Download 4.2 Posology and method of administration 4.4 Special warnings

2012 ‫אפריל‬
,‫ה‬/‫ת נכבד‬/‫ רוקח‬,‫ה‬/‫ה נכבד‬/‫רופא‬
Certican 0.1 mg, 0.25 mg dispersible tablet:‫הנדון‬
‫ טבליות מסיסות‬,‫ מ"ג‬0.25 ,‫ מ"ג‬0.1 ‫סרטיקן‬
:‫התכשירים שבנדון רשומים בישראל להתוויות הבאות‬
Certican is indicated for the prophylaxis of organ rejection in adult patients at low to moderate immunological risk receiving an
allogeneic renal or cardiac transplant. Certican should be used in combination with ciclosporin for microemulsion and
corticosteroids.
Certican dispersible 0.1 mg and 0.25 mg contain 0.1mg and 0.25 mg Everolimus, respectively
:‫המרכיב הפעיל‬
:‫ כפי שמפורטים להלן‬,‫ אושרו עדכונים בעלון לרופא ולצרכן‬2012 ‫במרץ‬
(‫ קו חוצה משמעו מחיקת טקסט‬,‫)קו תחתי משמעו תוספת טקסט‬
‫עלון לרופא‬
‫תוספות ועדכונים בסעיף‬
4.2
Posology and method of administration
Black patients
...
Currently the efficacy and safety data are too limited to allow specific recommendations for use of everolimus in Bblack patients.
...
Patients with impaired hepatic function
Whole blood trough levels (C0) of everolimus should be closely monitored in patients with impaired hepatic function. For patients
with mild or moderate hepatic impairment (Child-Pugh Class A or B), the dose should be reduced to approximately one-halftwothirds of the normal dose. if two of the following conditions apply: bilirubin > 34 micro mol/L (> 2 mg/dL), albumin < 35 g/L (<
3.5 g/dL), INR> 1.3 (prothrombin time> 4 sec prolongation) For patients with moderate to severe hepatic impairment (Child-pugh
B or C) the dose should be reduced to approximately one half of the normal dose. Further dose titration should be based on
therapeutic drug monitoring (see section 5.2 Pharmacokinetic properties). Everolimus has not been evaluated in patients with
severe hepatic impairment (Child-Pugh Class C, see section 4.4 Special warnings and precautions for use).
Therapeutic Drug Monitoring
...
Based on exposure-efficacy and exposure-safety analysis, patients achieving everolimus whole blood trough levels (C0) ≥ 3.0
ng/mL have been found to have a lower incidence of biopsy-proven acute rejection in both renal and cardiacheart transplantation
than patients whose trough levels (C0) are below 3.0 ng/mL.
:‫תוספות ועדכונים בסעיף‬
4.4
Special warnings and precautions for use
...
Severe lLiver function imprint
Everolimus has not been studied in patients with severe hepatic impairment. Close monitoring of everolimus whole
blood trough levels (C0) and everolimus dose adjustment is recommended in patients with impaired hepatic function
(see section 4.2 Posology and method of administration)is therefore recommended.
...
Interstitial lung disease/ non-infectious pneumonitis
...
Cases of ILD have been reported with Certican which generally resolve on drug interruption with or without glucocorticoid
therapy. However, fatal cases have also occurred (see section 4.8 Undesirable effects).
:‫תוספות ועדכונים בסעיף‬
4.5
Interaction with other medicinal products and other forms of interaction
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Midazolam (CYP3A4A substrate)
In a two-period, fixed-sequence, crossover drug interaction study, 25 healthy subjects received a single oral 4 mg dose of
midazolam in period 1. In period 2, they received everolimus 10 mg once-daily for 5 days and a single 4 mg dose of midazolam
with the last dose of everolimus. The Cmax of midazolam increased 1.25-fold (90% CI, 1.14 – 1.37) and the AUCinf increased
1.30-fold (1.22 – 1.39). The half-life of midazolam was unaltered. This study indicated that everolimus is a weak inhibitor of
CYP3A4.
:‫תוספות ועדכונים בסעיף‬
Novartis Pharma Services AG
Israeli Branch
36 Shacham St., Ramat Siv, Petach-Tikva
P.O.B 7759, Petach Tikva 49250, Israel
Tel: 972-3-9201123 Fax: 972-3-9229331
‫נוברטיס פארמה סרויסס איי ג'י‬
‫סניף ישראל‬
‫תקוה‬-‫ פתח‬,‫ רמת סיב‬,36 ‫רח' שחם‬
49250 ‫תקוה‬-‫ פתח‬7759 .‫ד‬.‫ת‬
03-9229331 :‫ פקס‬03-9201123 :‫טלפון‬
1
4.8
Undesirable effects
...
lower rate of viral infections, primarily due to CMV in renal and heart transplant recipient and BK virus in renal transplant
recipients, has been shown with the currently-recommended Certican-based immunosuppressive regimen (see section 5.1
Pharmacodynamic properties – clinical studies).
:‫עדכונים בסעיף‬
5 Pharmacological properties
5.1 Pharmacodynamics properties
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Clinical studies
Kidney Renal transplantation
...
Heart Cardiac transplantation
In the phase III cardiac heart study (B253), Certican 1.5 mg/day and 3 mg/day, in combination with standard doses of ciclosporin
for microemulsion and corticosteroids, were both compared with azathioprine (AZA) 1-3 mg/kg/day.
...
5.2 Pharmacokinetic properties
...
Hepatic impairment
Relative to the AUC of everolimus in subjects with normal hepatic function, the average AUC in 7 patients with mild hepatic
impairment (Child-Pugh Class A) was 1.6-fold higherThe average AUC of everolimus; in two independently studied groups of 8
patients with moderate hepatic impairment (Child-Pugh Class B) the average AUC was 2.1-fold and 3.3-fold higher; and in 6
patients with severe hepatic impairment (Child-Pugh Class C) the average AUC was 3.6-fold higher.was twice as high as that
found in 8 healthy subjects. For patients with mild hepatic impairment (Child-Pugh Class A), the dose should be reduced to
approximately two-thirds of the normal dose. For patients with moderate or severe hepatic impairment (Child-Pugh B or C) the
dose should be reduced to one half of the normal dose. Further dose titration should be based on therapeutic drug monitoring AUC
was positively correlated with serum bilirubin concentration and with prolongation of prothrombin time and negatively correlated
with serum albumin concentration. The AUC of everolimus tended to be greater than that in healthy subjects if bilirubin was > 34
micro mol/L, INR was > 1.3 (prothrombin time > 4 sec prolongation) and/or albumin concentration was < 35 g/L. The impact of
severe hepatic impairment (Child-Pugh Class C) has not been assessed but the effect on the AUC of everolimus is likely to be as
large as, or larger than, the effect of moderate impairment (see section 4.2 Posology and method of administration).
...
Exposure-response relationships
The average everolimus trough concentration (C0) over the first 6 months post-transplant was related to the incidence of biopsyconfirmed acute rejection and of thrombocytopenia in kidneyrenal and heart cardiac transplant patients (see Table 10).
Table 10
Renal Kidney transplantation
Trough level (C0) (ng/mL)
≤ 3.4
3.5-4.5
4.6-5.7
5.8-7.7
7.8-15.0
Freedom from rejection
68%
81%
86%
81%
91%
Thrombocytopenia (< 100 x 109/L)
10%
9%
7%
14%
17%
Cardiac Heart transplantation
Trough level (C0) (ng/mL
≤ 3.5
3.6-5.3
5.4-7.3
7.4-10.2
10.3-21.8
Freedom from rejection
65%
69%
80%
85%
85%
5%
5%
6%
8%
9%
Thrombocytopenia (< 75 x 109/L)
‫עלון לצרכן‬
:‫תוספות ועידכונים בסעיף‬
:‫תגובות בין תרופתיות‬
...
.‫ או ניתנת כתרופת הרגעה לפני או במהלך ניתוח או הליכים רפואיים אחרים‬,‫ תרופה המשמשת לטיפול בפרכוסים חריפים‬,‫מידאזולם‬
.‫ידי פניה לבעל הרישום‬-‫ וניתן לקבלם מודפסים על‬,‫העלונים לרופא ולצרכן נשלחו למאגר התרופות שבאתר משרד הבריאות‬
,‫בברכה‬
‫מגר' נעמה אור‬
‫רוקחת ממונה‬
Novartis Pharma Services AG
Israeli Branch
36 Shacham St., Ramat Siv, Petach-Tikva
P.O.B 7759, Petach Tikva 49250, Israel
Tel: 972-3-9201123 Fax: 972-3-9229331
‫נוברטיס פארמה סרויסס איי ג'י‬
‫סניף ישראל‬
‫תקוה‬-‫ פתח‬,‫ רמת סיב‬,36 ‫רח' שחם‬
49250 ‫תקוה‬-‫ פתח‬7759 .‫ד‬.‫ת‬
03-9229331 :‫ פקס‬03-9201123 :‫טלפון‬
2