BRIEF SUMMARY

FOSTAMATINIB- (April 2018)

Indn-  To treat thrombocytopenia in adult patients with persistent or chronic immune thrombocytopenia (ITP) 

Comp-  Tablets: 100 mg, 150 mg . • Initiate  at 100 mg orally twice daily with or without food. After 4 weeks, increase to 150 mg twice daily, if needed, to achieve platelet count at least 50 x 109 /L as necessary to reduce the risk of bleeding.

ADR-  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

CI-   None

Pat Inform-

  • Hypertension:                                                                                                             Inform patients that periodic monitoring of their blood pressure is required, as high blood pressure has occurred in patients taking the medicine. 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.

• Hepatotox

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U.S. FDA APPROVED  DRUGS DURING 2018

Sr.No-  7

 PATIENT COUNSELING INFORMATION-                                                                   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.

• 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 .

• Diarrhea:                                                                                                                   Advise patients to use supportive care measures, and if diarrhea becomes severe, it may necessitate interruption, reduction, or discontinuation of TAVALISSE.

 • 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.

• Advise patients to inform their healthcare providers of all their medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products. 

• 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.

Advise females of reproductive potential to use effective contraception during treatment and for at least 1 month after receiving the last dose of TAVALISSE

• Lactation- Advise lactating women not to breastfeed during treatment with        TAVALISSE and for at least 1 month after the last dose ..

• 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.

Manufactured for: Rigel Pharmaceuticals, Inc., 1180 Veterans Blvd., South San Francisco, CA 94080 USA

Manufactured by: Patheon Whitby, 111 Consumers Drive, Whitby, Ontario L1N 525 Canada © Rigel Pharmaceuticals, Inc. All rights reserved. TAVALISSE is a trademark of Rigel Pharmaceuticals, Inc.

 CLINICAL PHARMACOLOGY-

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.

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.

Cardiac Electrophysiology- At 2 times the maximum recommended dose, TAVALISSE did not prolong the QT interval to a clinically relevant extent.

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).

Absorption-                                                                                                                   After oral administration of TAVALISSE, 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 TAVALISSE 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%  

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-                                                                                                        TAVALISSE 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 TAVALISSE, 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 Nglucuronide. 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 TAVALISSE is not altered based   on age, sex, race/ethnicity. In addition, the pharmacokinetics of TAVALISSE 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-                                                                                                            Pharmacolgical studies-No significant interactions were seen with concomitant use of TAVALISSE 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 TAVALISSE-   Strong CYP3A4 inhibitor:               Concomitant use of ketoconazole (200 mg twice daily for 3.5 days) with a single dose of 80 mg TAVALISSE (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 TAVALISSE increased R406 AUC by 39% and Cmax by 6% . 

 USE IN SPECIFIC POPULATIONS

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 womanThere are no available data in pregnant women to inform the drug-associated risk.

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.

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.

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.

3.Females and Males of Reproductive Potential Pregnancy-                                   Testing Based on animal studies, TAVALISSE can cause fetal harm when administered to a pregnant woman

 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.                                                                                                 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.].

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.

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.

 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..