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TAVALISSE is a brand name for Fostamatinib, supplied as a tablet. The medicine, its uses, side effects and dosage are the same regardless of brand.
Used for: TAVALISSE™ (fostamatinib disodium hexahydrate) is indicated for the treatment of thrombocytopenia in adult patients with chronic immune thrombocytopenia (ITP) who have had an insufficient response to other treatments. TAVALISSE treatment should be initiated and remain under the supervision of a physician who is…
Verbatim from this product's HC label. Tap a section to expand.
1 Dosing Considerations The following factors should be considered when dosing TAVALISSE: TAVALISSE dosing requirements must be individualised based on the patient’s platelet counts and tolerability. [see Recommended Dose and Dosage Adjustment].
Drug Interactions Concomitant use with strong CYP3A4 inhibitors increases exposure to R406. Monitor for toxicities that may require TAVALISSE dose modifications when given with a strong CYP3A4 inhibitor. TAVALISSE should not be used with strong CYP3A4 inducers [see Recommended Dose and Dosage Adjustment and DRUG INTERACTIONS].
2 Recommended Dose and Dosage Adjustment Initiate TAVALISSE at a dose of 100 mg taken orally twice daily. After 4 weeks, if platelet count has not increased to at least 50 × 109/L, increase TAVALISSE dose to 150 mg twice daily. Use the lowest dose of TAVALISSE to achieve and maintain a platelet count of at least 50 × 109 /L as necessary to reduce the risk of bleeding.
A daily dose of 300 mg must not be exceeded. Efficacy has not been established at lower doses recommended for the management of adverse reactions. Page 5 of 33 Discontinuation Discontinue TAVALISSE after 12 weeks of treatment if the platelet count does not increase to at least 50 ×109/L.
Dose interruption, reduction, or discontinuation may be required to manage adverse reactions including diarrhea, hypertension, hepatotoxicity, and neutropenia (see Table 2). A dose reduction schedule is provided in Table 1, based on daily dose.
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 TAVALISSE should be taken in the morning. 2 If further dose reduction below 100 mg/day is required, discontinue TAVALISSE.
The recommended dose modifications for adverse reactions are provided in Table 2. Table 2 Recommended Dose Modifications and Management for Specific Adverse Reactions Adverse Reaction Recommended Action Hypertension Stage 1: systolic 130-139 or diastolic 80-89 mmHg Initiate or increase dosage of antihypertensive medication and adjust until blood pressure (BP) is controlled.
If the BP target is not met, reduce TAVALISSE to next lower daily dose (See Table 1).
1 Adverse Reaction Overview The following clinically important adverse reactions can become serious: hypertension, hepatotoxicity, diarrhea and neutropenia [see WARNINGS AND PRECAUTIONS]. Page 12 of 33 The most common adverse reactions associated with TAVALISSE in the ITP placebo-controlled studies were diarrhea, hypertension, nausea, epistaxis, dizziness, and alanine aminotransferase increased.
Serious adverse reactions associated with TAVALISSE included febrile neutropenia, diarrhea, pneumonia, and hypertensive crisis (1% of patients each). Severe adverse reactions in patients receiving TAVALISSE included dyspnea and hypertension (2% each), neutropenia, chest pain, diarrhea, dizziness, pneumonia, and hypoxia (all 1%).
Adverse reactions that led to drug withdrawal in patients receiving TAVALISSE included pneumonia, alanine amino transferase, diarrhea, chest pain, abdominal pain, and neutropenia. Adverse reactions leading to drug interruption in more than 1 patient receiving TAVALISSE were ALT increased, diarrhea, and influenza-like illness.
Adverse reactions leading to dose reduction in more than 1 patient receiving TAVALISSE were diarrhea and hypertension. Many adverse reactions associated with TAVALISSE were manageable with dose reduction/interruption and medication [see WARNINGS AND PRECAUTIONS, DOSAGE AND ADMINISTRATION].
2 Clinical Trial Adverse Reactions Because clinical trials are conducted under very specific conditions, the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice. Adverse reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.
The safety profile of TAVALISSE is based on 2 Placebo-Controlled Phase 3 studies (C788-047 and C788-048) and one Phase 3 open-label extension study (C788-049). A total of 150 patients (102 TAVALISSE, 48 placebo) received study drug in the 2 Placebo-Controlled studies.
Bone remodelling Since TAVALISSE was shown in vitro to target SYK and other tyrosine kinases that are involved in bone metabolism (VEGFR, RET), any potential untargeted effects on bone remodelling or formation remain undetermined. Based on non-clinical data, the potential risks in actively growing bones include chondrodystrophy and growth plate dysplasia.
TAVALISSE is therefore not indicated in children and young adults where epiphyseal fusion has not yet occurred. Closer monitoring of patients with osteoporosis and patients with fractures is also recommended. The benefit risk of continuing therapy in these patients should be thoroughly evaluated by the Prescriber.
Cardiovascular Hypertension Hypertension was reported in 28% of patients (17% mild, 9% moderate, 2% severe,1% serious) treated with TAVALISSE (13% of placebo-treated patients). Hypertensive crisis occurred in 1 patient treated with TAVALISSE.
Hypertension resulted in dose reduction or interruption in 4 TAVALISSE-treated patients (no placebo-treated patients) and resulted in discontinuation in 1 patient treated with TAVALISSE. Patients with pre-existing hypertension are possibly more susceptible to the hypertensive effects of TAVALISSE.
Approximately 20% of TAVALISSE-treated patients (17% of placebo-treated patients) required intervention for hypertension-related events, either an increase in antihypertensive medications and/or a new antihypertensive medication. Hypertension was Route of Administration Dosage Form / Strength/Composition Non-medicinal Ingredients Oral tablet 100 mg 150 mg Magnesium stearate Mannitol Povidone Sodium bicarbonate Sodium starch glycolate Film coating* *Contains polyvinyl alcohol, titanium dioxide, polyethylene glycol 3350, talc, iron oxide yellow and iron oxide red Page 9 of 33 unresolved in 5% of patients at end of study.
Monitor blood pressure every 2 weeks until stable, then monthly. Adjust or initiate antihypertensive therapy to control blood pressure during TAVALISSE therapy. If increased blood pressure persists, interrupt, reduce or discontinue TAVALISSE [see DOSAGE AND ADMINISTRATION, Recommended Dose and Dosage Adjustment].
TAVALISSE is contraindicated: in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.
during pregnancy [See WARNINGS AND PRECAUTIONS, Sexual Health and Special Populations]
Not medical advice. Always read the patient information leaflet and follow your prescriber or pharmacist.
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Stage 2:
BP ≥140-159 mmHg systolic and/or ≥90-99 mmHg diastolic Initiate or increase dosage of antihypertensive medication, and adjust until BP is controlled. If BP remains ≥140 systolic and/or ≥90 mmHg diastolic, reduce TAVALISSE to next lower daily dose (See Table 1).
BP 160-179 mmHg systolic or 100-109 mmHg diastolic Initiate or increase dosage of antihypertensive medication, and adjust until BP is controlled. If BP remains ≥160-179 systolic or ≥100-109 diastolic, interrupt or discontinue TAVALISSE.
Page 6 of 33 Adverse Reaction Recommended Action Hypertensive crisis:
BP ≥180 systolic and/or ≥110 mmHg Or symptomatic at any BP level Interrupt or discontinue TAVALISSE. Initiate or increase dosage of antihypertensive medication, and adjust until BP is controlled. If BP returns to less than the target BP, resume TAVALISSE at same daily dose.
If repeat BP is ≥160/100 mmHg despite aggressive antihypertensive treatment, discontinue TAVALISSE. Hepatotoxicity AST or ALT ≥3x to <5 x ULN If patient is symptomatic (nausea, vomiting, abdominal pain), interrupt TAVALISSE. 5x ULN and total BL remains <2x ULN.
Resume TAVALISSE at next lower daily dose (See Table 1). 5x ULN and total BL remains <2x ULN. Interrupt or reduce dose of TAVALISSE if ALT or AST remains 3 to 5x ULN and total BL remains <2 x ULN. 5x ULN) and total BL remains <2x ULN.
AST or ALT ≥5 x ULN and total BL <2 x ULN Interrupt TAVALISSE. 5x ULN and total BL remains <2x ULN; resume TAVALISSE at next lower daily dose (See Table 1). If AST or ALT persist at ≥5x ULN for 2 weeks or more, discontinue TAVALISSE.
AST or ALT ≥3 x ULN and total BL >2 x ULN Discontinue TAVALISSE. Elevated unconjugated (indirect) BL in absence of other LFT abnormalities and no signs of liver impairment. Continue TAVALISSE with frequent monitoring since isolated increase in unconjugated (indirect) BL may be due to UGT1A1 inhibition.
Diarrhea Diarrhea Manage diarrhea using supportive measures (dietary changes, hydration and/or antidiarrheal medication) early after the onset until symptom(s) have resolved. If symptom(s) become severe (Grade 3 or above), interrupt TAVALISSE.
If diarrhea improves to mild (Grade 1), resume TAVALISSE at the next lower daily dose (See Table 1). 5 x 109/L). Resume TAVALISSE 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; LFT = liver function tests (AST, ALT, total BL with fractionation if elevated, alkaline phosphatase); ANC = absolute neutrophil count Drug Interactions Concomitant use with strong CYP3A4 inhibitors increases exposure to R406 (the major active metabolite).
Monitor for toxicities of TAVALISSE that may require TAVALISSE dose modifications (see Table 1) when given concurrently with a strong CYP3A4 inhibitor [see DRUG INTERACTIONS]. TAVALISSE should not be used with strong CYP3A4 inducers [see DRUG INTERACTIONS].
Renal Impairment:
No dose adjustment is necessary in patients with renal impairment.
Hepatic Impairment:
TAVALISSE should not be used in patients with severe hepatic impairment. In patients with mild or moderate hepatic impairment, liver […]
Median duration of exposure to fostamatinib and placebo was similar between the 2 treatment groups. Table 4 presents the drug-related adverse events reported in at least 2% of TAVALISSE-treated patients and reported more frequently than in placebo patients in the Placebo-Controlled Period.
5) *All patients initially received study drug at 100 mg twice daily (or matching placebo). Nearly 90% of patients were dose escalated to 150 mg twice daily (or matching placebo) based on platelet count and tolerability at Week 4 or later.
3 Less Common Clinical Trial Adverse Reactions The list below represents the drug-related adverse events reported in less than 2% of TAVALISSE-treated patients in the Placebo-Controlled Period. 4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data Changes in ALT, AST and Absolute Neutrophil Counts from baseline to post-treatment study assessment have been identified during TAVALISSE clinical trials (See Table 5).
0 x […]
Heart Rate and Conduction Abnormalities In a dedicated clinical electrocardiographic (ECG) assessment study in healthy subjects, dose- dependent mild heart rate lowering effect and uncorrected PR interval prolongation were observed that were not considered clinically relevant.
[see ACTION AND CLINICAL PHARMACOLOGY, Cardiac Electrophysiology]. In the Phase 3 clinical program, no apparent cardiac safety issues were observed when TAVALISSE was administered to patients with low heart rate (less than 60 beats per minute).
Due to the limited number of patients studied, the use of TAVALISSE in patients with very low heart rate (less than 50 beats per minute) should be carefully considered to determine whether the therapeutic benefit outweighs the potential risk.
Driving and Operating Machinery Patients should avoid driving or using machines if feeling dizzy. Gastrointestinal Diarrhea occurred in 31% of patients (21% mild, 10% moderate, 1% severe, 1% serious) treated with TAVALISSE (15% of placebo-treated patients).
Antidiarrheal medication was administered in 13% of TAVALISSE-treated patients and 10% of placebo-treated patients. Diarrhea events led to dose interruption or reduction in 5% of patients, discontinuation in 1% of patients, and was unresolved in 3% of patients treated with TAVALISSE at the end of the study.
Monitor patients for the development of diarrhea. Manage diarrhea using supportive care measures, including dietary changes, hydration and/or antidiarrheal medication, early after the onset of symptoms. Interrupt, dose reduce, or discontinue TAVALISSE if diarrhea becomes severe (Grade 3 or above).
[see DOSAGE AND ADMINISTRATION, Recommended Dose and Dosage Adjustment]. Nausea was reported in 19% of TAVALISSE-treated patients (8% of placebo-treated patients). Abdominal pain was reported by 7% of TAVALISSE-treated patients (4% of placebo-treated patients).
Hematologic Neutropenia Neutropenia occurred in 7% of patients treated with TAVALISSE; febrile neutropenia and severe neutropenia occurred in 1% of patients each, and neutrophil decrease in 9 TAVALISSE-treated patients (no placebo-treated patients).
Dose interruption or reduction was required in 4 patients and study drug discontinuation in 1 patient. Patients with neutropenia may be more susceptible to infections. Monitor ANC monthly, and monitor for infection during treatment. Manage toxicity with TAVALISSE interruption, reduction or discontinuation [see DOSAGE AND ADMINISTRATION, Recommended Dose and Dosage Adjustment].
Hepatic Page 10 of 33 Drug-related hepatic disorder events, mainly elevated transaminases (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]), occurred in 16% of patients receiving TAVALISSE (alanine aminotransferase increased in 11%, aspartate aminotransferase increased in 9% of TAVALISSE-treated patients, with some patients experiencing both) (2% of placebo-treated patients).
Drug-related hepatic disorder events were mild in 10% and moderate in 6% of TAVALISSE-treated patients. Laboratory testing showed maximum AST and /or ALT levels more than 3 × the upper limit of normal (ULN) in 9% of patients receiving TAVALISSE (no placebo-treated patients).
[see ADVERSE REACTIONSAbnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data] Elevated transaminases associated with TAVALISSE led to dose reduction or interruption in 6 patients and discontinuation in 1 patient.
Elevated transaminases recovered to baseline levels within 6 weeks of onset. Monitor liver function tests monthly during treatment. If ALT or AST increase more than 3 × ULN, interrupt, reduce or discontinue TAVALISSE to manage elevated transaminases.
TAVALISSE may be associated with hyperbilirubinemia, particularly in patients with genetic polymorphisms of UGT1A1 (Gilbert’s […]