Copiktra Drug Information

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. Limitations of Use: COPIKTRA is not indicated or recommended for the treatment of any patients with CLL or SLL as initial or second line treatment due to an increased risk of treatment-related mortality.

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.

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.

Dosage Modifications for Adverse Reactions

Manage toxicities per Table 1 with dose reduction, treatment hold, or discontinuation of COPIKTRA. Table 1. COPIKTRA Recommended dose modification levels for COPIKTRA are presented in Table 2.

Table 2.

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).

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 After the inducer has been discontinued for at least 14 days, resume COPIKTRA at the dose taken prior to initiating the moderate CYP3A4 inducer

Clinical Trial Experience

Because clinical trials are conducted under widely variable conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared with rates in clinical trials of another drug and may not reflect the rates observed in practice. Summary of Clinical Trial Experience in B-cell Malignancies The data described below reflect exposure to COPIKTRA in two single-arm, open-label clinical trials, one open-label extension clinical trial, and one randomized, open-label, actively controlled clinical trial totaling 442 patients with previously treated hematologic malignancies primarily including CLL/SLL (69%) and FL (22%). Patients were treated with COPIKTRA 25 mg BID until unacceptable toxicity or progressive disease.

Patients had a median of 2 prior therapies. The trials required hepatic transaminases at least ≤ 3 times upper limit of normal (ULN), total bilirubin ≤ 1.5 times ULN, and serum creatinine ≤ 1.5 times ULN. Patients were excluded for prior exposure to a PI3K inhibitor within 4 weeks.

Serious adverse reactions were reported in 289 patients (65%). Adverse reactions resulted in treatment discontinuation in 156 patients (35%), most often due to diarrhea or colitis, infection, and rash. COPIKTRA was dose reduced in 104 patients (24%) due to adverse reactions, most often due to diarrhea or colitis and transaminase elevation.

Common Adverse Reactions Table 4 summarizes common adverse reactions in patients receiving COPIKTRA 25 mg BID, and Table 5 summarizes the treatment-emergent laboratory abnormalities. The most common adverse reactions (reported in ≥ 20% of patients) were diarrhea or colitis, neutropenia, rash, fatigue, pyrexia, cough, nausea, upper respiratory infection, pneumonia, musculoskeletal pain, and anemia. Table 4.

Table 5. Summary of Clinical Trial Experience in CLL/SLL DUO Study The safety data below reflects exposure in a randomized, open-label, actively controlled clinical trial for adult patients with CLL or SLL who received at least one prior therapy. Of 313 patients treated, 158 received COPIKTRA monotherapy and 155 received ofatumumab.

The 442-patient safety analysis above includes patients from DUO. COPIKTRA was administered at 25 mg BID in 28-day treatment cycles until unacceptable toxicity or progressive disease. The trial excluded patients with prior autologous transplant within 6 months or allogeneic transplant, prior exposure to a PI3K inhibitor or a Bruton's tyrosine kinase (BTK) inhibitor, and uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenic purpura.

COPIKTRA was discontinued in 57 patients (36%), most often due to diarrhea or colitis, infection, and rash. COPIKTRA was dose reduced in 46 patients (29%) due to adverse reactions, most often due to diarrhea or colitis and rash. Common Adverse Reactions Table 6 summarizes selected adverse reactions in Study 1, and Table 7 summarizes treatment-emergent laboratory abnormalities.

Table 6. Common Nonhematologic Adverse Reactions (≥ 10% Incidence) in Patients with CLL/SLL Receiving COPIKTRA (DUO) Table 7. The data above are not an adequate basis for comparison of rates between the study drug and the active control.

Long-Term Safety Follow-Up The comparative safety data from the 5 year follow up in those treated with either COPIKTRA (n=158) or ofatumumab (n=155) were analyzed in adult patients with CLL or SLL as part of a randomized, open-label, actively controlled clinical trial (DUO). The most common fatal adverse reactions in the COPIKTRA arm were infections and respiratory adverse reactions, occurring in 9% and 3% of patients, respectively.

Effects of Other Drugs on COPIKTRA Strong CYP3A4 Inhibitors Coadministration with a strong CYP3A4 inhibitor increases duvelisib AUC, which may increase the risk of COPIKTRA toxicities. Reduce COPIKTRA dosage when co-administered with a strong CYP3A4 inhibitor. Strong and Moderate CYP3A4 Inducers Coadministration with a strong or moderate CYP3A4 inducer decreases duvelisib area under the curve (AUC), which may reduce COPIKTRA efficacy.

Avoid coadministration of strong or moderate CYP3A4 inducers with COPIKTRA. If coadministration with a moderate CYP3A4 inducer cannot be avoided, increase the COPIKTRA dose.

Effects of COPIKTRA on Other Drugs CYP3A4 Substrates Coadministration with COPIKTRA increases AUC of a sensitive CYP3A4 substrate which may increase the risk of toxicities of these drugs. Consider reducing the dose of the sensitive CYP3A4 substrate and monitor for signs of toxicities of the co-administered sensitive CYP3A4 substrate.

Pregnancy Risk Summary Based on findings from animal studies and the mechanism of action, COPIKTRA can cause fetal harm when administered to a pregnant woman. There are no available data in pregnant women to inform the drug-associated risk. In animal reproduction studies, administration of duvelisib to pregnant rats and rabbits during organogenesis caused adverse developmental outcomes including embryo-fetal mortality (resorptions, post-implantation loss, and decreased viable fetuses), alterations to growth (lower fetal weights) and structural abnormalities (malformations) at maternal doses 10 times and 39 times the MRHD of 25 mg BID in rats and rabbits, respectively (see Data ).

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. 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 respectively.

Data Animal Data In an embryo-fetal development study in rats, pregnant animals received daily oral doses of duvelisib of mg/kg/day during the period of organogenesis. Administration of duvelisib at doses ≥ 50 mg/kg/day resulted in adverse developmental outcomes including reduced fetal weights and external abnormalities (bent tail and fetal anasarca), and doses ≥ 150 mg/kg/day resulted in maternal toxicity including mortality and no live fetuses (100% resorption) in surviving dams. In another study in pregnant rats receiving oral doses of duvelisib up to 35 mg/kg/day during the period of organogenesis, no maternal or embryo-fetal effects were observed.

The dose of 50 mg/kg/day in rats is approximately 10 -times the MRHD of 25 mg BID. Administration of duvelisib at doses ≥ 100 mg/kg/day resulted in maternal toxicity (body weight losses or lower mean body weights and increased mortality) and adverse developmental outcomes (increased resorptions and post-implantation loss, abortion, and decreased numbers of viable fetuses). The dose of 100 mg/kg/day in rabbits is approximately 39 times the MRHD of 25 mg BID.

Pediatric Use Safety and effectiveness of COPIKTRA have not been established in pediatric patients. Pediatric studies have not been conducted.