Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2021 Publisher: Instituto Grifols, S.A., Can Guasc, 2 Parets del Vallès, 08150 Barcelona Spain
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Pregnancy (see section 4.6).
Information is based on ITP placebo-controlled population unless specified.
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.
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).
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).
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 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 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, including pneumonia and respiratory tract infections, have been reported during clinical trials (see section 4.8).
The patient should be monitored for infection during treatment. The benefit risk of continuing therapy during an infection should be evaluated by the physician.
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.
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%.
Coadministration of fostamatinib with 150 mg ranitidine, an H2-blocker that increases gastric pH did not have clinically relevant impact on R406 exposure.
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%.
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%.
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.
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.
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.
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.
Women of childbearing potential must use effective contraception during treatment and at least one month after the last dose.
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).
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.
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.
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.
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 included dyspnea and hypertension (both 2%); and neutropenia, arthralgia, chest pain, diarrhoea, dizziness, nephrolithiasis, pain in extremity, toothache, syncope and hypoxia (all 1%).
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, headache | |
| 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 |
The most commonly reported adverse reactions associated with fostamatinib were hypertension, liver function test abnormaltities, diarrhoea, neutropenia and infections.
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 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.
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).
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.
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.
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.
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.
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 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:
Ireland: HPRA Pharmacovigilance, Website: www.hpra.ie
United Kingdom: Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store
Not applicable.
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