2.1 Recommended 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.

2.2 Monitoring

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.

2.3 Dose Modification for Adverse Reactions

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.

2.4 Dose Modification for Drug Interactions

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)].

2.5 Discontinuation

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)].

5.1 Hypertension

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)].

5.2 Hepatotoxicity

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)].

5.3 Diarrhea

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)].

5.4 Neutropenia

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)].

5.5 Embryo-Fetal Toxicity

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)].

6.1 Clinical Trials Experience

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.

7.1 Effect of Other Drugs on TAVALISSE

7.2 Effect of TAVALISSE on Other Drugs

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

8.4 Pediatric Use

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.

8.5 Geriatric Use

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.

12.1 Mechanism of Action

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.

12.2 Pharmacodynamics

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.

12.3 Pharmacokinetics

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 Cmax 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).

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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.

Randomized, 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 randomized 2:1 to TAVALISSE or placebo for 24 weeks; randomization was stratified with respect to prior splenectomy and severity of thrombocytopenia. Stable concurrent ITP therapy (glucocorticoids [< 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 88% of patients at Week 4 or later. Patients who did not respond to treatment after 12 weeks, as well as patients who completed the 24-week double blind study, were eligible to enroll in open-label extension study (FIT-3).

Patients enrolled in the placebo-controlled studies had a median age of 54 years (range: 20 to 88), and the majority were female (61%) and were White (93%). Prior ITP treatments were varied, 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 8.45 years, and 35% had undergone splenectomy. At baseline, the median platelet count was 16 × 109/L (with almost half [45]%) less than 15 × 109/L) and 47% were on stable ITP therapy.

In Study FIT-1, 76 patients were randomized; 51 to the TAVALISSE group and 25 to the placebo group. In Study FIT-2, 74 patients were randomized; 50 to the TAVALISSE group and 24 to the placebo group. The efficacy of TAVALISSE was based on stable platelet response (at least 50 ×109/L on at least 4 of the 6 visits between Weeks 14 to 24). Study outcomes for FIT-1 and FIT-2 are shown in Table 5.

In the FIT-1 and FIT-2 studies a total of 47 patients in the TAVALISSE arm had received a prior TPO-RA treatment; among these patients, 8 patients (17%) achieved a stable response to TAVALISSE. All 8 patients had previously discontinued TPO-RA due to loss of effect. Rescue medication was required by 30% and 45% of patients receiving TAVALISSE or placebo, respectively.

During the placebo-controlled studies, the incidence of bleeding occurred in 29% and 37% of patients in the TAVALISSE and placebo arms, respectively. Moderate, severe and serious bleeding events are described in Table 6. All severe events led to hospitalizations.

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.