Indications for: TAVALISSE
Thrombocytopenia in adults with chronic immune thrombocytopenia (ITP) who have had insufficient response to previous treatment.
Tavalisse was studied in two placebo-controlled efficacy and safety studies (referred to as FIT-1 [ClinicalTrials.gov Identifiers: NCT02076399] and FIT-2 [NCT02076412]), and in an open-label extension study referred to as FIT-3 (ClinicalTrials.gov Identifier: NCT 02077192).
Randomized, Placebo-Controlled Studies
- A total of 150 patients with persistent or chronic ITP, who had an insufficient response to previous treatment were enrolled in two identical, double-blind, placebo-controlled studies that were conducted in different countries.
- Patients were randomized 2:1 to Tavalisse or placebo for 24 weeks; randomization was stratified with respect to prior splenectomy and severity of thrombocytopenia.
- Stable concurrent ITP therapy was allowed, and rescue therapy was permitted, if needed.
- All patients initially received the study drug at 100 mg twice daily (or matching placebo).
- Based on platelet count and tolerability, dose escalation to 150 mg twice daily (or matching placebo) was undertaken in 88% of patients at Week 4 or later.
- Patients who did not respond to treatment after 12 weeks, as well as patients who completed the 24-week double blind study, were eligible to enroll in open-label extension study (FIT-3).
- At baseline, the median platelet count was 16×109/L (with almost half % <15×109/L) and 47% were on stable ITP therapy.
- In Study FIT-1 (n=76), 51 patients were randomized to the Tavalisse group and 25 to the placebo group.
- In Study FIT-2 (n=74), 50 patients were randomized to the Tavalisse group and 24 to the placebo group.
- The efficacy of Tavalisse was based on stable platelet response (at least 50×109/L on at least 4 of the 6 visits between Weeks 14 to 24).
- Results in FIT-1 showed 18% of the Tavalisse group achieved stable platelet response vs 0% in the placebo group (P =.03). While in FIT-2, 16% of the Tavalisse group achieved stable platelet response vs 4% in the placebo group (P-value not significant).
- The FIT-3 trial is an open label extension study.
- Patients from FIT-1 and FIT-2 who completed 24 weeks of treatment, or who did not respond to treatment any time after 12 weeks, were eligible to enroll in this study.
- Patients designated as responders (defined as achievement of platelet count of at least 50×109/L) at the time of roll over continued in the extension study at their current trial dose and regimen.
- Patients who entered the extension study as non-responders (defined as platelet count <50×109/L) received Tavalisse 100 mg twice daily regardless of their dose and regimen in the prior study.
- For the FIT-3 trial (n=123), 44 patients were previously randomized to placebo; 79 patients were previously randomized to Tavalisse.
- Stable response was prospectively defined as no 2 visits (at least 4 weeks apart) with a platelet count <50×109/L, without an intervening visit with a platelet count of at least 50×109/L, within a period of 12 weeks following initial achievement of the target platelet count.
- Sixty-one of the 123 subjects (50%) have discontinued from the study early.
- In the prospective analysis, the 44 patients treated with placebo in the prior study were evaluated for stable response for Tavalisse. Ten of these subjects (23%) met the criteria for stable response.
Among the patients who achieved stable response in FIT-1, FIT-2 and FIT-3 trials, 18 patients maintained the platelet count of at least 50×109/L for 12 months or longer.
≥18yrs: Initially 100mg twice daily. Increase to 150mg twice daily if platelet count not at ≥50x109/L after 4 weeks. Discontinue if insufficient increase in platelet count after 12 weeks. Dose modifications: see full labeling.
<18yrs: not recommended.
Monitor CBCs, including platelets, monthly until stable count (≥50x109/L) achieved, then periodically thereafter. Monitor LFTs monthly. Discontinue if AST/ALT >5xULN for ≥2wks or ≥3xULN and total bilirubin >2xULN. Monitor blood pressure every 2 weeks until stable dose established, then monthly thereafter. Interrupt or discontinue dose if hypertensive crisis (>180/120mmHg) occurs; discontinue if repeat BP >160/100mmHg for >4 weeks. Temporarily interrupt if severe diarrhea (Grade ≥3) occurs; resume at next lower daily dose if improved to Grade 1. Monitor ANC monthly and for infection. Temporarily interrupt if ANC <1x109/L occurs and remains low after 72hrs until resolved; resume at next lower daily dose. Use lowest effective dose. Embryo-fetal toxicity. Use effective contraception during and for ≥1 month after last dose. Pregnancy; confirm negative status prior to initiation. Nursing mothers: not recommended (during and for ≥1 month after last dose).
Tyrosine kinase inhibitor.
Concomitant strong CYP3A4 inducers: not recommended. Concomitant strong CYP3A4 inhibitors or substrates; monitor for toxicity. May potentiate concomitant BCRP (eg, rosuvastatin) or P-gp (eg, digoxin) substrates: monitor for toxicity.
Diarrhea, hypertension, nausea, respiratory infection, dizziness, ALT/AST increase, rash, abdominal pain, fatigue, chest pain, neutropenia.
The mean terminal half-life of R406 is ~15 (± 4.3) hours. Following an oral dose of Tavalisse, ~80% of the R406 metabolite is excreted in feces; ~20% excreted in the urine. The major component excreted in urine was R406 N-glucuronide.
Generic Drug Availability: