These Highlights Do Not Include All The Information Needed To Use Tavalisse®

Strong CYP3A4 Inhibitors

Concomitant use with strong CYP3A4 inhibitors increases exposure to R406 (the major active metabolite), which may increase the risk of adverse reactions. Monitor for toxicities of TAVALISSE that may require dose reduction (see Table 1) when given concurrently with a strong CYP3A4 inhibitor [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)].

Store at room temperature, 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Do not remove desiccants.

Diarrhea occurred in 31% of patients treated with TAVALISSE. Severe diarrhea occurred in 1% of patients treated with TAVALISSE. 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 (2.3)].

There is no specific antidote for overdose with TAVALISSE, and the amount of R406 (the pharmacologically active metabolite of fostamatinib) cleared by dialysis is negligible. In the event of an overdose, monitor patient closely for signs and symptoms of adverse reactions, and treat the reactions with supportive care [see Warnings and Precautions (5)].

Fostamatinib is a tyrosine kinase inhibitor. TAVALISSE is formulated with the disodium hexahydrate salt of fostamatinib, a phosphate prodrug that converts to its pharmacologically active metabolite, R406, in vivo.

The chemical name for fostamatinib disodium hexahydrate is disodium (6-[[5-fluoro-2-(3,4,5-trimethoxyanilino) pyrimidin-4-yl]amino]-2,2-dimethyl-3-oxo-pyrido[3,2-b][1,4]oxazin-4-yl)methyl phosphate hexahydrate. The molecular formula is C₂₃H₂₄FN₆Na₂O₉P∙6H₂O, and the molecular weight is 732.52. The structural formula is:

Fostamatinib disodium is a white to off-white powder that is practically insoluble in pH 1.2 aqueous buffer, slightly soluble in water, and soluble in methanol.

Each TAVALISSE oral tablet contains 100 mg or 150 mg fostamatinib, equivalent to 126.2 mg or 189.3 mg fostamatinib disodium hexahydrate, respectively.

The inactive ingredients in the tablet core are mannitol, sodium bicarbonate, sodium starch glycolate, povidone, and magnesium stearate. The inactive ingredients in the film coating are polyvinyl alcohol, titanium dioxide, polyethylene glycol 3350, talc, iron oxide yellow, and iron oxide red.

After obtaining baseline assessments:

• Monitor CBCs, including platelet counts, monthly until a stable platelet count (at least 50 × 10⁹/L) is achieved. Thereafter, continue to monitor CBCs, including neutrophils, regularly.
• Monitor liver function tests (LFTs) (e.g., ALT, AST, and bilirubin) monthly.
• Monitor blood pressure every 2 weeks until establishment of a stable dose, then monthly thereafter.

Neutropenia occurred in 6% of patients treated with TAVALISSE; febrile neutropenia occurred in 1% of patients.

Monitor the ANC monthly, and for infection during treatment. Manage toxicity with TAVALISSE interruption, reduction or discontinuation [see Dosage and Administration (2.3)].

Hypertension can occur with TAVALISSE treatment; hypertensive crisis occurred in 1% of patients. Patients with pre-existing hypertension may be more susceptible to the hypertensive effects of TAVALISSE.

Monitor blood pressure every 2 weeks until stable, then monthly and adjust or initiate antihypertensive therapy to ensure maintenance of blood pressure control during TAVALISSE therapy. If increased blood pressure persists despite appropriate therapy, TAVALISSE interruption, reduction or discontinuation may be necessary [see Dosage and Administration (2.3)].

Safety and effectiveness in pediatric patients have not been established. TAVALISSE is not recommended for use in patients less than 18 years of age because adverse effects on actively growing bones were observed in nonclinical studies. In subchronic, chronic, and carcinogenicity studies of TAVALISSE, chondrodystrophy of the femoral head was seen in rodents. In a study in juvenile rabbits, growth plate dysplasia was observed in the proximal femur and femoro-tibial joint, and bone marrow cellularity was reduced in the femur and sternum.

Of the 102 patients with ITP who received TAVALISSE, 28 (27%) were 65 years of age and older, while 11 (11%) were 75 years of age and older. 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 TAVALISSE, 11 (39%) patients experienced hypertension versus 2 (18%) placebo compared to 17 (23%) in patients under 65 of age versus 4 (11%) placebo. No overall differences in effectiveness were observed in these patients compared to younger patients.

Elevated liver function tests (LFTs), mainly ALT and AST, can occur with TAVALISSE.

In the placebo-controlled studies, laboratory testing showed maximum ALT/AST levels more than 3 × the upper limit of normal (ULN) in 9% of patients receiving TAVALISSE [see Adverse Reactions (6.1)]. For most patients, transaminases recovered to baseline levels within 2 to 6 weeks of dose-modification.

Monitor liver function tests monthly during treatment. If ALT or AST increase more than 3 × ULN, manage hepatotoxicity using TAVALISSE interruption, reduction, or discontinuation [see Dosage and Administration (2.3)].

TAVALISSE was studied in two placebo-controlled efficacy and safety studies (referred to as FIT-1 [NCT02076399] and FIT-2 [NCT02076412]), and in an open-label extension study referred to as FIT-3 (NCT 02077192).

Discontinue TAVALISSE after 12 weeks of treatment if the platelet count does not increase to a level sufficient to avoid clinically important bleeding [see Clinical Studies (14)].

None.

The following clinically important adverse reactions, that can become serious are described elsewhere in the labeling:

• Hypertension [see Warnings and Precautions (5.1) ]
• Hepatotoxicity [see Warnings and Precautions (5.2) ]
• Diarrhea [see Warnings and Precautions (5.3) ]
• Neutropenia [see Warnings and Precautions (5.4) ]

• Strong CYP3A4 Inhibitors: Concomitant use with a strong CYP3A4 inhibitor increases exposure to R406 (the major active metabolite).(7)
• Strong CYP3A4 Inducers: Concomitant use is not recommended. (7)

Mean treatment-related increases of 2.93 mmHg in systolic blood pressure and 3.53 mmHg in diastolic blood pressure over placebo were observed following TAVALISSE doses of 100 mg twice daily for 28 days. About 31% of patients in the TAVALISSE group experienced blood pressures ≥140/90 mmHg compared to 15% of patients in the placebo group. Blood pressure returned to baseline within 1 week following TAVALISSE discontinuation in 58% (11 of 19) of patients in the TAVALISSE group who had blood pressures ≥140/90 mmHg.

TAVALISSE is a prodrug that is converted in the gut to the major active metabolite, R406. Mean (± standard deviation [SD]) exposure estimates of R406 are 550 (± 270) ng/mL for C_max and 7080 (± 2670) ng∙h/mL for AUC. R406 exposure is approximately dose proportional up to 200 mg twice daily (1.3 times the 150 mg dosage). R406 accumulates approximately 2- to 3-fold upon twice daily dosing at 100–160 mg (0.67 to 1.06 times the 150 mg dosage).

Initiate TAVALISSE at a dose of 100 mg taken orally twice daily. After a month, 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 at least 50 × 10⁹/L as necessary to reduce the risk of bleeding.

TAVALISSE may be taken with or without food. In the case of a missed dose of TAVALISSE, instruct patients to take their next dose at its regularly scheduled time.

TAVALISSE is indicated for the treatment of thrombocytopenia in adult patients with chronic immune thrombocytopenia (ITP) who have had an insufficient response to a previous treatment.

Fostamatinib is a tyrosine kinase inhibitor with demonstrated activity against spleen tyrosine kinase (SYK). The major metabolite of fostamatinib, R406, inhibits signal transduction of Fc-activating receptors and B-cell receptor. The fostamatinib metabolite R406 reduces antibody-mediated destruction of platelets.

Based on findings from animal studies and its mechanism of action, TAVALISSE can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of fostamatinib to pregnant rats and rabbits during organogenesis caused adverse developmental outcomes including embryo-fetal mortality (post-implantation loss), alterations to growth (lower fetal 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. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for at least 1 month after the last dose. [see Use in Specific Populations (8.1) and Clinical Pharmacology (12.1)].

• Hypertension: Monitor blood pressure every 2 weeks until stable, then monthly. Manage hypertension using standard antihypertensive treatment and, if needed, interrupt, reduce or discontinue TAVALISSE. (5.1)
• Hepatotoxicity: Monitor LFTs monthly. If LFT levels are elevated, interrupt, reduce or discontinue TAVALISSE. (5.2)
• Diarrhea: Manage diarrhea with supportive measures. If diarrhea becomes severe, interrupt, reduce or discontinue TAVALISSE. (5.3)
• Neutropenia: Monitor ANC monthly, and for infection. If neutrophil count decreases below 1.0 × 10⁹/L, interrupt, reduce or discontinue TAVALISSE. (5.4)
• Embryo-Fetal Toxicity: TAVALISSE can cause fetal harm. Advise patients of potential risk to a fetus and to use effective contraception. (5.5 )

• Initiate TAVALISSE at 100 mg orally twice daily with or without food. After 4 weeks, increase to 150 mg twice daily, if needed, to achieve platelet counts of at least 50 × 10⁹/L as necessary to reduce the risk of bleeding. (2.1)
• Manage adverse reactions using dose reduction, interruption of treatment, or discontinuation. (2.3)
• Discontinue TAVALISSE after 12 weeks of treatment if the platelet count does not increase to a level sufficient to avoid clinically important bleeding. (2.5)

TAVALISSE is available as:

• 100 mg tablet: orange, film-coated, round, biconvex tablets debossed with "100" on one side and "R" on the reverse side.
• 150 mg tablet: orange, film-coated, oval, biconvex tablets debossed with "150" on one side and "R" on the reverse side.

• Pregnancy: Advise women of the risk to a fetus. (8.1)
• Lactation: Advise women not to breastfeed. (8.2)

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

TAVALISSE was studied in two randomized, double-blind, placebo-controlled trials that were identical in design. The data described below reflect exposure to TAVALISSE in 102 patients with chronic ITP who had received one or more prior ITP treatment(s). Groups were stratified with respect to splenectomy and severity of thrombocytopenia. Patients randomized to the TAVALISSE arm received 100 mg orally twice daily. Based upon platelet count and tolerability, if a patient's platelet count did not increase to at least 50 × 10⁹/L, the TAVALISSE dose could be increased to 150 mg twice daily after one month. In the placebo controlled studies, the median duration of TAVALISSE exposure in these studies was 86 days (range 8 to 183) [see Clinical Studies (14) for additional details for patients on TAVALISSE].

In the ITP double-blind studies, serious adverse drug reactions were febrile neutropenia, diarrhea, pneumonia, and hypertensive crisis, which each occurred in 1% of patients receiving TAVALISSE. In addition, severe adverse reactions observed in patients receiving TAVALISSE included dyspnea and hypertension (both 2%); and neutropenia, arthralgia, chest pain, diarrhea, dizziness, nephrolithiasis, pain in extremity, toothache, syncope and hypoxia (all 1%) [see Warnings and Precautions (5.1)]. Table 3 presents the common adverse reactions from these studies.

Advise the patient to read the FDA-approved patient labeling (Patient Information).

• Hypertension:
  
  Inform patients that periodic monitoring of their blood pressure is required, as high blood pressure has occurred in patients taking TAVALISSE. Inform patients of the signs and symptoms of hypertension. Advise patients to undergo routine blood pressure monitoring and to contact their health care provider if blood pressure is elevated or if they experience signs or symptoms of hypertension [see Warnings and Precautions (5.1)].
• Hepatotoxicity:
  
  Inform patients that periodic monitoring of their liver enzymes is required, and any elevations (which may indicate liver injury) will be managed appropriately, including interruption, reduction, or discontinuation of TAVALISSE [see Warnings and Precautions (5.2)].
• Diarrhea:
  
  Advise patients to use supportive care measures, and if diarrhea becomes severe, it may necessitate interruption, reduction, or discontinuation of TAVALISSE [see Warnings and Precautions (5.3)].
• Neutropenia:
  
  Inform patients that monitoring of their complete blood counts is required, and a decrease in neutrophils may necessitate interruption, reduction, or discontinuation of TAVALISSE [see Warnings and Precautions (5.4)].
• Advise patients to inform their healthcare providers of all their medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products [see Drug Interactions (7)].
• Embryo-Fetal Toxicity
  
  Advise females to inform their healthcare provider if they are pregnant or become pregnant. Inform female patients of the potential risk to a fetus [see Use in Specific Populations (8.1)].
  
  Advise females of reproductive potential to use effective contraception during treatment and for at least 1 month after receiving the last dose of TAVALISSE [see Warnings and Precautions (5.5) and Use in Specific Populations (8.1, 8.3)].
• Lactation
  
  Advise lactating women not to breastfeed during treatment with TAVALISSE and for at least 1 month after the last dose [see Use in Specific Populations (8.2)].
• Inform patients that TAVALISSE may be taken with or without food. In the case of a missed dose of TAVALISSE, instruct patients to take their next dose at its regularly scheduled time.

TAVALISSE 100 mg tablets are round, biconvex, orange, film-coated tablets debossed with "100" on one side and "R" on the reverse side.

TAVALISSE 150 mg tablets are oval, biconvex, orange, film-coated tablets debossed with "150" on one side and "R" on the reverse side.

TAVALISSE dose modification is recommended based on individual safety and tolerability. Management of some adverse reactions may require dose-interruption, reduction, or discontinuation.

A dose reduction schedule is provided in Table 1, based on daily dose. 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.

The recommended dose modifications for adverse reactions are provided in Table 2.

Concomitant use with a strong CYP3A4 inhibitor 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 (7.1)].

NDC 71332-001-01

Rx only

Tavalisse ^®

(fostamatinib) tablets

100 mg

60 Tablets

NDC 71332-002-01

Rx only

Tavalisse ^®

(fostamatinib) tablets

150 mg

60 Tablets

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.

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 dosages as high as 40 mg/kg/day, which is 6.7 times the MRHD. All mating and fertility parameters in female rats were unaffected by dosages as high as 11 mg/kg/day (which is 1.8 times the MRHD), but a slight decrease in pregnancy rates and an increase in post-implantation loss were seen at 25 mg/kg/day, which is 4.2 times the MRHD.

Strong CYP3A4 Inhibitors

Concomitant use with strong CYP3A4 inhibitors increases exposure to R406 (the major active metabolite), which may increase the risk of adverse reactions. Monitor for toxicities of TAVALISSE that may require dose reduction (see Table 1) when given concurrently with a strong CYP3A4 inhibitor [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)].

Store at room temperature, 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Do not remove desiccants.

Diarrhea occurred in 31% of patients treated with TAVALISSE. Severe diarrhea occurred in 1% of patients treated with TAVALISSE. 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 (2.3)].

There is no specific antidote for overdose with TAVALISSE, and the amount of R406 (the pharmacologically active metabolite of fostamatinib) cleared by dialysis is negligible. In the event of an overdose, monitor patient closely for signs and symptoms of adverse reactions, and treat the reactions with supportive care [see Warnings and Precautions (5)].

Fostamatinib is a tyrosine kinase inhibitor. TAVALISSE is formulated with the disodium hexahydrate salt of fostamatinib, a phosphate prodrug that converts to its pharmacologically active metabolite, R406, in vivo.

The chemical name for fostamatinib disodium hexahydrate is disodium (6-[[5-fluoro-2-(3,4,5-trimethoxyanilino) pyrimidin-4-yl]amino]-2,2-dimethyl-3-oxo-pyrido[3,2-b][1,4]oxazin-4-yl)methyl phosphate hexahydrate. The molecular formula is C₂₃H₂₄FN₆Na₂O₉P∙6H₂O, and the molecular weight is 732.52. The structural formula is:

Fostamatinib disodium is a white to off-white powder that is practically insoluble in pH 1.2 aqueous buffer, slightly soluble in water, and soluble in methanol.

Each TAVALISSE oral tablet contains 100 mg or 150 mg fostamatinib, equivalent to 126.2 mg or 189.3 mg fostamatinib disodium hexahydrate, respectively.

The inactive ingredients in the tablet core are mannitol, sodium bicarbonate, sodium starch glycolate, povidone, and magnesium stearate. The inactive ingredients in the film coating are polyvinyl alcohol, titanium dioxide, polyethylene glycol 3350, talc, iron oxide yellow, and iron oxide red.

After obtaining baseline assessments:

• Monitor CBCs, including platelet counts, monthly until a stable platelet count (at least 50 × 10⁹/L) is achieved. Thereafter, continue to monitor CBCs, including neutrophils, regularly.
• Monitor liver function tests (LFTs) (e.g., ALT, AST, and bilirubin) monthly.
• Monitor blood pressure every 2 weeks until establishment of a stable dose, then monthly thereafter.

Neutropenia occurred in 6% of patients treated with TAVALISSE; febrile neutropenia occurred in 1% of patients.

Monitor the ANC monthly, and for infection during treatment. Manage toxicity with TAVALISSE interruption, reduction or discontinuation [see Dosage and Administration (2.3)].

Hypertension can occur with TAVALISSE treatment; hypertensive crisis occurred in 1% of patients. Patients with pre-existing hypertension may be more susceptible to the hypertensive effects of TAVALISSE.

Monitor blood pressure every 2 weeks until stable, then monthly and adjust or initiate antihypertensive therapy to ensure maintenance of blood pressure control during TAVALISSE therapy. If increased blood pressure persists despite appropriate therapy, TAVALISSE interruption, reduction or discontinuation may be necessary [see Dosage and Administration (2.3)].

Safety and effectiveness in pediatric patients have not been established. TAVALISSE is not recommended for use in patients less than 18 years of age because adverse effects on actively growing bones were observed in nonclinical studies. In subchronic, chronic, and carcinogenicity studies of TAVALISSE, chondrodystrophy of the femoral head was seen in rodents. In a study in juvenile rabbits, growth plate dysplasia was observed in the proximal femur and femoro-tibial joint, and bone marrow cellularity was reduced in the femur and sternum.

Of the 102 patients with ITP who received TAVALISSE, 28 (27%) were 65 years of age and older, while 11 (11%) were 75 years of age and older. 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 TAVALISSE, 11 (39%) patients experienced hypertension versus 2 (18%) placebo compared to 17 (23%) in patients under 65 of age versus 4 (11%) placebo. No overall differences in effectiveness were observed in these patients compared to younger patients.

Elevated liver function tests (LFTs), mainly ALT and AST, can occur with TAVALISSE.

In the placebo-controlled studies, laboratory testing showed maximum ALT/AST levels more than 3 × the upper limit of normal (ULN) in 9% of patients receiving TAVALISSE [see Adverse Reactions (6.1)]. For most patients, transaminases recovered to baseline levels within 2 to 6 weeks of dose-modification.

Monitor liver function tests monthly during treatment. If ALT or AST increase more than 3 × ULN, manage hepatotoxicity using TAVALISSE interruption, reduction, or discontinuation [see Dosage and Administration (2.3)].

TAVALISSE was studied in two placebo-controlled efficacy and safety studies (referred to as FIT-1 [NCT02076399] and FIT-2 [NCT02076412]), and in an open-label extension study referred to as FIT-3 (NCT 02077192).

Discontinue TAVALISSE after 12 weeks of treatment if the platelet count does not increase to a level sufficient to avoid clinically important bleeding [see Clinical Studies (14)].

None.

The following clinically important adverse reactions, that can become serious are described elsewhere in the labeling:

• Hypertension [see Warnings and Precautions (5.1) ]
• Hepatotoxicity [see Warnings and Precautions (5.2) ]
• Diarrhea [see Warnings and Precautions (5.3) ]
• Neutropenia [see Warnings and Precautions (5.4) ]

• Strong CYP3A4 Inhibitors: Concomitant use with a strong CYP3A4 inhibitor increases exposure to R406 (the major active metabolite).(7)
• Strong CYP3A4 Inducers: Concomitant use is not recommended. (7)

Mean treatment-related increases of 2.93 mmHg in systolic blood pressure and 3.53 mmHg in diastolic blood pressure over placebo were observed following TAVALISSE doses of 100 mg twice daily for 28 days. About 31% of patients in the TAVALISSE group experienced blood pressures ≥140/90 mmHg compared to 15% of patients in the placebo group. Blood pressure returned to baseline within 1 week following TAVALISSE discontinuation in 58% (11 of 19) of patients in the TAVALISSE group who had blood pressures ≥140/90 mmHg.

TAVALISSE is a prodrug that is converted in the gut to the major active metabolite, R406. Mean (± standard deviation [SD]) exposure estimates of R406 are 550 (± 270) ng/mL for C_max and 7080 (± 2670) ng∙h/mL for AUC. R406 exposure is approximately dose proportional up to 200 mg twice daily (1.3 times the 150 mg dosage). R406 accumulates approximately 2- to 3-fold upon twice daily dosing at 100–160 mg (0.67 to 1.06 times the 150 mg dosage).

Initiate TAVALISSE at a dose of 100 mg taken orally twice daily. After a month, 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 at least 50 × 10⁹/L as necessary to reduce the risk of bleeding.

TAVALISSE may be taken with or without food. In the case of a missed dose of TAVALISSE, instruct patients to take their next dose at its regularly scheduled time.

TAVALISSE is indicated for the treatment of thrombocytopenia in adult patients with chronic immune thrombocytopenia (ITP) who have had an insufficient response to a previous treatment.

Fostamatinib is a tyrosine kinase inhibitor with demonstrated activity against spleen tyrosine kinase (SYK). The major metabolite of fostamatinib, R406, inhibits signal transduction of Fc-activating receptors and B-cell receptor. The fostamatinib metabolite R406 reduces antibody-mediated destruction of platelets.

Based on findings from animal studies and its mechanism of action, TAVALISSE can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of fostamatinib to pregnant rats and rabbits during organogenesis caused adverse developmental outcomes including embryo-fetal mortality (post-implantation loss), alterations to growth (lower fetal 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. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for at least 1 month after the last dose. [see Use in Specific Populations (8.1) and Clinical Pharmacology (12.1)].

• Hypertension: Monitor blood pressure every 2 weeks until stable, then monthly. Manage hypertension using standard antihypertensive treatment and, if needed, interrupt, reduce or discontinue TAVALISSE. (5.1)
• Hepatotoxicity: Monitor LFTs monthly. If LFT levels are elevated, interrupt, reduce or discontinue TAVALISSE. (5.2)
• Diarrhea: Manage diarrhea with supportive measures. If diarrhea becomes severe, interrupt, reduce or discontinue TAVALISSE. (5.3)
• Neutropenia: Monitor ANC monthly, and for infection. If neutrophil count decreases below 1.0 × 10⁹/L, interrupt, reduce or discontinue TAVALISSE. (5.4)
• Embryo-Fetal Toxicity: TAVALISSE can cause fetal harm. Advise patients of potential risk to a fetus and to use effective contraception. (5.5 )

• Initiate TAVALISSE at 100 mg orally twice daily with or without food. After 4 weeks, increase to 150 mg twice daily, if needed, to achieve platelet counts of at least 50 × 10⁹/L as necessary to reduce the risk of bleeding. (2.1)
• Manage adverse reactions using dose reduction, interruption of treatment, or discontinuation. (2.3)
• Discontinue TAVALISSE after 12 weeks of treatment if the platelet count does not increase to a level sufficient to avoid clinically important bleeding. (2.5)

TAVALISSE is available as:

• 100 mg tablet: orange, film-coated, round, biconvex tablets debossed with "100" on one side and "R" on the reverse side.
• 150 mg tablet: orange, film-coated, oval, biconvex tablets debossed with "150" on one side and "R" on the reverse side.

• Pregnancy: Advise women of the risk to a fetus. (8.1)
• Lactation: Advise women not to breastfeed. (8.2)

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

TAVALISSE was studied in two randomized, double-blind, placebo-controlled trials that were identical in design. The data described below reflect exposure to TAVALISSE in 102 patients with chronic ITP who had received one or more prior ITP treatment(s). Groups were stratified with respect to splenectomy and severity of thrombocytopenia. Patients randomized to the TAVALISSE arm received 100 mg orally twice daily. Based upon platelet count and tolerability, if a patient's platelet count did not increase to at least 50 × 10⁹/L, the TAVALISSE dose could be increased to 150 mg twice daily after one month. In the placebo controlled studies, the median duration of TAVALISSE exposure in these studies was 86 days (range 8 to 183) [see Clinical Studies (14) for additional details for patients on TAVALISSE].

In the ITP double-blind studies, serious adverse drug reactions were febrile neutropenia, diarrhea, pneumonia, and hypertensive crisis, which each occurred in 1% of patients receiving TAVALISSE. In addition, severe adverse reactions observed in patients receiving TAVALISSE included dyspnea and hypertension (both 2%); and neutropenia, arthralgia, chest pain, diarrhea, dizziness, nephrolithiasis, pain in extremity, toothache, syncope and hypoxia (all 1%) [see Warnings and Precautions (5.1)]. Table 3 presents the common adverse reactions from these studies.

Advise the patient to read the FDA-approved patient labeling (Patient Information).

• Hypertension:
  
  Inform patients that periodic monitoring of their blood pressure is required, as high blood pressure has occurred in patients taking TAVALISSE. Inform patients of the signs and symptoms of hypertension. Advise patients to undergo routine blood pressure monitoring and to contact their health care provider if blood pressure is elevated or if they experience signs or symptoms of hypertension [see Warnings and Precautions (5.1)].
• Hepatotoxicity:
  
  Inform patients that periodic monitoring of their liver enzymes is required, and any elevations (which may indicate liver injury) will be managed appropriately, including interruption, reduction, or discontinuation of TAVALISSE [see Warnings and Precautions (5.2)].
• Diarrhea:
  
  Advise patients to use supportive care measures, and if diarrhea becomes severe, it may necessitate interruption, reduction, or discontinuation of TAVALISSE [see Warnings and Precautions (5.3)].
• Neutropenia:
  
  Inform patients that monitoring of their complete blood counts is required, and a decrease in neutrophils may necessitate interruption, reduction, or discontinuation of TAVALISSE [see Warnings and Precautions (5.4)].
• Advise patients to inform their healthcare providers of all their medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products [see Drug Interactions (7)].
• Embryo-Fetal Toxicity
  
  Advise females to inform their healthcare provider if they are pregnant or become pregnant. Inform female patients of the potential risk to a fetus [see Use in Specific Populations (8.1)].
  
  Advise females of reproductive potential to use effective contraception during treatment and for at least 1 month after receiving the last dose of TAVALISSE [see Warnings and Precautions (5.5) and Use in Specific Populations (8.1, 8.3)].
• Lactation
  
  Advise lactating women not to breastfeed during treatment with TAVALISSE and for at least 1 month after the last dose [see Use in Specific Populations (8.2)].
• Inform patients that TAVALISSE may be taken with or without food. In the case of a missed dose of TAVALISSE, instruct patients to take their next dose at its regularly scheduled time.

TAVALISSE 100 mg tablets are round, biconvex, orange, film-coated tablets debossed with "100" on one side and "R" on the reverse side.

TAVALISSE 150 mg tablets are oval, biconvex, orange, film-coated tablets debossed with "150" on one side and "R" on the reverse side.

TAVALISSE dose modification is recommended based on individual safety and tolerability. Management of some adverse reactions may require dose-interruption, reduction, or discontinuation.

A dose reduction schedule is provided in Table 1, based on daily dose. 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.

The recommended dose modifications for adverse reactions are provided in Table 2.

Concomitant use with a strong CYP3A4 inhibitor 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 (7.1)].

NDC 71332-001-01

Rx only

Tavalisse ^®

(fostamatinib) tablets

100 mg

60 Tablets

NDC 71332-002-01

Rx only

Tavalisse ^®

(fostamatinib) tablets

150 mg

60 Tablets

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.

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 dosages as high as 40 mg/kg/day, which is 6.7 times the MRHD. All mating and fertility parameters in female rats were unaffected by dosages as high as 11 mg/kg/day (which is 1.8 times the MRHD), but a slight decrease in pregnancy rates and an increase in post-implantation loss were seen at 25 mg/kg/day, which is 4.2 times the MRHD.