‫בטיחות)‬
‫מידע בטיחות)‬
‫החמרה (( מידע‬
‫על החמרה‬
‫הודעה על‬
‫הודעה‬
‫תאריך _______________‪12.90.22‬‬
‫שם תכשיר‬
‫באנגלית______‪0.5mg, _caps‬‬
‫מספר רישום‪:‬‬
‫‪Agrylin‬‬
‫‪1117529454‬‬
‫שם בעל הרישום___‪Medison Pharma Ltd‬‬
‫השינויים בעלון מסומנים ברקע צהוב‬
‫עלון לצרכן‬
‫פרטים על השינוי‪/‬ים המבוקש‪/‬ים‬
‫פרק בעלון‬
‫טקסט נוכחי‬
‫טקסט חדש‬
‫חומרים ‪-‬אנטינאופלסטים‬
‫קבוצה תרפויטית‬
‫חומרים תרומבוליטים‬
‫תגובות בין‪-‬‬
‫תרופתיות‪:‬‬
‫עליך להודיע לרופא המטפל אם‬
‫הינך נוטל אחת מהתרופות‬
‫הבאות‪:‬‬
‫פלווקסמין (לטיפול בדכאון);‬
‫אומפרזול (לטיפול בבעיות‬
‫מערכת העיכול כגון רפלוקס או‬
‫אולקוס); תיאופילין( באסתמה‬
‫או בעיות נשימה‬
‫חריפות);תכשירים לטיפול‬
‫בהפרעות לב כגון‬
‫מילרינון‪,‬אנוקסימון‪,‬אמרינון‪,‬‬
‫אולפירון וסילוסטזול; אספירין‬
‫ותכשירים אחרים המשפיעים‬
‫על התסיות בדם‪.‬‬
‫תופעות לוואי‬
‫בנוסף לפעילות הרצויה של‬
‫התרופה‪ ,‬בזמן השימוש בה‬
‫עלולות להופיע תופעות לוואי‪,‬‬
‫כגון‪ :‬שלשול‪,‬‬
‫בחילה‪/‬הקאות‪,‬שלשול‬
‫כאב ראש‪ ,‬סחרחורת‪ ,‬כאב בטן‪,‬‬
‫חולשה‪ ,‬חום‪ ,‬כאבים‪ ,‬גזים‪,‬‬
‫חוסר תיאבון‪ ,‬דלקת גרון‪,‬‬
‫פעימות לב מואצות‬
‫בנוסף לפעילות הרצויה של התרופה‪ ,‬בזמן‬
‫השימוש בה‬
‫עלולות להופיע תופעות לוואי‪ ,‬כגון‪ :‬שלשול‪,‬‬
‫בחילה‪/‬הקאות‪,‬שלשול‬
‫כאב ראש(מיגרנה)‪ ,‬סחרחורת‪ ,‬כאב בטן‪,‬‬
‫חולשה‪ ,‬חום‪ ,‬כאבים‪ ,‬גזים‪ ,‬חוסר תיאבון‪,‬‬
‫דלקת גרון‪,‬‬
‫פעימות לב מואצות‪,‬הפרעות בעין (ראיה‬
‫מעוותת‪,‬כפל ראיה)‪ ,‬הפרעות באוזן(טיניטוס‬
‫תופעות לוואי‬
‫הדורשות‬
‫התייחסות‬
‫מיוחדת‬
‫גירוי או פריחה בעור‪ ,‬בצקת‪,‬‬
‫דפיקות לב מואצות‪ ,‬כאב בחזה‪,‬‬
‫קשיי נשימה‪ ,‬צואה דמית או‬
‫שחורה‪ ,‬עור או עיניים צהובים‪,‬‬
‫עייפות או חולשה‬
‫מוגברת – אם הינך מזהה אחת‬
‫מהתופעות האלה פנה לרופא‬
‫מיד‪.‬‬
‫בכל מקרה שבו הינך מרגיש‪/‬ה‬
‫גירוי או פריחה בעור‪ ,‬בצקת‪ ,‬דפיקות לב‬
‫מואצות הקשורות לחולשה ‪,‬התעלפות‪ ,‬כאב‬
‫בחזה חמור‪,‬‬
‫קשיי נשימה‪ ,‬צואה דמית או שחורה‪ ,‬עור או‬
‫עיניים צהובים‪ ,‬עייפות או חולשה‬
‫מוגברת‪ ,‬קוצר נשימה ‪,‬במיוחד כאשר צבע‬
‫השפתיים או העור הופך לכחלחל ‪,‬כאב בטן‬
‫חמור או הפרעות במערכת העיכול ‪,‬הקאת דם‪.‬‬
‫– אם הינך מזהה אחת מהתופעות האלה פנה‬
‫עליך להודיע לרופא המטפל אם הינך נוטל‬
‫אחת מהתרופות הבאות‪:‬‬
‫פלווקסמין (לטיפול בדכאון); אומפרזול‬
‫(לטיפול בבעיות מערכת העיכול כגון רפלוקס‬
‫או אולקוס); תיאופילין( באסתמה או בעיות‬
‫נשימה חריפות);תכשירים לטיפול בהפרעות לב‬
‫כגון מילרינון‪,‬אנוקסימון‪,‬אמרינון‪ ,‬אולפירון‬
‫וסילוסטזול; אספירין ותכשירים אחרים‬
‫המשפיעים על הטסיות בדם‪ .‬בשילוב עם‬
‫אספירין‪ ,‬ישנה אפשרות של עליה בסיכון‬
‫לשטפי דם(דימומים)‬
.‫לרופא מיד‬
‫ה תופעות לוואי‬/‫בכל מקרה שבו הינך מרגיש‬
‫ או עם חל שינוי‬,‫שלא צוינו בעלון זה‬
,‫בהרגשתך הכללית‬
.‫עלייך להתייעץ עם הרופא מיד‬
‫תופעות לוואי שלא צוינו בעלון‬
‫ או עם חל שינוי בהרגשתך‬,‫זה‬
,‫הכללית‬
.‫עלייך להתייעץ עם הרופא מיד‬
‫עלון לרופא‬
‫ים‬/‫ים המבוקש‬/‫פרטים על השינוי‬
‫טקסט חדש‬

At the doses recommended
for use in the treatment of
essential
thrombocythaemia,
anagrelide may - potentiate
the effects of other
medicinal products that
inhibit or modify platelet
function e.g. acetylsalicylic
acid. In two clinical
interaction studies in
healthy subjects, coadministration of singledose anagrelide 1mg and
acetylsalicylic acid 900mg
or repeat-dose anagrelide
1mg once daily and
acetylsalicylic acid 75mg
once daily showed greater
anti-platelet aggregation
effects than administration
of acetylsalicylic acid
alone. In the repeat-dose
study, there was a shortlived decrease in ex vivo
collagen-induced platelet
aggregation beyond the
effects of acetylsalicylic
acid alone for the first 2
hours after administration.
‫טקסט נוכחי‬
‫פרק בעלון‬
At the doses recommended for
use in the treatment of essential
thrombocythaemia, anagrelide
may theoretically potentiate the
effects of other medicinal
products that inhibit or modify
platelet function e.g.
acetylsalicylic acid.
In two clinical interaction
studies in healthy subjects, co-
Interaction with
other medicinal
administration of single-dose
anagrelide 1mg and
acetylsalicylic acid 900mg or
repeat-dose anagrelide 1mg
once daily and acetylsalicylic
acid 75mg once daily showed
greater anti-platelet
aggregation effects than
administration of
acetylsalicylic acid alone. In
products

Co-administered anagrelide
1mg and acetylsalicylic
acid 900mg single-doses
had no effect on bleeding
time, prothrombin time
(PT) or activated partial
thromboplastin time
(aPTT). In some ET
patients concomitantly
treated by anagrelide and
acetylsalicylic acid, major
haemorrhages occurred.
Therefore, the potential
risks and benefits of the
concomitant use of
anagrelide with
acetylsalicylic acid should
be assessed, particularly in
patients with a high risk
profile for haemorrhage,
before treatment is
commenced. Anagrelide
may cause intestinal
disturbance in some
patients and compromise
the absorption of hormonal
oral contraceptives.
-
the repeat-dose study, there
was a short-lived decrease in
ex vivo collagen-induced
platelet aggregation beyond the
effects of acetylsalicylic acid
alone for the first 2 hours after
administration. Coadministered anagrelide 1mg
and acetylsalicylic acid 900mg
single-doses had no effect on
bleeding time, prothrombin
time (PT) or activated partial
thromboplastin time (aPTT).
The clinical relevance of this
interaction in ET patients is
unknown
• Anagrelide may cause
intestinal disturbance in some
patients and compromise the
absorption of hormonal oral
contraceptives.
• A preclinical in vivo
pharmacokinetic interaction
study in the dog investigating
the potential effects of
anagrelide and hydroxyurea
when given in combination
demonstrated no adverse
effects on the kinetics of either
medicinal product.
The following convention was
used for frequency of adverse
drug reactions: very common
(≥1/10); common (≥1/100,
The following convention was
used for frequency of adverse
Undesirable effects
<1/10); uncommon (≥ 1/1,000,
<1/100); rare (≥1/10,000,
<1/1,000).
drug reactions: very common
(>1/10); common (>1/100,
<1/10); uncommon (>1/1,000,
Blood and lymphatic system
disorders
Common: Anaemia
Uncommon:
Thrombocytopaenia,
pancytopaenia, ecchymosis,
haemorrhage
Metabolism and nutrition
disorders
Common: Fluid retention
Uncommon: Oedema, weight
loss
Rare: Weight gain
<1/100); rare (>1/10,000,
<1/1,000).
Blood and lymphatic system
disorders
Common: Anaemia
Uncommon:
Thrombocytopaenia,
pancytopaenia, ecchymosis,
haemorrhage
Metabolism and nutrition
Nervous system disorders
Very common: Headache
Common: Dizziness
Uncommon: Paraesthesia,
insomnia, depression,
confusion, hypoaesthesia,
nervousness, dry mouth,
amnesia
Rare: Somnolence, abnormal
coordination, dysarthria,
migraine
disorders
Common: Fluid retention
Uncommon: Oedema, weight
loss
Rare: Weight gain
Nervous system disorders
Very common: Headache
Common: Dizziness
-
Uncommon: Paraesthesia,
Eye disorders
Rare: Vision abnormal,
diplopia
insomnia, depression,
Ear and labyrinth disorders
Rare: Tinnitus
nervousness, dry mouth,
Cardiac disorders
Common: Palpitations,
tachycardia
Uncommon: Congestive heart
failure, hypertension,
arrhythmia, atrial fibrillation,
supraventricular tachycardia,
ventricular tachycardia,
syncope
Rare: Angina pectoris,
myocardial infarction,
Rare: Somnolence, abnormal
confusion, hypoaesthesia,
amnesia
coordination, dysarthria
Special senses
Rare: Vision abnormal,
tinnitus, diplopia
Cardiac disorders
Common: Palpitations,
cardiomegaly, cardiomyopathy,
pericardial effusion,
vasodilatation, - postural
hypotension
- Respiratory, thoracic and
mediastinal disorders
Uncommon: Dyspnoea,
epistaxis, pleural effusion,
pneumonia
Rare: Pulmonary hypertension,
Pulmonary infiltrates
Not known: Allergic alveolitis
Gastrointestinal disorders
Common: Nausea, diarrhoea,
abdominal pain, flatulence,
vomiting
Uncommon: Dyspepsia,
anorexia, pancreatitis,
constipation, gastrointestinal
haemorrhage, gastrointestinal
disorder
Rare: Colitis, gastritis, gingival
bleeding,
Hepatobiliary disorders
Uncommon : Hepatic enzymes
increased
Not known : Hepatitis
tachycardia
Uncommon: Congestive heart
failure, hypertension,
arrhythmia, atrial fibrillation,
supraventricular tachycardia,
ventricular tachycardia,
syncope
Rare: Angina pectoris,
myocardial infarction,
cardiomegaly, pericardial
effusion, vasodilatation,
migraine, postural hypotension
Respiratory and thoracic
disorders
Uncommon: Dyspnoea,
epistaxis, pleural effusion,
pneumonia
Rare: Pulmonary infiltrates
Gastrointestinal disorders
Common: Nausea, diarrhoea,
abdominal pain, flatulence,
Skin and subcutaneous tissue
disorders
Common: Rash
Uncommon: Alopecia, skin
discolouration, pruritus
Rare: Dry skin
vomiting
Uncommon: Dyspepsia,
anorexia, pancreatitis,
constipation, gastrointestinal
haemorrhage, gastrointestinal
Musculoskeletal and connective
tissue disorders
disorder
Uncommon: Myalgia,
Rare: Colitis, gastritis, gingival
arthralgia, back pain
bleeding,
Renal and urinary disorders
Hepatobiliary disorders
Uncommon: Impotence
Rare: Nocturia, renal failure
Uncommon : Hepatic enzymes
Not Known : Tubulointerstitial
increased
nephritis
Not known : Hepatitis
-
Skin and subcutaneous tissue
General disorders and
administration site conditions
Common: Fatigue
Uncommon: Chest pain,
weakness, chills, malaise, fever
Rare: Asthenia, pain, flu-like
syndrome
Common: Rash
Uncommon: Alopecia, skin
discolouration, pruritus
Rare: Dry skin
Musculoskeletal and
connective tissue disorders
Investigations
Rare: Blood creatinine
increased
Uncommon: Myalgia,
arthralgia, back pain
Renal and urinary disorders
Uncommon: Impotence
Rare: Nocturia, renal failure
Not Known : Tubulointerstitial
nephritis
Investigations
Rare: Blood creatinine
increased
General disorders and
administration site conditions
Common: Fatigue
Uncommon: Chest pain,
weakness, chills, malaise, fever
Rare: Asthenia, pain, flu-like
syndrome
Pharmacotherapeutic group:
Other antineoplastic agents
- ATC Code: L01XX35
Paediatric patients
An open label clinical study
with a 3 month treatment
period did not raise any safety
concerns for anagrelide in 17
children/adolescent patients
with ET (age range 7-14 years)
compared to 18 adult patients .
-Earlier during clinical
development a limited number
Pharmacotherapeutic group:
Proposed ATC Code:
L01XX35(Other
Antineoplastic Agents)
Paediatric patients
An open label clinical study
with a 3 month treatment
period did not raise any safety
Pharmacodynamic
properties
(12) of children (age range 5-17 concerns for anagrelide in 17
years) with essential
children/adolescent patients
thrombocythaemia were treated
with anagrelide.
with ET (age range 7-14 years)
-
compared to 18 adult patients .
earlier during clinical
development a limited number
(12) of children (age range 517 years) with essential
thrombocythaemia were treated
with anagrelide.
This medicine has been
authorized under "Exceptional
Circumstances".
This means that because of the
rarity of this disease it has been
impossible to get complete
information on this medicine.
The European Medicines
Agency (EMEA) will review
any new information which
may become available every
year and this Prescribing
Information will be updated as
necessary.
Anagrelide is primarily
metabolised by CYP1A2; less
than 1% is recovered in the
urine as anagrelide. Two major
urinary metabolites, 2-amino-5,
6-dichloro-3, 4dihydroquinazoline and - 3hydroxy anagrelide have been
identified. The mean recovery
of 2-amino-5, 6-dichloro-3, 4dihydroquinazoline in urine is
approximately 18-35% of the
administered dose.
Anagrelide is primarily
metabolised by CYP1A2; less
than 1% is recovered in the
urine as anagrelide. Two major
Pharmacokinetic
urinary metabolites, 2-amino-5, properties
6-dichloro-3, 4dihydroquinazoline and N(5,6-dichloro-3,4-
dihydroquinazalin-2-yl)-2Pharmacokinetic data from
healthy subjects established
that food decreases the Cmax
of anagrelide by 14% but
increases the AUC by 20%.
Food had a more significant
effect on the active metabolite
and decreased the Cmax by
29% although it had no effect
on the AUC.
As expected from its half-life,
there is no evidence for
anagrelide accumulation in the
plasma. Additionally these
results show no evidence of
auto-induction of the anagrelide
clearance.
Special populations
oxoacetamide have been
identified. The mean recovery
of 2-amino-5, 6-dichloro-3, 4dihydroquinazoline in urine is
approximately 18-35% of the
administered dose.
Pharmacokinetic data from
healthy subjects established
that food decreases the Cmax
of anagrelide by 14% but
increases the AUC by 20%.
Food had a more significant
effect on the active metabolite
and decreased the Cmax by
Paediatric patients
Pharmacokinetic data from
fasting children and adolescents
(age range 7 – 14 years) with
essential thrombocythaemia
indicate that dose and body
weight normalised exposure,
Cmax and AUC, of anagrelide
were lower in
children/adolescents compared
to adults. There was also a
trend to lower exposure to the
active metabolite. These
observations may be a
reflection of more efficient
metabolic clearance in younger
subjects.
29% although it had no effect
on the AUC.
As expected from its half-life,
there is no evidence for
anagrelide accumulation in the
plasma. Additionally these
results show no evidence of
auto-induction of the
anagrelide clearance.
Special populationsPaediatric
patients
Pharmacokinetic data from
Elderly
Pharmacokinetic data from
fasting elderly patients with ET
(age range 65-75 years)
compared to fasting adult
patients (age range 22-50 years)
indicate that the Cmax and
AUC of anagrelide were 36%
and 61% higher respectively in
elderly patients, but that the
fasting children and
adolescents (age range 7 – 14
years) with essential
thrombocythaemia indicate that
dose and body weight
normalised exposure, Cmax
Cmax and AUC of the active
metabolite, —-, 3-hydroxy
anagrelide were 42% and 37%
lower respectively in the
elderly patients. These
differences were likely to be
caused by lower presystemic
metabolism of anagrelide to —3-hydroxy anagrelide in the
elderly patients.
and AUC, of anagrelide were
lower in children/adolescents
compared to adults. There was
also a trend to lower exposure
to the active metabolite. These
observations may be a
reflection of more efficient
metabolic clearance in younger
subjects.
Elderly
Pharmacokinetic data from
fasting elderly patients with ET
(age range 65-75 years)
compared to fasting adult
patients (age range 22-50
years) indicate that the Cmax
and AUC of anagrelide were
36% and 61% higher
respectively in elderly patients,
but that the Cmax and AUC of
the active metabolite, 2-amino5, 6-dichloro-3, 4dihydroquinazoline, were 42%
and 37% lower respectively in
the elderly patients. These
differences were likely to be
caused by lower presystemic
metabolism of anagrelide to 2amino-5, 6-dichloro-3, 4dihydroquinazoline in the
elderly patients.