Idelalisib

Idelalisib is a selective inhibitor of PI3Kδ, the delta isoform of phosphatidylinositol 3-kinase. PI3Kδ is hyperactive in B-cell malignancies and central to the signalling pathways that drive proliferation, survival, homing and retention of malignant cells in lymphoid tissue and bone marrow. Unlike the p110α and p110β isoforms, p110δ is mainly expressed in white blood cells.

Mechanism of Action

• PI3Kδ inhibition: idelalisib blocks the binding of ATP to the catalytic domain of PI3Kδ. This stops phosphorylation of the key lipid second messenger phosphatidylinositol and prevents phosphorylation of Akt (protein kinase B).
• Apoptosis: it induces apoptosis and inhibits proliferation in malignant B-cell lines and in primary tumour cells.
• Homing and retention: by blocking CXCR4 and CXCR5 signalling, induced by the chemokines CXCL12 and CXCL13, it inhibits the homing and retention of malignant B cells in lymphoid tissues and bone marrow.
• Lymphocytosis: at the start of treatment a temporary rise in lymphocyte counts (at least 50% above baseline and above 5,000/mm³) is seen. It should not be taken as disease progression in the absence of other clinical findings.
• Cardiac electrophysiology: at 2.7 times the maximum recommended dose idelalisib did not prolong the QT/QTc interval (by less than 10 ms).
• Resistance: no mechanistic explanation for resistance to idelalisib has been identified in clinical studies.

Pharmacokinetics

• Absorption: peak plasma levels occur 2–4 hours after a dose with food and 0.5–1.5 hours when fasting. At steady state on 150 mg twice daily, the mean peak concentration and AUC are 1,953 ng/mL and 10,439 ng·h/mL for idelalisib, and 4,039 ng/mL and 39,744 ng·h/mL for its metabolite GS-563117. Exposure is roughly dose proportional from 50 to 100 mg and less than proportional above 100 mg. A high-fat meal raised the AUC by 36% without changing the peak, so it can be taken without regard to food.
• Distribution: 93–94% bound to plasma proteins; the blood-to-plasma ratio is about 0.5, and the apparent volume of distribution about 96 L.
• Metabolism: mainly by aldehyde oxidase, and to a lesser extent by CYP3A and UGT1A4. The only circulating metabolite, GS-563117, is inactive against PI3Kδ but is a strong CYP3A inhibitor.
• Elimination: terminal half-life 8.2 hours (range 1.9–37.2) and apparent clearance 14.9 L/h. After a radiolabelled 150 mg dose about 78% was excreted in faeces and 15% in urine.
• Special populations: gender and race have no clinically relevant effect on exposure. Exposure is expected to be higher in hepatic impairment (see Special Instructions).

• Chronic lymphocytic leukaemia (CLL): in combination with rituximab, in adults who have received at least one prior therapy, or as first-line treatment in the presence of 17p deletion or TP53 mutation in patients who are not eligible for any other therapies.
• Follicular lymphoma (FL): as monotherapy in adults whose disease is refractory to two prior lines of treatment.

• Hypersensitivity to idelalisib or to any of the excipients.

In clinical studies of haematologic malignancies, the most frequent reactions were infections (70%), neutropenia (55%), raised transaminases (53%), diarrhoea (48%), raised triglycerides (47%), pyrexia (36%), rash (30%) and lymphocytosis (21%). The most frequent severe (grade 3 or higher) reactions were infections (39%), neutropenia (33%), diarrhoea/colitis (22%), raised transaminases (15%) and lymphocytosis (13%).

Very common (≥1/10): infections (including Pneumocystis jirovecii pneumonia and cytomegalovirus infection, other opportunistic infections, and bacterial and viral infections such as pneumonia, bronchitis and sepsis); neutropenia; lymphocytosis; diarrhoea/colitis; raised transaminases; rash; pyrexia; raised triglycerides.

Common (≥1/100 to <1/10): pneumonitis; hepatocellular injury.

Uncommon (≥1/1,000 to <1/100): organising pneumonia.

Rare (≥1/10,000 to <1/1,000): Stevens-Johnson syndrome and toxic epidermal necrolysis.

Not known: drug reaction with eosinophilia and systemic symptoms (DRESS).

At grade 3 or higher, infections, neutropenia, lymphocytosis, diarrhoea/colitis and raised transaminases remained very common, while pneumonitis, hepatocellular injury, rash, pyrexia and raised triglycerides were common.

Infections were more frequent, including grade 3–4, than with control treatment; most were in the respiratory system or septic events, and both conventional and opportunistic pathogens, including Pneumocystis jirovecii and cytomegalovirus, were identified. Nearly all Pneumocystis jirovecii pneumonia cases, including fatal ones, occurred without prophylaxis, and some occurred after stopping idelalisib. Rash was generally mild to moderate and led to discontinuation in 2.1% of subjects. Cases of Stevens-Johnson syndrome, toxic epidermal necrolysis and DRESS occurred when idelalisib was given with other medicines associated with these syndromes (bendamustine, rituximab, allopurinol, amoxicillin, sulfamethoxazole/trimethoprim); the first two occurred within one month of the combination and some were fatal.

Idelalisib is cleared mainly by aldehyde oxidase and to a lesser extent by CYP3A and UGT1A4, and it and GS-563117 are substrates of P-glycoprotein and BCRP. GS-563117 is a strong CYP3A inhibitor, so idelalisib raises levels of many other medicines.

• CYP3A inducers (rifampicin, phenytoin, St John’s wort, carbamazepine): rifampicin cut idelalisib exposure by about 75%. Avoid moderate or strong inducers because efficacy may fall.
• CYP3A/P-gp inhibitors: ketoconazole raised idelalisib peak levels by 26% and AUC by 79%. No starting dose change is needed, but monitor adverse reactions more closely.
• Sensitive CYP3A substrates: oral midazolam exposure rose by about 440% (peak about 140%). The CYP3A inhibition is irreversible, so normal enzyme activity returns only over several days after idelalisib is stopped.
• Do not combine with: alfuzosin; amiodarone or quinidine; pimozide or quetiapine; ergotamine or dihydroergotamine; cisapride; lovastatin or simvastatin; sildenafil for pulmonary arterial hypertension; oral midazolam or triazolam. Salmeterol is not recommended, and colchicine should not be given to patients with renal or hepatic impairment.
• Combine only with monitoring or dose adjustment: warfarin (INR); opioids such as fentanyl, alfentanil, methadone and buprenorphine/naloxone (respiratory depression, sedation); sedatives and hypnotics such as buspirone, clorazepate, diazepam, estazolam, flurazepam and zolpidem; trazodone; carbamazepine; calcium channel blockers; azole antifungals; clarithromycin and telithromycin (consider alternatives to clarithromycin if creatinine clearance is below 60 mL/min); rifabutin (neutropenia, uveitis); hepatitis C protease inhibitors; dasatinib, nilotinib, vincristine and vinblastine; bosentan; ciclosporin, sirolimus and tacrolimus; budesonide and fluticasone; atorvastatin; tadalafil and sildenafil for erectile dysfunction. The SmPC of the other product should always be consulted.
• Other enzyme substrates: caution with narrow-therapeutic-index medicines handled by CYP2C8 (paclitaxel) or by inducible enzymes such as CYP2C9, CYP2C19, CYP2B6 and UGT (warfarin, phenytoin, S-mephenytoin). Inhibition of intestinal P-gp, which could raise exposure to sensitive substrates such as dabigatran etexilate, cannot be excluded.
• Food: avoid grapefruit products, which inhibit CYP3A metabolism and may raise idelalisib levels; avoid St John’s wort. Tablets may be taken with or without food.

Treatment is conducted by a physician experienced in the use of anti-cancer therapies. Tablets are swallowed whole, not chewed or crushed, with or without food.

Recommended Dose

• 150 mg twice daily, continued until disease progression or unacceptable toxicity. It is given with rituximab in CLL and alone in follicular lymphoma.

Dose Modification

• Raised transaminases: withhold in grade 3 or 4 elevation (ALT/AST above 5 times the upper limit of normal). When values return to grade 1 or below (ALT/AST up to 3 times the upper limit), resume at 100 mg twice daily; if it does not recur, the dose can be raised again to 150 mg twice daily at the physician’s discretion. If it recurs, withhold until grade 1 or less, then consider restarting at 100 mg twice daily.
• Diarrhoea/colitis: withhold in grade 3 or 4. Once grade 1 or below, resume at 100 mg twice daily, with re-escalation to 150 mg if it does not recur.
• Pneumonitis: withhold if suspected. After resolution, and if re-treatment is appropriate, resume at 100 mg twice daily. Stop permanently in moderate or severe symptomatic pneumonitis or organising pneumonia.
• Rash: withhold in grade 3 or 4. Once grade 1 or below, resume at 100 mg twice daily, with re-escalation if it does not recur.
• Neutropenia: with absolute neutrophil count (ANC) 1,000 to below 1,500/mm³, maintain dosing. With ANC 500 to below 1,000/mm³, maintain dosing and monitor ANC at least weekly. With ANC below 500/mm³, interrupt dosing and monitor at least weekly until ANC is at least 500/mm³, then resume at 100 mg twice daily.
• Severe skin reactions: interrupt if Stevens-Johnson syndrome, toxic epidermal necrolysis or DRESS is suspected, and stop permanently if confirmed.

Missed Dose

If a dose is missed by up to 6 hours, take it as soon as possible and continue the usual schedule. If more than 6 hours late, skip it and resume the usual schedule.

Special Populations

• Elderly (65 years or older): no specific dose adjustment.
• Renal impairment: no adjustment in mild (creatinine clearance 60–80 mL/min), moderate (30–59 mL/min) or severe (15–29 mL/min) impairment.
• Hepatic impairment: no adjustment when starting in mild (Child-Pugh A) or moderate (Child-Pugh B) impairment, but monitor adverse reactions more closely. For severe impairment there are too few data for a dose recommendation: use with caution and intensified monitoring.
• Children and adolescents: safety and efficacy below 18 years have not been established.

Serious Infections and Prophylaxis

Idelalisib must not be started in patients with any evidence of ongoing systemic bacterial, fungal or viral infection. Serious and fatal infections have occurred, including opportunistic infections such as Pneumocystis jirovecii pneumonia (PJP) and cytomegalovirus (CMV).

• PJP prophylaxis must be given to all patients throughout idelalisib treatment and for 2 to 6 months after stopping. The length of post-treatment prophylaxis is a matter of clinical judgement and may take account of risk factors such as concomitant corticosteroids and prolonged neutropenia.
• Respiratory monitoring: patients are monitored for respiratory signs and symptoms throughout treatment and should report new respiratory symptoms promptly.
• CMV: regular clinical and laboratory monitoring is recommended in patients with positive CMV serology at the start or other evidence of past CMV infection. CMV viraemia without clinical signs needs careful monitoring. With viraemia and clinical signs, consider interrupting idelalisib until the infection resolves; if resuming is judged worthwhile, consider pre-emptive CMV therapy.
• Progressive multifocal leukoencephalopathy (PML) has been reported with prior or concomitant immunosuppressive therapies associated with PML. Consider it in patients with new or worsening neurological, cognitive or behavioural signs; if suspected, suspend treatment until PML is excluded and consider referral to a neurologist, MRI (preferably with contrast), and cerebrospinal fluid testing for JC viral DNA.

Neutropenia

Grade 3 or 4 neutropenia, including febrile neutropenia, has occurred. Blood counts are monitored at least every 2 weeks for the first 6 months of treatment, and at least weekly while ANC is below 1,000/mm³.

Hepatotoxicity

Grade 3 and 4 ALT and AST elevations (above 5 times the upper limit of normal) and hepatocellular injury, including hepatic failure, have been reported. Rises were generally seen within the first 12 weeks and reversed with interruption; 26% of patients who resumed at a lower dose had a recurrence. ALT, AST and total bilirubin are monitored every 2 weeks for the first 3 months, then as clinically indicated, and weekly if grade 2 or higher elevations occur until values return to grade 1 or below. Idelalisib has not been studied in chronic active hepatitis, including viral hepatitis, so use caution in active hepatitis.

Diarrhoea and Colitis

Severe drug-related colitis occurred relatively late (months after starting), sometimes with rapid worsening, and resolved within a few weeks with dose interruption and symptomatic treatment (for example enteric budesonide). Experience in patients with a history of inflammatory bowel disease is very limited.

Pneumonitis and Organising Pneumonia

Cases, some fatal, have been reported. In serious lung events interrupt idelalisib and look for another explanation; stop it permanently if moderate or severe symptomatic pneumonitis or organising pneumonia is diagnosed.

Severe Skin Reactions

Stevens-Johnson syndrome, toxic epidermal necrolysis and DRESS have occurred, with fatal outcomes when idelalisib was given with other medicines associated with these syndromes. Interrupt idelalisib if suspected and stop permanently if confirmed.

Pregnancy, Breastfeeding and Fertility

• Contraception: idelalisib may cause foetal harm. Women of childbearing potential must use highly effective contraception during treatment and for 1 month after stopping. It is unknown whether idelalisib reduces the effectiveness of hormonal contraceptives, so women using them should add a barrier method.
• Pregnancy: not recommended during pregnancy or in women of childbearing potential not using contraception; animal studies showed reproductive toxicity.
• Breastfeeding: it is not known whether idelalisib or its metabolites enter human milk, and a risk to the infant cannot be excluded, so breastfeeding should be stopped during treatment.
• Fertility: no human data; animal studies indicate possible harmful effects on fertility and foetal development.

Excipients

The 100 mg tablet contains the azo colouring agent sunset yellow FCF (E110), which may cause allergic reactions. Each tablet contains less than 1 mmol (23 mg) of sodium, essentially sodium-free.

Effect on Driving

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

Zydelig tablets need no special storage conditions. They are supplied in a high-density polyethylene bottle with a polypropylene child-resistant closure, holding 60 film-coated tablets and a polyester coil; each carton contains one bottle.

5 years.

Prescription only (Rx), subject to restricted medical prescription (Annex II B), with treatment conducted by a physician experienced in the use of anti-cancer therapies. Idelalisib is taken at home, so it is supplied to the patient or to the treating clinic on prescription.