ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
Xagrid 0.5 mg hard capsules
Each hard capsule contains 0.5 mg anagrelide (as anagrelide hydrochloride)
Excipients
Each hard capsule contains lactose monohydrate (53.7 mg) and anhydrous lactose (65.8 mg).
For a full list of excipients, see section 6.1
Hard capsule.
An opaque white hard capsule imprinted with S 063.
4.1 Therapeuticindications
Xagrid is indicated for the reduction of elevated platelet counts in at risk essential thrombocythaemia
(ET) patients who are intolerant to their current therapy or whose elevated platelet counts are not
reduced to an acceptable level by their current therapy.
An at risk patient
An at risk essential thrombocythaemia patient is defined by one or more of the following features:
•
> 60 years of age or
•
a platelet count > 1000 x 10
9
/l or
•
a history of thrombo-haemorrhagic events.
Treatment with Xagrid should be initiated by a clinician with experience in the management of
essential thrombocythaemia.
The recommended starting dose of anagrelide is 1 mg/day, which should be administered orally in two
divided doses (0.5 mg/dose).
The starting dose should be maintained for at least one week. After one week the dose may be titrated,
on an individual basis, to achieve the lowest effective dose required to reduce and/or maintain a
platelet count below 600 x 10
9
/l and ideally at levels between 150 x 10
9
/l and 400 x 10
9
/l. The dose
increment must not exceed more than 0.5 mg/day in any one-week and the recommended maximum
single dose should not exceed 2.5 mg (see section 4.9). During clinical development doses of
10 mg/day have been used.
The effects of treatment with anagrelide must be monitored on a regular basis (see section 4.4). If the
starting dose is > 1 mg/day platelet counts should be performed every two days during the first week
of treatment and at least weekly thereafter until a stable maintenance dose is reached. Typically, a fall
in the platelet count will be observed within 14 to 21 days of starting treatment and in most patients an
adequate therapeutic response will be observed and maintained at a dose of 1 to 3 mg/day (for further
information on the clinical effects refer to section 5.1).
2
Elderly
The observed pharmacokinetic differences between elderly and young patients with ET (see section
5.2) do not warrant using a different starting regimen or different dose titration step to achieve an
individual patient-optimised anagrelide regimen.
During clinical development approximately 50% of the patients treated with anagrelide were over 60
years of age and no age specific alterations in dose were required in these patients. However, as
expected, patients in this age group had twice the incidence of serious adverse events (mainly cardiac).
Renal impairment
Currently, there are no specific pharmacokinetic data for this patient population and the potential risks
and benefits of anagrelide therapy in a patient with impairment of renal function should be assessed
before treatment is commenced.
Hepatic impairment
Currently, there are no specific pharmacokinetic data for this patient population. However, hepatic
metabolism represents the major route of drug clearance and liver function may therefore be expected
to influence this process. Therefore it is recommended that patients with moderate or severe hepatic
impairment are not treated with anagrelide
.
The potential risks and benefits of anagrelide therapy in a
patient with mild impairment of hepatic function should be assessed before treatment is commenced
(see sections 4.3 and 4.4).
Paediatric patients
The experience in children is limited; anagrelide should be used in this patient group with caution (see
sections 5.1 and 5.2).
Hypersensitivity to anagrelide or to any of the excipients.
Patients with moderate or severe hepatic impairment.
Patients with moderate or severe renal impairment (creatinine clearance < 50 ml/min).
Hepatic impairment
The potential risks and benefits of anagrelide therapy in a patient with mild impairment of hepatic
function should be assessed before treatment is commenced. It is not recommended in patients with
elevated transaminases (> 5 times the upper limit of normal) (see sections 4.2 and 4.3).
Renal impairment
The potential risks and benefits of anagrelide therapy in a patient with impairment of renal function
should be assessed before treatment is commenced (see sections 4.2 and 4.3).
Monitoring
Therapy requires close clinical supervision of the patient which will include a full blood count
(haemoglobin and white blood cell and platelet counts), and assessment of liver function (ALT and
AST) and renal function (serum creatinine and urea) tests.
Platelets
The platelet count will increase within 4 days of stopping treatment with Xagrid capsules and will
return to pre-treatment levels within 10 to 14 days.
3
Cardiovascular
Cases of cardiomegaly and congestive heart failure have been reported (see section 4.8). Anagrelide
should be used with caution in patients of any age with known or suspected heart disease, and only if
the potential benefits of therapy outweigh the potential risks.
Anagrelide is an inhibitor of cyclic AMP
phosphodiesterase III and because of its
positive inotropic effects, a pre-treatment cardiovascular
examination (including further investigation such as echocardiography, electrocardiogram) is
recommended. Patients should be monitored during treatment for evidence of cardiovascular effects
that may require further cardiovascular examination and investigation.
Paediatric patients
Limited data are available on the use of anagrelide in the paediatric population and anagrelide should
be used in this patient group with caution
(see sections 5.1 and 5.2).
Clinically relevant interactions
Anagrelide is an inhibitor of cyclic AMP phosphodiesterase III (PDE III). Concomitant use of
anagrelide with other PDE III inhibitors such as milrinone, amrinone, enoximone, olprinone and
cilostazol is not recommended.
Excipients
Xagrid contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp
lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
Limited pharmacokinetic and/or pharmacodynamic studies investigating possible interactions between
anagrelide and other medicinal products have been conducted.
Drug interactions: effects of other substances on anagrelide
•
Anagrelide is primarily metabolised by CYP1A2. It is known that CYP1A2 is inhibited by
several medicinal products, including fluvoxamine and omeprazole, and such medicinal
products could theoretically adversely influence the clearance of anagrelide.
•
In vivo
interaction studies in humans have demonstrated that digoxin and warfarin do not affect
the pharmacokinetic properties of anagrelide.
Drug interactions: effects of anagrelide on other substances
•
Anagrelide demonstrates some limited inhibitory activity towards CYP1A2 which may present a
theoretical potential for interaction with other co-administered medicinal products sharing that
clearance mechanism e.g. theophylline.
•
Anagrelide is an inhibitor of PDE III. The effects of medicinal products with similar properties
such as the inotropes milrinone, enoximone, amrinone, olprinone and cilostazol may be
exacerbated by anagrelide.
•
In vivo
interaction studies in humans have demonstrated that anagrelide does not affect the
pharmacokinetic properties of digoxin or warfarin.
•
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.
•
A clinical interaction study performed in healthy subjects showed that co-administration of
repeat-dose anagrelide 1 mg once daily and acetylsalicylic acid 75 mg once daily may enhance
the anti-platelet aggregation effects of each drug compared with administration of acetylsalicylic
acid alone. Therefore, due to the lack of data in ET patients, the potential risks 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 initiated.
•
Anagrelide may cause intestinal disturbance in some patients and compromise the absorption of
hormonal oral contraceptives.
4
Food interactions
•
Food delays the absorption of anagrelide,
but does not significantly alter systemic exposure.
•
The effects of food on bioavailability are not considered clinically relevant to the use of
anagrelide.
Pregnancy
There are no adequate data from the use of anagrelide in pregnant women.
Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is
unknown.
Use of Xagrid during pregnancy is not recommended. If Xagrid is used during pregnancy, or if the
patient becomes pregnant while using the medicinal product, she should be advised of the potential
risk to the foetus.
Women of child-bearing potential should use adequate birth-control measures during treatment with
anagrelide.
Lactation
It is not known whether anagrelide hydrochloride is excreted in milk. Since many medicinal products
are excreted in human milk and because of the potential for adverse reactions in breast-feeding infants,
mothers should discontinue breast-feeding when taking Xagrid.
No studies on the effects on the ability to drive and use machines have been performed.
In clinical development, dizziness was commonly reported. Patients are advised not to drive or
operate machinery while taking Xagrid if dizziness is experienced.
The safety of anagrelide has been examined in 4 open label clinical studies. In 3 of the studies 942
patients who received anagrelide at a mean dose of approximately 2 mg/day were assessed for safety.
In these studies 22 patients received anagrelide for up to 4 years.
In the later study 3660 patients who received anagrelide at a mean dose of approximately 2 mg/day
were assessed for safety. In this study 34 patients received anagrelide for up to 5 years.
The most commonly reported drug related adverse reactions were headache occurring at
approximately 14%, palpitations occurring at approximately 9%, fluid retention and nausea both
occurring at approximately 6%, and diarrhoea occurring at 5%. These adverse drug reactions are
expected based on the pharmacology of anagrelide (inhibition of PDE III). Gradual dose titration may
help diminish these effects (see section 4.2).
The following convention was used for frequency of adverse drug reactions: Very common (≥ 1/10);
Common (≥ 1/100 to < 1/10); Uncommon (≥ 1/1,000 to < 1/100); Rare (≥ 1/10,000 to < 1/1,000);
Very rare (< 1/10,000), not known (cannot be estimated from the available data).
Blood and lymphatic system disorders
Common: Anaemia
Uncommon: Thrombocytopenia, pancytopenia, ecchymosis, haemorrhage
Metabolism and nutrition disorders
Common: Fluid retention
Uncommon: Oedema, weight loss
Rare:
Weight gain
5
Nervous system disorders
Very common: Headache
Common: Dizziness
Uncommon: Paraesthesia, insomnia, depression, confusion, hypoaesthesia, nervousness, dry
mouth, amnesia
Rare:
Somnolence, abnormal coordination, dysarthria, migraine
Eye disorders
Rare:
Vision abnormal, diplopia
Ear and labyrinth disorders
Rare:
Tinnitus
Cardiac disorders
Common: Palpitations, tachycardia
Uncommon: Congestive heart failure, hypertension, arrhythmia, atrial fibrillation, supraventricular
tachycardia, ventricular tachycardia, syncope
Rare:
Angina pectoris, myocardial infarction, 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
Skin and subcutaneous tissue disorders
Common: Rash
Uncommon: Alopecia, skin discoloration, pruritus
Rare:
Dry skin
Musculoskeletal and connective tissue disorders
Uncommon: Myalgia, arthralgia, back pain
Renal and urinary disorders
Uncommon: Impotence
Rare:
Nocturia, renal failure
Not known:
Tubulointerstitial nephritis
General disorders and administration site conditions
Common: Fatigue
Uncommon: Chest pain, weakness, chills, malaise, fever
Rare:
Asthenia, pain, flu-like syndrome
Investigations
Rare:
Blood creatinine increased
6
There have been a small number of post-marketing case reports of intentional overdose with
anagrelide. Reported symptoms include sinus tachycardia and vomiting. Symptoms resolved with
conservative management.
A specific antidote for anagrelide has not been identified. In case of overdose, close clinical
supervision of the patient is required; this includes monitoring of the platelet count for
thrombocytopenia. Dose should be decreased or stopped, as appropriate, until the platelet count
returns to within the normal range.
Xagrid, at higher than recommended doses, has been shown to produce reductions in blood pressure
with occasional instances of hypotension. A single 5 mg dose of anagrelide can lead to a fall in blood
pressure usually accompanied by dizziness.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Other antineoplastic agents, ATC Code: L01XX35
The specific mechanism of action by which anagrelide
reduces platelet count is not yet fully
understood although it has been confirmed that anagrelide is platelet selective from
in vitro
and
in vivo
study information.
In vitro
studies of human megakaryocytopoiesis established that anagrelide’s inhibitory actions on
platelet formation in man are mediated via retardation of maturation of megakaryocytes, and reducing
their size and ploidy. Evidence of similar
in vivo
actions was observed in bone marrow biopsy
samples from treated patients.
Anagrelide is an inhibitor of cyclic AMP phosphodiesterase III.
The safety and efficacy of anagrelide as a platelet lowering agent have been evaluated in four open-
label, non-controlled clinical trials (study numbers 700-012, 700-014, 700-999 and 13970-301)
including more than 4000 patients with myeloproliferative disorders (MPDs). In patients with essential
thrombocythaemia complete response was defined as a decrease in platelet count to ≤ 600 x 10
9
/l or a
≥ 50% reduction from baseline and maintenance of the reduction for at least 4 weeks. In studies
700-012, 700-014, 700-999 and study 13970-301 the time to complete response ranged from 4 to 12
weeks. Clinical benefit in terms of thrombohaemorrhagic events has not been convincingly
demonstrated.
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 (12) of children (age range 5 - 17 years)
with essential thrombocythaemia were treated with anagrelide.
This medicine has been authorised 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 SPC will be updated as necessary.
7
5.2
Pharmacokinetic properties
Following oral administration of anagrelide in man, at least 70% is absorbed from the gastrointestinal
tract. In fasted subjects, peak plasma levels occur about 1 hour after a 0.5 mg dose; the plasma half-
life is short, approximately 1.3 hours. Dose proportionality has been found in the dose range 0.5 mg to
2 mg.
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, 4-dihydroquinazoline and 3-hydroxy
anagrelide have been identified. The mean recovery of 2-amino-5, 6-dichloro-3, 4-dihydroquinazoline
in urine is approximately 18-35% of the administered dose.
Pharmacokinetic data from healthy subjects established that food decreases the C
max
of anagrelide by
14%, but increases the AUC by 20%. Food had a more significant effect on the active metabolite and
decreased the C
max
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
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, C
max
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 C
max
and AUC of anagrelide were 36%
and 61% higher respectively in elderly patients, but that the C
max
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.
5.3 Preclinical safety data
Repeated dose toxicity
Following repeated administration of anagrelide, at doses of 1 mg/kg/day or higher, subendocardial
haemorrhage and focal myocardial necrosis occurred in dogs.
Reproductive toxicology
Maternally toxic doses of anagrelide (60 mg/kg/day and above) in rats and rabbits were associated
with increased embryo resorption and foetal mortality.
Mutagenic and carcinogenic potential
Studies on the genotoxic potential of anagrelide did not identify any mutagenic or clastogenic effects.
In a two-year rat carcinogenicity study, non-neoplastic and neoplastic findings were observed and
related or attributed to an exaggerated pharmacological effect. Among them, the incidence of adrenal
phaeochromocytomas was increased relative to control in males at all dose levels (≥ 3 mg/kg/day) and
in females receiving 10 mg/kg/day and above. The lowest dose in males (3 mg/kg/day) corresponds to
37 times the human AUC exposure after a 1 mg twice daily dose. Uterine adenocarcinomas, of
epigenetic origin, could be related to an enzyme induction of CYP1 family. They were observed in
females receiving 30 mg/kg/day, corresponding to 572 times the human AUC exposure after a 1 mg
twice daily dose.
8
Currently, there is no clinical evidence that these findings are of relevance to human use.
6.1 List of excipients
Capsule contents
Povidone (E1201)
Anhydrous lactose
Lactose monohydrate
Microcrystalline cellulose (E460)
Crospovidone
Magnesium stearate
Capsule shell
Gelatin
Titanium dioxide (E171)
Printing ink
Shellac
Strong ammonium solution
Potassium hydroxide (E525)
Black iron oxide (E172)
6.2 Incompatibilities
Not applicable
6.3 Shelflife
4 years
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
High-density polyethylene (HDPE) bottles with child-resistant closures and desiccant containing 100
capsules.
6.6 Special precautions for disposal
No special requirements.
Shire Pharmaceutical Contracts Ltd
Hampshire International Business Park
Chineham
Basingstoke
Hampshire RG24 8EP
United Kingdom
9
8. MARKETING AUTHORISATION NUMBER
EU/1/04/295/001
Date of first authorisation: 16/11/2004
Date of latest renewal: 16/11/2009
Detailed information on this product is available on the website of the European Medicines Agency
(EMEA)
http://www.ema.europa.eu
10
ANNEX II
A.
MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE
FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
C.
11
A. MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer responsible for batch release
Wasdell Packaging Limited, Upper Mills Estate, Bristol Road, Stonehouse, Gloucestershire,
GL10 2BJ, United Kingdom
B. CONDITIONS OF THE MARKETING AUTHORISATION
•
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product
Characteristics, section 4.2).
•
OTHER CONDITIONS
The holder of this marketing authorisation must inform the European Commission about the marketing
plans for the medicinal product authorised by this decision.
Shire will continue to submit yearly Periodic Safety Update Reports (PSURs) unless otherwise
specified by the CHMP.
C. SPECIFIC OBLIGATIONS TO BE FULFILLED BY THE MARKETING
AUTHORISATION HOLDER
The Marketing Authorisation Holder shall complete the following programme of studies within the
specified time frame, the results of which shall form the basis of the annual reassessment of the
benefit/risk profile.
Clinical aspects
:
1.
Shire will conduct a Post Authorisation Safety Study (PASS), Study
SPD422-401:
A non-interventional, post authorisation safety study, to continuously monitor safety and
pregnancy outcomes in a cohort of at-risk Essential Thrombocythaemia (ET) subjects exposed to
Xagrid compared to other conventional cytoreductive treatments.
Objectives
:
Primary
To continuously monitor safety and pregnancy outcomes in a cohort of at-risk ET subjects
exposed to Xagrid compared to other conventional cytoreductive treatments.
Secondary
Efficacy (platelet reduction, incidence of thrombohaemorrhagic events).
Drug utilisation (drug type, drug dose, duration of exposure).
Updates and progress reports were provided at 6 monthly intervals for 5 years post-approval on
patients treated with Xagrid. Study recruitment was closed in April 2009, with a commitment to
follow up all patients for 5 years to obtain specific information on safety and pregnancy
outcomes. Following the 5 year review annual reports will be provided.
Study recruitment was initiated during May 2005. The tenth safety update report is expected in
November 2010 as part of the sixth Annual Reassessment.
12
2.
Shire will conduct a randomised, comparative study in patients with ET, Study
SPD422-403
: A
Phase IIIb, randomised study to compare the efficacy, tolerability and safety of anagrelide
hydrochloride versus hydroxyurea in high-risk patients with essential thrombocythaemia.
Objectives
:
Primary
:
To compare the safety of anagrelide and hydroxyurea in short and long term usage of up to three
years with particular reference to cardiovascular safety (as assessed by echocardiography).
Secondary
:
To compare the efficacy of anagrelide and hydroxyurea in terms of the platelet count after 6
months of treatment.
To compare the efficacy of anagrelide and hydroxyurea in terms of the platelet count after 3
months of treatment.
To compare the efficacy of anagrelide and hydroxyurea in terms of the number of patients
achieving a complete response.
To compare the cytoreductive impact of anagrelide and hydroxyurea on white blood cell and red
blood cell lines.
To investigate the tolerability of anagrelide and hydroxyurea in short and long term usage of up
to three years.
To investigate the effects of anagrelide and hydroxyurea on incidence of disease related
thrombotic and haemorrhagic events.
To compare the average time to response following treatment with anagrelide or hydroxyurea.
The study will include a centralized and blinded review of the echocardiographs as part of the
assessment of the effect of both treatments on LVEF.
Interim safety reports were provided every 6 months for 5 years post-approval. Following the 5
year review annual reports with progress and recruitment updates will be provided alongside the
standard PSURs. The final study report will be provided 4 months after data base lock.
Study recruitment was initiated during January 2006. The tenth safety update report is expected
in November 2010 as part of the sixth Annual Reassessment.
3.
Shire will provide an annual update of all published data concerning the efficacy and safety of
anagrelide in ET patients alongside the annual PSURs.
The sixth annual update is expected as part of the sixth Annual Reassessment Report in
November 2010.
13
ANNEX III
LABELLING AND PACKAGE LEAFLET
14
A. LABELLING
15
PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE
PACKAGING
OUTER CARTON AND BOTTLE LABEL
1.
Xagrid 0.5 mg hard capsules
Anagrelide
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
One hard capsule contains 0.5 mg anagrelide (as anagrelide hydrochloride).
3.
LIST OF EXCIPIENTS
Xagrid capsules also contain lactose. See the package leaflet for further information.
4.
100 hard capsules
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
This medicinal product does not require any special storage conditions.
16
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Shire Pharmaceutical Contracts Ltd
Basingstoke
RG24 8EP
United Kingdom
EU/1/04/295/001
13. MANUFACTURER’S BATCH NUMBER
LOT
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Xagrid
17
B. PACKAGE LEAFLET
18
PACKAGE LEAFLET: INFORMATION FOR THE USER
Xagrid 0.5 mg hard capsules
anagrelide
Read all of this leaflet carefully before you start taking this medicine
•
Keep this leaflet. You may need to read it again.
•
If you have further questions, please ask your doctor or pharmacist.
•
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
•
If any of the side effects get serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet:
1.
What Xagrid is and what it is used for
2.
Before you take Xagrid
3.
How to take Xagrid
4.
Possible side effects
5.
How to store Xagrid
6.
Further information
1. WHAT XAGRID IS AND WHAT IT IS USED FOR
Xagrid is a medicine which interferes with the development of platelets. It reduces the number of
platelets produced by the bone marrow, which results in a decrease in the platelet count in the blood
towards a more normal level. For this reason it is used to treat patients with essential
thrombocythaemia.
Essential thrombocythaemia is a condition which occurs when the bone marrow produces too many of
the blood cells known as platelets. Large numbers of platelets in the blood can cause serious problems
with blood circulation and clotting.
2. BEFORE YOU TAKE XAGRID
Do not take Xagrid
•
If you are allergic (hypersensitive) to anagrelide or any of the other ingredients of Xagrid;
Check the ingredients of Xagrid listed in Section 6 of this leaflet. An allergic reaction may be
recognised as a rash, itching, swollen face or lips, or shortness of breath;
•
If you have moderate or severe liver problems;
•
If you have moderate or severe kidney problems.
Take special care with Xagrid
Before treatment with Xagrid, tell your doctor:
•
If you have or think you might have a problem with your heart;
•
If you have any problems with your liver or kidneys;
•
If you are pregnant or breastfeeding;
•
If you have been told by a doctor that you have an intolerance to some sugars.
Taking other medicines
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines,
including medicines obtained without a prescription.
19
Tell your doctor if you are taking any of the following medicines:
•
Fluvoxamine, used to treat depression;
•
Omeprazole, used to treat gastro-intestinal problems like reflux oesophagitis and duodenal and
gastric ulcers;
•
Theophylline, used to treat severe asthma and breathing problems;
•
Medicines used to treat heart disorders, for example, milrinone, enoximone, amrinone,
olprinone and cilostazol;
•
Acetylsalicylic acid (aspirin), used to treat mild to moderate pain, for example, headaches;
•
Other medicines used to treat conditions affecting the platelets in your blood.
Xagrid or these medicines may not work properly if taken together.
If you are not sure, speak to your doctor or pharmacist for advice.
Taking Xagrid with food and drink
Your capsules may be taken with food or after a meal or on an empty stomach. For more information
on how to take your medicine, please refer to section 3.
Pregnancy and breast-feeding
Tell your doctor if you are pregnant or are planning to become pregnant. Xagrid should not be taken
by pregnant women. Women who are at risk of becoming pregnant should make sure that they are
using effective contraception when taking Xagrid. Speak to your doctor if you need advice with
contraception.
Tell your doctor if you are breast-feeding or if you are planning to breast-feed your baby. Xagrid
should not be taken while breast-feeding. You must stop breast-feeding if you are taking Xagrid.
Driving and using machines
Dizziness has been reported by some patients taking Xagrid. Do not drive or use machines if you feel
dizzy.
Important information about some of the ingredients of Xagrid
Lactose is an ingredient in Xagrid. If you have been told that you have an intolerance to some sugars,
contact your doctor before taking the capsules.
3. HOW TO TAKE XAGRID
Always take Xagrid exactly as your doctor has told you. You should check with your doctor or
pharmacist if you are not sure.
The amount of Xagrid that people take can be different, and this depends on your condition. Your
doctor will prescribe the best dose for you. There is limited information on the use of Xagrid in
children and adolescents and therefore Xagrid should be used with caution.
The usual starting dose of Xagrid is 1 mg (2 of these capsules) per day, taken as one capsule twice a
day, for at least one week.
After this time, your doctor may either increase or decrease the number of capsules that you take to
find the dose best suited to you and which treats your condition most effectively.
Your capsules should be swallowed whole with a glass of water. They may be taken with food or after
a meal or on an empty stomach. It is best to take the capsules at the same time every day.
Do not
take more capsules than your doctor has recommended.
20
Your doctor will ask you to have blood tests at regular intervals to check that your medicine is
working effectively.
If you take more Xagrid than you should
If you take more Xagrid than you should or if someone else has taken your medicine, tell a doctor or
pharmacist immediately. Show them the pack of Xagrid.
If you forget to take Xagrid
Take your capsules as soon as you remember. Take your next dose at the usual time. Do not take a
double dose to make up for forgotten individual doses.
4. POSSIBLE SIDE EFFECTS
Like all medicines, Xagrid can cause side effects, although not everybody gets them. If you are
worried, speak to your doctor.
Serious side effects:
Severe chest pain, palpitations associated with dizziness or feeling faint, fainting, severe abdominal or
gastro-intestinal pain, vomiting blood or passing bloody or black stools, breathing difficulties or
shortness of breath, particularly if your lips or skin turn a bluish colour. These have not occurred
commonly, but are serious conditions.
If you notice any of these side effects, contact your doctor
immediately.
Very common side effects (affect more than 1 user in 10):
Headache.
Common side effects (affect 1 to 10 users in 100):
Dizziness (rarely when standing up or getting out of bed), tiredness, palpitations (awareness of a
forceful heartbeat which may be rapid or irregular), nausea, diarrhoea, stomach pain, indigestion and
wind, vomiting, anaemia (a small reduction in red blood cell count and iron deficiency), fluid retention
(including swelling of your ankles) or rash.
Uncommon side effects (affect 1 to 10 users in 1,000):
A feeling of weakness or feeling unwell, high blood pressure, chills or fever, heartburn, anorexia,
constipation, bruising, localised swelling with fluid (oedema), weight loss, muscle aches, painful
joints, back pain, reduced feeling or tingling in toes or fingers, sleeplessness, depression, confusion,
nervousness, dry mouth, loss of memory, allergic coughing, breathlessness, nosebleed, lung infection,
hair loss, skin itching or discolouration, impotence, or an increase in liver enzymes. Your doctor may
do a blood test which may show an increase in your liver enzymes.
Rare side effects (affect 1 to 10 users in 10,000):
Heart attack, bleeding gums, weight gain, heart muscle disease, loss of coordination, difficulty in
speaking, dry skin, migraine, visual disturbances or double vision, ringing in the ears, increased need
to pass water at night, pain, ‘flu-like’ symptoms.
The following side effects have been reported but it is not known exactly how often they occur:
•
Hepatitis (inflammation of the liver) with an increase in liver enzymes
•
Allergic alveolitis (inflammation of the lungs)
•
Tubulointerstitial nephritis (inflammation of the kidneys).
If any of these side effects cause you a problem, speak to your doctor. If you notice any side effects
not mentioned in this leaflet, please inform your doctor or pharmacist.
21
5.
HOW TO STORE XAGRID
Keep out of the reach and sight of children.
Do not use Xagrid after the expiry date which is stated on the carton after EXP. The expiry date refers
to the last day of that month.
This medicine does not require any special storage conditions.
If your doctor stops your medicine, do not keep any leftover capsules unless your doctor tells you to.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
6.
FURTHER INFORMATION
What Xagrid contains
The active substance is anagrelide. Each capsule contains 0.5 mg anagrelide (as anagrelide
hydrochloride).
The other ingredients are:
Capsule contents: povidone (E1201), crospovidone, anhydrous lactose, lactose monohydrate,
microcrystalline cellulose (E460) and magnesium stearate.
Capsule shell: gelatin and titanium dioxide (E171).
Printing ink: shellac, strong ammonium solution, potassium hydroxide (E525), black iron oxide
(E172).
What Xagrid looks like and contents of the pack
Xagrid is supplied as opaque, white, hard capsules. They are marked with ‘S 063’.
The capsules are provided in bottles containing 100 hard capsules.
Marketing Authorisation Holder
Shire Pharmaceutical Contracts Limited
Hampshire International Business Park
Chineham, Basingstoke
Hampshire
RG24 8EP
United Kingdom
Tel: +44(0) 1256 894000
Fax: +44(0) 1256 894708
Email: medinfoglobal@shire.com
Manufacturer
Wasdell Packaging Limited
Upper Mills Estate
Bristol Road, Stonehouse
Gloucestershire
GL10 2BJ
United Kingdom
22
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
България, Česká Republika, Latvija, Lietuva,
Magyarország, Österreich, Polska, România,
Slovenija, Slovenská republika
Shire Pharmaceuticals Ltd
Hampshire International Business Park
Chineham, Basingstoke
Hampshire, RG24 8EP
Великобритания, Velká Británie, Lielbritānija,
Jungtinė Karalystė, Nagy-Britannia, Vereinigtes
Königreich, Wielka Brytania, Marea Britanie,
Velika Britanija, Vel’ká Británia
Teл/Tel: +44 1256 894 000
België/Belgique/Belgien/
Luxembourg/Luxemburg/Nederland
Shire Belgium BVBA
Lambroekstraat 5C
B-1831 Diegem
België/Belgique
Tél/Tel: +32 2 711 02 30
Italia
Shire Italia S.p.A
Corso Italia, 29
I-50123, Firenze
Tel: +39 055 288860
Danmark
Swedish Orphan Biovitrum A/S
Wilders Plads 5
DK-1403 København K
Tlf: +45 32 96 68 69
Kύπρος
Genesis Pharma (Cyprus) Ltd
Αμφιπόλεως 2
1
ος
όροφος, 2025 Στρόβολος
Τηλ: +357 22 76 99 46
Deutschland
Shire Deutschland GmbH
Friedrichstrasse 149
D-10117 Berlin
Tel: +49 30 206 582 0
Malta
Vivian Corporation Ltd
Sanitas Building, Tower Str.
Msida MSD 1824
Tel: +356 21 320338
Eesti
United Pharma Services UAB
PK 209,
Tartu, 50002
Tel: +372 55596234
Norge
Swedish Orphan Biovitrum AS
Trollåsveien 6
N-1414 Trollåsen
Tlf: +47 66 82 34 00
Ελλάδα
Genesis Pharma S.A.
Λ. Κηφισίας 274
Χαλάνδρι, GR-152 32
Αθήνα
Τηλ: +30 210 877 1500
Portugal
Shire Pharmaceuticals Ibérica, S.L.
Paseo Pintor Rosales, 44 Bajo Izda.
E-28008 Madrid
Espanha
Tel: +34 915 500 691
23
España
Shire Pharmaceuticals Ibérica, S.L.
Paseo Pintor Rosales, 44 Bajo Izda.
E-28008 Madrid
Tel: +34 915 500 691
Suomi/Finland
Oy Swedish Orphan Biovitrum AB
Keilaranta 19 (7
th
Floor)
FIN-02150 Espoo
Puh/Tel: +358 201 558 840
France
Shire France S.A.
88, rue du Dôme
F-92514 Boulogne-Billancourt Cedex
Tél: +33 1 46 10 90 00
Sverige
Swedish Orphan Biovitrum Sverige AB
SE-112 76 Stockholm
Tel: +46 8 697 2000
Ireland
Shire Pharmaceuticals Ltd
Hampshire International Business Park
Chineham, Basingstoke
Hampshire, RG24 8EP
United Kingdom
Tel: 1800 818 016
United Kingdom
Shire Pharmaceuticals Ltd
Hampshire International Business Park
Chineham, Basingstoke
Hampshire, RG24 8EP
Tel: 0800 055 6614
Ísland
Swedish Orphan Biovitrum A/S
Wilders Plads 5
DK-1403 Kaupmannahöfn K
Danmörk
Sími: +45 32 96 68 69
This leaflet was last approved in
This medicine has been authorised 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 on the medicine every
year and this leaflet will be updated as necessary.
Detailed information on this medicine is available on the European Medicines Agency (EMEA) web
site:
http://www.ema.europa.eu.
There are also links to other websites about rare diseases and
treatments.
24
Source: European Medicines Agency
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