Zydelig

Zydelig

Therapeutic indication

CLL patients

Mechanism of action

Idelalisib inhibits phosphatidylinositol 3-kinase p110δ (PI3Kδ), which is hyperactive in B-cell malignancies and is central to multiple signalling pathways that drive proliferation, survival, homing, and retention of malignant cells in lymphoid tissues and bone marrow. Idelalisib is a selective inhibitor of adenosine-5’-triphosphate (ATP) binding to the catalytic domain of PI3Kδ, resulting in inhibition of the phosphorylation of the key lipid second prevention of Akt (protein kinase B) phosphorylation. Idelalisib induces apoptosis and inhibits proliferation in cell lines derived from malignant B-cells and in primary tumour cells. Through inhibition of chemokine receptors CXCR4 and CXCR5 signalling induced by the chemokines CXCL12 and CXCL13, respectively, idelalisib inhibits homing and retention of malignant B-cells in the tumour microenvironment including lymphoid tissues and the bone marrow.

Reimbursement modalities

Reimbursement conditions for CLL from 2nd line

a) This speciality is eligible for reimbursement for treatment of adult patients with chronic lymphocytic leukaemia (CLL) in combination with 8 cycles of rituximab.

Reimbursement is permitted as long as the patient is or has been eligible for treatment according to the latest criteria of the international working group on CLL (IWCLL) after

in patients who are not or have not been candidates for treatment based on a purine analogue for one of the following reasons:

• stable disease

• progression during treatment

• progression within 30 months of the first dose

Reimbursement conditions for CLL patients with 17p deletion or TP53 mutation

This speciality is eligible for reimbursement for treatment of adult patients with chronic lymphocytic leukaemia (CLL) in combination with 8 cycles of rituximab.

Reimbursement is permitted as long as the patient is or has been eligible for treatment according to the latest criteria of the international working group on CLL (IWCLL) in cases where the presence of a 17p deletion or TP53 mutation has been demonstrated.

Reimbursement conditions in refractory FL

This speciality is eligible for reimbursement for treatment of adult patients with follicular lymphoma which is refractory to two previous lines of treatment.

Additional conditions for reimbursement of Zydelig®

b) The number of packs eligible for reimbursement is based on a maximum dose of 2 x 150 mg daily

c) Reimbursement of the speciality must be requested by a specialist doctor in internal medicine with a specialist medical qualification in clinical haematology

d) Reimbursement is permitted on the basis of an electronic request submitted by the qualified pecialist doctor identified via the e-Health platform, as referred to under point c), who undertakes

• to submit the supporting documentation to the doctor advising the health insurance institution in response to a simple request

• to stop the reimbursable treatment in the event of disease progression as defined according to the most recent IWCLL criteria

e) Reimbursement is only provided if the relevant hospital pharmacist, before dispensing the speciality, has a copy of the agreement referred to in d)

messenger phosphatidylinositol and 

Administration and dosage

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

Posology

The recommended dose of Zydelig is 150 mg, taken orally, 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 modifications

Toxicity

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 (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 patient populations 

Elderly 

No specific dose adjustment is required for elderly patients (aged ≥ 65 years) (see section 5.2).

Hepatic impairment 

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

Renal impairment 

No dose adjustment is required for patients with mild, moderate, or severe renal impairment (see section 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).

Contraindications

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

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 (see section 4.4).

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 drug 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.

 

Medicinal product 
Expected effect of idelalisib on drug levels 
Clinical recommendation upon co-administration with idelalisib 

 

ANTICONVULSANTS 
Carbamazepine
↑ serum concentrations
Anticonvulsant drug 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.
Medicinal product 
Expected effect of idelalisib on drug levels 
Clinical recommendation upon co-administration with idelalisib  

 

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.


Medicinal product 
Expected effect of idelalisib on drug levels 
Clinical recommendation upon co-administration with idelalisib 
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 drugs 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 drugs 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.

 

Drug-food interactions

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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.

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.

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 idelalisib. 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, idelalisib should be interrupted and the patient treated accordingly. Treatment must be discontinued for moderate or severe symptomatic pneumonitis.

Stevens-Johnson syndrome and toxic epidermal necrolysis 

Cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) with fatal outcomes have been reported when idelalisib was administered concomitantly with other medicinal products associated with these syndromes. If SJS or TEN is suspected, idelalisib should be immediately interrupted and the patient treated accordingly.

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.

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.

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 

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

 

Initial work-up before start of treatment

See: Special warnings and precautions for use

Concomitant Treatment in CLL

Response evaluation

 

Undesirable effects

Summary of the safety profile

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 535 subjects with haematologic malignancies, including 399 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).

Tabulated list of adverse reactions

The adverse drug reactions reported with idelalisib alone or in combination with anti‑CD20 monoclonal antibodies (rituximab or ofatumumab) are provided in Table 1.  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 1: Adverse drug reactions reported in clinical studies in subjects with haematologic malignancies receiving idelalisib

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
Common
Respiratory, thoracic and mediastinal disorders
Pneumonitis
Common
Common
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
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, rash, rash erythematous, rash generalised, rash macular, rash maculo-papular, rash papular, rash pruritic, skin disorder, and exfoliative rash.

Description of selected adverse reactions

Infections
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 1.7% of subjects.  In studies 312‑0116/0117 and 312‑0119, rash (reported as dermatitis exfoliative, rash, rash erythematous, rash generalised, rash macular, rash maculo-papular, rash papular, rash pruritic, and skin disorder) occurred in 28.3% of subjects who received idelalisib + an anti‑CD20 monoclonal antibody (rituximab or ofatumumab) and 7.7% who received an anti‑CD20 monoclonal antibody only (rituximab or ofatumumab).  Of these, 4.9% who received idelalisib + an anti‑CD20 monoclonal antibody (rituximab or ofatumumab) and 1.0% who received an anti‑CD20 monoclonal antibody only (rituximab or ofatumumab) had rash of Grade 3, and no subjects had an adverse event of Grade 4.  Rash typically resolved with treatment (e.g., topical and/or oral steroids, diphenhydramine) and dose interruption for severe cases.

Stevens-Johnson syndrome and toxic epidermal necrolysis

Rarely, cases of SJS and TEN have occurred when idelalisib was administered concomitantly with other medicinal products associated with these syndromes (bendamustine, rituximab, allopurinol, and amoxicillin).  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 national reporting system:

Belgium

Federal Agency for Medicines and Health Products

Division Vigilance

EUROSTATION II

Place Victor Horta, 40/ 40

B-1060 Bruxelles

Web site: www.afmps.be

e-mail: adversedrugreactions@fagg-afmps.be

Luxembourg

Direction de la Santé – Division de la Pharmacie et des Médicaments

Villa Louvigny – Allée Marconi

L-2120 Luxembourg

Web site:  http://www.ms.public.lu/fr/activites/pharmacie-medicament/index.html

 

MARKETING AUTHORISATION HOLDER

Gilead Sciences International Ltd

Cambridge

CB21 6GT

United Kingdom

MARKETING AUTHORISATION NUMBER(S)

EU/1/14/938/001

EU/1/14/938/002

DATE OF REVISION OF THE TEXT

11/2017

 

MODE OF DELIVERY

Prescription only.

 

PRICE

 3800€ (ex-factory)

4153.82€ (public price)

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu


For the full SmPC visit: