TAVALISSE™ ( fostamatinib disodium hexahydrate ) tablets |
BRIEF SUMMARY OF PRESCRIBING INFORMATION — CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION |
1 INDICATIONS AND USAGE |
Table 4 : Elevations in Hepatic Transaminases During Placebo-Controlled Clinical Studies |
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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 .
3 DOSAGE FORMS AND STRENGTHS
TAVALISSE is available as : 100 mg tablet : orange , film-coated , round , biconvex tablets debossed with
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Enzyme |
Maximum Level of Elevation |
Number of Patients (%)
TAVALISSE
Placebo
( N = 102 )
( N = 48 )
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“ 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 .
4 CONTRAINDICATIONS
None .
5 WARNINGS AND PRECAUTIONS 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 x 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 x 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 . 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 ADVERSE REACTIONS 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 x 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 )
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Alanine aminotransferase
( ALT ) and / or Aspartate aminotransferase ( AST )
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> 3 and ≤5 x ULN
> 5 and ≤10 x ULN
≥10 x ULN
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3 ( 3 )
5 ( 5 )
1 ( 1 )
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0
0
0
|
Adverse Reaction
Mild %
TAVALISSE ( N = 102 ) Placebo ( N = 48 ) Moderate %
Severe %
TOTAL %
Mild %
Moderate %
Severe %
Diarrhea ¹ 21 10 1 31 13 2 0 15 Hypertension ² 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 ³ 7 4 0 11 6 0 0 6 Rash⁴ 8 1 0 9 2 0 0 2 Abdominal pain⁵ 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 6 3 2 1 6 0 0 0 0
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 . 1 Includes diarrhea and frequent bowel movement . ² Includes hypertension , blood pressure ( BP ) increased , BP diastolic abnormal , and BP diastolic increased . ³ Includes upper respiratory tract infection , respiratory tract infection , lower respiratory tract infection , and viral upper respiratory tract infection . 4 Includes rash , rash erythematous and rash macular . 5 Includes abdominal pain , and abdominal pain upper . 6 Includes neutropenia and neutrophil count decreased .
7 DRUG INTERACTIONS 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 )].
8 USE IN SPECIFIC POPULATIONS 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 .
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 .
10 OVERDOSAGE 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 )].
© 2018 Rigel Pharmaceuticals , Inc . All rights reserved . | TAVA _ ITP-18060 0418 | 0418 TAVALISSE is a trademark of Rigel Pharmaceuticals , Inc .