4.1. Therapeutic indications

Zydelig is indicated in combination with rituximab for the treatment of adult patients with chronic lymphocytic leukaemia (CLL):

• who have received at least one prior therapy (see section 4.4), or

• as first line treatment in the presence of 17p deletion or TP53 mutation in patients who are not eligible for any other therapies (see section 4.4).

Zydelig is indicated as monotherapy for the treatment of adult patients with follicular lymphoma (FL) that is refractory to two prior lines of treatment (see section 4.4).

4.2. Posology and method of administration

Treatment with Zydelig should be conducted by a physician experienced in the use of anti-cancer therapies.

Posology

The recommended dose is 150 mg idelalisib twice daily. Treatment should be continued until disease progression or unacceptable toxicity.

If the patient misses a dose of Zydelig within 6 hours of the time it is usually taken, the patient should take the missed dose as soon as possible and resume the normal dosing schedule. If a patient misses a dose by more than 6 hours, the patient should not take the missed dose and simply resume the usual dosing schedule.

Dose modification

Elevated liver transaminases

Treatment with Zydelig must be withheld in the event of a Grade 3 or 4 aminotransferase elevation (alanine aminotransferase [ALT]/aspartate aminotransferase [AST] > 5 x upper limit of normal [ULN]). Once values have returned to Grade 1 or below (ALT/AST ≤ 3 x ULN), treatment can be resumed at 100 mg twice daily.

If the event does not recur, the dose can be re-escalated to 150 mg twice daily at the discretion of the treating physician.

If the event recurs, treatment with Zydelig must be withheld until the values return to Grade 1 or less, after which re-initiation at 100 mg twice daily may be considered at the discretion of the physician (see sections 4.4 and 4.8).

Diarrhoea/colitis

Treatment with Zydelig must be withheld in the event of Grade 3 or 4 diarrhoea/colitis. Once diarrhoea/colitis has returned to Grade 1 or below, treatment can be resumed at 100 mg twice daily. If diarrhoea/colitis does not recur, the dose can be re-escalated to 150 mg twice daily at the discretion of the treating physician (see section 4.8).

Pneumonitis

Treatment with Zydelig must be withheld in the event of suspected pneumonitis. Once pneumonitis has resolved and if re-treatment is appropriate, resumption of treatment at 100 mg twice daily can be considered. Treatment with Zydelig must be permanently discontinued in the event of moderate or severe symptomatic pneumonitis or organising pneumonia (see sections 4.4 and 4.8).

Rash

Treatment with Zydelig must be withheld in the event of Grade 3 or 4 rash. Once rash has returned to Grade 1 or below, treatment can be resumed at 100 mg twice daily. If rash does not recur, the dose can be re-escalated to 150 mg twice daily at the discretion of the treating physician (see section 4.8).

Neutropenia

Treatment with Zydelig should be withheld in patients while absolute neutrophil count (ANC) is below 500 per mm3. ANC should be monitored at least weekly until ANC is ≥ 500 per mm3 when treatment can be resumed at 100 mg twice daily (see section 4.4).

ANC 1 000 to < 1 500/mm3

ANC 500 to < 1 000/mm3

ANC < 500/mm3

Maintain Zydelig dosing.

Maintain Zydelig dosing.

Monitor ANC at least weekly.

Interrupt Zydelig dosing.

Monitor ANC at least weekly until ANC ≥ 500/mm3, then may resume Zydelig dosing at 100 mg twice daily.

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 (creatinine clearance (CrCl) = 60 – 80 mL/min), moderate (CrCl = 30 – 59 mL/min), or severe (CrCl = 15 – 29 mL/min) renal impairment (see section 5.2).

Hepatic impairment

No dose adjustment is required when initiating treatment with Zydelig in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment, but an intensified monitoring of adverse reactions is recommended (see sections 4.4 and 5.2).

There is insufficient data to make dose recommendations for patients with severe hepatic impairment. Therefore, caution is recommended when administering Zydelig in this population and an intensified monitoring of adverse reactions is recommended (see sections 4.4 and 5.2).

Paediatric population

The safety and efficacy of Zydelig in children under the age of 18 years have not been established. No data are available.

Method of administration

Zydelig is for oral use. Patients should be instructed to swallow the tablet whole. The film-coated tablet should not be chewed or crushed. The film-coated tablet can be taken with or without food (see section 5.2).

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4. Special warnings and precautions for use

Serious infections

Treatment with Zydelig should not be initiated in patients with any evidence of ongoing systemic bacterial, fungal, or viral infection.

Serious and fatal infections have occurred with idelalisib, including opportunistic infections such as Pneumocystis jirovecii pneumonia (PJP) and cytomegalovirus (CMV). Prophylaxis for PJP should therefore be administered to all patients throughout idelalisib treatment, and for a period of 2 to 6 months after discontinuation. The duration of post-treatment prophylaxis should be based on clinical judgment and may take into account a patient's risk factors such as concomitant corticosteroid treatment and prolonged neutropenia (see section 4.8).

Patients should be monitored for respiratory signs and symptoms throughout treatment. Patients should be advised to report new respiratory symptoms promptly.

Regular clinical and laboratory monitoring for CMV infection is recommended in patients with positive CMV serology at the start of treatment with idelalisib or with other evidence of a history of CMV infection. Patients with CMV viraemia without associated clinical signs of CMV infection should be carefully monitored. For patients with evidence of CMV viraemia and clinical signs of CMV infection, consideration should be given to interrupting idelalisib until the infection has resolved. If the benefits of resuming idelalisib are judged to outweigh the risks, consideration should be given to administering pre-emptive CMV therapy.

Cases of progressive multifocal leukoencephalopathy (PML) have been reported following the use of idelalisib within the context of prior or concomitant immunosuppressive therapies that have been associated with PML. Physicians should consider PML in the differential diagnosis in patients with new or worsening neurological, cognitive or behavioural signs or symptoms. If PML is suspected then appropriate diagnostic evaluations should be undertaken and treatment suspended until PML is excluded. If any doubt exists, referral to a neurologist and appropriate diagnostic measures for PML including MRI scan preferably with contrast, cerebrospinal fluid (CSF) testing for JC viral DNA and repeat neurological assessments should be considered.

Neutropenia

Treatment-emergent Grade 3 or 4 neutropenia, including febrile neutropenia, have occurred in patients treated with idelalisib. Blood counts should be monitored in all patients at least every 2 weeks for the first 6 months of treatment with idelalisib, and at least weekly in patients while ANC is less than 1 000 per mm3 (see section 4.2).

Hepatotoxicity

Elevations in ALT and AST of Grade 3 and 4 (> 5 x ULN) have been observed in clinical studies of idelalisib. There have also been reports of hepatocellular injury including hepatic failure. Increases in liver transaminases were generally observed within the first 12 weeks of treatment, and were reversible with dose interruption (see section 4.2). In patients who resumed idelalisib at a lower dose, 26% had recurrence of ALT/AST elevation. Treatment with Zydelig must be withheld in the event of Grade 3 or 4 ALT/AST elevation and liver function monitored. Treatment may be resumed at a lower dose once values have returned to Grade 1 or below (ALT/AST ≤ 3 x ULN).

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' ALT, AST, and total bilirubin must be monitored weekly until the values return to Grade 1 or below.

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 idelalisib. Caution is recommended when administering Zydelig in this population.

Chronic hepatitis

Idelalisib 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.

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) (see section 4.2).

There is very limited experience from the treatment of patients with a history of inflammatory bowel disease.

Pneumonitis and organising pneumonia

Cases of pneumonitis and organising pneumonia (some with fatal outcome) have been reported with idelalisib. In patients presenting with serious lung events, idelalisib should be interrupted and the patient assessed for an explanatory aetiology. If either moderate or severe symptomatic pneumonitis or organising pneumonia is diagnosed, appropriate treatment should be initiated and idelalisib must be permanently discontinued.

Severe cutaneous reactions

Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS) have occurred with idelalisib. Cases of SJS and TEN with fatal outcomes have been reported when idelalisib was administered concomitantly with other medicinal products associated with these syndromes. If SJS, TEN or DRESS is suspected, idelalisib should be interrupted and the patient assessed and treated accordingly. If a diagnosis of SJS, TEN, or DRESS is confirmed, idelalisib should be permanently discontinued.

CYP3A inducers

Idelalisib 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 idelalisib plasma concentrations may result in decreased efficacy, co-administration of Zydelig with moderate or strong CYP3A inducers should be avoided (see section 4.5).

CYP3A substrates

The primary metabolite of idelalisib, GS-563117, is a strong CYP3A4 inhibitor. Thus, idelalisib 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 idelalisib is co-administered with other medicinal products, the Summary of Product Characteristics (SmPC) for the other product must be consulted for the recommendations regarding co-administration with CYP3A4 inhibitors. Concomitant treatment of idelalisib 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.

Women of childbearing potential

Women of childbearing potential must use highly effective contraception while taking idelalisib and for 1 month after stopping treatment (see section 4.6). Women using hormonal contraceptives should add a barrier method as a second form of contraception since it is currently unknown whether idelalisib may reduce the effectiveness of hormonal contraceptives.

Excipients with known effect

Zydelig contains the azo colouring agent sunset yellow FCF (E110), which may cause allergic reactions.

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.

4.5. Interaction with other medicinal products and other forms of interaction

Idelalisib is metabolised primarily via aldehyde oxidase, and to a lesser extent via CYP3A and glucuronidation (UGT1A4). Its primary metabolite is GS-563117, which is not pharmacologically active. Idelalisib and GS-563117 are substrates of P-gp and BCRP.

Effect of other medicinal products on idelalisib pharmacokinetics

CYP3A inducers

A clinical drug interaction study found that co-administration of a single dose of 150 mg idelalisib with rifampicin (a strong CYP3A inducer) resulted in a ~75% reduction in idelalisib AUCinf. Co-administration of Zydelig with moderate or strong CYP3A inducers such as rifampicin, phenytoin, St. John's wort, or carbamazepine should be avoided as this may result in decreased efficacy.

CYP3A/P-gp inhibitors

A clinical drug interaction study found that co-administration of a single dose of 400 mg idelalisib with 400 mg once daily ketoconazole (a strong CYP3A, P-gp and BCRP inhibitor) resulted in a 26% increase in Cmax and a 79% increase in AUCinf of idelalisib. No initial dose adjustment of idelalisib is considered necessary when administered with CYP3A/P-gp inhibitors, but an intensified monitoring of adverse reactions is recommended.

Effect of idelalisib on the pharmacokinetics of other medicinal products

CYP3A substrates

The primary metabolite of idelalisib, GS-563117, is a strong CYP3A inhibitor. A clinical drug interaction study found that co-administration of idelalisib with midazolam (a sensitive CYP3A substrate) resulted in a ~140% increase in Cmax and a ~440% increase in AUCinf of midazolam due to the CYP3A inhibition by GS-563117. Co-administration of idelalisib with CYP3A substrates may increase their systemic exposures and increase or prolong their therapeutic activity and adverse reactions. In vitro, the CYP3A4 inhibition was irreversible, and return to normal enzyme activity is therefore expected to take several days after stopping idelalisib administration.

Potential interactions between idelalisib and co-administered medicinal products that are CYP3A substrates are listed in Table 1 (increase is indicated as “↑”). This list is not exhaustive and is intended to serve as guidance only. In general, the SmPC for the other product must be consulted for the recommendations regarding co-administration with CYP3A4 inhibitors (see section 4.4).

Table 1: Interactions between idelalisib and other medicinal products that are CYP3A substrates

Medicinal product

Expected effect of idelalisib on medicinal product levels

Clinical recommendation upon co-administration with idelalisib

ALPHA-1 ADRENORECEPTOR ANTAGONISTS

Alfuzosin

↑ serum concentrations

Idelalisib should not be co-administered with alfuzosin.

ANALGESICS

Fentanyl, alfentanil, methadone, buprenorphine/naloxone

↑ serum concentrations

Careful monitoring of adverse reactions (e.g., respiratory depression, sedation) is recommended.

ANTIARRHYTHMICS

Amiodarone, quinidine

Bepridil, disopyramide, lidocaine

↑ serum concentrations

↑ serum concentrations

Idelalisib should not be co-administered with amiodarone or quinidine.

Clinical monitoring is recommended.

ANTI-CANCER AGENTS

Tyrosine kinase inhibitors such as dasatinib and nilotinib, also vincristine and vinblastine

↑ serum concentrations

Careful monitoring of the tolerance to these anti-cancer agents is recommended.

ANTICOAGULANTS

Warfarin

↑ serum concentrations

It is recommended that the international normalised ratio (INR) be monitored upon co-administration and following ceasing treatment with idelalisib.

ANTICONVULSANTS

Carbamazepine

↑ serum concentrations

Anticonvulsant medicinal product levels should be monitored.

ANTIDEPRESSANTS

Trazodone

↑ serum concentrations

Careful dose titration of the antidepressant and monitoring for antidepressant response is recommended.

ANTI-GOUT

Colchicine

↑ serum concentrations

Dose reductions of colchicine may be required. Idelalisib should not be co-administered with colchicine to patients with renal or hepatic impairment.

ANTI-HYPERTENSIVES

Amlodipine, diltiazem, felodipine, nifedipine, nicardipine

↑ serum concentrations

Clinical monitoring of therapeutic effect and adverse reactions is recommended.

ANTI-INFECTIVES

Antifungals

Ketoconazole, itraconazole, posaconazole, voriconazole

↑ serum concentrations

Clinical monitoring is recommended.

Antimycobacterials

Rifabutin

↑ serum concentrations

Increased monitoring for rifabutin-associated adverse reactions including neutropenia and uveitis is recommended.

HCV protease inhibitors

Boceprevir, telaprevir

↑ serum concentrations

Clinical monitoring is recommended.

Macrolide antibiotics

Clarithromycin, telithromycin

↑ serum concentrations

No dose adjustment of clarithromycin is required for patients with normal renal function or mild renal impairment (creatinine clearance [CrCl] 60-90 mL/min). Clinical monitoring is recommended for patients with CrCl < 90 mL/min. For patients with CrCl < 60 mL/min, alternative antibacterials should be considered.

Clinical monitoring is recommended for telithromycin.

ANTI-PSYCHOTICS/NEUROLEPTICS

Quetiapine, pimozide

↑ serum concentrations

Idelalisib should not be co-administered with quetiapine or pimozide.

Alternative medicinal products, such as olanzapine, may be considered.

ENDOTHELIN RECEPTOR ANTAGONISTS

Bosentan

↑ serum concentrations

Caution should be exercised and patients closely observed for bosentan-related toxicity.

ERGOT ALKALOIDS

Ergotamine, dihydroergotamine

↑ serum concentrations

Idelalisib should not be co-administered with ergotamine or dihydroergotamine.

GASTROINTESTINAL MOTILITY AGENTS

Cisapride

↑ serum concentrations

Idelalisib should not be co-administered with cisapride.

GLUCOCORTICOIDS

Inhaled/nasal corticosteroids:

Budesonide, fluticasone

Oral budesonide

↑ serum concentrations

↑ serum concentrations

Clinical monitoring is recommended.

Clinical monitoring is recommended for increased signs/symptoms of corticosteroid effects.

HMG CO-A REDUCTASE INHIBITORS

Lovastatin, simvastatin

Atorvastatin

↑ serum concentrations

↑ serum concentrations

Idelalisib should not be co-administered with lovastatin or simvastatin.

Clinical monitoring is recommended and a lower starting dose of atorvastatin may be considered. Alternatively, switching to pravastatin, rosuvastatin, or pitavastatin may be considered.

IMMUNOSUPPRESSANTS

Ciclosporin, sirolimus, tacrolimus

↑ serum concentrations

Therapeutic monitoring is recommended.

INHALED BETA AGONIST

Salmeterol

↑ serum concentrations

Concurrent administration of salmeterol and idelalisib is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia.

PHOSPHODIESTERASE INHIBITORS

Sildenafil

Tadalafil

Sildenafil, tadalafil

↑ serum concentrations

↑ serum concentrations

↑ serum concentrations

For pulmonary arterial hypertension:

Idelalisib should not be co-administered with sildenafil.

Caution should be exercised, including consideration of dose reduction, when co-administering tadalafil with idelalisib.

For erectile dysfunction:

Particular caution must be used and dose reduction may be considered when prescribing sildenafil or tadalafil with idelalisib with increased monitoring for adverse events.

SEDATIVES/HYPNOTICS

Midazolam (oral), triazolam

Buspirone, clorazepate, diazepam, estazolam, flurazepam, zolpidem

↑ serum concentrations

↑ serum concentrations

Idelalisib should not be co-administered with midazolam (oral) or triazolam.

Concentration monitoring of sedatives/hypnotics is recommended and dose reduction may be considered.

CYP2C8 substrates

In vitro, idelalisib both inhibited and induced CYP2C8, but it is not known whether this translates to an in vivo effect on CYP2C8 substrates. Caution is advised if Zydelig is used together with narrow therapeutic index medicinal products that are substrates of CYP2C8 (paclitaxel).

Substrates of inducible enzymes (e.g., CYP2C9, CYP2C19, CYP2B6 and UGT)

In vitro, idelalisib was an inducer of several enzymes, and a risk for decreased exposure and thereby decreased efficacy of substrates of inducible enzymes such as CYP2C9, CYP2C19, CYP2B6 and UGT cannot be excluded. Caution is advised if Zydelig is used together with narrow therapeutic index medicinal products that are substrates of these enzymes (warfarin, phenytoin, S-mephenytoin).

BCRP, OATP1B1, OATP1B3 and P-gp substrates

Co-administration of multiple doses of idelalisib 150 mg twice daily to healthy subjects resulted in comparable exposures for rosuvastatin (AUC 90% CI: 87, 121) and digoxin (AUC 90% CI: 98, 111), suggesting no clinically relevant inhibition of BCRP, OATP1B1/1B3 or systemic P-gp by idelalisib. A risk for P-gp inhibition in the gastrointestinal tract, that could result in increased exposure of sensitive substrates for intestinal P-gp such as dabigatran etexilate, cannot be excluded.

Paediatric population

Interaction studies have only been performed in adults.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential / contraception

Based on findings in animals, idelalisib may cause foetal harm. Women should avoid becoming pregnant while taking Zydelig, and for up to 1 month after ending treatment. Therefore, women of childbearing potential must use highly effective contraception while taking Zydelig and for 1 month after stopping treatment. It is currently unknown whether idelalisib may reduce the effectiveness of hormonal contraceptives, and therefore women using hormonal contraceptives should add a barrier method as a second form of contraception.

Pregnancy

There are no or limited amount of data from the use of idelalisib in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3).

Zydelig is not recommended during pregnancy and in women of childbearing potential not using contraception.

Breast-feeding

It is not known whether idelalisib and its metabolites are excreted in human milk.

A risk to the newborns/infants cannot be excluded.

Breast-feeding should be discontinued during treatment with Zydelig.

Fertility

No human data on the effect of idelalisib on fertility are available. Animal studies indicate the potential for harmful effects of idelalisib on fertility and foetal development (see section 5.3).

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

Summary of the safety profile

In clinical studies of subjects with hematologic malignancies who received idelalisib, the most frequently reported adverse reactions were: infections (70%), neutropenia (55%), transaminases increased (53%), diarrhoea (48%), triglycerides increased (47%), pyrexia (36%), rash (30%) and lymphocytosis (21%). The most frequently reported severe adverse reactions (≥ Grade 3) were: infections (39%), neutropenia (33%), diarrhoea/colitis (22%), transaminases increased (15%) and lymphocytosis (13%).

Tabulated list of adverse reactions

Assessment of adverse reactions is based on two Phase 3 studies (study 312-0116 and study 312-0119) and six Phase 1 and 2 studies. Study 312-0116 was a randomised, double-blind, placebo-controlled study in which 110 subjects with previously treated CLL received idelalisib + rituximab. In addition, 86 subjects from this study who were randomised to receive placebo + rituximab went on to receive idelalisib as a single agent in an extension study (study 312-0117). Study 312-0119 was a randomised, controlled, open-label study in which 173 subjects with previously treated CLL received idelalisib + ofatumumab. The Phase 1 and 2 studies assessed the safety of idelalisib in a total of 536 subjects with haematologic malignancies, including 400 subjects who received idelalisib (any dose) as a single agent and 136 subjects who received idelalisib in combination with an anti-CD20 monoclonal antibody (rituximab or ofatumumab).

The adverse drug reactions reported with idelalisib alone or in combination with anti-CD20 monoclonal antibodies (rituximab or ofatumumab) are provided in Table 2. Adverse reactions are listed by system organ class and frequency. Frequencies are defined as follows: 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), very rare (< 1/10 000), and not known (cannot be estimated from available data).

Table 2: Adverse drug reactions reported in clinical studies in subjects with haematologic malignancies receiving idelalisib and post-marketing.

Reaction

Any grade

Grade ≥ 3

Infections and infestations

Infections (including Pneumocystis jirovecii pneumonia and CMV)*

Very common

Very common

Blood and lymphatic system disorders

Neutropenia

Very common

Very common

Lymphocytosis**

Very common

Very common

Respiratory, thoracic and mediastinal disorders

Pneumonitis

Common

Common

Organising pneumonia****

Uncommon

Uncommon

Gastrointestinal disorders

Diarrhoea/colitis

Very common

Very common

Hepatobiliary disorders

Transaminase increased

Very common

Very common

Hepatocellular injury

Common

Common

Skin and subcutaneous tissue disorders

Rash***

Very common

Common

Stevens-Johnson syndrome/ toxic epidermal necrolysis****

Rare

Rare

Drug reaction with eosinophilia and systemic symptoms (DRESS)****

Not known

Not known

General disorders and administration site conditions

Pyrexia

Very common

Common

Investigations

Increased triglycerides

Very common

Common

* Comprised of opportunistic infections as well as bacterial and viral infections such as pneumonia, bronchitis, and sepsis.

** Idelalisib-induced lymphocytosis should not be considered progressive disease in the absence of other clinical findings (see section 5.1).

*** Includes the preferred terms dermatitis exfoliative generalised, drug eruption, rash, rash erythematous, rash generalised, rash macular, rash maculo-papular, rash papular, rash pruritic, rash pustular, rash vesicular, papule, skin plaque, and exfoliative rash.

**** Observed in post-marketing data

Description of selected adverse reactions

Infections (see section 4.4)

Higher frequencies of infections overall, including Grade 3 and 4 infections, were observed in the idelalisib arms compared to the control arms of idelalisib clinical studies. Most frequently observed were infections in the respiratory system and septic events. In many instances the pathogen was not identified; however, both conventional and opportunistic pathogens, including PJP and CMV, were among those identified. Nearly all PJP infections, including fatal cases, occurred in the absence of PJP prophylaxis. There have been cases of PJP after stopping idelalisib treatment.

Rash

Rash was generally mild to moderate and resulted in discontinuation of treatment in 2.1% of subjects. In studies 312-0116/0117 and 312-0119, rash (reported as dermatitis exfoliative generalised, drug eruption, rash, rash erythematous, rash generalised, rash macular, rash maculo-papular, rash papular, rash pruritic, rash pustular, rash vesicular, papule and skin plaque) occurred in 31.1% of subjects who received idelalisib + an anti-CD20 monoclonal antibody (rituximab or ofatumumab) and 8.2% who received an anti-CD20 monoclonal antibody only (rituximab or ofatumumab). Of these, 5.7% who received idelalisib + an anti-CD20 monoclonal antibody (rituximab or ofatumumab) and 1.5% who received an anti-CD20 monoclonal antibody only (rituximab or ofatumumab) had rash of Grade 3, and no subjects had an adverse reaction of Grade 4. Rash typically resolved with treatment (e.g., topical and/or oral steroids, diphenhydramine) and dose interruption for severe cases (see section 5.3, phototoxicity).

Severe cutaneous reactions (see section 4.4)

Cases of SJS, TEN and DRESS have occurred when idelalisib was administered concomitantly with other medicinal products associated with these syndromes (bendamustine, rituximab, allopurinol, amoxicillin, and sulfamethoxazole / trimethoprim). SJS or TEN occurred within one month of the medicinal combination and fatal outcomes have resulted.

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 Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

4.9. Overdose

If overdose occurs the patient must be monitored for evidence of toxicity (see section 4.8). Treatment of overdose with Zydelig consists of general supportive measures including monitoring of vital signs as well as observation of the clinical status of the patient.