Special Warning : אזהרת שימוש

4.3   Special warnings and precautions for use

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 co- administered 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.

Effects on Driving