Tavlesse

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



 

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This medicinal product is subject to additional monitoring. This will allow quick identification of 
new safety information. Healthcare professionals are asked to report any suspected adverse reactions. 
See section 4.8 for how to report adverse reactions. 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
TAVLESSE 100 mg film-coated tablets 
TAVLESSE 150 mg film-coated tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
TAVLESSE 100 mg film-coated tablets 
Each film-coated tablet contains 126.2 mg of fostamatinib disodium hexahydrate equivalent to 100 mg 
fostamatinib 
 
Excipient(s) with known effect 
Each 100 mg tablet contains 23 mg sodium (from excipients and fostamatinib disodium hexahydrate).  
 
TAVLESSE 150 mg film-coated tablets 
Each film-coated tablet contains 189.3 mg of fostamatinib disodium hexahydrate equivalent to 150 mg 
fostamatinib. 
 
Excipient(s) with known effect 
Each 150 mg tablet contains 34 mg sodium (from excipients and fostamatinib disodium hexahydrate).  
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Film-coated tablet. 
 
TAVLESSE 100 mg film-coated tablets 
Approximately 9.0 mm round, biconvex, dark orange film-coated tablet debossed “100” on one side 
and “R” on the other side.  
 
TAVLESSE 150 mg film-coated tablets 
Approximately 7.25 mm x 14.5 mm oval, biconvex, light orange film-coated tablet debossed “150” on 
one side and “R” on the other side. 
 
 
4. CLINICAL PARTICULARS 
 
4.1. Therapeutic indications 
 
TAVLESSE is indicated for the treatment of chronic immune thrombocytopenia (ITP) in adult patients 
who are refractory to other treatments (see section 5.1). 
 
4.2. Posology and method of administration 
 
Fostamatinib treatment should be initiated and remain under the supervision of a physician who is 
experienced in the treatment of haematological diseases. 
 



 

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Posology 
 
Fostamatinib dosing requirements must be individualised based on the patient’s platelet counts. The 
lowest dose of fostamatinib to achieve and maintain a platelet count of at least 50,000/µL should be 
used. Dose adjustments are based upon the platelet count response and tolerability (see table 2). 
 
The recommended starting dose of fostamatinib is 100 mg twice daily.  
 
After initiating fostamatinib, the dose can be increased to 150 mg twice daily after 4 weeks based on 
platelet count and tolerability. A daily dose of 300 mg daily must not be exceeded. 
 
Missed dose 
In the case of a missed dose of fostamatinib, patients should take their next dose at its regularly 
scheduled time. 
 
Discontinuation 
 
Treatment with fostamatinib should be discontinued after 12 weeks of fostamatinib therapy if the 
platelet count does not increase to a level sufficient to avoid clinically important bleeding. 
 
Monitoring and dose modifications 
 
Fostamatinib dose modification is recommended based on tolerability and platelet counts. 
Management of some adverse reactions may require dose interruption, reduction, or discontinuation 
(see table 1 and table 2).  
 
Clinical haematology, blood pressure and liver function tests should be monitored regularly 
throughout therapy with fostamatinib (see section 4.4.) and the dosing should be adjusted as outlined 
in table 1. For example, if a patient is on the maximum dose at the time of an adverse reaction, the first 
dose reduction would be from 300 mg/day to 200 mg/day. 
 
Table 1: Dose reduction schedule 

Daily Dose 
Administered as: 

AM PM 
300 mg/day 150 mg 150 mg 
200 mg/day 100 mg 100 mg 
150 mg/day 150 mg1 --- 
100 mg/day2 100 mg1 --- 

1 Once daily fostamatinib should be taken in the morning. 
2 If further dose reduction below 100 mg/day is required, discontinue fostamatinib. 
 
The recommended dose modifications for adverse reactions are provided in table 2.  
 



 

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Table 2: Recommended dose modifications for adverse reactions 
Adverse reaction Recommended action 

Hypertension 
Stage 1: systolic between 
130-139 or diastolic between 
80-89 mmHg 

Initiate or increase dose of antihypertensive medication for 
patients with increased cardiovascular risk, and adjust as needed 
until blood pressure (BP) is controlled. 
If the BP target is not met after 8 weeks, reduce fostamatinib to 
next lower daily dose (refer to table 1). 

Stage 2: systolic at least 140 or 
diastolic at least 90 mmHg 

Initiate or increase dose of antihypertensive medication, and 
adjust as needed until BP is controlled. 
If BP remains 140/90 mmHg or higher for more than 8 weeks, 
reduce fostamatinib to next lower daily dose (refer to table 1). 
If BP remains 160/100 mmHg or higher for more than 4 weeks 
despite aggressive antihypertensive therapy, interrupt or 
discontinue fostamatinib. 

Hypertensive crisis: systolic over 
180 and/or diastolic over 
120 mmHg 

Interrupt or discontinue fostamatinib. 
Initiate or increase dose of antihypertensive medication, and 
adjust as needed until BP is controlled. If BP returns to less than 
the target BP, resume fostamatinib at same daily dose. 
If repeat BP is 160/100 mmHg or higher for more than 4 weeks 
despite aggressive antihypertensive treatment, discontinue 
fostamatinib.  

Hepatotoxicity 
AST/ALT is 3 x ULN or higher 
and less than 5 x ULN  

If patient is symptomatic (e.g., nausea, vomiting, abdominal 
pain): 
Interrupt fostamatinib. 
Recheck LFTs every 72 hours until ALT/AST values are no 
longer elevated (below 1.5 x ULN) and total BL remains less 
than 2 x ULN. 
Resume fostamatinib at next lower daily dose (refer to table 1). 
If patient is asymptomatic: 
Recheck LFTs every 72 hours until ALT/AST are below 
1.5 x ULN) and total BL remains less than 2 x ULN. 
Consider interruption or dose reduction of fostamatinib if 
ALT/AST and TBL remain in this category (AST/ALT is 3 to 5 x 
ULN; and total BL remains less than 2 x ULN). 
If interrupted, resume fostamatinib at next lower daily dose (refer 
to table 1) when ALT/AST are no longer elevated (below 
1.5 x ULN) and total BL remains less than 2 x ULN. 

AST/ALT is 5 x ULN or higher 
and total BL is less than 2 x 
ULN 

Interrupt fostamatinib. 
Recheck LFTs every 72 hours: 
If AST and ALT decrease, recheck until ALT and AST are no 
longer elevated (below 1.5 x ULN) and total BL remains less 
than 2 x ULN; resume fostamatinib at next lower daily dose 
(refer to table 1). 
If AST/ALT persist at 5 x ULN or higher for 2 weeks or more, 
discontinue fostamatinib.  

AST/ALT is 3 x ULN or higher 
and total BL is greater than 2 x 
ULN 

Discontinue fostamatinib. 

Elevated unconjugated (indirect) 
BL in absence of other LFT 
abnormalities  

Continue fostamatinib with frequent monitoring since isolated 
increase in unconjugated (indirect) BL may be due to UGT1A1 
inhibition. 

Diarrhoea 
Diarrhoea Manage diarrhoea using supportive measures (e.g., dietary 

changes, hydration and/or antidiarrhoeal medication) early after 
the onset until symptom(s) have resolved.  



 

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Adverse reaction Recommended action 
If symptom(s) become severe (Grade 3 or above), temporarily 
interrupt fostamatinib. 
If diarrhoea improves to mild (Grade 1), resume fostamatinib at 
the next lower daily dose (refer to table 1). 

Neutropenia 
Neutropenia If absolute neutrophil count decreases (ANC less than 

1.0 x 109/L) and remains low after 72 hours, temporarily interrupt 
fostamatinib until resolved (ANC greater than 1.5 x 109/L). 
Resume fostamatinib at the next lower daily dose (refer to 
table 1). 

ALT = alanine aminotransferase; AST = aspartate aminotransferase; BP = blood pressure; BL = bilirubin;  
ULN = upper limit of normal; ANC = absolute neutrophil count 

 
Special populations 
 
Renal impairment 
No dose adjustment is necessary in patients with renal impairment.  
 
Hepatic impairment 
Fostamatinib should not be used in patients with severe hepatic impairment. In patients with mild or 
moderate hepatic impairment, monitoring of liver function throughout therapy with fostamatinib 
should be done. Dose regimen adjustment according to platelet counts and tolerability may be required 
(see table 1 and table 2, and section 4.4).  
 
Elderly 
No dose adjustment is necessary in elderly patients.  
 
Paediatric population 
Fostamatinib should not be used in children and adolescents less than 18 years of age because of 
adverse reactions on actively growing bones observed in nonclinical studies (see section 5.3). 
 
Method of administration  
 
Fostamatinib is for oral use. 
 
The tablets should be taken twice daily, whole with or without food (see section 5.2). In the event of 
gastric upset, tablets may be taken with food. 
 
4.3. Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
Pregnancy (see section 4.6). 
 
4.4. Special warnings and precautions for use 
 
Information is based on ITP placebo-controlled population unless specified.  
 
Excipients:  
 
TAVLESSE 100 mg film-coated tablets contains 23 mg sodium per tablet, equivalent to 1.2% of the 
WHO recommended maximum daily intake of 2 g sodium for an adult. 
 
TAVLESSE 150 mg film-coated tablets contains 34 mg sodium per tablet, equivalent to 1.7% of the 
WHO recommended maximum daily intake of 2 g sodium for an adult. 
 



 

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Hypertension 
 
Over the range of doses studied in healthy volunteers, the effect of R406 (the major active metabolite 
of fostamatinib) on BP appears to be dose-dependent and varies among subjects. In the ITP placebo-
controlled population, increased blood pressure, including the development of hypertension, was 
reported in patients treated with fostamatinib. Hypertensive crisis occurred in 1 (1%) patient. Patients 
with pre-existing hypertension may be more susceptible to the hypertensive effects of fostamatinib. In 
clinical studies, the blood pressure effects resolved within a week of discontinuing treatment.  
 
The patient’s blood pressure should be monitored every two weeks until stable, then monthly, and 
adjust or initiate antihypertensive therapy to ensure maintenance of blood pressure control during 
fostamatinib therapy. If increased blood pressure persists despite appropriate therapy, the physician 
should consider fostamatinib dose interruption, reduction or discontinuation (see section 4.2). 
 
Liver function test abnormalities and risk of hepatotoxicity 
 
In the placebo-controlled studies, laboratory testing showed maximum ALT/AST levels more than 3 x 
the upper limit of normal (ULN) in 9% of patients receiving fostamatinib and no patients receiving 
placebo.  
 
Sparse data suggest an increase risk of hyperbilirubinemia in patients with genetic polymorphisms of 
UGT1A1, e.g. Gilbert, the physician should monitor these patients frequently (see section 4.2). 
 
For all patients, transaminases recovered generally to baseline levels within 2 to 6 weeks of dose-
modification. The physician should monitor liver function tests monthly during treatment. If ALT or 
AST increase more than 3 x ULN, the physician should manage hepatotoxicity by treatment 
interruption, reduction or discontinuation. Concomitant total bilirubin increases greater than 2 X ULN 
should lead to treatment discontinuation (see section 4.2). 
 
Complete blood counts (CBCs) 
 
The physician should monitor CBCs, including platelet counts, monthly until a stable platelet count (of 
at least 50,000/µL) is achieved. Thereafter, the physician should continue to monitor CBCs, including 
neutrophils, regularly. 
 
Diarrhoea 
 
Diarrhoea is the most common adverse reaction with fostamatinib treatment, but severe diarrhoea 
occurred in 1% of patients. Patients should be monitored for the development of diarrhoea and 
managed by using supportive care measures (e.g., dietary changes, hydration and/or antidiarrhoeal 
medication) early after the onset of symptoms. If diarrhoea becomes severe (Grade 3 or above), 
administration of fostamatinib should be interrupted, reduced, or discontinued (see section 4.2). 
 
Neutropenia 
 
Neutropenia occurred in 7% of patients treated with fostamatinib; febrile neutropenia occurred in 1% 
of patients. Patients with neutropenia may be more susceptible to infections.  
 
The physician should monitor the absolute neutrophil count monthly. The physician should manage 
toxicity with fostamatinib interruption, reduction or discontinuation (see section 4.2). 
 
Infections 
 
Infections, including pneumonia and respiratory tract infections, have been reported during clinical 
trials (see section 4.8).  
 



 

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The patient should be monitored for infection during treatment. The benefit risk of continuing therapy 
during an infection should be evaluated by the physician. 
 
Bone remodeling 
 
Since fostamatinib was shown in vitro to not only target SYK but also other tyrosine kinases that are 
involved in the bone metabolism (e.g., VEGFR, RET), any potential untargeted effects on bone 
remodelling or formation remain undetermined, especially in patients with osteoporosis, patients with 
fractures or young adults where epiphyseal fusion has not yet occurred. Closer monitoring in these 
patients is therefore recommended. The benefit risk of continuing therapy during the healing of a bone 
fracture should be thoroughly evaluated by the physician. 
 
4.5. Interaction with other medicinal products and other forms of interaction 
 
Effects of other medicinal products on fostamatinib 
 
Concomitant use of rifampicin, a strong CYP3A4 inducer (600 mg once daily for 8 days) with a single 
dose of 150 mg fostamatinib decreased R406 AUC by 75% and Cmax by 59%. 
 
Concomitant use of fostamatinib with strong CYP3A4 inducers decreases exposure to R406, which 
may result in reduced efficacy. Therefore, concomitant use of fostamatinib with strong CYP3A4 
inducers is not recommended. 
 
Concomitant use of fostamatinib with strong CYP3A4 inhibitors increases exposure to R406 (the 
major active metabolite), which may increase the risk of adverse reactions. The patient should be 
monitored for toxicities of fostamatinib that may require dose reduction (see table 2) when given 
concurrently with strong CYP3A4 inhibitors. For treatment with strong CYP3A4 inhibitor of shorter 
periods, e.g. antifungals or antibacterial treatment, dose reductions could be warranted from the 
beginning of the additional treatment. A two-fold reduction in dose frequency (i.e. from 150 mg twice 
daily to 150 mg once daily or 100 mg twice daily to 100 mg once daily) of fostamatinib in the 
presence of a strong CYP3A4 inhibitor is warranted. The physician should consider resuming the 
fostamatinib dose that was used prior to concomitant use of a strong CYP3A4 inhibitor 2 to 3 days 
after discontinuation of the inhibitor. 
 
Concomitant use of ketoconazole, a strong CYP3A4 inhibitor (200 mg twice daily for 3.5 days) with a 
single dose of 80 mg fostamatinib (0.53 times the 150 mg dose) increased R406 AUC by 102% and 
Cmax by 37%.  
 
Other medicinal products with strong CYP3A4 inhibition potential when coadministered with 
fostamatinib are: 
 
boceprevir, cobicistat, conivaptan, danoprevir and ritonavir, elvitegravir and ritonavir, grapefruit 
juice, indinavir and ritonavir, itraconazole, ketoconazole, lopinavir and ritonavir, paritaprevir and 
ritonavir and (ombitasvir and/or dasabuvir), posaconazole, ritonavir, saquinavir and ritonavir, 
telaprevir, tipranavir and ritonavir, troleandomycin, voriconazole, clarithromycin, diltiazem, 
idelalisib, nefazodone, nelfinavir 
 
Concomitant use of verapamil, a moderate CYP3A4 inhibitor (80 mg three times daily for 4 days) 
with a single dose of 150 mg fostamatinib increased R406 (the major active metabolite) AUC by 39% 
and Cmax by 6%. 
 
Increase in gastric pH does not affect exposure of R406 
 
Coadministration of fostamatinib with 150 mg ranitidine, an H2-blocker that increases gastric pH did 
not have clinically relevant impact on R406 exposure.  
 



 

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Effects of fostamatinib on other medicinal products 
 
CYP3A4 substrate  
Concomitant use of fostamatinib may increase systemic exposure of some CYP3A4 substrate 
medicinal products. Patients should be monitored for toxicities of CYP3A4 substrate medicinal 
products, that may require dose reduction when given concurrently with fostamatinib.  
 
Concomitant use of simvastatin (single dose 40 mg) with fostamatinib 100 mg administered twice 
daily increased simvastatin AUC by 64% and Cmax by 113% and simvastatin acid AUC by 66% and 
Cmax by 83%. 
 
Concomitant use of midazolam (single dose 7.5 mg) with fostamatinib 100 mg administered twice 
daily increased midazolam AUC by 23% and Cmax by 9%. 
 
Concomitant use of a combined hormonal contraceptive containing 0.03 mg ethinylestradiol with 
fostamatinib 100 mg administered twice daily increased AUC by 28% and Cmax by 34%. 
 
BCRP and P-gp substrate 
Concomitant use of fostamatinib may increase concentrations of P-gp substrates (e.g. digoxin) and 
BCRP substrates (e.g. rosuvastatin). The toxicities of these drugs should be monitored as a dose 
reduction may be required when given concurrently with fostamatinib. For rosuvastatin, shift to 
another treatment should be considered and for digoxin, additional therapeutic drug monitoring could 
be necessary. 
 
Concomitant use of rosuvastatin (single dose 20 mg) with fostamatinib 100 mg administered twice 
daily increased rosuvastatin AUC by 95% and Cmax by 88%. 
 
Concomitant use of digoxin (0.25 mg once daily) fostamatinib 100 mg administered twice daily 
increased digoxin AUC by 37% and Cmax by 70%. 
 
CYP2C8 substrate 
Concomitant use of fostamatinib does not affect the exposure of CYP2C8 substrate drugs. No dose 
adjustment of CYP2C8 substrate drug is necessary.  
 
Concomitant use of pioglitazone (single dose 30 mg) with fostamatinib 100 mg administered twice 
daily increased pioglitazone AUC by 18% and decreased Cmax by 17%. Hydroxyl-pioglitazone AUC 
and Cmax decreased by 10% and by 9%, respectively. 
 
Effect on warfarin 
Since SYK-inhibition may have potential effects on platelet aggregation, anticoagulant activity (e.g. 
INR) where relevant should be monitored when anticoagulants with narrow therapeutic index such as 
warfarin, are co-administered with fostamatinib. 
 
Co-administration with JAK-inhibitor, TPO-RAs, rituximab and other immune-modulating agents has 
not been investigated. 
 
In vitro studies 
 
Fostamatinib is an inhibitor of the human P-gp efflux transporter in vitro. 
 
CYP3A4 and UGT1A9 are involved in the metabolism of R406. R406 is a substrate of P-gp but not of 
other major transporters (OAT1/3, OCT2, OATP1B1/3, MRP2, and BCRP). R406 can inhibit 
CYP3A4 and BCRP, and can induce CYP2C8 activity. R406 is not an inhibitor of CYP2C8 and 
UGT2B7.  
 



 

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R406 is an inhibitor of UGT1A1. Inhibition of UGT1A1 may result in increased unconjugated 
bilirubin in the absence of other LFT abnormalities. Patients should be monitored for toxicity for drugs 
that are metabolised extensively by UGT1A1. 
 
Although R406 shows no inhibitory activity against UGT2B7 in vitro and is considered as a weak 
UGT1A1 inhibitor in vivo, the effect on other UGTs has not been determined. The potential of PK 
DDI for co-administration with acetaminophen therefore remains undetermined. 
 
4.6. Fertility, pregnancy and lactation 
 
Women of childbearing potential/contraception 
 
Women of childbearing potential must use effective contraception during treatment and at least one 
month after the last dose. 
 
Pregnancy 
 
Based on findings from animal studies and its mechanism of action, fostamatinib can cause foetal 
harm when administered to a pregnant woman. Pregnant women should be advised about the potential 
risk to a foetus  
 
Pregnancies occurring during clinical trials resulted in healthy newborns as well as 
stillbirths/spontaneous abortions and miscarriages (see sections 4.3 and 5.3).  
 
If a patient becomes pregnant while taking fostamatinib, therapy should be discontinued. Fostamatinib 
is contraindicated during pregnancy (see sections 4.3 and 5.3). 
 
Breast-feeding 
 
It is unknown whether fostamatinib/metabolites are excreted in human milk. 
 
Available pharmacodynamic/toxicological data in animals have shown excretion of fostamatinib 
metabolites in milk (see section 5.3) A risk to the newborns/infants cannot be excluded. Breast-feeding 
should be discontinued during treatment with fostamatinib and for at least one month after the last 
dose.  
 
Fertility 
 
There are no data on the effect of fostamatinib on human fertility. Based on the finding of reduced 
pregnancy rates in animal studies, fostamatinib may affect female fertility (see section 5.3). 
 
Studies in animals have shown no adverse effect on male fertility. Given there is no evidence for 
mutagenic or clastogenic potential, there is no concern for male-mediated birth defects. 
 
4.7. Effects on ability to drive and use machines 
 
Fostamatinib is not expected to influence the ability to drive or to use machines. The patient should 
avoid driving cars or using machines if feeling dizzy. 
 
4.8. Undesirable effects 
 
Summary of the safety profile 
 
In the ITP placebo-controlled studies, serious adverse drug reactions were febrile neutropenia, 
diarrhoea, pneumonia, and hypertensive crisis, which each occurred in 1% of patients receiving 
fostamatinib. In addition, severe adverse reactions observed in patients receiving fostamatinib 



 

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included dyspnea and hypertension (both 2%); and neutropenia, arthralgia, chest pain, diarrhoea, 
dizziness, nephrolithiasis, pain in extremity, toothache, syncope and hypoxia (all 1%).  
 
Tabulated list of adverse reactions 
 
The adverse reactions are presented from the placebo-controlled clinical trials and organised according 
to primary system organ class (SOC) for each preferred term in MedDRA. The adverse reactions are 
ranked by frequency within each SOC, and presented in order of decreasing seriousness. Frequencies 
are defined as 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) and not known (cannot be estimated from the 
available data). 
 
Table 3: Tabulated list of the adverse reactions 
MedDRA SOC Frequency Adverse reactions 
Infections and infestations Uncommon Pneumonia 

Common Upper respiratory tract infection, respiratory tract 
infection, bronchitis, lower respiratory tract 
infection, viral upper respiratory tract infection 

Blood and lymphatic 
disorders 

Common Neutropenia, febrile neutropenia 

Nervous system disorders Very common Dizziness 
Common Dysgeusia 

Vascular disorders Very 
Common 

Hypertension 

Uncommon Hypertensive crisis 
Gastrointestinal disorders Very common Diarrhoea, nausea, frequent bowel movement 

Common Abdominal pain upper, abdominal pain 
Skin and subcutaneous 
tissue disorders 

Common Rash, rash erythematous, rash macular 

General disorders and 
administration site 
conditions 

Common Chest pain, fatigue, influenza like illness 

Investigations Very common Alanine aminotransferase increased, aspartate 
aminotransferase increased, blood pressure (BP) 
increased, BP diastolic abnormal, BP diastolic 
increased, BP systolic increased, hepatic enzyme 
increased, liver function test abnormal 

Common Neutrophil count decreased 
 
Description of selected adverse reactions 
 
The most commonly reported adverse reactions associated with fostamatinib were hypertension, liver 
function test abnormaltities, diarrhoea, neutropenia and infections. 
 
Hypertension 
 
Increases in blood pressure were dose dependent in early studies with fostamatinib in healthy subjects 
(see section 4.4). Hypertension events were reversible within days after dose discontinuation in these 
subjects.  
 
In the ITP placebo-controlled population, hypertension-related adverse reactions were reported for 
27.5% of patients receiving fostamatinib and 12.5% of patients receiving placebo in the placebo-
controlled studies. Hypertension-related adverse reactions were mostly mild or moderate in severity, 
with 2 patients receiving fostamatinib and 1 subject receiving placebo experiencing severe 
hypertension. Hypertensive crises was reported as a serious adverse reaction and occurred in 1 (1%) 
patient receiving fostamatinib. Dose modification (reduction or interruption) was required for 4 



 

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patients receiving fostamatinib and no placebo patients. Study drug was withdrawn due to a 
hypertension-related adverse reaction in 1 patient receiving placebo and no patients receiving 
fostamatinib.  
 
Approximately 20% of patients receiving fostamatinib required at least 1 intervention for 
hypertension-related events: increase in antihypertensive medications and/or a new antihypertensive 
medication.  
 
Liver function test abnormalities and risk of hepatotoxicity 
 
Mild to moderate increases in liver enzymes (ALT and AST) were observed in fostamatinib treated 
subjects in phase 1 studies in healthy volunteers, occurring more frequently at the higher doses tested 
(250 mg oral twice daily). These changes were mild and all were reversible (see section 4.4).  
 
In the ITP placebo-controlled population, transaminase elevation adverse reactions (ALT increased 
and AST increased) were reported in 11% and 9% of patients receiving fostamatinib. All transaminase 
elevations were mild or moderate in severity and dose modification (dose reduction or dose 
interruption) was required in 8 patients. One patient discontinued fostamatinib due to a transaminase 
elevation (ALT increased); this event resolved after discontinuation of treatment.  
 
In the ITP placebo-controlled population, laboratory testing showed maximum ALT/AST levels more 
than 3 x the upper limit of normal (ULN) in 9% of patients receiving fostamatinib and no patients 
receiving placebo. Maximum ALT and/or AST levels were > 10 x ULN in 1 patient receiving 
fostamatinib. Transaminase elevations recovered to baseline levels within 2 to 4 weeks of dose 
modification. The median (range) time to onset of transaminase elevation was 58 days (43 to 127), and 
the median (range) duration of each event was 14.5 days (6 to 28 days). 
 
Diarrhoea 
 
Gastrointestinal complaints, specifically noninfectious diarrhoea events, were among the most 
common adverse reactions reported in patients treated with fostamatinib throughout the clinical 
development program. Non-infectious diarrhoea events are considered definitely related to 
fostamatinib treatment (see section 4.4).  
 
In the placebo-controlled ITP population, noninfectious diarrhoea was the most commonly reported GI 
complaint, occurring in 31% of subjects receiving fostamatinib. Noninfectious diarrhoea events were 
most frequently mild-to-moderate in severity. The majority of subjects with moderate diarrhoea 
received antidiarrhoeal agents (loperamide) to mitigate their symptoms. Severe diarrhoea was reported 
in 1% of patients receiving fostamatinib during the placebo-controlled period. Dose modification 
(interruption or reduction) was reported for approximately 5% of subjects receiving fostamatinib; 
however study drug was discontinued because of adverse events (AEs) of diarrhoea in a single 
fostamatinib subject during the placebo-controlled period.  
 
Approximately 25% of patients receiving fostamatinib experienced noninfectious diarrhoea during the 
first 12 weeks of treatment during the placebo-controlled period. Among the patients receiving 
fostamatinib who had moderate or severe diarrhoea, the median time to the first occurrence of 
moderate or severe diarrhoea was 57 days and the median duration of the events was approximately 
15 days.  
 
Neutropenia 
 
In the initial Phase 1 human subject study, it was observed that at higher fostamatinib doses (up to 
300 mg twice daily), the biologically active component of fostamatinib produced significant 
reductions in neutrophils, which were rapidly reversible upon discontinuation of therapy (see section 
4.4). The rapidity of the recovery suggested a compartment effect more than an effect on progenitors. 
This effect on neutrophils was observed in all clinical programs. 
 



 

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In the placebo-controlled ITP population, neutropenia adverse reactions were reported for 7% of 
patients in the fostamatinib group and no patients in the placebo group. Most neutropenia adverse 
reactions were not associated with an infection and were mild or moderate in severity. Severe 
neutropenia was reported in 2 patients; 1 of these was a serious adverse reaction of febrile neutropenia 
that was attributed to an unknown infection. Three patients required dose modification for neutropenia 
per protocol, and study drug was discontinued due to neutropenia in 1 patient. All neutropenia adverse 
reactions except 1 resolved by the end of the study.  
 
In the placebo-controlled ITP population, 2 patients receiving fostamatinib and no patients receiving 
placebo had a decrease in neutrophils to between ≥ 0.5 and < 1.0 × 109/L. Seven patients receiving 
fostamatinib and 1 patient receiving placebo had neutrophil counts decrease to between ≥ 1.0 and 
< 1.5 × 109/L. No patient had a decrease in neutrophils to < 0.5 × 109/L. 
 
Infections 
 
In the placebo-controlled ITP population, infection adverse reactions were reported in 30% of patients 
receiving fostamatinib and 20% of patients receiving placebo (see section 4.4). Infections involving 
the respiratory tract accounted for 60% of the adverse events in the fostamatinib group and 40% of the 
events in the placebo group. No systemic opportunistic infections were reported in the fostamatinib 
program. Serious adverse reactions for infection were uncommon. Severe infection events included 
pneumonia and influenza-like illness (1 patient each in the fostamatinib group) and sepsis (1 patient in 
the placebo group). One patient in the fostamatinib group discontinued study treatment due to an 
infection (pneumonia). Neutropenia was rarely associated with infection.  
 
Elderly population  
 
Of the total number of patients in clinical studies of fostamatinib, 16.4% were 65 years of age and 
older, while 2.4% were 75 years of age and older. In general, incidences of adverse reactions were 
higher in the older population.  
 
In patients 65 years of age and older, 6 (21%) patients experienced serious adverse events and 5 (18%) 
experienced adverse events leading to treatment withdrawal while in patients under 65 years of age, 
7 (9%) and 5 (7%) experienced serious adverse events and adverse events leading to treatment 
withdrawal, respectively. In patients 65 years of age and older who received fostamatinib, 11 (39%) 
patients experienced hypertension versus 2 (18%) placebo compared to 17 (23%) in patients under 
65 years of age versus 4 (11%) placebo. 
 
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 
 
There is no specific antidote for overdose with fostamatinib, and the amount of R406 cleared by 
dialysis is negligible. There has not been any experience of overdose in the clinical development 
program. In the event of an overdose, the physician should monitor the patient closely for signs and 
symptoms of adverse reactions as described in section 4.2, and treat the reactions with supportive care.  
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1. Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antihemorrhagics, other systemic haemostatics. ATC code: B02BX09 



 

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Mechanism of action 
 
Fostamatinib mediates its activity effectively through its major metabolite, R406, which is a tyrosine 
kinase inhibitor with demonstrated activity against spleen tyrosine kinase (SYK). R406 inhibits signal 
transduction of B-cell receptors and Fc-activating receptors, which play a key role in antibody-
mediated cellular responses. The fostamatinib metabolite R406 reduces antibody-mediated destruction 
of platelets. 
 
Clinical efficacy and safety 
 
The efficacy and safety of fostamatinib has been demonstrated in two Phase III, randomised, double-
blind, placebo-controlled studies (C788-047 and C788-048) in adult patients with previously treated 
persistent (3-12 months since diagnosis) or chronic (greater than 12 months since diagnosis) ITP.  
 
Randomised, placebo-controlled studies 
A total of 150 patients with persistent or chronic ITP, who had an insufficient response to previous 
treatment (which included corticosteroids, immunoglobulins, splenectomy, and/or a thrombopoietin 
receptor agonists) were enrolled in two identical, double-blind, placebo-controlled studies that were 
conducted in different countries.  
 
For each study, patients were randomised 2:1 to fostamatinib or placebo for 24 weeks; randomisation 
was stratified with respect to prior splenectomy and severity of thrombocytopenia. Stable concurrent 
ITP therapy (glucocorticoids [less than 20 mg prednisone equivalent per day], azathioprine, or 
danazol) was allowed, and rescue therapy was permitted, if needed. All patients initially received 
study drug at 100 mg twice daily (or matching placebo). Based on platelet count and tolerability, dose 
escalation to 150 mg twice daily (or matching placebo) was undertaken in 86% of patients at Week 4 
or later.  
 
Patients enrolled in the placebo-controlled studies had a median age of 54 years old (range: 20 to 
88 years; median age in C788-047 was 57.0 and in C788-048 was 49.5 years), and the majority were 
female (61%) and were white (93%). Prior ITP treatments were varied (median of 3, range of 1-14), 
with the most common including corticosteroids (94%), immunoglobulins (53%), and thrombopoietin 
receptor agonists (TPO-RA) (48%). Most patients had chronic ITP (93%), with a median time since 
ITP diagnosis of 8.5 years, and 35% had undergone splenectomy. At baseline, the median platelet 
count was 16,000/µL (with almost half [45%] less than 15,000/µL) and 47% were on stable ITP 
therapy. Of the 102 patients with ITP who received fostamatinib, 28 (27%) were 65 years of age and 
older while 11 (11%) were 75 years of age and older. 
 
In Study C788-047, 76 patients were randomised; 51 to the fostamatinib group and 25 to the placebo 
group. In Study C788-048, 74 patients were randomised; 50 to the fostamatinib group and 24 to the 
placebo group. The efficacy of fostamatinib was based on the primary endpoint of stable platelet 
response (at least 50,000/µL on at least 4 of the 6 visits between Weeks 14 to 24). Study outcomes for 
C788-047 and C788-048 are shown in table 4. 
 



 

14 

Table 4: Study outcomes from placebo-controlled clinical studies 

Study 
Outcomes 

Statistical 
Parameters 

Study C788-047 Study C788-048 Pooled studies 
Refractory 
population6 

Fosta 
(N=51) 

PBO 
(N=25) 

Fosta 
(N=50) 

PBO 
(N=24) 

Fosta 
(N=101) 

PBO 
(N=49) 

Fosta 
(N= 72) 

PBO 
(N=33) 

Stable 
platelet 
response1,2 

n (%) 8 (16) 0 (0) 9 (18) 1 (4) 17 (17) 1 (2) 10 (14) 0 (0) 
CI 95% (5.7, 25.7) (0, 0) (7.4, 28.7) (0, 12.2) (9.5, 24.1) (0, 6.0) (5.9, 21.9) (0.0, 0.0) 
p-value p3 = 0.0471 NS p3=0.0071 P3=0.0287 

Eligible for 
C788-0494 at 
Week 125 

n (%) 28 (55) 22 (88) 33 (66) 19 (79) 61 (60) 41 (84) 43 (60) 29 (88) 

Completed 
study 
(Week 24) 

n (%) 12 (24) 1 (4) 13 (26) 2 (8) 25 (25) 3 (6) 16 (22) 1 (3) 

1 Includes all patients with platelet counts and excludes patients whose platelet counts were measured following 
rescue therapy after Week 10.  

2 Stable platelet response was prospectively defined as a platelet count of at least 50,000/µL on at least 4 of the 
6 visits between Weeks 14 and 24. 

3 p-value from Fisher Exact test 
4 C788-049: open label extension study 
5 Patients who did not respond to treatment after 12 weeks were eligible to enrol in open-label extension study. 
6 Refractory patient population defined as the subgroup of patients who had received three or more prior other 

ITP therapies 
Fosta = fostamatinib; PBO = placebo; NS = Did not demonstrate a statistically significant difference between 

treatment arms 
 
An initial therapeutic response (platelet count ≥ 50,000/μL) was observed within 6 weeks for most 
responders (11 of 17 responders) and within 12 weeks for all stable responders. 
 
Among patients who were stable responders, the median platelet count increased to 95,000/µL across 
post-baseline visits with a maximum of 150,000/µL. Rescue medication was required by 30% and 
45% of patients receiving fostamatinib or placebo, respectively. 
 
During the placebo-controlled studies, the incidence of bleeding occurred in 29% and 37% of patients 
in the fostamatinib and placebo arms, respectively. The incidence of moderate or severe 
bleeding-related adverse events (AEs) (16.3% vs. 9.9%) and serious adverse events (SAEs) (10.2% vs 
5.0%) was about twice as high in the placebo group compared with the fostamatinib group. Only one 
subject treated with fostamatinib experienced a severe bleeding-related event (contusion), while three 
subjects treated with placebo experienced severe events (gastrointestinal haemorrhage, menorrhagia 
and petechiae). In sum, there were trends for reduced bleeding-related AEs with fostamatinib 
compared to placebo; differences between the groups were not statistically significant.  
 
Subset analyses 
Platelet count responses for patients treated with TAVLESSE were further analysed as shown in table 
5. Results are shown for both the pooled population (from Studies C788-047 and C788-048) and a 
refractory patient population defined as the subgroup of patients who had received three or more prior 
other ITP therapies. For all platelet count parameters, the results for the pooled population are 
comparable to the refractory patient population. 
 
Table 5: Summary of platelet count parameters by subgroup – pooled patient population 

(C788-047 and C788-048) and refractory patient population 

Parameters 

Pooled Population 
Fostamatinib 

N=101 

Refractory Patient Population 
Fostamatinib 

N=72 
Subject With Platelet Response (≥50000/µL) at Week 12, n (%)  
    Yes 23 (22.8%) 14 (19.4%) 
    No 78 (77.2%) 58 (80.6%) 
Change From Baseline in Platelet Count (/µL) at Week 12  
    Median 4000 3000 
    Range (-15000, 220000) (-5000, 159000) 



 

15 

Median Platelet Count (/µL) Over Time  
    Median 22000 16750 
    Range (1000, 254500) (1000, 105500) 
 
Extension Study 
The C788-049 trial is an open label extension study. Patients from C788-047 and C788-048 who 
completed 24 weeks of treatment, or who did not respond to treatment after 12 weeks, were eligible to 
enrol in this study. Patients remained blinded to their treatment assignment from the previous study 
(fostamatinib or placebo), so their starting dose in this study was based on their final platelet count. 
 
For the C788-049 trial, 123 patients were enrolled, 44 patients previously randomised to placebo and 
79 patients previously randomised to fostamatinib.  
 
Placebo Crossover: In a prospectively defined analysis, the 44 subjects treated with placebo in the 
prior study were evaluated for stable response for fostamatinib (from the first 24 weeks of the study) 
with their placebo data as the comparator for this objective measure. Ten of these subjects (22.7%) 
(including a single subject who was classified as a placebo responder in the prior study) met the 
criteria for stable response. Thus, the difference in response from fostamatinib compared with placebo 
was 20.5% (95% CI = 8.5-32.4).  
 
Extension: Among the patients who achieved stable response in C788-047, C788-048 and C788-049 
trials, 18 subjects maintained the platelet count of at least 50,000/µL for 12 months or longer. 
 
Paediatric population 
 
The European Medicines Agency has waived the obligation to submit the results of studies with 
fostamatinib in all subsets of the paediatric population for the treatment of thrombocytopenia for 
patients with chronic immune thrombocytopenia (ITP), who have had an insufficient response to a 
previous treatment (e.g., corticosteroids), (see section 4.2 for information on paediatric use). 
 
5.2. Pharmacokinetic properties 
 
Absorption 
 
Following oral administration, the prodrug fostamatinib is rapidly converted to its active metabolite 
R406, presumably via enzymes in the gut.  
 
After oral administration of fostamatinib, the mean absolute bioavailability of R406 was 55% with 
high variability (range 30 – 85 %). The median Tmax of R406 is approximately 1.5 hours (range: 1 to 
4 hours). Negligible levels of fostamatinib were found in plasma.  
 
After a single 150 mg oral dose of fostamatinib, mean (± standard deviation [SD]) exposure estimates 
of R406 are 550 (± 270) ng/mL for Cmax and 7080 (± 2670) ng/mL for AUC. R406 exposure is 
approximately dose proportional up to 200 mg twice daily (1.3 times the 150 mg dose). R406 
accumulates approximately 2- to 3-fold upon twice daily dosing at 100–160 mg (0.67 to 1.06 times the 
150 mg dose). 
 
Distribution 
 
Fostamatinib is highly bound to plasma proteins (98.3% in human plasma) and distributes reversibly 
into blood cells. The mean (± SD) volume of distribution at steady-state of R406 is 256 (± 92) L. 
 
Metabolism 
 
Fostamatinib is metabolised in the gut by alkaline phosphatase to the major active metabolite, R406. 
R406 is extensively metabolised, primarily through pathways of CYP450-mediated oxidation (by 
CYP3A4) and glucuronidation (by UDP glucuronosyltransferase [UGT]1A9). R406 is the 



 

16 

predominant moiety in the systemic circulation, and there was minimal exposure to any R406 
metabolites. 
 
Elimination/Excretion 
 
In humans, the mean (± SD) terminal half-life of R406 is approximately 15 (± 4.3) hours. 
Approximately 20% of the administered radioactivity was recovered in the urine, primarily in the form 
of an N-glucuronide of R406. Renal elimination of parent drug was low. The remaining radioactivity 
(~80%) was recovered in the faeces, mainly represented by 2 major metabolites of R406.  
 
Linearity/non-linearity 
 
R406 pharmacokinetics is linear and exposure is approximately dose-proportional up to 200 mg twice 
daily (1.3 times the 150 mg dose). R406 accumulates approximately 2- to 3-fold upon twice daily 
dosing at 100-160 mg (0.67 to 1.06 times the 150 mg dose). 
 
Food interaction  
 
Administration of fostamatinib with a high-calorie, high-fat meal (deriving approximately 150, 250, 
and 500–600 calories from protein, carbohydrate, and fat, respectively) increased R406 AUC by 23% 
and Cmax by 15%, indicating fostamatinib can be administered with or without food. 
 
Special populations 
 
Population pharmacokinetics analyses indicate fostamatinib is not altered based on age, sex, 
race/ethnicity.  
 
The pharmacokinetics of fostamatinib is not altered in subjects with renal impairment (creatinine 
clearance [CLcr] = 30 to < 50 mL/min, estimated by Cockcroft Gault equation and end stage renal 
disease requiring dialysis), or hepatic impairment (Child-Pugh Class A, B and C). 
 
5.3. Preclinical safety data 
 
In two fostamatinib 4-week rat studies (with the calcium and sodium salts), chondrodystrophy of the 
femoral head was observed in some animals in the highest dose groups (that were still juvenile/young 
during the treatment interval) and was not fully reversible by the end of the recovery period. 
 
In a 1-month study in juvenile rabbits, fostamatinib produced growth plate dysplasia in the proximal 
femur and femoro-tibial joint and reduced bone marrow cellularity in the femur and sternum at 30 and 
60 mg/kg/day. Increased degenerate/necrotic ovarian follicles occurred in females at all fostamatinib 
dose levels (including 10 mg/kg/day). The changes noted in the growth plates and ovaries are 
consistent with an anti-angiogenic effect. 
 
Fostamatinib was not carcinogenic in a 2-year study in mice when administered daily by oral gavage 
at doses up to 500/250 mg/kg/day, and was not carcinogenic in rats when administered by oral gavage 
at 45 mg/kg/day. Fostamatinib and its major active metabolite (R406) were not mutagenic in an in 
vitro bacterial reverse mutation (Ames) assay or clastogenic in an in vitro human lymphocyte 
chromosomal aberration assay or an in vivo mouse bone marrow micronucleus assay.  
 
Studies in animals have shown no adverse effect on male fertility. Given there is no evidence for 
mutagenic or clastogenic potential, there is no concern for male-mediated birth defects. In a fertility 
study with oral fostamatinib, all mating (e.g., time to mating, breeding proficiency), sperm 
assessments (e.g., number and motility), and organ weight (e.g., paired testis weight) parameters in 
male rats were unaffected by doses as high as 40 mg/kg/day. This dose yields an AUC of R406 
approximately 3.8 times that of the MRHD. All mating and fertility parameters in female rats were 
unaffected by doses as high as 11 mg/kg/day. This dose would yield an AUC of R406 similar to that of 



 

17 

the MRHD. A slight decrease in pregnancy rates and an increase in post-implantation loss were seen at 
25 mg/kg/day. This dose would yield an AUC of R406 2.6 times that of the MRHD. 
 
In animal reproduction studies, administration of fostamatinib to pregnant rats and rabbits during 
organogenesis caused adverse developmental outcomes including embryo-foetal mortality (post-
implantation loss), alterations to growth (lower foetal weights), and structural abnormalities 
(variations and malformations) at maternal exposures (AUCs) approximately 0.3 and 10 times the 
human exposure at the maximum recommended human dose (MRHD) respectively. 
 
A slight decrease in pregnancy rates and an increase in post-implantation loss in female rats was 
observed. Nonclinical studies have established that the administration of fostamatinib during 
pregnancy can increase the risk of embryonic loss, retard growth, and promote specific malformations 
of the kidney (including agenesis) and associated urogenital (e.g. ureter) tissues, as well as 
variations/malformations in major vessel and skeletal development. These effects are consistent with 
known targets of fostamatinib, including Syk (target), VEGFR-2 (off target) and Ret-kinase (off 
target). Based on nonclinical studies, any latent issues with female fertility is not expected after 
fostamatinib is withdrawn. 
 
In pregnant rats and rabbits, R406 was found to cross the placenta. In general, the maternal plasma 
R406 concentrations were greater than the foetal plasma R406 concentrations. 
 
In rodents, R406 was detected in maternal milk in concentrations 5- to 10-fold higher than in maternal 
plasma. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1. List of excipients 
 
Tablet core 
Mannitol 
Sodium hydrogen carbonate 
Sodium starch glycolate, (type A) 
Povidone (K30) 
Magnesium stearate 
 
Film-coating 
Poly(vinyl alcohol) 
Titanium dioxide 
Macrogol (3350)  
Talc 
Iron oxide yellow 
Iron oxide red 
 
6.2. Incompatibilities 
 
Not applicable.  
 
6.3. Shelf life 
 
3 years 
 
6.4. Special precautions for storage 
 
This medicinal product does not require any special temperature storage conditions. Store in the 
original package to protect from moisture. Keep the bottle tightly closed. 
 



 

18 

6.5. Nature and contents of container  
 
White high density polyethylene (HDPE) bottle with an aluminium foil tamper evident seal and a 
white polypropylene (PP) child-resistant cap, together with two white opaque HDPE desiccant 
canisters containing silica gel. 
 
Pack sizes of 30 and 60 film-coated tablets. Not all pack sizes may be marketed. 
 
6.6. Special precautions for disposal  
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements.  
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Instituto Grifols, S.A. 
Can Guasc, 2 - Parets del Vallès 
08150 Barcelona - Spain 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
TAVLESSE 100 mg film-coated tablets 
EU/1/19/1405/001 
 
TAVLESSE 150 mg film-coated tablets 
EU/1/19/1405/002 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 09 january 2020 
 
 
10. DATE OF REVISION OF THE TEXT 

  



 

19 

 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURER 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 

 



 

20 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE  
 
Name and address of the manufacturer(s) responsible for batch release 
 
Instituto Grifols, S.A. 
Can Guasc, 2 - Parets del Vallès 
08150 Barcelona – Spain 
 
 
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 
 

 Periodic safety update reports (PSURs) 
 
The requirements for submission of PSURs 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. 
 
The marketing authorisation holder (MAH) shall submit the first PSUR for this product within 6 
months following authorisation. 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE 

USE OF THE MEDICINAL PRODUCT 
 
 Risk management plan (RMP) 
 
The marketing authorisation holder (MAH) shall perform the required pharmacovigilance activities 
and interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing authorisation 
and any agreed subsequent updates of the RMP. 
 
An updated RMP should be submitted: 
 At the request of the European Medicines Agency; 
 Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result of 
an important (pharmacovigilance or risk minimisation) milestone being reached. 

 
  



 

21 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
 
  



 

22 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 



 

23 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
OUTER CARTON 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
TAVLESSE 100 mg film-coated tablets  
fostamatinib 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 126.2 mg of fostamatinib disodium hexahydrate equivalent to 100 mg 
of fostamatinib. 
 
 
3. LIST OF EXCIPIENTS 
 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
60 film-coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use 
Do not remove desiccants. 
 
 
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 temperature storage conditions. Store in the 
original package to protect from moisture. Keep the bottle tightly closed. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 



 

24 

 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Instituto Grifols, S.A. 
Can Guasc, 2 - Parets del Vallès 
08150 Barcelona - Spain 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/19/1405/001 (100 mg film-coated tablets) 
 
 
13. BATCH NUMBER 
 
LOT 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
 
15. INSTRUCTIONS ON USE 
 
 
 
16. INFORMATION IN BRAILLE 
 
TAVLESSE 100 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC  
SN  
NN 



 

25 

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING 
 
BOTTLE LABEL 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
TAVLESSE 100 mg film-coated tablets  
fostamatinib 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 126.2 mg of fostamatinib disodium hexahydrate equivalent to 100 mg 
of fostamatinib. 
 
 
3. LIST OF EXCIPIENTS 
 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
60 film-coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use 
Do not remove desiccants. 
 
 
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 temperature storage conditions. Store in the 
original package to protect from moisture. Keep the bottle tightly closed. 
 



 

26 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Instituto Grifols, S.A. 
Can Guasc, 2 - Parets del Vallès 
08150 Barcelona - Spain 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/19/1405/001 (100 mg film-coated tablets) 
 
 
13. BATCH NUMBER 
 
LOT 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
 
15. INSTRUCTIONS ON USE 
 
 
 
16. INFORMATION IN BRAILLE 
 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 



 

27 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON  
 
OUTER CARTON 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
TAVLESSE 150 mg film-coated tablets  
fostamatinib 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 189.3 mg of fostamatinib disodium hexahydrate equivalent to 150 mg 
of fostamatinib. 
 
 
3. LIST OF EXCIPIENTS 
 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
60 film-coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use 
Do not remove desiccants. 
 
 
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 temperature storage conditions. Store in the 
original package to protect from moisture. Keep the bottle tightly closed. 
 



 

28 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Instituto Grifols, S.A. 
Can Guasc, 2 - Parets del Vallès 
08150 Barcelona - Spain 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/19/1405/002 (150 mg film-coated tablets) 
 
 
13. BATCH NUMBER 
 
LOT 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
 
15. INSTRUCTIONS ON USE 
 
 
 
16. INFORMATION IN BRAILLE 
 
TAVLESSE 150 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC  
SN  
NN 
 



 

29 

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING 
 
BOTTLE LABEL 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
TAVLESSE 150 mg film-coated tablets  
fostamatinib 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 189.3 mg of fostamatinib disodium hexahydrate equivalent to 150 mg 
of fostamatinib. 
 
 
3. LIST OF EXCIPIENTS 
 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
60 film-coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use 
Do not remove desiccants. 
 
 
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 temperature storage conditions. Store in the 
original package to protect from moisture. Keep the bottle tightly closed. 
 
 



 

30 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Instituto Grifols, S.A. 
Can Guasc, 2 - Parets del Vallès 
08150 Barcelona - Spain 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/19/1405/002 (150 mg film-coated tablets) 
 
 
13. BATCH NUMBER 
 
LOT 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
 
15. INSTRUCTIONS ON USE 
 
 
 
16. INFORMATION IN BRAILLE 
 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA  
 
  



 

31 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



 

32 

Package leaflet: Information for the patient 
 

TAVLESSE 100 mg film-coated tablets 
TAVLESSE 150 mg film-coated tablets 

fostamatinib disodium hexahydrate 
 

This medicine is subject to additional monitoring. This will allow quick identification of new 
safety information. You can help by reporting any side effects you may get. See the end of section 4 
for how to report side effects. 
 
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 any further questions, ask your doctor, pharmacist or nurse. 
 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, pharmacist or nurse. This includes any possible 

side effects not listed in this leaflet. See section 4. 
 
What is in this leaflet 
1. What TAVLESSE is and what it is used for  
2. What you need to know before you take TAVLESSE 
3. How to take TAVLESSE 
4. Possible side effects  
5. How to store TAVLESSE 
6. Contents of the pack and other information 
 
1. What TAVLESSE is and what it is used for 
 
What TAVLESSE is 
TAVLESSE contains the active substance fostamatinib. It specifically targets an enzyme called spleen 
tyrosine kinase, that plays an important part in the destruction of platelets. In this way TAVLESSE 
limits platelet destruction by the immune system and increases platelet count in the body. This helps 
reduce the risk of severe bleeding. 
 
What TAVLESSE is used for 
TAVLESSE is used to treat adults with low platelet counts due to chronic immune thrombocytopenia 
(ITP) when an earlier treatment for ITP has not worked well enough. ITP is an autoimmune disease, in 
which the body’s own immune system attacks and destroys platelets in the blood. Platelets are needed 
to help create clots and stop bleeding. 
 
2. What you need to know before you take TAVLESSE  
 
Do not take TAVLESSE 
 if you are allergic to fostamatinib or any of the other ingredients in this medicine (listed in 

section 6).  
 if you are pregnant. 
 
Warnings and precautions 
Talk to your doctor or pharmacist before taking TAVLESSE, about all of your medical conditions, 
particularly if you: 
 have high blood pressure, 
 have liver problems, 
 are pregnant or plan to become pregnant,  
 are breastfeeding or plan to breastfeed.  
 



 

33 

Tell your doctor, pharmacist or nurse immediately if you get any of the following symptoms while you 
are taking this medicine: 
 if you have high blood pressure (hypertension). New or worsening high blood pressure is common 

in people treated with TAVLESSE and can be severe. Your doctor will check your blood pressure 
regularly during treatment with this medicine. If needed, your doctor may start you on blood 
pressure medicine or change your current medicine to treat your blood pressure. Tell your doctor 
or pharmacist if you get headaches, confusion, dizziness, chest pain or shortness of breath.  

 if your skin and eyes appear yellowish (jaundice) or if you get abdominal pain and swelling, 
swelling in your legs and ankles, itchy skin, abnormal dark urine, pale stool colour or bloody or 
tar-coloured stool, chronic fatigue, feeling or being sick in the stomach, and loss of appetite. 
Changes in liver function blood tests are common with this medicine. These may be symptoms of 
liver problems. Liver problems may occur and can be severe. Your doctor will regularly carry out 
blood tests to check how well your liver is working during treatment with this medicine. 

 if you get diarrhoea. This is common in people treated with this medicine and can be severe. Tell 
your doctor or pharmacist if you get diarrhoea during treatment with this medicine. Your doctor 
may recommend changes in your diet, drinking more water, or give an antidiarrhoeal medicine to 
limit your symptoms. 

 if you get a high fever (a sign of serious infection), chills, feel sick, or have a general feeling of 
being unwell. Your doctor will regularly do blood tests to check your white blood cell counts, and 
you may be told about a decrease in your white blood cell counts (neutropenia). Decreases in your 
white blood cell count are common with this medicine and can be severe. This may increase your 
risk of infection, including serious infections.  

 
Children and adolescents 
TAVLESSE should not be used in patients less than 18 years of age. This medicine has not been 
studied in this age group.  
 
Other medicines and TAVLESSE 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines. 
 
Taking TAVLESSE with certain other medicines may affect how the other medicines work and other 
medicines may affect how TAVLESSE works. 
In particular, tell your doctor if you are taking anything in this list: 
 Ketoconazole, this medicine is typically used to treat fungal infections. 
 Rifampicin, this medicine is typically used to treated bacterial infections. 
 Simvastatin and rosuvastatin, these medicines are typically used to treat high cholesterol. 
 Digoxin, this medicine is typically used to treat various heart conditions such as atrial fibrillation, 

atrial flutter and heart failure. 
 Midazolam, this medicine is typically used for sedation or to treat anxiety. 
 Anticoagulants, this medicine is typically used to prevent blood clotting.  
 Nelfinavir, this medicine is typically used to treat HIV infection. 
 Verapamil, this medicine it typically used to treat various heart conditions such as high blood 

pressure. 
 Ranitidine, this medicine is typically used to treat heart burn. 
 Ethinylestradiol, this medicine is typically used for birth control. 
 Pioglitazone, this medicine is typically used to treat type 2 diabetes.  
 
Pregnancy, breast-feeding and fertility 
 
Pregnancy 
TAVLESSE should not be used during pregnancy. It can cause harm or birth defects to your unborn 
baby. 
 
If you are pregnant, if think you may be pregnant or if you are planning to have a baby, ask your 
doctor or pharmacist for advice before taking this medicine. 



 

34 

 
If you are a woman who could become pregnant, you must use reliable contraception while you are 
taking TAVLESSE, and you must continue to use reliable contraception for at least 1 month after 
taking your last dose. 
 
Contact your doctor straight away if you become pregnant while taking this medicine.  
 
Breast-feeding 
TAVLESSE is not recommended while breast-feeding. You should not breastfeed during treatment 
with TAVLESSE and for at least 1 month after your last dose. 
 
If you are breast-feeding, or are planning to breast-feed, ask your doctor or pharmacist for advice 
before taking this medicine. 
 
Fertility  
TAVLESSE may affect the ability of a woman to get pregnant and have a child. Talk to your doctor if 
this is a concern for you. There is no impact on males. 
 
TAVLESSE contains sodium 
 
TAVLESSE 100 mg film-coated tablets contains 23 mg sodium (main component of cooking/table 
salt) per tablet. This is equivalent to 1.2% of the recommended maximum daily dietary intake of 
sodium for an adult. 
 
TAVLESSE 150 mg film-coated tablets contains 34 mg sodium (main component of cooking/table 
salt) per tablet. This is equivalent to 1.7% of the recommended maximum daily dietary intake of 
sodium for an adult. 
 
3. How to take TAVLESSE 
 
How much to take 
Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor 
or pharmacist if you are not sure.  
 
Before starting treatment, your doctor will measure your platelet count. 
 
The recommended dose of TAVLESSE is 100 mg twice daily (one tablet of 100 mg).  
 
However, your doctor will check your platelet counts during your treatment with TAVLESSE and may 
change your dose as needed. 
 
After starting treatment with TAVLESSE, the dose can be increased to 150 mg twice daily (one tablet 
of 150 mg) based on platelet count and tolerability. A daily dose of 300 mg (two tablets of 150 mg) 
daily must not be exceeded. 
 
If you do not respond to treatment with fostamatinib, your doctor will stop treatment  
 
If you have liver problems or high blood pressure, your doctor may start you on a lower dose. 
If you get serious side effects (such as high blood pressure, liver problems, diarrhoea or a decrease in 
white blood cell counts), your doctor may lower your dose or stop your treatment temporarily or 
permanently. 
 
How to take TAVLESSE 
Swallow the tablets whole with water.  
 
TAVLESSE can be taken with food or between meals. 
 



 

35 

In case of stomach upset, take the tablets with food. 
 
If you are sick 
If you are sick at any time after taking TAVLESSE, do not take an additional tablet. Take your next 
dose at its regularly scheduled time. 
 
If you take more TAVLESSE than you should 
If you take too much TAVLESSE, call your doctor or pharmacist right away or go to the nearest 
hospital emergency room. 
 
If you forget to take TAVLESSE 
Do not take a double dose to make up for a forgotten tablet. Take your next dose at its regularly 
scheduled time. 
 
If you stop taking TAVLESSE 
It is important to take TAVLESSE for as long as your doctor prescribes it. Do not stop taking this 
medicine unless your doctor tells you to. 
 
If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Serious side effects 
TAVLESSE may cause serious side effects. Tell your doctor immediately if you have any of the 
following serious side effects, either for the first time or if they get worse (see also section 2): 
 high fever. Fever has been associated with low levels of white blood cells (febrile neutropenia) or 

infection 
 diarrhoea 
 infection and inflammation of the lungs (pneumonia). Symptoms include feeling short of breath, 

chest pain and producing discoloured mucus 
 jaundice, abdominal pain and swelling, swelling in your legs and ankles, itchy skin, abnormal dark 

urine, pale stool colour or bloody or tar-coloured stool, chronic fatigue, feeling or being sick in the 
stomach, loss of appetite. These may be symptoms of liver problems.  

 severe increase of blood pressure that can lead to a stroke (hypertensive crisis). Symptoms are 
headache, confusion, dizziness. 

 
Other side effects 
Besides the serious side effects mentioned above, you may also get other side effects. 
 
Very common (may affect more than 1 in 10 people): 
 gastrointestinal disorders such as diarrhoea, feeling or being sick in the stomach, and frequent 

bowel movement 
 high blood pressure 
 abnormal blood test results showing how your liver is working 
 dizziness 
 
Common (may affect up to 1 in 10 people): 
 low white blood cell count or neutropenia 
 stomach pain 
 chest pain 
 tiredness (fatigue) 
 flu-like symptoms  
 infections of the nose and throat, such as sore throat and the common cold 
 infection of the windpipe, such as bronchitis 



 

36 

 taste changes 
 rash  
 
Reporting of side effects 
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please 
tell your doctor or your pharmacist. 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 TAVLESSE 
 
Keep this medicine out of the sight and reach of children.  
 
This medicinal product does not require any special temperature storage conditions. Store in the 
original package to protect from moisture. Keep the bottle tightly closed. 
 
Do not use this medicine after the expiry date which is stated on the bottle after EXP. The expiry date 
refers to the last day of that month. 
 
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. 
 
6. Contents of the pack and other information 
 
What TAVLESSE contains  
- The active substance is fostamatinib disodium hexahydrate. 

TAVLESSE 100 mg film-coated tablets 
TAVLESSE 150 mg film-coated tablets  

- The other ingredients are: 
 Mannitol, sodium hydrogen carbonate, sodium starch glycolate (type A), povidone (K30), 

magnesium stearate  
 Film-coating: poly(vinyl alcohol), titanium dioxide, macrogol (3350), talc, iron oxide 

yellow, iron oxide red 
 
What TAVLESSE looks like and contents of the pack 
 
TAVLESSE 100 mg film-coated tablets 
The tablet is round, curved on both sides with a dark orange film coat. The commercial tablets are 
debossed with “R” on one side and “100” on the reverse side. 
Available in bottle of 30 and 60 film-coated tablets. Each bottle has 2 desiccants. 
Not all pack sizes may be marketed. 
 
TAVLESSE 150 mg film-coated tablets 
The tablet is oval, curved on both sides, with a light orange film coat. The commercial tablets are 
debossed with “R” on one side and “150” on the reverse side. 
Available in bottle of 30 and 60 film-coated tablets. Each bottle has 2 desiccants. 
Not all pack sizes may be marketed.  
 
Marketing Authorisation Holder and Manufacturer 
Instituto Grifols, S.A. 
Can Guasc, 2 - Parets del Vallès 
08150 Barcelona - Spain 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 



 

37 

AT/BE/BG/CY/EE/EL/ES/HR/HU/IE/LV/ 
LT/LU/MT/NL/RO/SI/SK 
Instituto Grifols, S.A. 
Tel: +34 93 571 01 00 
 

CZ 
Grifols S.R.O. 
Tel: +4202 2223 1415 
 

DE 
Grifols Deutschland GmbH 
Tel: +49 69 660 593 100 
 

DK/FI/IS/NO/SE 
Grifols Nordic AB 
Tel: +46 8 441 89 50 

FR 
Grifols France 
Tél: +33 (0)1 53 53 08 70 
 

IT 
Grifols Italia S.p.A. 
Tel: +39 050 8755 113 

PL 
Grifols Polska Sp. z o. o. 
Tel: +48 22 378 85 60 
 

PT 
Grifols Portugal, Lda. 
Tel: +351 219 255 200 

UK 
Grifols UK Ltd. 
Tel: +44 845 2413090 

 

 
This leaflet was last revised in <{MM/YYYY}><{month YYYY}>. 
 
Detailed information on this medicine is available on the European Medicines Agency web site:  
https://www.ema.europa.eu/en 
 
 


	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 MARKETINGAUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVEUSE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET