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Fostamatinib Disodium Hexahydrate Tablets

TABLE OF CONTENTS

1. DESCRIPTION 8. USE IN SPECIFIC POPULATIONS
2. INDICATIONS AND USAGE 9. OVERDOSAGE
3. DOSAGE AND ADMINISTRATION 10. MECHANISM OF ACTION
4. CONTRAINDICATIONS 11. PHARMACODYNAMICS
5. WARNINGS AND PRECAUTIONS 12. PHARMACOKINETICS
6. ADVERSE REACTIONS 13. HOW SUPPLIED/STORAGE AND HANDLING
7. DRUG INTERACTIONS

 

1. DESCRIPTION

Fostamatinib is a tyrosine kinase inhibitor. Fostamatinib 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 structural formula is:

Empirical formula: C23H24FN6Na2O9P·6H2O - Molecular weight: 732.52 g/mol

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 fostamatinib 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.

2. INDICATIONS AND USAGE

Fostamatinib 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 AND ADMINISTRATION

3.1 Recommended Dosage

Initiate fostamatinib at a dose of 100 mg taken orally twice daily. After a month, if platelet count has not increased to at least 50 x 109/L, increase fostamatinib dose to 150 mg twice daily.

Use the lowest dose of fostamatinib to achieve and maintain a platelet count at least 50 x 109/L as necessary to reduce the risk of bleeding.

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

3.2 Monitoring

After obtaining baseline assessments:

• Monitor CBCs, including platelet counts, monthly until a stable platelet count (at least 50 x 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.

3.3 Dose Modification for Adverse Reactions

Fostamatinib 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.

Table 1: Dose Reduction Schedule

1 Once daily fostamatinib should be taken in the morning.

2 If further dose reduction below 100 mg/day is required, discontinue fostamatinib.

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

Table 2: Recommended Dose Modifications and Management for Specific Adverse Reactions

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); AST/ALT = AST or ALT

3.4 Dose Modification for Drug Interactions

Concomitant use with a strong CYP3A4 inhibitor increases exposure to R406 (the major active metabolite). Monitor for toxicities of fostamatinib that may require fostamatinib dose modifications (see Table 1) when given concurrently with a strong CYP3A4 inhibitor [see Drug Interactions (7.1)].

3.5 Discontinuation

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

4. CONTRAINDICATIONS

None.

5. WARNINGS AND PRECAUTIONS

5.1 Hypertension

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

Monitor blood pressure every 2 weeks until stable, then monthly and adjust or initiate antihypertensive therapy to ensure maintenance of blood pressure control during fostamatinib therapy. If increased blood pressure persists despite appropriate therapy, fostamatinib interruption, reduction or discontinuation may be necessary [see Dosage and Administration (3.3)].

5.2 Hepatotoxicity

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

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 fostamatinib [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 fostamatinib interruption, reduction, or discontinuation [see Dosage and Administration (3.3)].

5.3 Diarrhea

Diarrhea occurred in 31% of patients treated with fostamatinib. Severe diarrhea occurred in 1% of patients treated with fostamatinib. 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 fostamatinib if diarrhea becomes severe (Grade 3 or above) [see Dosage and Administration (3.3)].

5.4 Neutropenia

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

Monitor the ANC monthly, and for infection during treatment. Manage toxicity with fostamatinib interruption, reduction or discontinuation [see Dosage and Administration (3.3)].

5.5 Embryo-Fetal Toxicity

Based on findings from animal studies and its mechanism of action, fostamatinib 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].

6. ADVERSE REACTIONS

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)]

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.

Fostamatinib was studied in two randomized, double-blind, placebo-controlled trials that were identical in design. The data described below reflect exposure to fostamatinib 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 fostamatinib 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 109/L, the fostamatinib dose could be increased to 150 mg twice daily after one month. In the placebo controlled studies, the median duration of fostamatinib exposure in these studies was 86 days (range 8 to 183) [see Clinical Studies] for additional details for patients on fostamatinib].

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 fostamatinib. In addition, severe adverse reactions observed in patients receiving fostamatinib 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)

ALT = Alanine aminotransferase AST = Aspartate aminotransferase

Note: Common adverse reactions defined as all adverse reactions occurring ata rate of ≥ 5% of patients in the fostamatinib 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.

Table 4: Elevations in Hepatic Transaminases During Placebo-Controlled Clinical Studies

7. DRUG INTERACTIONS

7.1 Effect of Other Drugs on Fostamatinib

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 fostamatinib that may require dose reduction (see Table 1) when given concurrently with a strong CYP3A4 inhibitor [see Dosage and Administration (3.4) and Clinical Pharmacology].

Strong CYP3A4 Inducers

Concomitant use with a strong CYP3A4 inducer reduces exposure to R406. Concomitant use of fostamatinib with strong CYP3A4 inducers is not recommended [see Clinical Pharmacology].

7.2 Effect of Fostamatinib on Other Drugs

CYP3A4 Substrates

Concomitant use of fostamatinib may increase concentrations of some CYP3A4 substrate drugs. Monitor for toxicities of CYP3A4 substrate drug that may require dosage reduction when given concurrently with fostamatinib [see Clinical Pharmacology].

BCRP Substrates

Concomitant use of fostamatinib 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 fostamatinib [see Clinical Pharmacology].

P-Glycoprotein (P-gp) Substrates

Concomitant use of fostamatinib 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 fostamatinib [see Clinical Pharmacology].

8. USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Based on findings from animal studies and the mechanism of action, fostamatinib can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology].

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 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 fostamatinib, advise a lactating woman not to breastfeed during treatment with fostamatinib and for at least 1 month after the last dose.

8.3 Females and Males of Reproductive Potential

Pregnancy Testing

Based on animal studies, fostamatinib 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 fostamatinib.

Contraception

Females

Based on animal studies, fostamatinib 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 fostamatinib and for at least 1 month after the last dose.

Infertility

There are no data on the effect of fostamatinib on human fertility. Based on the finding of reduced pregnancy rates in animal studies, fostamatinib 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. Fostamatinib 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 fostamatinib, 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 fostamatinib, 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 fostamatinib, 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.

9. OVERDOSAGE

There is no specific antidote for overdose with fostamatinib, 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)].

10. 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.

11. 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 fostamatinib doses of 100 mg twice daily for 28 days. About 31% of patients in the fostamatinib 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 fostamatinib discontinuation in 58% (11 of 19) of patients in the fostamatinib group who had blood pressures ≥140/90 mmHg.

Cardiac Electrophysiology

At 2 times the maximum recommended dose, fostamatinib did not prolong the QT interval to a clinically relevant extent.

12. PHARMACOKINETICS

Fostamatinib 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).

Absorption

After oral administration of fostamatinib, the absolute bioavailability of R406 was 55%. The median tmax of R406 is approximately 1.5 hours (range: 1 to 4 hours). Negligible levels of fostamatinib were found in plasma.

Effect of Food

Administration of fostamatinib with a high-calorie, high-fat meal (deriving approximately 150, 250, and 500–600 calories from protein, carbohydrate, and fat, respectively) increased R406 AUC by 23% and Cmax by 15% [see Dosage and Administration (3.1)].

Distribution

In in vitro studies, the R406 is 98.3% protein bound in human plasma. The red blood cell to plasma concentration ratio is approximately 2.6. The mean (± SD) volume of distribution at steady-state of R406 is 256 (± 92) L.

Elimination

The mean (± SD) terminal half-life of R406 is approximately 15 (± 4.3) hours.

Metabolism

Fostamatinib is metabolized in the gut by alkaline phosphatase to the major active metabolite, R406. R406 is extensively metabolized, primarily through pathways of CYP450-mediated oxidation (by CYP3A4) and glucuronidation (by UDP glucuronosyltransferase [UGT]1A9). R406 is the predominant moiety in the systemic circulation, and there was minimal exposure to any R406 metabolites.

Excretion

Following an oral dose of fostamatinib, approximately 80% of the R406 metabolite is excreted in feces with approximately 20% excreted in the urine. The major component excreted in urine was R406 N-glucuronide. The major components excreted in feces were R406, O-desmethyl R406 and a metabolite produced by gut bacteria from the O-desmethyl metabolite of R406.

Specific Populations

Population pharmacokinetics analyses indicate fostamatinib is not altered based on age, sex, race/ethnicity. In addition, the pharmacokinetics of fostamatinib is not altered in patients with renal impairment (creatinine clearance [CLcr] ≥ 30 to < 50 mL/min, estimated by Cockcroft Gault equation and end stage renal disease requiring dialysis), or hepatic impairment (Child-Pugh Class A, B and C).

Drug Interaction Studies

Clinical Pharmacology Studies

No significant interactions were seen with concomitant use of fostamatinib with the following drugs: methotrexate (OAT1/3 transporters), midazolam (CYP3A4 substrate), microgynon (ethinyl estradiol and levonorgestrel), warfarin, pioglitazone (CYP2C8 substrate) and ranitidine (H2-antagonist that increases gastric pH).

Effect of Other Drugs on Fostamatinib

Strong CYP3A4 inhibitor: Concomitant use of ketoconazole (200 mg twice daily for 3.5 days) with a single dose of 80 mg fostamatinib (0.53 times the 150 mg dosage) increased R406 AUC by 102% and Cmax by 37%.

Moderate CYP3A4 Inhibitor: Concomitant use of verapamil (80 mg three times daily for 4 days) with a single dose of 150 mg fostamatinib increased R406 AUC by 39% and Cmax by 6% .

CYP3A4 inducer: Concomitant use of rifampicin (600 mg once daily for 8 days) with a single dose of 150 mg fostamatinib decreased R406 AUC by 75% and Cmax by 59% .

Effect of Fostamatinib on Other Drugs

CYP3A4 substrate: Concomitant use of simvastatin (single dose 40 mg) with 100 mg twice daily fostamatinib increased simvastatin AUC by 64% and Cmax by 113% and simvastatin acid AUC by 64% and Cmax by 83%.

BCRP substrate: Concomitant use of rosuvastatin (single dose 20 mg) with 100 mg twice daily fostamatinib increased rosuvastatin AUC by 95% and Cmax by 88%.

P-gp substrate: Concomitant use of digoxin (0.25 mg once daily) with 100 mg twice daily fostamatinib increased digoxin AUC by 37% and Cmax by 70% .

In Vitro Studies

Fostamatinib is an inhibitor of the human P-gp efflux transporter in vitro.

CYP3A4 and UGT1A9 are involved in the metabolism of R406. R406 is a substrate of P-gp but not of other major transporters (OAT1/3, OCT2, OATP1B1/3, MRP2, and BCRP). R406 can inhibit CYP3A4 and BCRP, and can induce CYP2C8 activity.

R406 is an inhibitor of UGT1A1. Inhibition of UGT1A1 may result in increased unconjugated bilirubin in the absence of other LFT abnormalities.

13. HOW SUPPLIED/STORAGE AND HANDLING

How Supplied:

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.

100 mg tablets: Available in bottle of 60 with 2 desiccant canisters NDC 71332-001-01

150 mg tablets: Available in bottle of 60 with 2 desiccant canisters NDC 71332-002-01

Storage and Handling:

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

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Rev 04/18