Niraparib

Niraparib is a potent, selective inhibitor of the poly(ADP-ribose) polymerase enzymes PARP-1 and PARP-2, which recognise damaged DNA and help to repair it. Blocking these enzymes leaves DNA damage unrepaired in tumour cells and leads to their death. In Akeega, niraparib is combined with abiraterone acetate, an inhibitor of CYP17 (androgen biosynthesis), for prostate cancer with BRCA 1/2 mutations.

Mechanism of Action

• PARP inhibition: PARP-1 and PARP-2 detect DNA damage, such as single-strand breaks, and recruit the repair machinery. Niraparib inhibits their enzymatic activity and is about 100-fold more selective for PARP-1 and PARP-2 than for other members of the PARP family.
• PARP–DNA complexes: in vitro, niraparib-induced cytotoxicity may involve both inhibition of PARP activity and increased formation of PARP–DNA complexes, which results in DNA damage, apoptosis and cell death.
• Synthetic lethality: cells that cannot repair double-strand breaks by homologous recombination, for example because of BRCA1 or BRCA2 mutations, rely on PARP-mediated repair. When PARP is inhibited, DNA damage accumulates, and genomic instability and cell death follow.
• Activity regardless of BRCA status: cytotoxicity occurred in tumour cell lines with or without BRCA1/2 deficiency. In mice carrying patient-derived ovarian cancer xenografts, niraparib reduced tumour growth in BRCA-mutant tumours, in BRCA wild-type tumours with homologous recombination deficiency and in BRCA wild-type tumours without detectable deficiency.
• Off-target effects: in vitro studies suggest that niraparib also inhibits the dopamine, noradrenaline and serotonin transporters, which may explain the rises in pulse rate and blood pressure seen with treatment.

Pharmacokinetics

• Absorption: after a single 300 mg dose niraparib is measurable in plasma within 30 minutes and peaks after 3 to 5 hours. Absolute bioavailability is about 73%, indicating minimal first-pass loss. Exposure rises in proportion to dose between 30 mg and 400 mg once daily, and niraparib accumulates about 2- to 3-fold with repeated daily dosing. A high-fat meal did not significantly change exposure to the capsules (peak concentration 22% lower, AUC 10% higher). Tablets and capsules are bioequivalent: one 300 mg tablet and three 100 mg capsules were compared in 108 patients with solid tumours.
• Distribution: about 83% bound to plasma proteins, mainly albumin. The apparent volume of distribution is about 1,206 L in a 70 kg patient with cancer, which indicates extensive tissue distribution.
• Metabolism: carboxylesterases convert niraparib mainly to M1, a major inactive metabolite, which is then glucuronidated to M10. M1 and M10 are the main circulating metabolites.
• Elimination: the mean terminal half-life after a single 300 mg dose ranged from 44 to 54 hours (about 2 days) across studies, and apparent total clearance was about 15.9 L/h in patients with cancer. Niraparib is eliminated through the hepatobiliary and renal routes. After a radiolabelled 300 mg dose, an average of 47.5% of the radioactivity was recovered in urine and 38.8% in faeces over 21 days.
• Special populations: no dose adjustment is needed in mild to moderate renal impairment or mild hepatic impairment, and moderate hepatic impairment lowers the recommended starting dose of Zejula (see Administration and Dosage). For Akeega, moderate hepatic impairment increases exposure to both abiraterone and niraparib.

Ovarian, fallopian tube and primary peritoneal cancer (Zejula as monotherapy)

• First-line maintenance treatment: adults with advanced epithelial (FIGO stages III and IV) high-grade ovarian, fallopian tube or primary peritoneal cancer who are in response (complete or partial) following completion of first-line platinum-based chemotherapy.
• Maintenance treatment of platinum-sensitive relapse: adults with platinum-sensitive relapsed high-grade serous epithelial ovarian, fallopian tube or primary peritoneal cancer who are in response (complete or partial) to platinum-based chemotherapy.
• Zejula capsules and Zejula tablets have the same indications.

Prostate cancer (Akeega, niraparib with abiraterone acetate, always taken with prednisone or prednisolone)

• Metastatic hormone-sensitive prostate cancer (mHSPC): adults with BRCA 1/2 mutations (germline and/or somatic), in combination with androgen deprivation therapy (ADT).
• Metastatic castration-resistant prostate cancer (mCRPC): adults with BRCA 1/2 mutations (germline and/or somatic) in whom chemotherapy is not clinically indicated.

• Zejula, hypersensitivity: to niraparib or to any of the excipients.
• Zejula, breastfeeding: during treatment and for 1 month after the last dose.
• Akeega, hypersensitivity: to the active substances or to any of the excipients.
• Akeega, pregnancy: women who are or may become pregnant.
• Akeega, severe hepatic impairment: Child-Pugh class C.
• Akeega, radium-223: Akeega with prednisone or prednisolone must not be combined with radium-223 (Ra-223) treatment.

In the pooled PRIMA and NOVA trials (851 patients on Zejula monotherapy), reactions in at least 10% of patients were nausea, anaemia, thrombocytopenia, fatigue, constipation, vomiting, headache, insomnia, decreased platelet count, neutropenia, abdominal pain, decreased appetite, diarrhoea, dyspnoea, hypertension, asthenia, dizziness, decreased neutrophil count, cough, arthralgia, back pain, decreased white blood cell count and hot flush. The most common serious reactions (more than 1%) were thrombocytopenia and anaemia. Frequencies below are for all grades with a fixed 300 mg starting dose.

Very common (≥1/10): urinary tract infection; thrombocytopenia, anaemia, neutropenia, leukopenia; decreased appetite; insomnia; headache, dizziness; palpitations; hypertension; dyspnoea, cough, nasopharyngitis; nausea, constipation, vomiting, abdominal pain, diarrhoea, dyspepsia; back pain, arthralgia; fatigue, asthenia.

Common (≥1/100 to <1/10): bronchitis, conjunctivitis; myelodysplastic syndrome/acute myeloid leukaemia; hypersensitivity (including angioedema, urticaria and anaphylactic reaction); hypokalaemia; anxiety, depression, cognitive impairment (memory or concentration); dysgeusia; tachycardia; epistaxis; dry mouth, abdominal distension, mucosal inflammation, stomatitis; photosensitivity, rash; myalgia; peripheral oedema; increased gamma-glutamyltransferase, AST, ALT, alkaline phosphatase and blood creatinine; decreased weight.

Uncommon (≥1/1,000 to <1/100): pancytopenia, febrile neutropenia; confusional state; pneumonitis.

Rare (≥1/10,000 to <1/1,000): posterior reversible encephalopathy syndrome (PRES); hypertensive crisis.

Severe (grade 3 or 4) reactions are most often thrombocytopenia, anaemia and neutropenia. Reactions in patients who started on 200 mg because of body weight or platelet count were of similar or lower frequency than with a fixed 300 mg start. Important serious reactions are haematological toxicity, myelodysplastic syndrome/acute myeloid leukaemia (including fatal cases), hypertension with hypertensive crisis, and PRES.

Akeega (niraparib with abiraterone acetate and prednisone or prednisolone): in the pooled AMPLITUDE and MAGNITUDE data (559 patients), reactions in more than 10% were anaemia (51.9%), hypertension (40.1%), fatigue (39.7%), musculoskeletal pain (35.8%), constipation (34.7%), nausea (28.6%), hypokalaemia (22.0%), thrombocytopenia (20.9%), neutropenia (19.7%), oedema (18.1%), respiratory tract infections (17.7%), dyspnoea (16.6%) and others listed in the SmPC. The most frequent grade 3–4 reactions were anaemia (29.7%), hypertension (22.7%), hypokalaemia (9.3%), neutropenia (8.4%), thrombocytopenia (7.5%) and lymphopenia (5.2%). Less frequent but important reactions include pulmonary embolism, cardiac failure, arrhythmia and angina pectoris (common), myocardial infarction and myelodysplastic syndrome/acute myeloid leukaemia (uncommon), and adrenal insufficiency, pancytopenia, hypertensive crisis and PRES (frequency not known).

No clinical interaction studies have been performed with niraparib; the statements below come from in vitro data and the SmPC.

• Vaccines, immunosuppressants and cytotoxic medicines: the combination with vaccines or immunosuppressants has not been studied and data with cytotoxic medicines are limited, so use caution.
• CYP1A2 substrates: niraparib induces CYP1A2 in vitro. Take care with medicines metabolised by CYP1A2, especially those with a narrow therapeutic range (clozapine, theophylline, ropinirole).
• P-glycoprotein substrates: niraparib inhibits P-gp in vitro and may raise exposure to medicines sensitive to intestinal P-gp inhibition, such as dabigatran etexilate.
• BCRP substrates: niraparib inhibits BCRP in vitro. Take care with substrates such as irinotecan, rosuvastatin, simvastatin, atorvastatin and methotrexate, because their exposure may increase.
• Metformin: niraparib inhibits MATE1 and MATE2-K in vitro, so metformin levels may rise. Monitor blood glucose closely when niraparib is started or stopped; the metformin dose may need adjusting.
• Anticoagulants and platelet-lowering medicines: use with caution because of the risk of thrombocytopenia.
• Food: Zejula capsules can be taken with or without food; a high-fat meal had no significant effect on exposure.
• Akeega, CYP3A4 inducers: avoid strong CYP3A4 inducers unless there is no alternative, because they can lower abiraterone exposure.
• Akeega, radium-223: contraindicated with Akeega plus prednisone or prednisolone, because of more fractures and a trend to higher mortality with abiraterone. Do not start Ra-223 until at least 5 days after the last Akeega dose.
• Akeega, diabetes medicines: hypoglycaemia has been reported when abiraterone acetate with prednisone or prednisolone was given to patients taking pioglitazone or repaglinide, so monitor blood sugar.
• Akeega, muscle effects: use caution with medicines associated with myopathy or rhabdomyolysis. The Akeega SmPC lists further interactions in its section 4.5.

Treatment with Zejula should be started and supervised by a physician experienced in the use of anticancer medicinal products. Treatment with Akeega plus prednisone or prednisolone should be started and supervised by specialist physicians experienced in the medical treatment of prostate cancer.

Recommended Dose (Zejula)

• First-line maintenance in ovarian cancer: 200 mg (two 100 mg capsules or tablets) once daily. Patients who weigh at least 77 kg and have a baseline platelet count of at least 150,000/μL start on 300 mg (three 100 mg capsules or tablets) once daily.
• Recurrent (platinum-sensitive relapsed) ovarian cancer maintenance: 300 mg (three 100 mg capsules or tablets) once daily.
• Duration: continue until disease progression or toxicity.
• How to take it: swallow capsules whole with water, without chewing or crushing, with or without food. Tablets are advised without food (at least 1 hour before or 2 hours after a meal) or with a light meal. Take the dose at about the same time each day; taking it at bedtime may help to manage nausea.

Dose Adjustments for Side Effects (Zejula)

• General rule: first interrupt treatment (for no longer than 28 consecutive days) so the patient recovers, then restart at the same dose. If the reaction recurs, interrupt again and resume at the next lower dose. If reactions persist beyond a 28-day interruption, or cannot be managed by interruption and reduction, discontinue Zejula.
• Dose levels: from a 300 mg start, the first reduction is 200 mg/day and the second 100 mg/day (one capsule or tablet). From a 200 mg start, the first reduction is 100 mg/day and the next step is discontinuation. If a reduction below 100 mg/day is needed, discontinue.
• Non-haematological reactions: for treatment-related reactions of grade 3 or higher where prophylaxis is not feasible or the reaction persists despite treatment, withhold for up to 28 days or until resolution and resume at a reduced dose. At the second occurrence, withhold again for up to 28 days or until resolution and resume at a reduced dose or discontinue. A reaction of grade 3 or higher lasting more than 28 days on 100 mg/day means discontinuation.
• Blood counts: check weekly during the first month, then monthly and periodically. Weekly checks in the second month may be warranted on individual results.
• Platelets below 100,000/μL: at the first occurrence, withhold for up to 28 days and check counts weekly until platelets are back to at least 100,000/μL. Resume at the same or a reduced dose after clinical evaluation, and at a reduced dose if the count fell below 75,000/μL at any time. At the second occurrence, withhold for up to 28 days until platelets are again at least 100,000/μL and resume at a reduced dose. Discontinue if counts have not recovered within 28 days or the dose is already 100 mg daily.
• Neutrophils below 1,000/μL or haemoglobin below 8 g/dL: withhold for up to 28 days and check weekly until neutrophils are at least 1,500/μL or haemoglobin at least 9 g/dL, then resume at a reduced dose. Discontinue if values have not recovered within 28 days or the dose is already 100 mg daily.
• Reactions needing transfusion or growth-factor support: resume at a reduced dose. At a platelet count of 10,000/μL or less, consider platelet transfusion; with other bleeding risk factors, such as anticoagulant or antiplatelet medicines, consider interrupting them or transfusing at a higher platelet count.
• Confirmed MDS or AML: discontinue permanently.
• Low body weight in recurrent ovarian cancer: about 25% of NOVA patients weighed less than 58 kg and had more grade 3 or 4 reactions than heavier patients (78% against 53%). A 200 mg starting dose may be considered for patients under 58 kg.

Special Populations (Zejula)

• Elderly (65 years and over): no dose adjustment; clinical data are limited in patients aged 75 or over.
• Renal impairment: no adjustment in mild to moderate impairment. There are no data in severe impairment or end-stage renal disease on haemodialysis; use with caution.
• Hepatic impairment: no adjustment in mild impairment (AST above the upper limit of normal with total bilirubin at or below it, or any AST with bilirubin up to 1.5 times the upper limit). In moderate impairment (any AST with bilirubin above 1.5 and up to 3 times the upper limit) the starting dose is 200 mg once daily. There are no data in severe impairment (bilirubin above 3 times the upper limit); use with caution.
• ECOG performance status 2 to 4: no clinical data.
• Children and adolescents: safety and efficacy below 18 years have not been established.

Missed Dose

If a dose of Zejula is missed, take the next dose at its regularly scheduled time.

Akeega (Niraparib with Abiraterone Acetate)

• Before starting: BRCA status must be positive, established with a validated test, for both mHSPC and mCRPC.
• Dose: the recommended starting dose is 200 mg/1,000 mg (two 100 mg/500 mg tablets) as a single daily dose at about the same time every day. The 50 mg/500 mg tablet is available for dose reduction.
• Prednisone or prednisolone: 5 mg daily with Akeega for mHSPC, 10 mg daily for mCRPC.
• Castration: medical castration with a GnRH analogue continues in patients who have not had surgical castration.
• Duration: until disease progression or unacceptable toxicity.
• Dose adjustments: for non-haematological reactions of grade 3 or higher, interrupt treatment and give appropriate management; restart only once symptoms have resolved to grade 1 or baseline. For haematological toxicity of grade 3 or higher, or intolerable toxicity, interrupt rather than stop and consider supportive management; discontinue permanently if toxicity has not returned to acceptable levels within 28 days of interruption. The SmPC gives a dosing table for thrombocytopenia and neutropenia.
• Missed dose: take Akeega, prednisone or prednisolone as soon as possible on the same day and return to the normal schedule the next day. Do not take extra tablets to make up for it.

Haematological Toxicity

Thrombocytopenia, anaemia and neutropenia have been reported with Zejula. Patients with a lower body weight or lower baseline platelet count may be at higher risk of grade 3 or worse thrombocytopenia. A complete blood count is recommended weekly for the first month, then monthly for the next 10 months and periodically afterwards. Zejula should be stopped if severe, persistent haematological toxicity, including pancytopenia, has not resolved within 28 days of interruption. Anticoagulants and medicines known to lower the platelet count should be used with caution.

Myelodysplastic Syndrome and Acute Myeloid Leukaemia

Myelodysplastic syndrome or acute myeloid leukaemia (MDS/AML), including fatal cases, has been reported in clinical trials and after marketing with Zejula alone or in combination. In trials, treatment had lasted from 0.5 months to more than 4.9 years before MDS/AML developed. The cases were typical of secondary, cancer therapy-related disease: all patients had received platinum-containing chemotherapy, many had also had other DNA-damaging agents and radiotherapy, and some had a history of bone marrow suppression. In the NOVA trial the incidence was higher in the germline BRCA-mutated cohort (7.4%) than in the cohort without a germline BRCA mutation (1.7%). Suspected MDS/AML or prolonged haematological toxicity calls for referral to a haematologist, and Zejula is stopped if MDS/AML is confirmed.

Hypertension, Including Hypertensive Crisis

Hypertension, including hypertensive crisis, has been reported. Existing hypertension should be well controlled before treatment starts. Blood pressure is monitored at least weekly for two months, then monthly for the first year and periodically afterwards; home monitoring may suit some patients, who should contact their healthcare provider if it rises. Hypertension is treated with antihypertensive medicines and, if needed, a Zejula dose adjustment. Zejula is stopped in a hypertensive crisis or if medically significant hypertension cannot be controlled.

Posterior Reversible Encephalopathy Syndrome (PRES)

PRES is a rare, reversible neurological disorder that can present with rapidly evolving seizures, headache, altered mental status, visual disturbance or cortical blindness, with or without hypertension. It has been reported in patients receiving Zejula. The diagnosis needs confirmation by brain imaging, preferably MRI. If PRES occurs, treatment is stopped and the symptoms, including hypertension, are managed.

Akeega: Additional Warnings

• Haematological monitoring: blood counts weekly for the first month, every two weeks for the next two months, monthly for the first year and then every other month. Discontinue if severe persistent toxicity, including pancytopenia, does not resolve within 28 days of interruption. After an interruption for haematological reactions, restarting on the lower strength (two 50 mg/500 mg tablets) calls for liver function checks every two weeks for six weeks, because abiraterone exposure may rise.
• Hypertension: control existing hypertension first. Blood pressure at least weekly for two months, monthly for the first year and every other month thereafter.
• Hypokalaemia, fluid retention and cardiovascular reactions: abiraterone raises mineralocorticoid levels through CYP17 inhibition, which can cause hypertension, hypokalaemia and fluid retention; the corticosteroid given with Akeega reduces these effects. Take care in patients whose conditions could be worsened by low potassium (for example those taking cardiac glycosides) or fluid retention (heart failure, severe or unstable angina, recent myocardial infarction, ventricular arrhythmia, severe renal impairment). QT prolongation has been seen with hypokalaemia. Treat heart failure and optimise cardiac function before starting in patients at significant risk. Monitor for fluid retention and signs of heart failure every two weeks for three months, then monthly, and consider stopping Akeega if cardiac function falls clinically significantly.
• Hepatotoxicity: measure serum aminotransferases and total bilirubin before starting, every two weeks for the first three months, monthly for the rest of the first year, then every other month. Interrupt treatment if ALT or AST rises above 5 times the upper limit of normal, and re-treat only after a return to baseline and at a reduced dose. Stop permanently if ALT or AST exceeds 20 times the upper limit, or if ALT exceeds 3 times the upper limit together with total bilirubin above 2 times the upper limit without another cause. Moderate hepatic impairment raises exposure to abiraterone and niraparib, so use only if the benefit clearly outweighs the risk; do not use in severe impairment.
• Infections and pulmonary embolism: severe infections, including fatal COVID-19, and pulmonary embolism occurred more often with Akeega than with control. Monitor for signs of both.
• MDS/AML and PRES: reported with niraparib in ovarian cancer and, for MDS/AML, in prostate cancer studies; stop permanently if MDS/AML or PRES is confirmed.
• Hypoglycaemia and hyperglycaemia: check blood sugar in diabetes (see Drug Interactions); glucocorticoids can raise blood sugar.
• Corticosteroid withdrawal and stress: watch for adrenocortical insufficiency if prednisone or prednisolone is withdrawn, and watch for mineralocorticoid excess if Akeega continues. A higher corticosteroid dose may be needed around unusual stress.
• Bone density: bone density may decrease in men with advanced prostate cancer, and a glucocorticoid could add to this.
• Excipients: the tablets contain lactose and less than 1 mmol (23 mg) sodium per dose.

Pregnancy, Breastfeeding and Fertility

• Pregnancy test and contraception (Zejula): women of childbearing potential should not be pregnant when starting and need a pregnancy test before treatment. They must use highly effective contraception during therapy and for 6 months after the last dose.
• Pregnancy: Zejula should not be used in pregnancy. There are few or no data in pregnant women and animal reproduction studies have not been done, but the mechanism of action means niraparib could cause embryonic or foetal harm, including embryo-lethal and teratogenic effects.
• Breastfeeding: it is unknown whether niraparib passes into milk. Breastfeeding is contraindicated during treatment and for 1 month after the last dose.
• Fertility: there are no clinical data. A reversible reduction of spermatogenesis was seen in rats and dogs.
• Akeega: contraindicated in women who are or may become pregnant; see the Akeega SmPC for its contraception advice.

Lactose and Tartrazine

Zejula capsules contain 254.5 mg lactose monohydrate and 0.0172 mg of the colouring agent tartrazine (E102), which may cause allergic reactions. Zejula tablets contain 34.7 mg lactose monohydrate. Patients with rare hereditary galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take these medicines.

Effect on Driving

Zejula has a moderate influence on the ability to drive or use machines. Asthenia, fatigue, dizziness or difficulty concentrating can occur, and patients with these symptoms should take care.

• Zejula hard capsules: do not store above 30 °C. Supplied in perforated unit-dose Aclar/PVC/aluminium foil blisters in cartons of 28 × 1, 56 × 1 or 84 × 1 capsules; not all pack sizes may be marketed.
• Zejula film-coated tablets: no special storage temperature. Keep in the original package so the tablets do not absorb water in high humidity.
• Akeega: no special storage conditions.

No cold chain is needed. Keep out of the sight and reach of children.

• Zejula hard capsules: 3 years.
• Zejula film-coated tablets: 4 years.
• Akeega: 30 months.

Do not use after the expiry date on the pack.

Prescription only (Rx), on the prescription of a specialist experienced in anticancer treatment (for Akeega, a specialist in the medical treatment of prostate cancer). Zejula and Akeega are taken at home, so they are supplied to the patient or to the treating clinic on prescription. No cold-chain delivery is needed.