COPIKTRA Hard capsule Ref.[28036] Active ingredients:

General

The safety and efficacy of duvelisib after prior idelalisib use has not been established.

Infections

Serious, including fatal infections have occurred in patients receiving duvelisib. The most common serious infections were pneumonia, sepsis, and lower respiratory infections. Median time to onset of any grade infection was 3 months with 75% of cases occurring within 6 months (see section 4.8).

Any infections should be treated prior to initiation of duvelisib. Patients should be monitored for infection, including respiratory signs and symptoms, throughout treatment. Patients should be advised to report any new or worsening infections promptly (see Table 1 for management).

Serious, including fatal, PJP pneumonia occurred in patients taking duvelisib. Prophylaxis for PJP should, therefore, be administered to all patients (see Table 1). CMV reactivation/infection occurred in patients taking duvelisib. Prophylactic antivirals should be considered during treatment to prevent CMV infection including CMV reactivation (see Table 1).

Recommended prophylaxis

Any infections should be treated prior to initiation of duvelisib . Patients should be monitored for infection, including respiratory signs and symptoms, throughout treatment. Patients should be advised to report any new or worsening infections promptly (see Table 1 for management).

Prophylaxis for PJP should be provided during treatment with duvelisib. Following completion of duvelisib treatment, PJP prophylaxis should be continued until the absolute CD4+ T cell count is greater than 200 cells/µL.

Duvelisib should be withheld in patients with suspected PJP of any grade and discontinued if PJP is confirmed.

Prophylactic antivirals should be considered during duvelisib treatment to prevent CMV infection including CMV reactivation.

Diarrhoea or colitis

Serious, including fatal diarrhoea or colitis occurred in patients receiving duvelisib. The median time to onset of any grade diarrhoea or colitis was 4 months, with 75% of cases occurring by 8 months. The median event duration was 0.5 months. Patients should be advised to report any new or worsening diarrhoea (see Table 1 for management) (see section 4.8).

Cutaneous reactions

Serious, including fatal cutaneous reactions occurred in patients receiving duvelisib. Fatal cases included drug reaction with eosinophilia and systemic symptoms (DRESS) and toxic epidermal necrolysis (TEN). Median time to onset of any grade cutaneous reaction was 3 months, with a median event duration of 1 month (see section 4.8).

Presenting features for the serious cutaneous events were primarily described as pruritic, erythematous, or maculo-papular. Less common presenting features include exanthem, desquamation, erythroderma, skin exfoliation, keratinocyte necrosis, and papular rash. Patients should be advised to report any new or worsening cutaneous reactions (see Table 1 for management). All concomitant medicinal products should be reviewed and any medicinal products potentially contributing to the event should be discontinued.

Pneumonitis

Serious, including fatal, pneumonitis without an apparent infectious cause occurred in patients receiving duvelisib. Median time to onset of any grade pneumonitis was 4 months with 75% of cases occurring within 9 months (see section 4.8). The median event duration was 1 month, with 75% of cases resolving by 2 months (see Table 1 for management).

Hepatotoxicity

Grade 3 and 4 ALT and/or AST elevation developed in patients receiving duvelisib. Two percent of patients had both an ALT or AST greater than 3 x ULN and total bilirubin greater than 2 x ULN. Median time to onset of any grade transaminase elevation was 2 months with a median event duration of 1 month. Hepatic function should be monitored during treatment with duvelisib especially during the first three months of therapy on a monthly basis. This guideline applies for the patients who have only ALT and AST elevation.

Neutropenia

Grade 3 or 4 neutropenia occurred in patients receiving duvelisib. The median time to onset of Grade ≥3 neutropenia was 2 months with 75% of cases occurring within 4 months. Neutrophil counts should be monitored at least every 2 weeks for the first 2 months of duvelisib.

CYP3A4 inducers

Duvelisib exposure may be reduced when co-administered with strong CYP3A inducers. Since a reduction in duvelisib plasma concentrations may result in decreased efficacy, co-administration of duvelisib with strong CYP3A inducers should be avoided (see section 4.5).

CYP3A substrates

Duvelisib and its major metabolite, IPI-656, are strong CYP3A4 inhibitors. Thus, duvelisib has the potential to interact with medicinal products that are metabolised by CYP3A, which may lead to increased serum concentrations of the other product (see section 4.5). When duvelisib is coadministered with other medicinal products, the Summary of Product Characteristics (SmPC) for the other medicinal product must be consulted for the recommendations regarding co-administration with CYP3A4 inhibitors. Concomitant treatment of duvelisib with sensitive CYP3A substrates should be avoided and alternative medicinal products that are less sensitive to CYP3A4 inhibition should be used if possible.

Effect of other medicinal products on duvelisib pharmacokinetics

Strong and moderate CYP3A4 inducers

Co-administration of 600 mg once daily rifampin, a strong CYP3A inducer, for 7 days with a single oral 25 mg duvelisib dose in healthy adults (N=13) decreased duvelisib C_max by 66% and AUC by 82%. Co-administration with a strong CYP3A inducer decreases duvelisib area under the curve (AUC) (see section 5.2), which may reduce duvelisib efficacy. Co-administration of duvelisib with strong CYP3A4 inducers (e.g., apalutamide, carbamazepine, enzalutamide, mitotane, phenytoin, rifampin, St. John’s wort) should be avoided.

Co-administration of 200 mg twice daily etravirine, a moderate CYP3A inducer, for 10 days with a single oral 25 mg duvelisib dose in healthy adults (N = 20) decreased duvelisib C_max by 16% and AUC by 35%. Co-administration of duvelisib with moderate CYP3A inducers decreases AUC of duvelisib to less than 1.5-fold and dose reduction is not recommended. Examples of moderate CYP3A4 inducers are bosentan, efavirenz, etravirine, phenobarbital, primidone. If a moderate CYP3A4 inducer must be used, the patient should be closely monitored for potential lack of efficacy. Examples: bosentan, efavirenz, etravirine, phenobarbital, primidone.

Strong and moderate CYP3A inhibitors

Co-administration of a strong CYP3A inhibitor ketoconazole (at 200 mg twice daily (BID) for 5 days), with a single oral 10 mg dose of duvelisib in healthy adults (n= 16) increased duvelisib C_max by 1.7-fold and AUC by 4-fold. Due to time-dependent CYP3A4 auto-inhibition, duvelisib susceptibility to moderate and strong CYP3A4 inhibitors is decreased under steady-state conditions. Based on physiologically-based pharmacokinetic (PBPK) modelling and simulation , the increase in exposure to duvelisib is estimated to be ~1.6-fold at steady state in cancer patients when concomitantly used with strong CYP3A4 inhibitors such as ketoconazole and itraconazole.

Duvelisib dose should be reduced to 15 mg twice daily when co-administered with a strong CYP3A4 inhibitor (see section 4.2) (e.g., ketoconazole, indinavir, nelfinavir, ritonavir, saquinavir, clarithromycin, telithromycin, itraconazole, nefazodon, cobicistat, voriconazole and posaconazole, and grapefruit juice).

PBPK modelling and simulation estimated no clinically significant effect on duvelisib exposures from concomitantly used moderate CYP3A4 inhibitors. Dose reduction of duvelisib is not necessary when co-administered with moderate CYP3A4 inhibitors (see section 4.2) (e.g., aprepitant, ciprofloxacin, conivaptan, crizotinib, cyclosporine, diltiazem, dronedarone, erythromycin, fluconazole, fluvoxamine, imatinib, tofisopam, verapamil)

Effect of duvelisib on the pharmacokinetics of other medicinal products

CYP3A4 substrates

Co-administration of multiple doses of duvelisib 25 mg BID for 5 days with single oral 2 mg midazolam, a sensitive CYP3A4 substrate, in healthy adults (N = 14), increased in the midazolam AUC by 4.3-fold and C_max by 2.2-fold. PBPK simulations in cancer patients under steady state conditions have shown that the C_max and AUC of midazolam would increase by approximately 2.5-fold and ≥5-fold respectively. Co-administration of midazolam with duvelisib should be avoided.

Duvelisib and its major metabolite, IPI-656, are strong CYP3A4 inhibitors. Dose reduction of CYP3A4 substrate should be considered when co-administered with duvelisib,especially for medicinal products with narrow therapeutic index. Patients should be monitored for signs of toxicities of the coadministered sensitive CYP3A substrate. Examples of sensitive substrates include: alfentanil, avanafil, buspirone, conivaptan, darifenacin, darunavir, ebastine, everolimus, ibrutinib, lomitapide, lovastatin, midazolam, naloxegol, nisoldipine, saquinavir, simvastatin, sirolimus, tacrolimus, tipranavir, triazolam, vardenafil, budesonide, dasatinib, dronedarone, eletriptan, eplerenone, felodipine, indinavir, lurasidone, maraviroc, quetiapine, sildenafil, ticagrelor, tolvaptan. Examples of moderately sensitive substrsates include: alprazolam, aprepitant, atorvastatin, colchicine, eliglustat, pimozide, rilpivirine, rivaroxaban, tadalafil. This list is not exhaustive and is intended to serve as guidance only. The SmPC for the other product should be consulted for recommendations regarding co-administration with CYP3A4 inhibitors (see section 4.4).

Hormonal contraceptives

It is unknown whether duvelisib reduces the effectiveness of hormonal contraceptives. Therefore, women using hormonal contraceptives should be advised to add a barrier method as a second form of contraception (see section 4.6).

Proton pump inhibitors

Population Pharmacokinetic (POPPK) analysis has shown that proton pump inhibitors (PPI) do not affect the exposure of COPIKTRA. PPI may be co-administered with duvelisib.

Pregnancy

There are no data on the use of duvelisib in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity at clinically relevant exposures (see section 5.3). As a precautionary measure, it is preferable to avoid the use of Copiktra during pregnancy.

Breast-feeding

It is not known whether duvelisib and its metabolites are excreted in human milk. A risk to the breast-fed child cannot be excluded. Breast-feeding should be discontinued during treatment with Copiktra and for at least 1 month after the last dose.

Fertility

No human data on the effect of duvelisib on fertility are available. In rats, but not in monkeys, effects on testes were observed.

Copiktra has no or negligible influence on the ability to drive and use machines.

Summary of the safety profile

The most commonly reported adverse reactions (incidence ≥20%) are diarrhoea or colitis, neutropenia, rash, fatigue, pyrexia, cough, nausea, upper respiratory infection, pneumonia, musculoskeletal pain, and anaemia.

The most frequently reported serious adverse reactions were pneumonia, colitis and diarrhoea.

Tabulated list of adverse reactions

The adverse reactions reported with duvelisib treatment are listed by system organ class and frequency in Table 2. Frequencies are defined as very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000) and very rare (<1/10,000) and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 2. Adverse drug reactions reported in patients with haematologic malignancies receiving duvelisib (N=442):

¹ Grouped term for reactions with multiple preferred terms
² Pneumonitis includes the preferred terms: pneumonitis, interstitial lung disease, lung infiltration
³ Diarrhoea or colitis includes the preferred terms: colitis, enterocolitis, colitis microscopic, colitis ulcerative, diarrhoea, diarrhoea haemorrhagic
⁴ Rash includes the preferred terms: dermatitis (including allergic, exfoliative, perivascular), erythema (including multiforme), rash (including exfoliative, erythematous, follicular, generalized, macular & papular, pruritic, pustular), toxic epidermal necrolysis and toxic skin eruption, drug reaction with eosinophilia and systemic symptoms, drug eruption, StevensJohnson syndrome.
⁵ Transaminase elevation includes the preferred terms: alanine aminotransferase increased, aspartate aminotransferase increased, transaminases increased, hypertransaminasaemia, hepatocellular injury, hepatotoxicity
Note: Doses withheld for >42 days due to treatment-related toxicity will result in permanent discontinuation from treatment

Description of selected adverse reactions

Infections

The most common serious infections were pneumonia, sepsis, and lower respiratory infections. Median time to onset of any grade infection was 3 months (range: 1 day to 32 months), with 75% of cases occurring within 6 months. Infections should be treated prior to initiation of duvelisib. Patients should be advised to report any new or worsening signs and symptoms of infection.

For management of infections see sections 4.2 (Table 1) and 4.4.

Diarrhoea and colitis

The median time to onset of any grade diarrhoea or colitis was 4 months (range: 1 day to 33 months), with 75% of cases occurring by 8 months. The median event duration was 0.5 months (range: 1 day to 29 months; 75th percentile: 1 month). Patients should be advised to report any new or worsening diarrhea.

Non-infectious pneumonitis

Median time to onset of any grade pneumonitis was 4 months (range: 9 days to 27 months), with 75% of cases occurring within 9 months. The median event duration was 1 month, with 75% of cases resolving by 2 months.

Duvelisib should be withheld in patients who present with new or progressive pulmonary signs and symptoms such as cough, dyspnoea, hypoxia, interstitial infiltrates on a radiologic exam, or a decline by more than 5% in oxygen saturation and evaluate for etiology. If the pneumonitis is infectious, patients may be restarted on duvelisib at the previous dose once the infection, pulmonary signs and symptoms resolve.

Severe cutaneous reactions

Median time to onset of any grade cutaneous reaction was 3 months (range: 1 day to 29 months, 75th percentile: 6 months), with a median event duration of 1 month (range: 1 day to 37 months, 75th percentile: 2 months). Severe cutaneous reactions include rash, Stevens-Johnson Syndrome (SJS), Toxic Epidermal Necrosis (TEN) and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Not applicable.