית 1994
לא צוין
תאריך הכללה מקורי בסל
11/01/2018
הגבלות
תרופה מוגבלת לרישום ע'י רופא מומחה או הגבלה אחרת
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15.11.18 - עלון לצרכן אנגלית 15.11.18 - עלון לצרכן עברית 04.08.22 - עלון לצרכן עברית 15.11.18 - עלון לצרכן ערבית 07.10.18 - עלון לצרכן 04.08.22 - עלון לצרכן 02.06.22 - עלון לצרכן אנגלית 02.06.22 - עלון לצרכן עברית 02.06.22 - עלון לצרכן ערבית 13.12.22 - עלון לצרכן אנגלית 13.12.22 - עלון לצרכן עברית 13.12.22 - עלון לצרכן ערבית 09.04.24 - עלון לצרכן עברית 07.11.24 - עלון לצרכן אנגלית 07.11.24 - עלון לצרכן עברית 07.11.24 - עלון לצרכן ערבית 16.08.20 - החמרה לעלון 26.01.21 - החמרה לעלון 09.01.22 - החמרה לעלון 04.08.22 - החמרה לעלוןלתרופה במאגר משרד הבריאות
קבזרה 200 מ"ג