Indications : התוויות

4.1    Therapeutic indications

Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL)
COPIKTRA is indicated for the treatment of adult patients with relapsed or refractory CLL or SLL after at least two prior therapies.
Follicular Lymphoma (FL)
COPIKTRA is indicated for the treatment of adult patients with relapsed or refractory FL after at least two prior systemic therapies.

Posology

The recommended dose is 25 mg duvelisib twice daily. A cycle consists of 28 days. Treatment should be continued until disease progression or unacceptable toxicity.

Delayed or missed doses
Patients should be advised that if a dose is missed by less than 6 hours, the missed dose should be taken right away and the next dose should be taken as usual. If a dose is missed by more than 6 hours, patients should be advised to wait and to take the next dose at the usual time.

Dose modification for concomitant use with CYP3A4 inhibitors
The dose of Copiktra should be reduced to 15 mg twice daily when co-administered with strong CYP3A4 inhibitors (e.g. ketoconazole) [see section 4.5]. No dose adjustment is necessary when co- administered with moderate CYP3A4 inhibitors (e.g. fluconazole) but potential adverse reactions of duvelisib should be closely monitored.

Dose modifications for adverse reactions
Toxicities should be managed as per Table 1 with dose reduction, treatment hold, or discontinuation of Copiktra.

Table 1:     Copiktra dose modifications and toxicity management
Toxicity          Adverse reaction grade     Recommended management
Nonhematologic adverse reactions
• Withhold Copiktra until resolved
Grade 3 or higher infection       • Resume at the same or reduced dose (25 mg or 15 mg twice daily)
• Withhold Copiktra until resolved
• Resume at the same or reduced dose (25 mg or 15 mg twice daily)
Clinical CMV infection or         • If Copiktra is resumed, monitor patients for Infections             viremia (positive PCR or            CMV reactivation (by PCR or antigen test) at antigen test)                       least monthly. In clinical studies iNHL, FL (IPI-145-06) and CLL/SLL (IPI-145-07 the outcome of starting at same dose or reduction are comparable
• For suspected PJP, withhold Copiktra until
PJP                                 evaluated
• For confirmed PJP, discontinue Copiktra
Mild/moderate diarrhoea
(Grade 1-2, up to 6 stools per day over baseline) and responsive to anti-               • No change in dose diarrhoeal agents,                • Initiate supportive therapy with anti-diarrhoeal agents as appropriate
OR                                • Monitor at least weekly until resolved Non-infectious diarrhoea or colitis   Asymptomatic (Grade 1) colitis
Mild/moderate diarrhoea           • Withhold Copiktra until resolved (Grade 1-2, up to 6 stools        • Initiate supportive therapy with enteric acting per day over baseline) and          steroids (e.g., budesonide) unresponsive to                   • Monitor at least weekly until resolved anti-diarrhoeal agents            • Resume at a reduced dose (15 mg twice daily) Table 1:       Copiktra dose modifications and toxicity management
Toxicity           Adverse reaction grade      Recommended management Abdominal pain, stool with mucus or blood, change in • Withhold Copiktra until resolved bowel habits, peritoneal    • Initiate supportive therapy with enteric acting signs,                         steroids (e.g., budesonide) or systemic steroids
OR                          • Monitor at least weekly until resolved • Resume at a reduced dose (15 mg twice daily)
Severe diarrhoea (Grade 3, • For recurrent Grade 3 diarrhoea or recurrent >6 stools per day over         colitis of any grade, discontinue Copiktra baseline)
Life-threatening            • Discontinue Copiktra
• No change in dose
• Initiate supportive care with emollients, anti-
Grade 1-2 histamines (for pruritus), or topical steroids
• Monitor closely
• Withhold Copiktra until resolved
• Review all concomitant medications and discontinue any medication potentially contributing to the event
Cutaneous                                           • Initiate supportive care with steroids (topical reactions           Grade 3                           or systemic) and antihistamines for pruritus • Monitor at least weekly until resolved
• Resume at reduced dose (15 mg twice daily)
• If severe cutaneous reaction does not improve, worsens, or recurs, discontinue
Copiktra
Life-threatening                • Discontinue Copiktra
SJS, TEN, DRESS (any grade)                          • Discontinue Copiktra for any grade • Withhold Copiktra
• Treat with systemic steroid therapy
• If pneumonitis recovers to Grade 0 or 1,
Moderate (Grade 2)                Copiktra may be resumed at reduced dose (15 Pneumonitis         symptomatic pneumonitis           mg twice daily) without suspected
• If non-infectious pneumonitis recurs or infectious cause patient does not respond to steroid therapy,
discontinue Copiktra
Severe (Grade 3) or life-       • Discontinue Copiktra threatening pneumonitis         • Treat with systemic steroid therapy • Maintain Copiktra dose
3 to 5 × upper limit of
• Monitor at least weekly until return to normal (ULN) (Grade 2)
< 3 × ULN
• Withhold Copiktra and monitor at least
ALT/AST                                               weekly until return to < 3 × ULN elevation                                           • Resume Copiktra at same dose (25 mg twice > 5 to 20 × ULN (Grade 3) daily) for first occurrence or at a reduced dose
(15 mg twice daily) for subsequent occurrence
> 20 × ULN (Grade 4)            • Discontinue Copiktra


Table 1:          Copiktra dose modifications and toxicity management Toxicity              Adverse reaction grade      Recommended management Haematologic adverse reactions

Absolute neutrophil count          • Maintain Copiktra dose
(ANC) 0.5 to 1.0 × 109 /L          • Monitor ANC at least weekly
• Withhold Copiktra.
Neutropenia                                                • Monitor ANC until > 0.5 × 109 /L • Resume Copiktra at same dose (25 mg twice
ANC less than 0.5 × 109 /L daily) for first occurrence or at a reduced dose
(15 mg twice daily) for subsequent occurrence
Platelet count 25 to < 50 ×
• No change in dose
109 /L (Grade 3) with
• Monitor platelet counts at least weekly
Grade 1 bleeding
• Withhold Copiktra
Platelet count 25 to < 50 ×
Thrombocytopenia 109 /L (Grade 3) with        • Monitor platelet counts until ≥ 25 × 109 /L and resolution of bleeding (if applicable)
Grade 2 bleeding
• Resume Copiktra at the same dose (25 mg or twice daily) for first occurrence or resume at
Platelet count < 25 × 109 /L a reduced dose (15 mg twice daily) for
(Grade 4) subsequent occurrence
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
Note: Doses withheld for > 42 days due to treatment-related toxicity will result in permanent discontinuation from treatment

Special populations

Elderly
No specific dose adjustment is required for elderly patients (aged ≥ 65 years) (see section 5.2).
Renal impairment
No dose adjustment is required for patients with mild and moderate renal impairment. No data are available for severe and end-stage renal impairment with or without dialysis, (see sections 5.2).

Hepatic impairment
No dose adjustment of the starting dose is required for patients with hepatic impairment Child Pugh Class A, B, and C (see sections 4.4 and 5.2).

Paediatric population
The safety and efficacy of duvelisib in children aged 0 to 18 years has not been established. No data are available.
There is no relevant use of duvelisib in the paediatric population for the indication of CLL and FL.

Method of administration

Copiktra is for oral use and can be taken with or without food. The capsules should be swallowed whole. Patients should be advised not to open, break, or chew the capsules.