Fostamatinib

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

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. Tablets: 100 mg, 150 mg ( 3 )

None. None. ( 4 )

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 × 10 9 /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 )

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) ].

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) ] The most common adverse reactions (≥5% and more than placebo) are diarrhea, hypertension, nausea, respiratory infection, dizziness, ALT/AST increased, rash, abdominal pain, fatigue, chest pain and neutropenia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Rigel Pharmaceuticals, Inc. at 1-800-983-1329 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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 × 10 9 /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. Table 3: Incidence of Common (≥ 5%) Adverse Reactions from Double-Blind Clinical Studies (FIT 1 and FIT 2) Adverse Reaction TAVALISSE (N=102) Placebo (N=48) Mild % Moderate % Severe % TOTAL % Mild % Moderate % Severe % TOTAL % ALT = Alanine aminotransferase AST = Aspartate aminotransferase Note: Common adverse reactions defined as all adverse reactions occurring at a rate of ≥ 5% of patients in the TAVALISSE group and greater than placebo rate. Diarrhea Includes diarrhea and frequent bowel movement. 21 10 1 31 13 2 0 15 Hypertension Includes hypertension, blood pressure (BP) increased, BP diastolic abnormal, and BP diastolic increased. 17 9 2 28 10 0 2 13 Nausea 16 3 0 19 8 0 0 8 Dizziness 8 2 1 11 6 2 0 8 ALT increased 5 6 0 11 0 0 0 0 AST increased 5 4 0 9 0 0 0 0 Respiratory infection Includes upper respiratory tract infection, respiratory tract infection, lower respiratory tract infection, and viral upper respiratory tract infection. 7 4 0 11 6 0 0 6 Rash Includes rash, rash erythematous and rash macular. 8 1 0 9 2 0 0 2 Abdominal pain Includes abdominal pain, and abdominal pain upper. 5 1 0 6 2 0 0 2 Fatigue 4 2 0 6 0 2 0 2 Chest pain 2 3 1 6 2 0 0 2 Neutropenia Includes neutropenia and neutrophil count decreased. 3 2 1 6 0 0 0 0 Table 4: Elevations in Hepatic Transaminases During Placebo-Controlled Clinical Studies Enzyme Maximum Level of Elevation Number of Patients (%) TAVALISSE (N=102) Placebo (N=48) Alanine aminotransferase (ALT) and/or Aspartate aminotransferase (AST) >3 and ≤5 × ULN 3 (3) 0 >5 and ≤10 × ULN 5 (5) 0 ≥10 × ULN 1 (1) 0

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 )

7.1 Effect of Other Drugs on 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) ] . Strong CYP3A4 Inducers Concomitant use with a strong CYP3A4 inducer reduces exposure to R406. Concomitant use of TAVALISSE with strong CYP3A4 inducers is not recommended [see Clinical Pharmacology (12.3) ] .

7.2 Effect of TAVALISSE on Other Drugs CYP3A4 Substrates Concomitant use of TAVALISSE may increase concentrations of some CYP3A4 substrate drugs. Monitor for toxicities of CYP3A4 substrate drug that may require dosage reduction when given concurrently with TAVALISSE [see Clinical Pharmacology (12.3) ] . BCRP Substrates Concomitant use of TAVALISSE may increase concentrations of BCRP substrate drugs (e.g., rosuvastatin). Monitor for toxicities of BCRP substrate drug that may require dosage reduction when given concurrently with TAVALISSE [see Clinical Pharmacology (12.3) ] . P-Glycoprotein (P-gp) Substrates Concomitant use of TAVALISSE may increase concentrations of P-gp substrates (e.g., digoxin). Monitor for toxicities of the P-gp substrate drug that may require dosage reduction when given concurrently with TAVALISSE [see Clinical Pharmacology (12.3) ] .

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

8.1 Pregnancy Risk Summary Based on findings from animal studies and the mechanism of action, TAVALISSE can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) ]. There are no available data in pregnant women to inform the drug-associated risk. In animal reproduction studies, administration of fostamatinib to pregnant rats and rabbits during organogenesis caused adverse developmental outcomes that were directly attributed to exposure in utero to the major fostamatinib metabolite (R406) at maternal exposures (AUC) as low as 0.3 and 10 times the exposure in patients at the maximum recommended human dose (MRHD), respectively (see Data ). Advise pregnant women of the potential risk to a fetus. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. An estimated background risk of major birth defects and miscarriage for the chronic ITP population is 8% and 4-11%, respectively. Data Animal Data In a fertility and early embryonic development study in female rats, fostamatinib was administered orally for 15 days before mating to Day 7 of pregnancy, which caused a slight decrease in pregnancy rates and an increase in post-implantation loss were seen at maternal doses approximately 4.2 times the dose in patients at the MRHD. In embryo-fetal development studies, pregnant animals were orally administered fostamatinib during the period of organogenesis at doses up to 25 and 50 mg/kg/day in rats and rabbits, respectively. The adverse developmental outcomes included an increase in embryo-fetal mortality (post-implantation loss), alterations to growth (lower fetal weights), and structural abnormalities (variations and malformations). These effects occurred at maternal exposures (AUCs) of 3,763 ng.h/mL in rats and 111,105 ng.h/mL in rabbits that were approximately 0.3 and 10 times the human exposure at the MRHD in rats and rabbits, respectively. In a peri and postnatal development study in rats, fostamatinib was orally administered at doses of 2.5, 12.5, and 25 mg/kg/day from gestation day 7 until lactation day 20. The dose of 25 mg/kg/day was associated with maternal toxicity, including decreased body weights, body weight gains, and food consumption. At doses as low as 12.5 mg/kg/day fostamatinib caused increases in newborn mortality (neonatal mortality), alterations in growth and/or development (lower neonatal weights into post-weaning and structural abnormalities [malformations]). Functional impairment (delayed sexual maturation) was observed at 25 mg/kg/day. There was no evidence of neurobehavioral defects (maze learning and shuttle box avoidance) or immunological compromise (influenza host resistance challenge) in the F1 generation or latent untoward effects in the F2 generation. The maternal doses were approximately 2.1 and 4.2 times the MHRD in patients.

8.2 Lactation Risk Summary There are no data on the presence of fostamatinib and/or its metabolites in human milk, the effects on the breastfed child, or on milk production. In rodents, R406 (the major active metabolite) was detected in maternal milk in concentrations 5- to 10-fold higher than in maternal plasma. Because of the potential for serious adverse reactions in a breastfed child from TAVALISSE, advise a lactating woman not to breastfeed during treatment with TAVALISSE and for at least 1 month after the last dose.

8.3 Females and Males of Reproductive Potential Pregnancy Testing Based on animal studies, TAVALISSE can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1) ] . For females of reproductive potential, verify pregnancy status prior to initiating TAVALISSE. Contraception Females Based on animal studies, TAVALISSE can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1) ] . Advise females of reproductive potential to use effective contraception during treatment with TAVALISSE and for at least 1 month after the last dose. Infertility There are no data on the effect of TAVALISSE on human fertility. Based on the finding of reduced pregnancy rates in animal studies, TAVALISSE may affect female fertility [see Use in Specific Populations (8.1) ] .

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.

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.