Tavalisse

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.

None.

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)].

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

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.

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.

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)].

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.

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.

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)].

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.

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.

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% [see Dosage and Administration (2.1)].

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

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 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 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 Studies

Clinical Pharmacology 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% .

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

Effect of Tavalisse on Other Drugs

CYP3A4 substrate: Concomitant use of simvastatin (single dose 40 mg) with 100 mg twice daily Tavalisse 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 Tavalisse 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 Tavalisse increased digoxin AUC by 37% and Cmax by 70% .

In Vitro Studies

Tavalisse 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.

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

• Strong CYP3A4 Inhibitors: Concomitant use with a strong CYP3A4 inhibitor increases exposure to R406 (the major active metabolite).1

• Strong CYP3A4 Inducers: Concomitant use is not recommended.1

Tavalisse is part of the drug class:

• Protein kinase inhibitors

• If your symptoms or health problems do not get better or if they become worse, call your doctor.
• Do not share your drugs with others and do not take anyone else's drugs.
• Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
• Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
• Some drugs may have another patient information leaflet. Check with your pharmacist. If you have any questions about Tavalisse (fostamatinib), please talk with your doctor, nurse, pharmacist, or other health care provider.
• If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Signs of high blood pressure like very bad headache or dizziness, passing out, or change in eyesight.
• Signs of liver problems like dark urine, feeling tired, not hungry, upset stomach or stomach pain, light-colored stools, throwing up, or yellow skin or eyes.
• Very loose stools (diarrhea).
• Loose stools (diarrhea) that will not go away.
• Feeling confused.
• Chest pain.
• Shortness of breath.
• Low white blood cell counts have happened with this drug. This may lead to a higher chance of getting an infection. Call your doctor right away if you have signs of infection like fever, chills, or sore throat.