ZEJULA Hard capsule Ref.[7611] Active ingredients: Niraparib

Haematologic adverse reactions

Haematologic adverse reactions (thrombocytopenia, anaemia, neutropenia) have been reported in patients treated with Zejula (see section 4.8). Patients with lower body weight or lower baseline platelet count may be at increased risk of Grade 3+ thrombocytopenia (see section 4.2). Testing complete blood counts weekly for the first month, followed by monthly monitoring for the next 10 months of treatment and periodically after this time is recommended to monitor for clinically significant changes in any haematologic parameter during treatment (see section 4.2).

If a patient develops severe persistent haematologic toxicity including pancytopenia that does not resolve within 28 days following interruption, Zejula should be discontinued.

Due to the risk of thrombocytopenia, anticoagulants and medicinal products known to reduce the thrombocyte count should be used with caution (see section 4.8).

Myelodysplastic syndrome/acute myeloid leukaemia

Cases of myelodysplastic syndrome/acute myeloid leukemia (MDS/AML), including cases with fatal outcome, have been observed in patients treated with Zejula monotherapy or combination therapy in clinical trials and postmarketing (see section 4.8).

In clinical trials, the duration of Zejula treatment in patients prior to developing MDS/AML varied from 0.5 months to >4.9 years. The cases were typical of secondary, cancer therapy-related MDS/AML. All patients had received platinum-containing chemotherapy regimens and many had also received other DNA damaging agents and radiotherapy. Some of the patients had a history of bone marrow suppression. In the NOVA trial, the incidence of MDS/AML was higher in the gBRCAmut cohort (7.4%) than in the non-gBRCAmut cohort (1.7%).

For suspected MDS/AML or prolonged haematological toxicities, the patient should be referred to a haematologist for further evaluation. If MDS/AML is confirmed, Zejula treatment should be discontinued and the patient treated appropriately.

Hypertension, including hypertensive crisis

Hypertension, including hypertensive crisis, has been reported with the use of Zejula (see section 4.8). Pre-existing hypertension should be adequately controlled before starting Zejula treatment. Blood pressure should be monitored at least weekly for two months, monitored monthly afterwards for the first year and periodically thereafter during treatment with Zejula. Home blood pressure monitoring may be considered for appropriate patients with instruction to contact their health care provider in case of rise in blood pressure.

Hypertension should be medically managed with antihypertensive medicinal products as well as adjustment of the Zejula dose (see section 4.2), if necessary. In the clinical programme, blood pressure measurements were obtained on Day 1 of each 28-day cycle while the patient remained on Zejula. In most cases, hypertension was controlled adequately using standard antihypertensive treatment with or without Zejula dose adjustment (see section 4.2). Zejula should be discontinued in case of hypertensive crisis or if medically significant hypertension cannot be adequately controlled with antihypertensive therapy.

Posterior reversible encephalopathy syndrome (PRES)

There have been reports of PRES in patients receiving Zejula (see section 4.8). PRES is a rare, reversible, neurological disorder which can present with rapidly evolving symptoms including seizures, headache, altered mental status, visual disturbance, or cortical blindness, with or without associated hypertension. A diagnosis of PRES requires confirmation by brain imaging, preferably magnetic resonance imaging (MRI).

In case of PRES, it is recommended to discontinue Zejula and to treat specific symptoms including hypertension. The safety of reinitiating Zejula therapy in patients previously experiencing PRES is not known.

Pregnancy/contraception

Zejula should not be used during pregnancy or in women of childbearing potential not willing to use highly effective contraception during therapy and for 6 months after receiving the last dose of Zejula (see section 4.6). A pregnancy test should be performed on all women of childbearing potential prior to treatment.

Hepatic impairment

Patients with severe hepatic impairment could have increased exposure of niraparib based on data from patients with moderate hepatic impairment and should be carefully monitored (see sections 4.2 and 5.2).

Lactose

Zejula hard capsules contain lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Tartrazine (E102)

This medicinal product contains tartrazine (E102), which may cause allergic reactions.

Pharmacodynamic interactions

The combination of niraparib with vaccines or immunosuppressant agents has not been studied.

The data on niraparib in combination with cytotoxic medicinal products are limited. Therefore, caution should be taken if niraparib is used in combination with vaccines, immunosuppressant agents or with other cytotoxic medicinal products.

Pharmacokinetic interactions

Effect of other medicinal products on niraparib

Niraparib as a substrate of CYPs (CYP1A2 and CYP3A4)

Niraparib is a substrate of carboxylesterases (CEs) and UDP-glucuronosyltransferases (UGTs) in vivo. Oxidative metabolism of niraparib is minimal in vivo. No dose adjustment for Zejula is required when administered concomitantly with medicinal products known to inhibit (e.g. itraconazole, ritonavir, and clarithromycin) or induce CYP enzymes (e.g. rifampin, carbamazepine, and phenytoin).

Niraparib as a substrate of efflux transporters (P-gp, BCRP, and MATE1/2)

Niraparib is a substrate of P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP). However, due to its high permeability and bioavailability, the risk of clinically relevant interactions with medicinal products that inhibit these transporters is unlikely. Therefore, no dose adjustment for Zejula is required when administered concomitantly with medicinal products known to inhibit P-gp (e.g. amiodarone, verapamil) or BCRP (e.g. osimertinib, velpatasvir, and eltrombopag).

Niraparib is not a substrate of bile salt export pump (BSEP). The major primary metabolite M1 is not a substrate of P-gp, BCRP, or BSEP. Niraparib is not a substrate of MATE 1 or 2, while M1 is a substrate of both.

Niraparib as a substrate of hepatic uptake transporters (OATP1B1, OATP1B3, and OCT1)

Neither niraparib nor M1 is a substrate of organic anion transport polypeptide 1B1 (OATP1B1), 1B3 (OATP1B3), or organic cation transporter 1 (OCT1). No dose adjustment for Zejula is required when administered concomitantly with medicinal products known to inhibit OATP1B1 or 1B3 (e.g. gemfibrozil, ritonavir), or OCT1 (e.g. dolutegravir) uptake transporters.

Niraparib as a substrate of renal uptake transporters (OAT1, OAT3, and OCT2)

Neither niraparib nor M1 is a substrate of organic anion transporter 1 (OAT1), 3 (OAT3), and organic cation transporter 2 (OCT2). No dose adjustment for Zejula is required when administered concomitantly with medicinal products known to inhibit OAT1 (e.g. probenecid) or OAT3 (e.g. probenecid, diclofenac), or OCT2 (e.g. cimetidine, quinidine) uptake transporters.

Effect of niraparib on other medicinal products

Inhibition of CYPs (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4)

Neither niraparib nor M1 is an inhibitor of any active substance-metabolising CYP enzymes, namely CYP1A1/2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5.

Even though inhibition of CYP3A4 in the liver is not expected, the potential to inhibit CYP3A4 at the intestinal level has not been established at relevant niraparib concentrations. Therefore, caution is recommended when niraparib is combined with active substances the metabolism of which is CYP3A4-dependent and, notably, those having a narrow therapeutic range (e.g. ciclosporin, tacrolimus, alfentanil, ergotamine, pimozide, quetiapine, and halofantrine).

Inhibition of UDP-glucuronosyltransferases (UGTs)

Niraparib did not exhibit inhibitory effect against the UGT isoforms (UGT1A1, UGT1A4, UGT1A9, and UGT2B7) up to 200 µM in vitro. Therefore, the potential for a clinically relevant inhibition of UGTs by niraparib is minimal.

Induction of CYPs (CYP1A2 and CYP3A4)

Neither niraparib nor M1 is a CYP3A4 inducer in vitro. In vitro, niraparib weakly induces CYP1A2 at high concentrations and the clinical relevance of this effect could not be completely ruled out. M1 is not a CYP1A2 inducer. Therefore, caution is recommended when niraparib is combined with active substances the metabolism of which is CYP1A2-dependent and, notably, those having a narrow therapeutic range (e.g. clozapine, theophylline, and ropinirole).

Inhibition of efflux transporters (P-gp, BCRP, BSEP, and MATE1/2)

Niraparib is not an inhibitor of BSEP or MRP2. In vitro, niraparib inhibits P-gp very weakly and BCRP with an IC₅₀ = 161 µM and 5.8 µM, respectively. Therefore, a clinically meaningful interaction related to an inhibition of these efflux transporters, although unlikely, cannot be excluded. Caution is then recommended when niraparib is combined with substrates of BCRP (irinotecan, rosuvastatin, simvastatin, atorvastatin, and methotrexate).

Niraparib is an inhibitor of MATE1 and -2 with IC₅₀ of 0.18 µM and ≤0.14 µM, respectively. Increased plasma concentrations of co-administered medicinal products that are substrates of these transporters (e.g. metformin) cannot be excluded.

The major primary metabolite M1 does not appear to be an inhibitor of P-gp, BCRP, BSEP, MRP2 or MATE1/2.

Inhibition of hepatic uptake transporters (OATP1B1, OATP1B3, and OCT1)

Neither niraparib nor M1 is an inhibitor of organic anion transport polypeptide 1B1 (OATP1B1) or 1B3 (OATP1B3).

In vitro, niraparib weakly inhibits the organic cation transporter 1 (OCT1) with an IC₅₀ = 34.4 μM. Caution is recommended when niraparib is combined with active substances that undergo an uptake transport by OCT1 such as metformin.

Inhibition of renal uptake transporters (OAT1, OAT3, and OCT2)

Neither niraparib nor M1 inhibits organic anion transporter 1 (OAT1), 3 (OAT3), and organic cation transporter 2 (OCT2).

All clinical studies have only been performed in adults.

Women of childbearing potential/contraception in females

Women of childbearing potential should not become pregnant while on treatment and should not be pregnant at the beginning of treatment. A pregnancy test should be performed on all women of childbearing potential prior to treatment. Women of childbearing potential must use highly effective contraception during therapy and for 6 months after receiving the last dose of Zejula.

Pregnancy

There are no or limited amount of data from the use of niraparib in pregnant women. Animal reproductive and developmental toxicity studies have not been conducted. However, based on its mechanism of action, niraparib could cause embryonic or foetal harm, including embryo-lethal and teratogenic effects, when administered to a pregnant woman. Zejula should not be used during pregnancy.

Breast-feeding

It is unknown whether niraparib or its metabolites are excreted in human milk. Breast-feeding is contraindicated during administration of Zejula and for 1 month after receiving the last dose (see section 4.3).

Fertility

There are no clinical data on fertility. A reversible reduction of spermatogenesis was observed in rats and dogs (see section 5.3).

Zejula has moderate influence on the ability to drive or use machines. Patients who take Zejula may experience asthenia, fatigue, dizziness or difficulties concentrating. Patients who experience these symptoms should observe caution when driving or using machines.

Summary of the safety profile

ADRs of all grades occurring in ≥10% of the 851 patients receiving Zejula monotherapy in the pooled PRIMA (either 200 mg or 300 mg starting dose) and NOVA trials were nausea, anaemia, thrombocytopenia, fatigue, constipation, vomiting, headache, insomnia, platelet count decreased, neutropenia, abdominal pain, decreased appetite, diarrhoea, dyspnoea, hypertension, asthenia, dizziness, neutrophil count decreased, cough, arthralgia, back pain, white blood cell count decreased, and hot flush.

The most common serious adverse reactions > 1% (treatment-emergent frequencies) were thrombocytopenia and anaemia.

Tabulated list of adverse reactions

The following adverse reactions have been identified based on clinical trials and post-marketing surveillance in patients receiving Zejula monotherapy (see Table 4). Frequencies of occurrence of undesirable effects are based on pooled adverse events data generated from the PRIMA and NOVA studies (fixed starting dose of 300 mg/day) where patient exposure is known and defined as: 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); and very rare (<1/10,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 4. Tabulated list of adverse reactions:

^* CTCAE=Common Terminology Criteria for Adverse Events version 4.02
^** Based on niraparib clinical trial data. This is not limited to pivotal ENGOT-OV16 monotherapy study.
^† Includes hypersensitivity, drug hypersensitivity, anaphylactoid reaction, drug eruption, angioedema, and urticaria.
^†† Includes memory impairment, concentration impairment.

The adverse reactions noted in the group of patients who were administered a 200 mg starting dose of Zejula based on baseline weight or platelet count were of similar or lesser frequency compared to the group administered a fixed starting dose of 300 mg (Table 4).

See below for specific information regarding frequency of thrombocytopenia, anaemia and neutropenia.

Description of selected adverse reactions

Haematologic adverse reactions (thrombocytopenia, anaemia, neutropenia) including clinical diagnoses and/or laboratory findings generally occurred early during niraparib treatment with the incidence decreasing over time.

In the NOVA and PRIMA studies, patients eligible for Zejula therapy had the following baseline haematologic parameters: absolute neutrophil count (ANC) ≥1,500 cells/µL; platelets ≥100,000 cells/µL and haemoglobin ≥9 g/dL (NOVA) or ≥10 g/dL (PRIMA) prior to therapy. In the clinical programme, haematologic adverse reactions were managed with laboratory monitoring and dose modifications (see section 4.2).

In PRIMA, patients who were administered a starting dose of Zejula based on baseline weight or platelet count, Grade ≥3 thrombocytopenia, anaemia and neutropenia were reduced from 48% to 21%, 36% to 23% and 24% to 15%, respectively, compared to the group administered a fixed starting dose of 300 mg. Discontinuation due to thrombocytopenia, anaemia, and neutropenia occurred, respectively, in 3%, 3%, and 2% of patients.

Thrombocytopenia

In PRIMA, 39% of Zejula-treated patients experienced Grade ¾ thrombocytopenia compared to 0.4% of placebo-treated patients with a median time from first dose to first onset of 22 days (range: 15 to 335 days) and with a median duration of 6 days (range: 1 to 374 days). Discontinuation due to thrombocytopenia occurred in 4% of patients receiving niraparib.

In NOVA, approximately 60% of patients receiving Zejula experienced thrombocytopenia of any grade, and 34% of patients experienced Grade ¾ thrombocytopenia. In patients with baseline platelet count less than 180 × 10⁹/L, thrombocytopenia of any grade and Grade ¾ occurred in 76% and 45% of the patients, respectively. The median time to onset of thrombocytopenia regardless of grade and Grade ¾ thrombocytopenia was 22 and 23 days, respectively. The rate of new incidences of thrombocytopenia after intensive dose modifications were performed during the first two months of treatment from Cycle 4 was 1.2%. The median duration of thrombocytopenia events of any grade was 23 days, and the median duration of Grade ¾ thrombocytopenia was 10 days. Patients treated with Zejula who develop thrombocytopenia might have an increased risk of haemorrhage. In the clinical programme, thrombocytopenia was managed with laboratory monitoring, dose modification and platelet transfusion where appropriate (see section 4.2). Discontinuation due to thrombocytopenia events (thrombocytopenia and platelet count decreased) occurred in approximately 3% of the patients.

In the NOVA study, 48 of 367 (13%) of patients experienced bleeding with concurrent thrombocytopenia; all bleeding events concurrent with thrombocytopenia were Grade 1 or 2 in severity except for one event of Grade 3 petechiae and haematoma observed concurrently with a serious adverse reaction of pancytopenia. Thrombocytopenia occurred more commonly in patients whose baseline platelet count was less than 180 × 10⁹/L. Approximately 76% of patients with lower baseline platelets (<180 × 10⁹/L) who received Zejula experienced thrombocytopenia of any grade, and 45% of the patients experienced Grade ¾ thrombocytopenia. Pancytopenia has been observed in <1% of patients receiving niraparib.

Anaemia

In PRIMA, 31% of Zejula-treated patients experienced Grade ¾ anaemia compared to 2% of placebo-treated patients with a median time from first dose to first onset of 80 days (range: 15 to 533 days) and with a median duration of 7 days (range: 1 to 119 days). Discontinuation due to anaemia occurred in 2% of patients receiving niraparib.

In NOVA, approximately 50% of patients experienced anaemia of any grade, and 25% experienced Grade ¾ anaemia. The median time to onset of anaemia of any grade was 42 days, and 85 days for Grade ¾ events. The median duration of anaemia of any grade was 63 days, and 8 days for Grade ¾ events. Anaemia of any grade might persist during Zejula treatment. In the clinical programme, anaemia was managed with laboratory monitoring, dose modification (see section 4.2), and where appropriate with red blood cell transfusions. Discontinuation due to anaemia occurred in 1% of patients.

Neutropenia

In PRIMA, 21% of Zejula-treated patients experienced Grade ¾ neutropenia compared to 1% of placebo-treated patients with a median time from first dose to first onset of 29 days (range: 15 to 421 days) and with a median duration of 8 days (range: 1 to 42 days). Discontinuation due to neutropenia occurred in 2% of patients receiving niraparib.

In NOVA, approximately 30% of patients receiving Zejula experienced neutropenia of any grade, and 20% of patients experienced Grade ¾ neutropenia. The median time to onset of neutropenia of any grade was 27 days, and 29 days for Grade ¾ events. The median duration of neutropenia of any grade was 26 days, and 13 days for Grade ¾ events. In addition, Granulocyte-Colony Stimulating Factor (G-CSF) was administered to approximately 6% of patients treated with niraparib as concomitant therapy for neutropenia. Discontinuation due to neutropenia events occurred in 2% of patients.

Myelodysplastic syndrome/Acute myeloid leukaemia

In clinical studies, MDS/AML occurred in 1% patients treated with Zejula, with 41% of cases having a fatal outcome. The incidence was higher in patients with relapsed ovarian cancer who had received 2 or more lines of prior platinum chemotherapy and with gBRCAmut following 75 months survival follow-up. All patients had potential contributing factors for the development of MDS/AML, having received previous chemotherapy with platinum agents. Many had also received other DNA damaging agents and radiotherapy. The majority of reports were in gBRCAmut carriers. Some of the patients had a history of previous cancer or of bone marrow suppression.

In the PRIMA study, the incidence of MDS/AML was 0.8% in patients receiving Zejula and 0.4% in patients received placebo.

In the NOVA study in patients with relapsed ovarian cancer who had received at least two prior lines of platinum chemotherapy, the overall incidence of MDS/AML was 3.8% in patients receiving Zejula and 1.7% in patients receiving placebo at a follow-up of 75 months. In gBRCAmut and nongBRCAmut cohorts, the incidence of MDS/AML was 7.4% and 1.7% in patients receiving Zejula and 3.1% and 0.9% in patients receiving placebo, respectively.

Hypertension

In PRIMA, Grade ¾ hypertension occurred in 6% of Zejula-treated patients compared to 1% of placebo-treated patients with a median time from first dose to first onset of 50 days (range: 1 to 589 days) and with a median duration of 12 days (range: 1 to 61 days). Discontinuation due to hypertension occurred in 0% of patients.

In NOVA, hypertension of any grade occurred in 19.3% of patients treated with Zejula. Grade ¾ hypertension occurred in 8.2% of patients. Hypertension was readily managed with anti-hypertensive medicinal products. Discontinuation due to hypertension occurred in <1% of patients.

Paediatric population

No studies have been conducted in paediatric patients.

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 listed in Appendix V.

Not applicable.