Xagrid

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ANNEX I 

 

SUMMARY OF PRODUCT CHARACTERISTICS 

 



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1. NAME OF THE MEDICINAL PRODUCT 

 

Xagrid 0.5 mg hard capsules. 

 

 

2. QUALITATIVE AND QUANTITATIVE COMPOSITION 

 

Each hard capsule contains 0.5 mg anagrelide (as anagrelide hydrochloride). 

 

Excipient(s) with known effect 

Each hard capsule contains lactose monohydrate (53.7 mg) and anhydrous lactose (65.8 mg). 

 

For the full list of excipients, see section 6.1. 

 

 

3. PHARMACEUTICAL FORM 

 

Hard capsule. 

 

An opaque white hard capsule imprinted with S 063. 

 

 

4. CLINICAL PARTICULARS 

 

4.1 Therapeutic indications 

 

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 109/l or 

• a history of thrombo-haemorrhagic events. 
 

4.2 Posology and method of administration 

 

Treatment with Xagrid should be initiated by a clinician with experience in the management of 

essential thrombocythaemia. 

 

Posology 

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 109/l and ideally at levels between 150 x 109/l and 400 x 109/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 



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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). 

 

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 

There are limited pharmacokinetic data for this patient population. The potential risks and benefits of 

anagrelide therapy in a patient with impairment of renal function should be assessed before treatment 

is commenced (see section 4.3). 

 

Hepatic impairment 

There are limited pharmacokinetic data for this patient population. However, hepatic metabolism 

represents the major route of anagrelide 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 population 

The safety and efficacy of anagrelide in children have not been established. The experience in children 

and adolescents is very limited; anagrelide should be used in this patient group with caution. In the 

absence of specific paediatric guidelines, WHO diagnostic criteria for adult diagnosis of ET are 

considered to be of relevance to the paediatric population. Diagnostic guidelines for essential 

thrombocythemia should be followed carefully and diagnosis reassessed periodically in cases of 

uncertainty, with effort made to distinguish from hereditary or secondary thrombocytosis, which may 

include genetic analysis and bone marrow biopsy. 

 

Typically, cytoreductive therapy is considered in high-risk paediatric patients. 

 

Anagrelide treatment should only be initiated when the patient shows signs of disease progression or 

suffers from thrombosis. If treatment is initiated, the benefits and risks of treatment with anagrelide 

must be monitored regularly and the need for ongoing treatment evaluated periodically. 

 

Platelet targets are assigned on an individual patient basis by the treating physician. 

 

Discontinuation of treatment should be considered in paediatric patients who do not have a satisfactory 

treatment response after approximately 3 months. 

 

Currently available data are described in sections 4.4, 4.8, 5.1 and 5.2, but no recommendation on a 

posology can be made. 

 

Method of Administration 

For oral use. The capsules must be swallowed whole. Do not crush or dilute the contents in a liquid. 

 

4.3 Contraindications 

 

Hypersensitivity to anagrelide or to any of the excipients listed in section 6.1. 

Patients with moderate or severe hepatic impairment. 

Patients with moderate or severe renal impairment (creatinine clearance <50 ml/min). 

 



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4.4 Special warnings and precautions for use 
 

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), assessment of liver function (ALT and AST), 

renal function (serum creatinine and urea) and electrolytes (potassium, magnesium and calcium). 

 

Platelets 

The platelet count will increase within 4 days of stopping treatment with anagrelide and will return to 

pre-treatment levels within 10 to 14 days, possibly rebounding above baseline values. Therefore, 

platelets should be monitored frequently. 

 

Cardiovascular 

Serious cardiovascular adverse events including cases of torsade de pointes, ventricular tachycardia, 

cardiomyopathy, cardiomegaly and congestive heart failure have been reported (see section 4.8). 

 

Caution should be taken when using anagrelide in patients with known risk factors for prolongation of 

the QT interval, such as congenital long QT syndrome, a known history of acquired QTc prolongation, 

medicinal products that can prolong QTc interval and hypokalaemia. 

 

Care should also be taken in populations that may have a higher maximum plasma concentration 

(Cmax) of anagrelide or its active metabolite, 3-hydroxy anagrelide, e.g., hepatic impairment or use 

with CYP1A2 inhibitors (see section 4.5). 

 

Close monitoring for an effect on the QTc interval is advisable. 

 

A pre-treatment cardiovascular examination, including a baseline ECG and echocardiography is 

recommended for all patients prior to initiating therapy with anagrelide. All patients should be 

monitored regularly during treatment (e.g., ECG or echocardiography) for evidence of cardiovascular 

effects that may require further cardiovascular examination and investigation. Hypokalaemia or 

hypomagnesaemia must be corrected prior to anagrelide administration and should be monitored 

periodically during therapy. 

 

Anagrelide is an inhibitor of cyclic AMP phosphodiesterase III and because of its positive inotropic 

and chronotropic effects, anagrelide should be used with caution in patients of any age with known or 

suspected heart disease. Moreover, serious cardiovascular adverse events have also occurred in 

patients without suspected heart disease and with normal pre-treatment cardiovascular examination. 

 

Anagrelide should only be used if the potential benefits of therapy outweigh the potential risks. 

 

Pulmonary hypertension 

Cases of pulmonary hypertension have been reported in patients treated with anagrelide. Patients 

should be evaluated for signs and symptoms of underlying cardiopulmonary disease prior to initiating 

and during anagrelide therapy. 

 

Paediatric population 

Very 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 4.2, 4.8, 5.1 and 5.2). 



5 

 

As with the adult population, a full blood count and assessment of cardiac, hepatic and renal function 

should be undertaken before treatment and regularly during treatment. The disease may progress to 

myelofibrosis or AML. Although the rate of such progression is not known, children have a longer 

disease course and may, therefore, be at increased risk for malignant transformation, relative to adults. 

Children should be monitored regularly for disease progression according to standard clinical 

practices, such as physical examination, assessment of relevant disease markers and bone marrow 

biopsy. 

 

Any abnormalities should be evaluated promptly and appropriate measures taken, which may also 

include dose reduction, interruption or discontinuation. 

 

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. 

 

Use of concomitant anagrelide and acetylsalicylic acid has been associated with major haemorrhagic 

events (see section 4.5). 

 

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. 

 

4.5 Interaction with other medicinal products and other forms of interaction 

 

Limited pharmacokinetic and/or pharmacodynamic studies investigating possible interactions between 

anagrelide and other medicinal products have been conducted. 

 

Effects of other active substances on anagrelide 

• In vivo interaction studies in humans have demonstrated that digoxin and warfarin do not affect 
the pharmacokinetic properties of anagrelide. 

CYP1A2 inhibitors 

• Anagrelide is primarily metabolised by CYP1A2. It is known that CYP1A2 is inhibited by 
several medicinal products, including fluvoxamine and enoxacin, and such medicinal products 

could theoretically adversely influence the clearance of anagrelide. 

CYP1A2 inducers 

• CYP1A2 inducers (such as omeprazole) could decrease the exposure of anagrelide increasing its 
main active metabolite. The consequences on the safety and efficacy profile of anagrelide are not 

established. Therefore, clinical and biological monitoring is recommended in patients taking 

concomitant CYP1A2 inducers. If needed, anagrelide dose adjustment could be made. 

 

Effects of anagrelide on other active 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 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 active substance compared with administration of 



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acetylsalicylic acid alone. In some patients with ET concomitantly treated by acetylsalicylic acid 

and anagrelide, major haemorrhages occurred. Therefore, 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. 

 

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. 

 

Paediatric population 

Interaction studies have only been performed in adults. 

 

4.6 Fertility, pregnancy and lactation 
 

Women of child-bearing potential 

Women of child-bearing potential should use adequate birth-control measures during treatment with 

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. Therefore, 

Xagrid is not recommended during pregnancy. 

 

If anagrelide 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. 

 

Breast-feeding 

It is unknown whether anagrelide/metabolites are excreted in human milk. Available data in animals 

have shown excretion of anagrelide/metabolites in milk. A risk to the newborn/infant cannot be 

excluded. Breast-feeding should be discontinued during treatment with anagrelide. 

 

Fertility 

No human data on the effect of anagrelide on fertility are available. In male rats, there was no effect 

on fertility or reproductive performance with anagrelide. In female rats, using doses in excess of the 

therapeutic range, anagrelide disrupted implantation (see section 5.3). 

 

4.7 Effects on ability to drive and use machines 

 

In clinical development, dizziness was commonly reported. Patients are advised not to drive or operate 

machinery while taking anagrelide if dizziness is experienced. 

 

4.8 Undesirable effects 

 

Summary of the safety profile 

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 adverse reactions associated with anagrelide 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 



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expected based on the pharmacology of anagrelide (inhibition of PDE III). Gradual dose titration may 

help diminish these effects (see section 4.2). 

 

Tabulated list of adverse reactions 

Adverse reactions arising from clinical studies, post-authorisation safety studies and spontaneous 

reports are presented in the table below. Within the system organ classes they are listed under the 

following headings: 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). Within each frequency grouping, adverse reactions are presented in order of 

decreasing seriousness. 

 

MedDRA 

System Organ 

Class 

Frequency of adverse reactions 

Very 

common 

Common Uncommon Rare Not known 

Blood and 

lymphatic 

system 

disorders 

 Anaemia Pancytopenia 

Thrombocytopenia 

Haemorrhage 

Ecchymosis 

  

Metabolism and 

nutrition 

disorders 

 Fluid 

retention 

Oedema 

Weight loss 

Weight gain  

Nervous system 

disorders 

Headache Dizziness Depression 

Amnesia 

Confusion 

Insomnia 

Paraesthesia 

Hypoaesthesia 

Nervousness 

Dry mouth 

Migraine 

Dysarthria 

Somnolence 

Abnormal 

coordination 

 

Eye disorders    Diplopia 

Vision abnormal 

 

Ear and 

labyrinth 

disorders 

   Tinnitus  

Cardiac 

disorders 

 Tachycardia 

Palpitations 

Ventricular 

tachycardia 

Congestive heart 

failure 

Atrial fibrillation 

Supraventricular 

tachycardia 

Arrhythmia 

Hypertension 

Syncope 

Myocardial 

infarction 

Cardiomyopathy 

Cardiomegaly 

Pericardial 

effusion 

Angina pectoris 

Postural 

hypotension 

Vasodilatation  

Prinzmetal 

angina 

Torsade de 

pointes 

Respiratory, 

thoracic and 

mediastinal 

disorders 

  Pulmonary 

hypertension 

Pneumonia 

Pleural effusion 

Dyspnoea 

Epistaxis 

Pulmonary 

infiltrates 

Interstitial lung 

disease including 

pneumonitis and 

allergic alveolitis 

Gastrointestinal 

disorders 

 Diarrhoea 

Vomiting 

Abdominal 

pain 

Nausea 

Gastrointestinal 

haemorrhage 

Pancreatitis 

Anorexia 

Dyspepsia 

Colitis 

Gastritis 

Gingival 

bleeding 

  



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MedDRA 

System Organ 

Class 

Frequency of adverse reactions 

Very 

common 

Common Uncommon Rare Not known 

Flatulence Constipation 

Gastrointestinal 

disorder 

Hepatobiliary 

disorders 

  Hepatic enzymes 

increased 

 Hepatitis 

Skin and 

subcutaneous 

tissue disorders 

 Rash Alopecia 

Pruritus 

Skin discoloration 

Dry skin  

Musculoskeletal 

and connective 

tissue disorders 

  Arthralgia 

Myalgia 

Back pain 

  

Renal and 

urinary 

disorders 

  Impotence Renal failure 

Nocturia 

Tubulointerstitial 

nephritis 

General 

disorders and 

administration 

site conditions 

 Fatigue Chest pain 

Fever 

Chills 

Malaise 

Weakness 

Flu-like 

syndrome 

Pain 

Asthenia 

 

Investigations    Blood creatinine 

increased 

 

 

Paediatric population 

48 patients aged 6 through17 years (19 children and 29 adolescents) have received anagrelide for up to 

6.5 years either in clinical studies or as part of a disease registry (see section 5.1). 

The majority of adverse events observed were among those listed in the SmPC. However, safety data 

are limited and do not allow a meaningful comparison between adult and paediatric patients to be 

made (see section 4.4). 

 

Reporting of suspected adverse reactions 

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 

allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 

professionals are asked to report any suspected adverse reactions via the national reporting system 

listed in Appendix V. 

 

4.9 Overdose 

 

Post-marketing case reports of intentional overdose with anagrelide have been received. Reported 

symptoms include sinus tachycardia and vomiting. Symptoms resolved with conservative 

management. 

 

Anagrelide, 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. 

 

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. 

 

 

5. PHARMACOLOGICAL PROPERTIES 

 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


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5.1  Pharmacodynamic properties 

 

Pharmacotherapeutic group: Other antineoplastic agents, ATC Code: L01XX35. 

 

Mechanism of action 

The precise mechanism by which anagrelide reduces blood platelet count is unknown. In cell culture 

studies, anagrelide suppressed expression of transcription factors including GATA-1 and FOG-1 

required for megakaryocytopoiesis, ultimately leading to reduced platelet production. 

 

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. 

 

Clinical efficacy and safety 

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 neoplasms (MPNs). In patients with 

essential thrombocythaemia complete response was defined as a decrease in platelet count to 600 x 

109/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. 

 

Effects on heart rate and QTc interval 

The effect of two dose levels of anagrelide (0.5 mg and 2.5 mg single doses) on the heart rate and QTc 

interval was evaluated in a double-blind, randomised, placebo- and active-controlled, cross-over study 

in healthy adult men and women. 

 

A dose-related increase in heart rate was observed during the first 12 hours, with the maximum 

increase occurring around the time of maximal concentrations. The maximum change in mean heart 

rate occurred at 2 hours after administration and was +7.8 beats per minute (bpm) for 0.5 mg and 

+29.1 bpm for 2.5 mg. 

 

A transient increase in mean QTc was observed for both doses during periods of increasing heart rate 

and the maximum change in mean QTcF (Fridericia correction) was +5.0 msec occurring at 2 hours 

for 0.5 mg and +10.0 msec occurring at 1 hour for 2.5 mg. 

 

Paediatric population 

In an open-label clinical study in 8 children and 10 adolescents (including patients who were 

anagrelide treatment naïve or who had been receiving anagrelide for up to 5 years pre-study), median 

platelet counts were decreased to controlled levels after 12 weeks of treatment. The average daily dose 

tended to be higher in adolescents. 

 

In a paediatric registry study, median platelet counts were reduced from diagnosis and maintained for 

up to 18 months in 14 paediatric patients with ET (4 children, 10 adolescents) with anagrelide 

treatment. In earlier, open-label studies, median platelet count reductions were observed in 7 children 

and 9 adolescents treated for between 3 months and 6.5 years. 

 

The average total daily dose of anagrelide across all studies in paediatric patients with ET was highly 

variable, but overall the data suggest that adolescents could follow similar starting and maintenance 

doses to adults and that a lower starting dose of 0.5 mg/day would be more appropriate for children 

over 6 years (see sections 4.2, 4.4, 4.8, 5.2). In all paediatric patients, careful titration to a patient-

specific daily dose is needed. 

 



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5.2 Pharmacokinetic properties 
 

Absorption 

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 administration. Pharmacokinetic 

data from healthy subjects established that food decreases the Cmax of anagrelide by 14%, but increases 

the AUC by 20%. Food also decreased the Cmax of the active metabolite, 3-hydroxy anagrelide, by 

29%, although it had no effect on the AUC. 

 

Biotransformation 

Anagrelide is primarily metabolised by CYP1A2 to form, 3-hydroxy anagrelide, which is further 

metabolised via CYP1A2 to the inactive metabolite, 2-amino-5, 6-dichloro-3, 4-dihydroquinazoline. 

 

Elimination 

The plasma half-life of anagrelide is short, approximately 1.3 hours and as expected from its half-life, 

there is no evidence for anagrelide accumulation in the plasma. Less than 1% is recovered in the urine 

as anagrelide. The mean recovery of 2-amino-5, 6-dichloro-3, 4-dihydroquinazoline in urine is 

approximately 18-35% of the administered dose. 

 

Additionally these results show no evidence of auto-induction of the anagrelide clearance. 

 

Linearity 

Dose proportionality has been found in the dose range 0.5 mg to 2 mg. 

 

Paediatric population 

Pharmacokinetic data from exposed fasting children and adolescents (age range 7 through 16 years) 

with essential thrombocythaemia indicate that dose normalised exposure, Cmax and AUC, of anagrelide 

tended to be higher in children/adolescents compared with adults. There was also a trend to higher 

dose-normalised exposure to the active metabolite. 

 

Elderly  

Pharmacokinetic data from fasting elderly patients with ET (age range 65 through 75 years) compared 

to fasting adult patients (age range 22 through 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, 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 oral administration of anagrelide in dogs, subendocardial haemorrhage and focal 

myocardial necrosis was observed at 1mg/kg/day or higher in males and females with males being 

more sensitive. The no observed effect level (NOEL) for male dogs (0.3 mg/kg/day) corresponds to 

0.1-, 0.1-, and 1.6-fold the AUC in humans for anagrelide at 2 mg/day, and the metabolites BCH24426 

and RL603, respectively. 

 

Reproductive toxicology 

 

Fertility 

In male rats, anagrelide at oral doses up to 240 mg/kg/day (>1000 times a 2-mg/day dose, based on 

body surface area) was found to have no effect on fertility and reproductive performance. In female 

rats increases in pre- and post-implantation losses and a decrease in the mean number of live embryos 

was observed at 30 mg/kg/day. The NOEL (10 mg/kg/day) to this effect was 143-, 12- and 11-fold 

higher than the AUC in humans administered a dose of anagrelide 2 mg/day, and the metabolites 

BCH24426 and RL603, respectively. 

 



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Embryofoetal development studies 

Maternally toxic doses of anagrelide in rats and rabbits were associated with increased embryo 

resorption and foetal mortality. 

 

In a pre- and post-natal development study in female rats, anagrelide at oral doses of ≥10 mg/kg 

produced a non-adverse increase in gestational duration. At the NOEL dose (3 mg/kg/day), the AUCs 

for anagrelide and the metabolites BCH24426 and RL603 were 14-, 2- and 2-fold higher than the 

AUC in humans administered an oral dose of anagrelide 2 mg/day. 

 

Anagrelide at ≥60 mg/kg increased parturition time and mortality in the dam and foetus, respectively. 

At the NOEL dose (30 mg/kg/day), the AUCs for anagrelide and the metabolites BCH24426 and 

RL603 were 425-, 31- and 13-fold higher than the AUC in humans administered an oral dose of 

anagrelide 2 mg/day, respectively. 

 

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.  

 

 

6. PHARMACEUTICAL PARTICULARS 

 

6.1 List of excipients 

 

Capsule contents 

Povidone (E1201) 

Lactose, anhydrous 

Lactose monohydrate 

Cellulose, microcrystalline (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 Shelf life 

 

4 years 

 



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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. 

 

 

7. MARKETING AUTHORISATION HOLDER 

 

Shire Pharmaceuticals Ireland Limited 

Block 2 & 3 Miesian Plaza 

50 – 58 Baggot Street Lower 

Dublin 2 

Ireland 

 

 

8. MARKETING AUTHORISATION NUMBER 

 

EU/1/04/295/001 

 

 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 

 

Date of first authorisation: 16 November 2004 

Date of latest renewal: 18 July 2014 

 

 

10. DATE OF REVISION OF THE TEXT 

 

 

 

Detailed information on this product is available on the website of the European Medicines Agency 

http://www.ema.europa.eu. 

http://www.ema.europa.eu/


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ANNEX II 

 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH 

RELEASE 

B. CONDITIONS OR RESTRICTIONS REGARDING 

SUPPLY AND USE 

C. OTHER CONDITIONS AND REQUIREMENTS OF 

THE MARKETING AUTHORISATION 

D. CONDITIONS OR RESTRICTIONS WITH REGARD 

TO THE SAFE AND EFFECTIVE USE OF THE 

MEDICINAL PRODUCT 

  

   



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A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 

 

Name and address of the manufacturer(s) responsible for batch release 

 

Shire Pharmaceuticals Ireland Limited, Block 2 & 3 Miesian Plaza, 50 – 58 Baggot Street Lower 

Dublin 2, Ireland 

 

 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

 

Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product 

Characteristics, section 4.2). 

 

 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 

 

The holder of this marketing authorisation must inform the European Commission about the marketing 

plans for the medicinal product authorised by this decision. 

 

• Periodic Safety Update Reports 
 

The requirements for submission of periodic safety update reports for this medicinal product are set 

out in the list of Union reference dates (EURD list)) provided for under Article 107c(7) of Directive 

2001/83/EC and any subsequent updates published on the European medicines web-portal. 

 

 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE 
USE OF THE MEDICINAL PRODUCT 

 

• Risk Management Plan (RMP) 
 

Not applicable. 

 

 

 



15 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX III 

 

LABELLING AND PACKAGE LEAFLET 



16 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

A. LABELLING 

 



17 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE 

PACKAGING 

 

OUTER CARTON AND BOTTLE LABEL 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

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 

 

Also contains lactose. See leaflet for further information. 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

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 SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach 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. 

 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 



18 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Shire Pharmaceuticals Ireland Limited 

Dublin 2 

Ireland 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/04/295/001 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

Medicinal product subject to medical prescription. 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Xagrid (on the outer carton only) 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 

 

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 

 

PC: 

SN: 

NN: 



19 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

B. PACKAGE LEAFLET 

 



20 

Package leaflet: Information for the patient 

 

Xagrid 0.5 mg hard capsules 

anagrelide 

 

 

Read all of this leaflet carefully before you start taking this medicine because it contains 

important information for you. 

 

• Keep this leaflet. You may need to read it again. 

• If you have further questions, ask your doctor or pharmacist. 

• This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 
even if their signs of illness are the same as yours. 

• If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 
effects not listed in this leaflet. See section 4. 

 

What is in this leaflet: 

 

1. What Xagrid is and what it is used for 
2. What you need to know before you take Xagrid 
3. How to take Xagrid 
4. Possible side effects 
5. How to store Xagrid 
6. Contents of the pack and other information 
 

 

1. What Xagrid is and what it is used for 

 

Xagrid contains the active substance, anagrelide. 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. What you need to know before you take Xagrid 

 

Do not take Xagrid 

 

• If you are allergic to anagrelide or any of the other ingredients of this medicine (listed in section 
6). 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. 
 

Warnings and precautions 

 

Talk to your doctor before taking Xagrid: 

• If you have or think you might have a problem with your heart; 

• If you were born with or have family history of prolonged QT interval (seen on ECG, electrical 
recording of the heart), or you are taking other medicines that result in abnormal ECG changes 

or if you have low levels of electrolytes e.g., potassium, magnesium or calcium (see section 

“Other medicines and Xagrid”); 



21 

• If you have any problems with your liver or kidneys. 
 

In combination with acetylsalicylic acid (a substance present in many medicines used to relieve pain 

and lower fever, as well as to prevent blood clotting, also known as aspirin), there is an increased risk 

of major haemorrhages (bleeding) (see section “Other medicines and Xagrid”). 

 

Children and adolescents 

 

There is limited information on the use of Xagrid in children and adolescents and therefore this 

medicine should be used with caution. 

 

Other medicines and Xagrid 

 

Tell your doctor or pharmacist if you are taking or have recently taken or might take any other 

medicines. 

 

Tell your doctor if you are taking any of the following medicines: 

• Medicines that can alter your heart rhythm e.g., sotalol, amiodarone; 

• Fluvoxamine, used to treat depression; 

• Certain types of antibiotic, such as enoxacin, used to treat infections; 

• 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 (a substance present in many medicines used to relieve pain and lower 
fever, as well as to prevent blood clotting, also known as aspirin); 

• Other medicines used to treat conditions affecting the platelets in your blood, e.g., clopidogrel; 

• Omeprazole, used to reduce the amount of acid produced in the stomach; 

• Oral contraceptives: If you experience bad diarrhoea whilst taking this medicine, it may reduce 
how well the oral contraceptive works and use of an extra method of contraception is 

recommended (e.g., condom). See the instructions in the patient leaflet of the contraceptive pill 

you are taking. 

 

Xagrid or these medicines may not work properly if taken together. 

 

If you are not sure, speak to your doctor or pharmacist for advice. 

 

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. 

 

Xagrid contains lactose 

 

Lactose is an ingredient in this medicine. If you have been told that you have an intolerance to some 

sugars, contact your doctor before taking this medicine. 

 



22 

 

3. How to take Xagrid 

 

Always take Xagrid exactly as your doctor has told you. 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. 

 

The usual starting dose of Xagrid is 1 mg. You take this dose as one capsule of 0.5 mg twice a day, for 

at least a 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. Do not crush the capsules or dilute 

the contents in a liquid. You can take the capsules with food or after a meal or on an empty stomach. It 

is best to take the capsule(s) at the same time every day. 

 

Do not take more capsules than your doctor has recommended. 

 

Your doctor will ask you to have blood tests at regular intervals to check that your medicine is 

working effectively and that your liver and kidneys are working well. 

 

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 a forgotten dose. 

 

 

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: 

Uncommon: Heart failure (signs include shortness of breath, chest pain, swelling of the legs due to 

fluid build-up), severe problem with the rate or rhythm of the heartbeat (ventricular tachycardia, 

supraventricular tachycardia or atrial fibrillation), inflammation of the pancreas which causes severe 

abdominal and back pain (pancreatitis), vomiting blood or passing bloody or black stools, severe 

reduction in blood cells which can cause weakness, bruising, bleeding or infections (pancytopenia), 

pulmonary hypertension (signs include shortness of breath, swelling in legs or ankles, and lips and 

skin can turn bluish colour). 

Rare: Kidney failure (when you pass little or no urine), heart attack. 

 

If you notice any of these side effects, contact your doctor immediately. 

 

Very common side effects: may affect more than 1 in 10 people 

Headache. 

 

Common side effects: may affect up to 1 in 10 people 

Dizziness, tiredness, rapid heartbeat, irregular or strong heartbeat (palpitations), feeling sick (nausea), 

diarrhoea, stomach pain, wind, being sick (vomiting), reduction in red blood cell count (anaemia), 

fluid retention or rash. 



23 

 

Uncommon side effects: may affect up to 1 in 100 people 

A feeling of weakness or feeling unwell, high blood pressure, irregular heartbeat, fainting, chills or 

fever, indigestion, loss of appetite, constipation, bruising, bleeding, swelling (oedema), weight loss, 

muscle aches, painful joints, back pain, decreased or loss of feeling or sensation such as numbness, 

especially in the skin, abnormal feeling or sensation such as tingling and ‘pins and needles’, 

sleeplessness, depression, confusion, nervousness, dry mouth, loss of memory, breathlessness, 

nosebleed, serious lung infection with fever, shortness of breath, cough, phlegm; hair loss, skin itching 

or discolouration, impotence, chest pain, reduction in blood platelets, which increases the risk of 

bleeding or bruising (thrombocytopenia), accumulation of fluid around the lungs 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: may affect up to 1 in 1,000 people 

Bleeding gums, weight gain, severe chest pain (angina pectoris), heart muscle disease, (signs include 

fatigue, chest pain and palpitations), enlarged heart, accumulation of fluid around the heart, painful 

spasm of the blood vessels on the heart (while resting, usually at night or early morning) (Prinzmetal 

angina), loss of coordination, difficulty in speaking, dry skin, migraine, visual disturbances or double 

vision, ringing in the ears, dizziness on standing up (especially when getting up from a sitting or lying 

position), increased need to pass water at night, pain, ‘flu-like’ symptoms, sleepiness, widening of 

blood vessels, inflammation of the large bowel (signs include: diarrhoea, usually with blood and 

mucus, stomach pain, fever), inflammation of the stomach (signs include: pain, nausea, vomiting), 

area of abnormal density in the lung, increased creatinine level in blood tests, which may be a sign of 

kidney problems. 

 

The following side effects have been reported but it is not known exactly how often they occur: 

• Potentially life-threatening, irregular heartbeat (Torsade de pointes); 

• Inflammation of the liver, symptoms include nausea, vomiting, itching, yellowing of the skin 
and eyes, discoloration of stool and urine (hepatitis); 

• Lung inflammation (signs include fever, coughing, difficulty breathing, wheezing; which causes 
scaring of the lungs) (allergic alveolitis, including interstitial lung disease, pneumonitis); 

• Inflammation of the kidneys (tubulointerstitial nephritis). 
 

Reporting of side effects 

 

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 

not listed in this leaflet. You can also report side effects directly via the national reporting system 

listed in Appendix V. By reporting side effects, you can help provide more information on the safety 

of this medicine. 

 

 

5. How to store Xagrid 

 

Keep this medicine out of the sight and reach of children. 

 

Do not use this medicine after the expiry date which is stated on the carton and bottle label 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. 

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 

throw away medicines you no longer use. These measures will help protect the environment. 

 

 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


24 

6. Contents of the pack and other 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; lactose, anhydrous; lactose monohydrate; 

cellulose, microcrystalline (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. The bottle also contains a small 

sealed container. This contains a drying agent to keep the capsules dry. Keep the sealed container in 

the bottle. Do not remove or eat the drying agent. 

 

Marketing Authorisation Holder and Manufacturer 

 

Shire Pharmaceuticals Ireland Limited 

Block 2 & 3 Miesian Plaza 

50 – 58 Baggot Street Lower 

Dublin 2 

Ireland 

Tel: +800 66838470 

E-mail: medinfoEMEA@shire.com 

 

 

  

This leaflet was last revised in . 

 

Detailed information on this medicine is available on the European Medicines Agency web site: 

http://www.ema.europa.eu. There are also links to other websites about rare diseases and treatments. 

 

http://www.ema.europa.eu/

	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET