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Zydelig for treatment of follicular lymphoma and chronic lymphocytic leukemia: important safety information

In the EU ( European Union ), Zydelig ( Idelalisib ) is indicated in combination with Rituximab ( MabThera ) for the treatment of adult patients with chronic lymphocytic leukemia who have received at least one prior therapy; or as first-line treatment in the presence of 17p deletion or TP53 mutation in patients unsuitable for chemo-immunotherapy.
Zydelig has also been approved as a monotherapy for the treatment of adult patients with follicular lymphoma that is refractory to two prior lines of treatment. Zydelig is administered orally twice-daily and is available as 150 mg and 100 mg dose strengths.

Idelalisib is an oral inhibitor of phosphoinositide 3-kinase ( PI3K ) delta, a protein that plays a role in the activation, proliferation and viability of B cells, a critical component of the immune system.

Important safety information

Contraindications - Hypersensitivity to the active substance or to any excipients listed in the Zydelig summary of product characteristics.

Transaminase elevations - Elevations in ALT and AST of Grade 3 and 4 ( more than 5 x ULN ) have been observed in clinical studies of Zydelig.
These laboratory findings were generally observed within the first 12 weeks of treatment, were generally asymptomatic, and were reversible with dose interruption.
Most patients resumed treatment at a lower dose without recurrence. ALT, AST, and total bilirubin must be monitored in all patients every 2 weeks for the first 3 months of treatment, then as clinically indicated.
If Grade 2 or higher elevations in ALT and/or AST are observed, patients must be monitored weekly until the values return to Grade 1 or below.

Diarrhoea / colitis - Cases of severe drug-related colitis occurred relatively late ( months ) after the start of therapy, sometimes with rapid aggravation, but resolved within a few weeks with dose interruption and additional symptomatic treatment ( e.g., anti-inflammatory agents such as enteric Budesonide ).
There is very limited experience from the treatment of patients with a history of inflammatory bowel disease.

Pneumonitis - Cases of pneumonitis have been reported in clinical studies with Zydelig. Patients presenting with serious lung events that do not respond to conventional antimicrobial therapy should be assessed for drug-induced pneumonitis.
If pneumonitis is suspected, Zydelig should be interrupted and the patient treated accordingly.
Treatment must be discontinued for moderate or severe symptomatic pneumonitis.

CYP3A inducers - Zydelig exposure may be reduced when co-administered with CYP3A inducers such as Rifampicin, Phenytoin, St. John’s wort ( Hypericum perforatum ), or Carbamazepine.
Since a reduction in Zydelig plasma concentrations may result in decreased efficacy, co-administration of Zydelig with moderate or strong CYP3A inducers should be avoided.

CYP3A substrates - The primary metabolite of Zydelig, GS-563117, is a strong CYP3A4 inhibitor. Thus, Zydelig has the potential to interact with medicinal products that are metabolized by CYP3A, which may lead to increased serum concentrations of the other product.
Concomitant treatment of Zydelig with CYP3A substrates with serious and/or life-threatening adverse reactions ( e.g., Alfuzosin, Amiodarone, Cisapride, Pimozide, Quinidine, Ergotamine, Dihydroergotamine, Quetiapine, Lovastatin, Simvastatin, Sildenafil, Midazolam, Triazolam ) should be avoided and alternative medicinal products that are less sensitive to CYP3A4 inhibition should be used if possible.

Hepatic impairment - Intensified monitoring of adverse reactions is recommended in patients with impaired hepatic function as exposure is expected to be increased in this population, in particular in patients with severe hepatic impairment.
No patients with severe hepatic impairment were included in clinical studies of Zydelig. Caution is recommended when administering Zydelig in this population.

Chronic hepatitis - Zydelig has not been studied in patients with chronic active hepatitis including viral hepatitis. Caution should be exercised when administering Zydelig in patients with active hepatitis.

Women of childbearing potential - Women of childbearing potential must use highly effective contraception while taking Zydelig and for 1 month after stopping treatment. Women using hormonal contraceptives should add a barrier method as a second form of contraception since it is currently unknown whether Zydelig may reduce the effectiveness of hormonal contraceptives. ( Xagena )

Source: Gilead, 2014