COPIKTRA

2 DOSAGE AND ADMINISTRATION 25 mg orally, twice daily. Modify dosage for toxicity. ( 2.1 , 2.2 ) 2.1 Recommended Dosage The recommended dose of COPIKTRA is 25 mg administered as oral capsules twice daily (BID) with or without food. A cycle consists of 28 days. The capsules should be swallowed whole. Advise patients not to open, break, or chew the capsules. Advise patients that if a dose is missed by fewer than 6 hours, to take the missed dose right away and take the next dose as usual. If a dose is missed by more than 6 hours, advise patients to wait and take the next dose at the usual time. 2.2 Recommended Prophylaxis Provide prophylaxis for Pneumocystis jirovecii (PJP) during treatment with COPIKTRA. Following completion of COPIKTRA treatment, continue PJP prophylaxis until the absolute CD4+ T cell count is greater than 200 cells/µL. Withhold COPIKTRA in patients with suspected PJP of any grade, and discontinue if PJP is confirmed. Consider prophylactic antivirals during COPIKTRA treatment to prevent cytomegalovirus (CMV) infection including CMV reactivation. 2.3 Dosage Modifications for Adverse Reactions Manage toxicities per Table 1 with dose reduction, treatment hold, or discontinuation of COPIKTRA. Table 1. COPIKTRA Dose Modifications and Toxicity Management Abbreviations: ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate aminotransferase; CMV = cytomegalovirus; DRESS = drug reaction with eosinophilia and systemic systems; PCR = polymerase chain reaction; PJP = Pneumocystis jirovecii; pneumonia; SJS = Stevens-Johnson syndrome; TEN = toxic epidermal necrolysis; ULN = upper limit of normal Toxicity Adverse Reaction Grade Recommended Management Nonhematologic Adverse Reactions Infections Grade 3 or higher infection Withhold COPIKTRA until resolved Resume at the same or reduced dose (see Table 2 ) Clinical CMV infection or viremia (positive PCR or antigen test) Withhold COPIKTRA until resolved Resume at the same or reduced dose (see Table 2 ) If COPIKTRA is resumed, monitor patients for CMV reactivation (by PCR or antigen test) at least monthly PJP For suspected PJP, withhold COPIKTRA until evaluated For confirmed PJP, discontinue COPIKTRA Non-infectious Diarrhea or colitis Mild/moderate diarrhea (Grade 1-2, up to 6 stools per day over baseline) and responsive to antidiarrheal agents, OR Asymptomatic (Grade 1) colitis No change in dose Initiate supportive therapy with antidiarrheal agents as appropriate Monitor at least weekly until resolved Mild/moderate diarrhea (Grade 1-2, up to 6 stools per day over baseline) and unresponsive to antidiarrheal agents Withhold COPIKTRA until resolved Initiate supportive therapy with enteric acting steroids (e.g., budesonide) Monitor at least weekly until resolved Resume at a reduced dose (see Table 2 ) Abdominal pain, stool with mucus or blood, change in bowel habits, peritoneal signs, OR Severe diarrhea (Grade 3, >6 stools per day over baseline) Withhold COPIKTRA until resolved Initiate supportive therapy with enteric acting steroids (e.g., budesonide) or systemic steroids Monitor at least weekly until resolved Resume at a reduced dose (see Table 2 ) For recurrent Grade 3 diarrhea or recurrent colitis of any grade, discontinue COPIKTRA Life-threatening Discontinue COPIKTRA Cutaneous reactions Grade 1-2 No change in dose Initiate supportive care with emollients, anti-histamines (for pruritus), or topical steroids Monitor closely Grade 3 Withhold COPIKTRA until resolved Initiate supportive care with emollients, anti-histamines (for pruritus), or topical steroids Monitor at least weekly until resolved Resume at reduced dose (see Table 2 ) If severe cutaneous reaction does not improve, worsens, or recurs, discontinue COPIKTRA Life-threatening Discontinue COPIKTRA SJS, TEN, DRESS (any grade) Discontinue COPIKTRA Pneumonitis without suspected infectious cause Moderate (Grade 2) symptomatic pneumonitis Withhold COPIKTRA Treat with systemic steroid therapy If pneumonitis recovers to Grade 0 or 1, COPIKTRA may be resumed at reduced dose (see Table 2 ) If non-infectious pneumonitis recurs or patient does not respond to steroid therapy, discontinue COPIKTRA Severe (Grade 3) or life-threatening pneumonitis Discontinue COPIKTRA Treat with systemic steroid therapy ALT/AST elevation 3 to 5 × upper limit of normal (ULN) (Grade 2) Maintain COPIKTRA dose Monitor at least weekly until return to 5 to 20 × ULN (Grade 3) Withhold COPIKTRA and monitor at least weekly until return to 20 × ULN (Grade 4) Discontinue COPIKTRA Hematologic Adverse Reactions Neutropenia Absolute neutrophil count (ANC) 0.5 to 1.0 Gi/L Maintain COPIKTRA dose Monitor ANC at least weekly ANC less than 0.5 Gi/L Withhold COPIKTRA. Monitor ANC until > 0.5 Gi/L Resume COPIKTRA at same dose (first occurrence) or at a reduced dose for subsequent occurrence (see Table 2 ) Thrombocytopenia Platelet count 25 to < 50 Gi/L (Grade 3) with Grade 1 bleeding No change in dose Monitor platelet counts at least weekly Platelet count 25 to < 50 Gi/L (Grade 3) with Grade 2 bleeding or Platelet count < 25 Gi/L (Grade 4) Withhold COPIKTRA Monitor platelet counts until ≥ 25 Gi/L and resolution of bleeding (if applicable) Resume COPIKTRA at same dose (first occurrence) or resume at a reduced dose for subsequent occurrence (see Table 2 ) Recommended dose modification levels for COPIKTRA are presented in Table 2 . Table 2. Dose Modification Levels Dose Level Dose Initial Dose 25 mg twice daily Dose Reduction 15 mg twice daily Subsequent Dose Modification Discontinue COPIKTRA if patient is unable to tolerate 15 mg twice daily. 2.4 Dosage Modification for Concomitant Use with CYP3A4 Inhibitors Reduce COPIKTRA dose to 15 mg twice daily when coadministered with strong CYP3A4 inhibitors (e.g., ketoconazole) [see Drug Interactions ( 7.1 )] . 2.5 Dosage Modifications for Concomitant Use with CYP3A4 Inducers Avoid coadministration of COPIKTRA with strong CYP3A4 inducers. Avoid coadministration of COPIKTRA with moderate CYP3A4 inducers. If coadministration with a moderate CYP3A4 inducer cannot be avoided, increase the COPIKTRA dose on Day 12 of coadministration with the moderate CYP3A4 inducer as recommended in Table 3 . Table 3. Recommended Dosage Modifications for Use with Moderate CYP3A4 Inducers Initial COPIKTRA Dosage Recommended COPIKTRA Dosage 25 mg orally twice daily 40 mg orally twice daily 15 mg orally twice daily 25 mg orally twice daily After the inducer has been discontinued for at least 14 days, resume COPIKTRA at the dose taken prior to initiating the moderate CYP3A4 inducer [see Drug Interactions ( 7.1 ), Clinical Pharmacology ( 12.3 )]

See official label

1 INDICATIONS AND USAGE COPIKTRA is indicated for the treatment of adult patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) after at least two prior lines of systemic therapy.